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Similar to circadian rhythms that help regulate when we naturally fall asleep and wake up, microbial rhythms in our gut are naturally active at certain times of the day to help regulate our digestion.

Investigators from the University of California, San Diego sought out to track these microbial rhythms to determine whether aligning the times we eat to when our gut microbes are most active – time-restricted feeding (TRF) – can bolster our metabolic health. Their research was published recently in Cell Host & Microbe.

“Microbial rhythms are daily fluctuations in the composition and function of microbes living in our gut. Much like how our bodies follow an internal clock (circadian rhythm), gut microbes also have their own rhythms, adjusting their activities based on the time of day and when we eat,” said Amir Zarrinpar, MD, PhD, a gastroenterologist at UC San Diego School of Medicine, and senior author of the study.

Zarrinpar and his team were particularly interested in observing whether adopting the TRF approach counteracted the harmful metabolic effects often associated with consuming a high-fat diet.

The study is also notable for the team’s use of technology able to observe real-time microbial changes in the gut — something not previously attainable with existing metagenomics.

 

How the Study Evolved With New Tech

Researchers separated three groups of mice to analyze their microbiome activity: one on a high-fat diet with unrestricted access, another on the same high-fat diet within a TRF window of 8 hours per day, and a control group on a normal chow diet with unrestricted access.

“In mice, [their] microbial rhythms are well-aligned with their nocturnal lifestyle. For example, during their active (nighttime) period, certain beneficial microbial activities increase, helping digest food, absorb nutrients, and regulate metabolism,” said Zarrinpar. As a result, the team made sure the mice’s TRF window was at night or when they would normally be awake.

“We chose an 8-hour feeding window based on earlier research showing this time period allows mice to consume the same total calories as those with unlimited food access,” said Zarrinpar. “By controlling [the] calories in this way, we ensure any metabolic or microbial benefits we observe are specifically due to the timing of eating, rather than differences in total food intake.” 

But before any observations could be made, the team first needed a way to see real-time changes in the animals’ gut microbiomes.

Zarrinpar and his team were able to uncover this, thanks to metatranscriptomics, a technique used to capture real-time microbial activity by profiling RNA transcripts. Compared with the more traditional technique of metagenomics, which could only be used to identify which genes were present, metatranscriptomics provided more in-depth temporal and activity-related context, allowing the team to observe dynamic microbial changes.

“[Metatranscriptomics] helps us understand not just which microbes are present, but specifically what they are doing at any given moment,” said Zarrinpar. “In contrast, metagenomics looks only at microbial DNA, which provides information about what microbes are potentially capable of doing, but doesn’t tell us if those genes are actively expressed. By comparing microbial gene expression (using metatranscriptomics) and microbial gene abundance (using metagenomics) across different diet and feeding conditions in [light and dark] phases, we aimed to identify how feeding timing might influence microbial activity.” 

Because metagenomics focuses on stable genetic material, this technique cannot capture the real-time microbial responses to dietary timing presented in rapidly changing, short-lived RNA. At the same time, the instability of the RNA makes it difficult to test hypotheses experimentally and explains why researchers haven’t more widely relied on metatranscriptomics.

To overcome this difficulty, Zarrinpar and his team had to wait to take advantage of improved bioinformatics tools to simplify their analysis of complex datasets. “It took several years for us to analyze this dataset because robust computational tools for metatranscriptomic analysis were not widely available when we initially collected our samples. Additionally, sequencing costs were very high. To clearly identify microbial activity, we needed deep sequencing coverage to distinguish species-level differences in gene expression, especially for genes that are common across multiple types of microbes,” said Zarrinpar.

 

What They Found

After monitoring these groups of mice for 8 weeks, the results were revealed.

As predicted, the mice with unrestricted access to a high-fat diet exhibited signs of metabolic dysfunction due to disruptions in their circadian and microbial rhythms. “When mice have free access to a high-fat diet, their normal eating behavior changes significantly. Instead of limiting their activity and feeding to their active nighttime period, these mice begin to stay awake and eat during the day, which is their typical rest phase,” Zarrinpar explained.

“This unusual daytime activity interferes with important physiological processes. Consequently, the animals experience circadian misalignment, a condition similar to what human shift workers experience when their sleep-wake and eating cycles don’t match their internal biological clocks,” he continued. “This misalignment can negatively affect metabolism, immunity, and overall health, potentially leading to metabolic diseases.”

For the mice that consumed a high-fat diet within a TRF window, metabolic phenotyping demonstrated that their specific diet regimen had protected them from harmful high-fat induced effects including adiposity, inflammation, and insulin resistance.

Even more promising, the mice not only were protected from metabolic disruption but also experienced physiological improvements including glucose homeostasis and the partial restoration of the daily microbial rhythms absent in the mice with unrestricted access to a high-fat diet.

While the TRF approach did not fully restore the normal, healthy rhythmicity seen in the control mice, the researchers noted distinct shifts in microbial patterns that indicated time-dependent enrichment in genes attributed to lipid and carbohydrate metabolism.

 

Better Metabolic Health — and Better Tools for Researching It

Thankfully, the latest advancements in sequencing technology, including long-read sequencing methods, are making metatranscriptomics easier for research. “These newer platforms offer greater resolution at a lower cost, making metatranscriptomics increasingly accessible,” said Zarrinpar. With these emerging technologies, he believes metatranscriptomics will become a more standard, widely used method for researchers to better understand the influence of microbial activity on our health.

These tools, for example, enabled Zarrinpar and the team to delve deeper and focus on the transcription of a particular enzyme they identified as a pivotal influence in observable metabolic improvements: bile salt hydrolase (BSH), known to regulate lipid and glucose metabolism. The TRF approach notably enhanced the expression of the BSH gene during the daytime in the gut microbe Dubosiella newyorkensis, which has a functional human equivalent.

To determine why this happened, the team leveraged genetic engineering to insert several active BSH gene variants into a benign strain of gut bacteria to administer to the mice. The only variant to produce metabolic improvements was the one derived from Dubosiella newyorkensis; the mice who were given this BSH-expressing engineered native bacteria (ENB) had increased lean muscle mass, less body fat, lower insulin levels, enhanced insulin sensitivity, and better blood glucose regulation.

“It is still early to know the full clinical potential of this new BSH-expressing engineered native bacterium,” said Zarrinpar. “However, our long-term goal is to develop a therapeutic that can be administered as a single dose, stably colonize the gut, and provide long-lasting metabolic benefits.” Testing the engineered bacteria in obese and diabetic mice on a high-fat diet would be a next step to determine whether its potential indeed holds up. If proven successful, it could then be used to develop future targeted therapies and interventions to treat common metabolic disorders.

With this engineered bacteria, Zarrinpar and his team are hopeful that it alone can replicate the microbial benefits associated with following a TRF dietary schedule. “In our study, the engineered bacterium continuously expressed the enzyme DnBSH1, independently of dietary or environmental factors. As a result, the bacterium provided metabolic benefits similar to those seen with TRF, even without requiring the mice to strictly adhere to a TRF schedule,” said Zarrinpar.

“This suggests the exciting possibility that this engineered microbe might serve either as a replacement for TRF or as a way to enhance its beneficial effects,” he continued. “Further studies will help determine whether combining this ENB with TRF could provide additional or synergistic improvements in metabolic health.”

 

Looking Ahead

“As the pioneer of the single anastomosis duodenal switch which separates bile from food until halfway down the GI tract, I agree that bile is very important in controlling metabolism and glucose,” said Mitchell Roslin, MD, chief director of bariatric and metabolic surgery at Lenox Hill Hospital, and the Donald and Barbara Zucker School of Medicine, Hempstead, New York, who was not involved in the study. “Using enzymes or medications that work in the GI tract without absorption into the body is very interesting and has great potential. It is an early but exciting prospect.”

However, Roslin expressed some reservations. “I think we are still trying to understand whether the difference in microbiomes is the cause or effect/association. Is the microbiome the difference or is a different microbiome representative of a diet that has more fiber and less processed foods? Thus, while I find this academically fascinating, I think that there are very basic questions that need better answers, before we look at the transcription of bacteria.”

Furthermore, translating the metabolic results observed in mice to humans might not be as straightforward. “Small animal research is mandatory, but how the findings convert to humans is highly speculative,” said Roslin. “Mice that are studied are usually bred for medical research, with reduced genetic variation. Many animal models are more sensitive to time-restricted eating and caloric restriction than humans.”

While it requires further research and validation, this UC San Diego study nevertheless contributes to our overall understanding of host-microbe interactions. “We demonstrate that host circadian rhythms significantly influence microbial function, and conversely, these microbial functions can directly impact host metabolism,” said Zarrinpar. “Importantly, we now have a method to test how specific microbial activities affect host physiology by engineering native gut bacteria.”

Roslin similarly emphasized the importance of continued investment in exploring the microbial ecosystem inside us all. “There is wider evidence that bacteria and microbes are not just passengers using us for a ride but perhaps manipulating every action we take.”

A version of this article appeared on Medscape.com.

Similar to circadian rhythms that help regulate when we naturally fall asleep and wake up, microbial rhythms in our gut are naturally active at certain times of the day to help regulate our digestion.

Investigators from the University of California, San Diego sought out to track these microbial rhythms to determine whether aligning the times we eat to when our gut microbes are most active – time-restricted feeding (TRF) – can bolster our metabolic health. Their research was published recently in Cell Host & Microbe.

“Microbial rhythms are daily fluctuations in the composition and function of microbes living in our gut. Much like how our bodies follow an internal clock (circadian rhythm), gut microbes also have their own rhythms, adjusting their activities based on the time of day and when we eat,” said Amir Zarrinpar, MD, PhD, a gastroenterologist at UC San Diego School of Medicine, and senior author of the study.

Zarrinpar and his team were particularly interested in observing whether adopting the TRF approach counteracted the harmful metabolic effects often associated with consuming a high-fat diet.

The study is also notable for the team’s use of technology able to observe real-time microbial changes in the gut — something not previously attainable with existing metagenomics.

 

How the Study Evolved With New Tech

Researchers separated three groups of mice to analyze their microbiome activity: one on a high-fat diet with unrestricted access, another on the same high-fat diet within a TRF window of 8 hours per day, and a control group on a normal chow diet with unrestricted access.

“In mice, [their] microbial rhythms are well-aligned with their nocturnal lifestyle. For example, during their active (nighttime) period, certain beneficial microbial activities increase, helping digest food, absorb nutrients, and regulate metabolism,” said Zarrinpar. As a result, the team made sure the mice’s TRF window was at night or when they would normally be awake.

“We chose an 8-hour feeding window based on earlier research showing this time period allows mice to consume the same total calories as those with unlimited food access,” said Zarrinpar. “By controlling [the] calories in this way, we ensure any metabolic or microbial benefits we observe are specifically due to the timing of eating, rather than differences in total food intake.” 

But before any observations could be made, the team first needed a way to see real-time changes in the animals’ gut microbiomes.

Zarrinpar and his team were able to uncover this, thanks to metatranscriptomics, a technique used to capture real-time microbial activity by profiling RNA transcripts. Compared with the more traditional technique of metagenomics, which could only be used to identify which genes were present, metatranscriptomics provided more in-depth temporal and activity-related context, allowing the team to observe dynamic microbial changes.

“[Metatranscriptomics] helps us understand not just which microbes are present, but specifically what they are doing at any given moment,” said Zarrinpar. “In contrast, metagenomics looks only at microbial DNA, which provides information about what microbes are potentially capable of doing, but doesn’t tell us if those genes are actively expressed. By comparing microbial gene expression (using metatranscriptomics) and microbial gene abundance (using metagenomics) across different diet and feeding conditions in [light and dark] phases, we aimed to identify how feeding timing might influence microbial activity.” 

Because metagenomics focuses on stable genetic material, this technique cannot capture the real-time microbial responses to dietary timing presented in rapidly changing, short-lived RNA. At the same time, the instability of the RNA makes it difficult to test hypotheses experimentally and explains why researchers haven’t more widely relied on metatranscriptomics.

To overcome this difficulty, Zarrinpar and his team had to wait to take advantage of improved bioinformatics tools to simplify their analysis of complex datasets. “It took several years for us to analyze this dataset because robust computational tools for metatranscriptomic analysis were not widely available when we initially collected our samples. Additionally, sequencing costs were very high. To clearly identify microbial activity, we needed deep sequencing coverage to distinguish species-level differences in gene expression, especially for genes that are common across multiple types of microbes,” said Zarrinpar.

 

What They Found

After monitoring these groups of mice for 8 weeks, the results were revealed.

As predicted, the mice with unrestricted access to a high-fat diet exhibited signs of metabolic dysfunction due to disruptions in their circadian and microbial rhythms. “When mice have free access to a high-fat diet, their normal eating behavior changes significantly. Instead of limiting their activity and feeding to their active nighttime period, these mice begin to stay awake and eat during the day, which is their typical rest phase,” Zarrinpar explained.

“This unusual daytime activity interferes with important physiological processes. Consequently, the animals experience circadian misalignment, a condition similar to what human shift workers experience when their sleep-wake and eating cycles don’t match their internal biological clocks,” he continued. “This misalignment can negatively affect metabolism, immunity, and overall health, potentially leading to metabolic diseases.”

For the mice that consumed a high-fat diet within a TRF window, metabolic phenotyping demonstrated that their specific diet regimen had protected them from harmful high-fat induced effects including adiposity, inflammation, and insulin resistance.

Even more promising, the mice not only were protected from metabolic disruption but also experienced physiological improvements including glucose homeostasis and the partial restoration of the daily microbial rhythms absent in the mice with unrestricted access to a high-fat diet.

While the TRF approach did not fully restore the normal, healthy rhythmicity seen in the control mice, the researchers noted distinct shifts in microbial patterns that indicated time-dependent enrichment in genes attributed to lipid and carbohydrate metabolism.

 

Better Metabolic Health — and Better Tools for Researching It

Thankfully, the latest advancements in sequencing technology, including long-read sequencing methods, are making metatranscriptomics easier for research. “These newer platforms offer greater resolution at a lower cost, making metatranscriptomics increasingly accessible,” said Zarrinpar. With these emerging technologies, he believes metatranscriptomics will become a more standard, widely used method for researchers to better understand the influence of microbial activity on our health.

These tools, for example, enabled Zarrinpar and the team to delve deeper and focus on the transcription of a particular enzyme they identified as a pivotal influence in observable metabolic improvements: bile salt hydrolase (BSH), known to regulate lipid and glucose metabolism. The TRF approach notably enhanced the expression of the BSH gene during the daytime in the gut microbe Dubosiella newyorkensis, which has a functional human equivalent.

To determine why this happened, the team leveraged genetic engineering to insert several active BSH gene variants into a benign strain of gut bacteria to administer to the mice. The only variant to produce metabolic improvements was the one derived from Dubosiella newyorkensis; the mice who were given this BSH-expressing engineered native bacteria (ENB) had increased lean muscle mass, less body fat, lower insulin levels, enhanced insulin sensitivity, and better blood glucose regulation.

“It is still early to know the full clinical potential of this new BSH-expressing engineered native bacterium,” said Zarrinpar. “However, our long-term goal is to develop a therapeutic that can be administered as a single dose, stably colonize the gut, and provide long-lasting metabolic benefits.” Testing the engineered bacteria in obese and diabetic mice on a high-fat diet would be a next step to determine whether its potential indeed holds up. If proven successful, it could then be used to develop future targeted therapies and interventions to treat common metabolic disorders.

With this engineered bacteria, Zarrinpar and his team are hopeful that it alone can replicate the microbial benefits associated with following a TRF dietary schedule. “In our study, the engineered bacterium continuously expressed the enzyme DnBSH1, independently of dietary or environmental factors. As a result, the bacterium provided metabolic benefits similar to those seen with TRF, even without requiring the mice to strictly adhere to a TRF schedule,” said Zarrinpar.

“This suggests the exciting possibility that this engineered microbe might serve either as a replacement for TRF or as a way to enhance its beneficial effects,” he continued. “Further studies will help determine whether combining this ENB with TRF could provide additional or synergistic improvements in metabolic health.”

 

Looking Ahead

“As the pioneer of the single anastomosis duodenal switch which separates bile from food until halfway down the GI tract, I agree that bile is very important in controlling metabolism and glucose,” said Mitchell Roslin, MD, chief director of bariatric and metabolic surgery at Lenox Hill Hospital, and the Donald and Barbara Zucker School of Medicine, Hempstead, New York, who was not involved in the study. “Using enzymes or medications that work in the GI tract without absorption into the body is very interesting and has great potential. It is an early but exciting prospect.”

However, Roslin expressed some reservations. “I think we are still trying to understand whether the difference in microbiomes is the cause or effect/association. Is the microbiome the difference or is a different microbiome representative of a diet that has more fiber and less processed foods? Thus, while I find this academically fascinating, I think that there are very basic questions that need better answers, before we look at the transcription of bacteria.”

Furthermore, translating the metabolic results observed in mice to humans might not be as straightforward. “Small animal research is mandatory, but how the findings convert to humans is highly speculative,” said Roslin. “Mice that are studied are usually bred for medical research, with reduced genetic variation. Many animal models are more sensitive to time-restricted eating and caloric restriction than humans.”

While it requires further research and validation, this UC San Diego study nevertheless contributes to our overall understanding of host-microbe interactions. “We demonstrate that host circadian rhythms significantly influence microbial function, and conversely, these microbial functions can directly impact host metabolism,” said Zarrinpar. “Importantly, we now have a method to test how specific microbial activities affect host physiology by engineering native gut bacteria.”

Roslin similarly emphasized the importance of continued investment in exploring the microbial ecosystem inside us all. “There is wider evidence that bacteria and microbes are not just passengers using us for a ride but perhaps manipulating every action we take.”

A version of this article appeared on Medscape.com.

Similar to circadian rhythms that help regulate when we naturally fall asleep and wake up, microbial rhythms in our gut are naturally active at certain times of the day to help regulate our digestion.

Investigators from the University of California, San Diego sought out to track these microbial rhythms to determine whether aligning the times we eat to when our gut microbes are most active – time-restricted feeding (TRF) – can bolster our metabolic health. Their research was published recently in Cell Host & Microbe.

“Microbial rhythms are daily fluctuations in the composition and function of microbes living in our gut. Much like how our bodies follow an internal clock (circadian rhythm), gut microbes also have their own rhythms, adjusting their activities based on the time of day and when we eat,” said Amir Zarrinpar, MD, PhD, a gastroenterologist at UC San Diego School of Medicine, and senior author of the study.

Zarrinpar and his team were particularly interested in observing whether adopting the TRF approach counteracted the harmful metabolic effects often associated with consuming a high-fat diet.

The study is also notable for the team’s use of technology able to observe real-time microbial changes in the gut — something not previously attainable with existing metagenomics.

 

How the Study Evolved With New Tech

Researchers separated three groups of mice to analyze their microbiome activity: one on a high-fat diet with unrestricted access, another on the same high-fat diet within a TRF window of 8 hours per day, and a control group on a normal chow diet with unrestricted access.

“In mice, [their] microbial rhythms are well-aligned with their nocturnal lifestyle. For example, during their active (nighttime) period, certain beneficial microbial activities increase, helping digest food, absorb nutrients, and regulate metabolism,” said Zarrinpar. As a result, the team made sure the mice’s TRF window was at night or when they would normally be awake.

“We chose an 8-hour feeding window based on earlier research showing this time period allows mice to consume the same total calories as those with unlimited food access,” said Zarrinpar. “By controlling [the] calories in this way, we ensure any metabolic or microbial benefits we observe are specifically due to the timing of eating, rather than differences in total food intake.” 

But before any observations could be made, the team first needed a way to see real-time changes in the animals’ gut microbiomes.

Zarrinpar and his team were able to uncover this, thanks to metatranscriptomics, a technique used to capture real-time microbial activity by profiling RNA transcripts. Compared with the more traditional technique of metagenomics, which could only be used to identify which genes were present, metatranscriptomics provided more in-depth temporal and activity-related context, allowing the team to observe dynamic microbial changes.

“[Metatranscriptomics] helps us understand not just which microbes are present, but specifically what they are doing at any given moment,” said Zarrinpar. “In contrast, metagenomics looks only at microbial DNA, which provides information about what microbes are potentially capable of doing, but doesn’t tell us if those genes are actively expressed. By comparing microbial gene expression (using metatranscriptomics) and microbial gene abundance (using metagenomics) across different diet and feeding conditions in [light and dark] phases, we aimed to identify how feeding timing might influence microbial activity.” 

Because metagenomics focuses on stable genetic material, this technique cannot capture the real-time microbial responses to dietary timing presented in rapidly changing, short-lived RNA. At the same time, the instability of the RNA makes it difficult to test hypotheses experimentally and explains why researchers haven’t more widely relied on metatranscriptomics.

To overcome this difficulty, Zarrinpar and his team had to wait to take advantage of improved bioinformatics tools to simplify their analysis of complex datasets. “It took several years for us to analyze this dataset because robust computational tools for metatranscriptomic analysis were not widely available when we initially collected our samples. Additionally, sequencing costs were very high. To clearly identify microbial activity, we needed deep sequencing coverage to distinguish species-level differences in gene expression, especially for genes that are common across multiple types of microbes,” said Zarrinpar.

 

What They Found

After monitoring these groups of mice for 8 weeks, the results were revealed.

As predicted, the mice with unrestricted access to a high-fat diet exhibited signs of metabolic dysfunction due to disruptions in their circadian and microbial rhythms. “When mice have free access to a high-fat diet, their normal eating behavior changes significantly. Instead of limiting their activity and feeding to their active nighttime period, these mice begin to stay awake and eat during the day, which is their typical rest phase,” Zarrinpar explained.

“This unusual daytime activity interferes with important physiological processes. Consequently, the animals experience circadian misalignment, a condition similar to what human shift workers experience when their sleep-wake and eating cycles don’t match their internal biological clocks,” he continued. “This misalignment can negatively affect metabolism, immunity, and overall health, potentially leading to metabolic diseases.”

For the mice that consumed a high-fat diet within a TRF window, metabolic phenotyping demonstrated that their specific diet regimen had protected them from harmful high-fat induced effects including adiposity, inflammation, and insulin resistance.

Even more promising, the mice not only were protected from metabolic disruption but also experienced physiological improvements including glucose homeostasis and the partial restoration of the daily microbial rhythms absent in the mice with unrestricted access to a high-fat diet.

While the TRF approach did not fully restore the normal, healthy rhythmicity seen in the control mice, the researchers noted distinct shifts in microbial patterns that indicated time-dependent enrichment in genes attributed to lipid and carbohydrate metabolism.

 

Better Metabolic Health — and Better Tools for Researching It

Thankfully, the latest advancements in sequencing technology, including long-read sequencing methods, are making metatranscriptomics easier for research. “These newer platforms offer greater resolution at a lower cost, making metatranscriptomics increasingly accessible,” said Zarrinpar. With these emerging technologies, he believes metatranscriptomics will become a more standard, widely used method for researchers to better understand the influence of microbial activity on our health.

These tools, for example, enabled Zarrinpar and the team to delve deeper and focus on the transcription of a particular enzyme they identified as a pivotal influence in observable metabolic improvements: bile salt hydrolase (BSH), known to regulate lipid and glucose metabolism. The TRF approach notably enhanced the expression of the BSH gene during the daytime in the gut microbe Dubosiella newyorkensis, which has a functional human equivalent.

To determine why this happened, the team leveraged genetic engineering to insert several active BSH gene variants into a benign strain of gut bacteria to administer to the mice. The only variant to produce metabolic improvements was the one derived from Dubosiella newyorkensis; the mice who were given this BSH-expressing engineered native bacteria (ENB) had increased lean muscle mass, less body fat, lower insulin levels, enhanced insulin sensitivity, and better blood glucose regulation.

“It is still early to know the full clinical potential of this new BSH-expressing engineered native bacterium,” said Zarrinpar. “However, our long-term goal is to develop a therapeutic that can be administered as a single dose, stably colonize the gut, and provide long-lasting metabolic benefits.” Testing the engineered bacteria in obese and diabetic mice on a high-fat diet would be a next step to determine whether its potential indeed holds up. If proven successful, it could then be used to develop future targeted therapies and interventions to treat common metabolic disorders.

With this engineered bacteria, Zarrinpar and his team are hopeful that it alone can replicate the microbial benefits associated with following a TRF dietary schedule. “In our study, the engineered bacterium continuously expressed the enzyme DnBSH1, independently of dietary or environmental factors. As a result, the bacterium provided metabolic benefits similar to those seen with TRF, even without requiring the mice to strictly adhere to a TRF schedule,” said Zarrinpar.

“This suggests the exciting possibility that this engineered microbe might serve either as a replacement for TRF or as a way to enhance its beneficial effects,” he continued. “Further studies will help determine whether combining this ENB with TRF could provide additional or synergistic improvements in metabolic health.”

 

Looking Ahead

“As the pioneer of the single anastomosis duodenal switch which separates bile from food until halfway down the GI tract, I agree that bile is very important in controlling metabolism and glucose,” said Mitchell Roslin, MD, chief director of bariatric and metabolic surgery at Lenox Hill Hospital, and the Donald and Barbara Zucker School of Medicine, Hempstead, New York, who was not involved in the study. “Using enzymes or medications that work in the GI tract without absorption into the body is very interesting and has great potential. It is an early but exciting prospect.”

However, Roslin expressed some reservations. “I think we are still trying to understand whether the difference in microbiomes is the cause or effect/association. Is the microbiome the difference or is a different microbiome representative of a diet that has more fiber and less processed foods? Thus, while I find this academically fascinating, I think that there are very basic questions that need better answers, before we look at the transcription of bacteria.”

Furthermore, translating the metabolic results observed in mice to humans might not be as straightforward. “Small animal research is mandatory, but how the findings convert to humans is highly speculative,” said Roslin. “Mice that are studied are usually bred for medical research, with reduced genetic variation. Many animal models are more sensitive to time-restricted eating and caloric restriction than humans.”

While it requires further research and validation, this UC San Diego study nevertheless contributes to our overall understanding of host-microbe interactions. “We demonstrate that host circadian rhythms significantly influence microbial function, and conversely, these microbial functions can directly impact host metabolism,” said Zarrinpar. “Importantly, we now have a method to test how specific microbial activities affect host physiology by engineering native gut bacteria.”

Roslin similarly emphasized the importance of continued investment in exploring the microbial ecosystem inside us all. “There is wider evidence that bacteria and microbes are not just passengers using us for a ride but perhaps manipulating every action we take.”

A version of this article appeared on Medscape.com.

Treatment of metastatic renal cell carcinoma (RCC) is complex and requires careful analysis of risk and treatment options, an oncologist said at the July Association of VA Hematology and Oncology (AVAHO) seminar in Long Beach, California, regarding treating veterans with kidney cancer.

“We’ve come a long way in treating this disease, but individualizing therapy remains critical, especially in complex populations like our veterans,” said Matthew B. Rettig, MD, chief of Hematology-Oncology at the Veterans Affairs Greater Los Angeles Healthcare System and professor of Medicine and Urology at UCLA.

Rettig emphasized 2 critical early questions clinicians should consider when encountering metastatic RCC. First: Can the patient be treated with localized interventions such as metastasectomy, radiation therapy, or nephrectomy? These can be curative, Rettig said.

And second: Does the patient currently need systemic therapy? “[There are] a small subset of patients,” Rettig said, “who go into a durable, complete remission, dare I say ‘cure,’ with immunotherapeutic-based approaches.”

Rettig highlighted the International Metastatic Renal Cell Carcinoma Database Consortium criteria as a guide for clinicians as they determine the best strategy for treatment. The Database Consortium estimates survival in various lines of therapy by incorporating 6 prognostic factors: anemia, hypercalcemia, neutrophilia, thrombocytosis, performance status, and time from diagnosis to treatment. 

These criteria classify patients into favorable, intermediate, or poor risk categories that can guide first-line systemic therapy. The criteria also provide estimates of median survival. 

Rettig noted a “huge percentage” of veterans mirror the intermediate-risk demographics of clinical trial cohorts but often present with greater comorbidity burdens: “That plays into whether we treat and how we treat,” he said.

Rettig highlighted kidney cancer guidelines from the National Comprehensive Cancer Network and noted that several trials examined first-line use of combinations of vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) and checkpoint inhibitors. 

There’s a general theme in the findings, he said: “You have OS (overall survival) and PFS (progression-free survival) benefit in the intermediate/poor risk group, but only PFS benefit in the patients who have favorable-risk disease. And you see higher objective response rates with the combinations.

“If you have a patient who's highly symptomatic or has an organ system threatened by a metastasis, you'd want to use a combination that elicits a higher objective response rate,” Rettig added.

A TKI is going to be the most appropriate second-line therapy for patients who received a prior checkpoint inhibitor, Rettig said.

“Don't change to another checkpoint inhibitor,” he said. “We have enough phase 3 data that indicates checkpoint inhibitors are no longer really adding to benefit once they’ve had a checkpoint inhibitor.”

Rettig said to even consider checkpoint inhibitors for patients who are checkpoint inhibitor-naïve, especially given the potential for durable remissions. As for third-line therapy, he said, “we have both belzutifan and tivozanib, which have been shown to improve PFS. More studies are ongoing.”

There are many adverse events linked to TKIs, Rettig said, including cardiovascular problems, thrombosis, hypertension, heart failure, torsades de pointes, QT prolongation, and gastrointestinal toxicity. TKIs tend to be the major drivers of adverse events in combination therapy.

Rettig emphasized the shorter half-life of the TKI axitinib, which he said allows for easier management of toxicities: “That’s why it’s preferred in the VA RCC clinical pathway.”

Rettig discloses relationships with Ambrx, Amgen, AVEO, Bayer, INmune Bio, Johnson & Johnson Health Care Systems, Lantheus, Merck, Myovant, Novartis, ORIC, and Progenics.

Treatment of metastatic renal cell carcinoma (RCC) is complex and requires careful analysis of risk and treatment options, an oncologist said at the July Association of VA Hematology and Oncology (AVAHO) seminar in Long Beach, California, regarding treating veterans with kidney cancer.

“We’ve come a long way in treating this disease, but individualizing therapy remains critical, especially in complex populations like our veterans,” said Matthew B. Rettig, MD, chief of Hematology-Oncology at the Veterans Affairs Greater Los Angeles Healthcare System and professor of Medicine and Urology at UCLA.

Rettig emphasized 2 critical early questions clinicians should consider when encountering metastatic RCC. First: Can the patient be treated with localized interventions such as metastasectomy, radiation therapy, or nephrectomy? These can be curative, Rettig said.

And second: Does the patient currently need systemic therapy? “[There are] a small subset of patients,” Rettig said, “who go into a durable, complete remission, dare I say ‘cure,’ with immunotherapeutic-based approaches.”

Rettig highlighted the International Metastatic Renal Cell Carcinoma Database Consortium criteria as a guide for clinicians as they determine the best strategy for treatment. The Database Consortium estimates survival in various lines of therapy by incorporating 6 prognostic factors: anemia, hypercalcemia, neutrophilia, thrombocytosis, performance status, and time from diagnosis to treatment. 

These criteria classify patients into favorable, intermediate, or poor risk categories that can guide first-line systemic therapy. The criteria also provide estimates of median survival. 

Rettig noted a “huge percentage” of veterans mirror the intermediate-risk demographics of clinical trial cohorts but often present with greater comorbidity burdens: “That plays into whether we treat and how we treat,” he said.

Rettig highlighted kidney cancer guidelines from the National Comprehensive Cancer Network and noted that several trials examined first-line use of combinations of vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) and checkpoint inhibitors. 

There’s a general theme in the findings, he said: “You have OS (overall survival) and PFS (progression-free survival) benefit in the intermediate/poor risk group, but only PFS benefit in the patients who have favorable-risk disease. And you see higher objective response rates with the combinations.

“If you have a patient who's highly symptomatic or has an organ system threatened by a metastasis, you'd want to use a combination that elicits a higher objective response rate,” Rettig added.

A TKI is going to be the most appropriate second-line therapy for patients who received a prior checkpoint inhibitor, Rettig said.

“Don't change to another checkpoint inhibitor,” he said. “We have enough phase 3 data that indicates checkpoint inhibitors are no longer really adding to benefit once they’ve had a checkpoint inhibitor.”

Rettig said to even consider checkpoint inhibitors for patients who are checkpoint inhibitor-naïve, especially given the potential for durable remissions. As for third-line therapy, he said, “we have both belzutifan and tivozanib, which have been shown to improve PFS. More studies are ongoing.”

There are many adverse events linked to TKIs, Rettig said, including cardiovascular problems, thrombosis, hypertension, heart failure, torsades de pointes, QT prolongation, and gastrointestinal toxicity. TKIs tend to be the major drivers of adverse events in combination therapy.

Rettig emphasized the shorter half-life of the TKI axitinib, which he said allows for easier management of toxicities: “That’s why it’s preferred in the VA RCC clinical pathway.”

Rettig discloses relationships with Ambrx, Amgen, AVEO, Bayer, INmune Bio, Johnson & Johnson Health Care Systems, Lantheus, Merck, Myovant, Novartis, ORIC, and Progenics.

Treatment of metastatic renal cell carcinoma (RCC) is complex and requires careful analysis of risk and treatment options, an oncologist said at the July Association of VA Hematology and Oncology (AVAHO) seminar in Long Beach, California, regarding treating veterans with kidney cancer.

“We’ve come a long way in treating this disease, but individualizing therapy remains critical, especially in complex populations like our veterans,” said Matthew B. Rettig, MD, chief of Hematology-Oncology at the Veterans Affairs Greater Los Angeles Healthcare System and professor of Medicine and Urology at UCLA.

Rettig emphasized 2 critical early questions clinicians should consider when encountering metastatic RCC. First: Can the patient be treated with localized interventions such as metastasectomy, radiation therapy, or nephrectomy? These can be curative, Rettig said.

And second: Does the patient currently need systemic therapy? “[There are] a small subset of patients,” Rettig said, “who go into a durable, complete remission, dare I say ‘cure,’ with immunotherapeutic-based approaches.”

Rettig highlighted the International Metastatic Renal Cell Carcinoma Database Consortium criteria as a guide for clinicians as they determine the best strategy for treatment. The Database Consortium estimates survival in various lines of therapy by incorporating 6 prognostic factors: anemia, hypercalcemia, neutrophilia, thrombocytosis, performance status, and time from diagnosis to treatment. 

These criteria classify patients into favorable, intermediate, or poor risk categories that can guide first-line systemic therapy. The criteria also provide estimates of median survival. 

Rettig noted a “huge percentage” of veterans mirror the intermediate-risk demographics of clinical trial cohorts but often present with greater comorbidity burdens: “That plays into whether we treat and how we treat,” he said.

Rettig highlighted kidney cancer guidelines from the National Comprehensive Cancer Network and noted that several trials examined first-line use of combinations of vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs) and checkpoint inhibitors. 

There’s a general theme in the findings, he said: “You have OS (overall survival) and PFS (progression-free survival) benefit in the intermediate/poor risk group, but only PFS benefit in the patients who have favorable-risk disease. And you see higher objective response rates with the combinations.

“If you have a patient who's highly symptomatic or has an organ system threatened by a metastasis, you'd want to use a combination that elicits a higher objective response rate,” Rettig added.

A TKI is going to be the most appropriate second-line therapy for patients who received a prior checkpoint inhibitor, Rettig said.

“Don't change to another checkpoint inhibitor,” he said. “We have enough phase 3 data that indicates checkpoint inhibitors are no longer really adding to benefit once they’ve had a checkpoint inhibitor.”

Rettig said to even consider checkpoint inhibitors for patients who are checkpoint inhibitor-naïve, especially given the potential for durable remissions. As for third-line therapy, he said, “we have both belzutifan and tivozanib, which have been shown to improve PFS. More studies are ongoing.”

There are many adverse events linked to TKIs, Rettig said, including cardiovascular problems, thrombosis, hypertension, heart failure, torsades de pointes, QT prolongation, and gastrointestinal toxicity. TKIs tend to be the major drivers of adverse events in combination therapy.

Rettig emphasized the shorter half-life of the TKI axitinib, which he said allows for easier management of toxicities: “That’s why it’s preferred in the VA RCC clinical pathway.”

Rettig discloses relationships with Ambrx, Amgen, AVEO, Bayer, INmune Bio, Johnson & Johnson Health Care Systems, Lantheus, Merck, Myovant, Novartis, ORIC, and Progenics.

The US military has revised its grooming standards to remove medical exemptions for male facial hair, a policy change that may put careers at risk for thousands of service members. According to the updated guidelines, all soldiers must be clean-shaven on duty when in uniform or civilian clothes, with temporary exemptions for medical reasons and permanent exemptions for religious accommodations. 

The Army is the latest service branch to update its guidelines about beards: Soldiers with skin conditions will no longer be granted permanent medical waivers that allow them to avoid shaving. The Air Force and Space Force updated their guidance on grooming waivers in January, as did the Marine Corps in March. 

Defense Secretary Pete Hegseth, who ordered the guideline review, focused on grooming and appearance. In a Feb. 7 townhall with troops and department employees, he said, “It starts with the basic stuff, right? It’s grooming standards and uniform standards and training standards, fitness standards, all of that matters.”

Hegseth compared not enforcing grooming standards to the “broken windows” theory of policing: “I’m not saying if you violate grooming standards, you’re a criminal. The analogy is incomplete. But if you violate the small stuff and you allow it to happen, it creates a culture where the big stuff, you’re not held accountable for.”

The policy changes are particularly significant for soldiers who grow beards because they suffer from pseudofolliculitis barbae (PFB), an often-painful genetic condition that causes ingrown hairs. PFB produces flesh-colored or red follicular papules, which can be itchy, tender, and may bleed when shaved. Even if they heal, the lesions may lead to postinflammatory hyperpigmentation, scarring (including keloid scarring), and abscess. 

Although the updated standards affect all service members with beards, they draw ire from those who claim the rules disproportionately affect men of African descent. Up to 60% of Black men have PFB, according to the American Osteopathic College of Dermatology. According to the US Department of Defense (DoD) 2023 Demographics: Profile of the Military Community, service members who self-identify as Black or African American make up 17% of the total DoD military force (N = 2,034,426). Of 1,273,382 active-duty members, 18% are Black. Of 1,038,909 active-duty enlisted members, 20% are Black, and 9% of 234,473 active-duty officers are Black.

“Almost 65% of the US Air Force shaving waivers are held by Black men. And PFB is one of the most common reasons,” DanTasia Welch, MS, told Federal Practitioner. She, along with Richard P. Usatine, MD, and Candrice R. Heath, MD, wrote a recent review of the impact of PFB that was published in Federal Practitioner. 

“It is almost exclusively found in men of African descent,” Usatine said. “That just means if you have a policy that affects people with this condition, you are basically aiming that policy directly at Black men.”

“Pseudofolliculitis barbae, a lot of that just has to do with your shaving technique is what we’ve determined,” Steve Warren, an Army spokesman, told reporters in early July. “A vast majority of minority soldiers, African American soldiers, are within the standards all the time.” 

Usatine disagreed: “[PFB] is genetic, and whether you shave with or against the direction of the hairs, the problem is still there, and you can't just shave it away by ‘shaving correctly.’ They're going after one racial/ethnic group who has this problem, because almost everyone that has the problem is of African descent.”

The most effective management for PFB is to discontinue shaving. Grooming techniques and topical medications can be effective in treating mild-to-moderate cases of PFB, but more severe cases respond best to laser therapy. The Army, Navy, and Marine Corps advise laser therapy as a treatment option, but it has drawbacks. It is expensive and coded as a cosmetic procedure, and patients also may not have access to specialists experienced in performing the procedure in people with darker skin tones. Some patients may not want to permanently reduce the amount of hair that grows in the beard area for personal or religious reasons. 

A survey of Air Force members with 10,383 responses suggested that the men who had medical shaving waivers experienced longer times to promotion than those with no waiver. Most in the waiver group were Black or African American. 

The branches have handled the rule change in different ways. The Air Force, for example, which began tightening its standards on uniform and shaving waivers in January 2025, grants long-term shaving waivers only to airmen or guardians who have severe cases of PFB following consultation with medical practitioners. Air Force Surgeon General Lt. Gen. John DeGoes said in a video that the department’s 2020 (now expired) policy allowing 5-year shaving waivers did not give clinicians enough clarity on diagnosis by not differentiating between PFB and shaving irritation.

“They are 2 different things,” DeGoes said. “Ensuring a standardized approach to managing PFB is essential. And it is crucial that we provide consistent and effective care to our service members, enabling them to meet grooming standards while managing their condition.”

The new grooming policies leave many service members in an uncomfortable quandary: Keep the beard, run the risk of getting kicked out; keep shaving and put your skin and health at risk for complications; or receive laser treatment and have to deal with lack of beard hair after leaving the military.

Simply changing the rules isn’t enough. Candrice Heath, MD, told Federal Practitioner, “You need to always strike a balance. One of those points that’s always raised is about the facial equipment that's needed to protect during times of war.”

Heath called for more research funding to develop equipment, so people can have some facial hair if needed. “There is an opportunity to not just say, hey, this is an issue, but there's an opportunity for innovation here, to really think about it this problem in a different way, so that we are solution-focused.”

The US military has revised its grooming standards to remove medical exemptions for male facial hair, a policy change that may put careers at risk for thousands of service members. According to the updated guidelines, all soldiers must be clean-shaven on duty when in uniform or civilian clothes, with temporary exemptions for medical reasons and permanent exemptions for religious accommodations. 

The Army is the latest service branch to update its guidelines about beards: Soldiers with skin conditions will no longer be granted permanent medical waivers that allow them to avoid shaving. The Air Force and Space Force updated their guidance on grooming waivers in January, as did the Marine Corps in March. 

Defense Secretary Pete Hegseth, who ordered the guideline review, focused on grooming and appearance. In a Feb. 7 townhall with troops and department employees, he said, “It starts with the basic stuff, right? It’s grooming standards and uniform standards and training standards, fitness standards, all of that matters.”

Hegseth compared not enforcing grooming standards to the “broken windows” theory of policing: “I’m not saying if you violate grooming standards, you’re a criminal. The analogy is incomplete. But if you violate the small stuff and you allow it to happen, it creates a culture where the big stuff, you’re not held accountable for.”

The policy changes are particularly significant for soldiers who grow beards because they suffer from pseudofolliculitis barbae (PFB), an often-painful genetic condition that causes ingrown hairs. PFB produces flesh-colored or red follicular papules, which can be itchy, tender, and may bleed when shaved. Even if they heal, the lesions may lead to postinflammatory hyperpigmentation, scarring (including keloid scarring), and abscess. 

Although the updated standards affect all service members with beards, they draw ire from those who claim the rules disproportionately affect men of African descent. Up to 60% of Black men have PFB, according to the American Osteopathic College of Dermatology. According to the US Department of Defense (DoD) 2023 Demographics: Profile of the Military Community, service members who self-identify as Black or African American make up 17% of the total DoD military force (N = 2,034,426). Of 1,273,382 active-duty members, 18% are Black. Of 1,038,909 active-duty enlisted members, 20% are Black, and 9% of 234,473 active-duty officers are Black.

“Almost 65% of the US Air Force shaving waivers are held by Black men. And PFB is one of the most common reasons,” DanTasia Welch, MS, told Federal Practitioner. She, along with Richard P. Usatine, MD, and Candrice R. Heath, MD, wrote a recent review of the impact of PFB that was published in Federal Practitioner. 

“It is almost exclusively found in men of African descent,” Usatine said. “That just means if you have a policy that affects people with this condition, you are basically aiming that policy directly at Black men.”

“Pseudofolliculitis barbae, a lot of that just has to do with your shaving technique is what we’ve determined,” Steve Warren, an Army spokesman, told reporters in early July. “A vast majority of minority soldiers, African American soldiers, are within the standards all the time.” 

Usatine disagreed: “[PFB] is genetic, and whether you shave with or against the direction of the hairs, the problem is still there, and you can't just shave it away by ‘shaving correctly.’ They're going after one racial/ethnic group who has this problem, because almost everyone that has the problem is of African descent.”

The most effective management for PFB is to discontinue shaving. Grooming techniques and topical medications can be effective in treating mild-to-moderate cases of PFB, but more severe cases respond best to laser therapy. The Army, Navy, and Marine Corps advise laser therapy as a treatment option, but it has drawbacks. It is expensive and coded as a cosmetic procedure, and patients also may not have access to specialists experienced in performing the procedure in people with darker skin tones. Some patients may not want to permanently reduce the amount of hair that grows in the beard area for personal or religious reasons. 

A survey of Air Force members with 10,383 responses suggested that the men who had medical shaving waivers experienced longer times to promotion than those with no waiver. Most in the waiver group were Black or African American. 

The branches have handled the rule change in different ways. The Air Force, for example, which began tightening its standards on uniform and shaving waivers in January 2025, grants long-term shaving waivers only to airmen or guardians who have severe cases of PFB following consultation with medical practitioners. Air Force Surgeon General Lt. Gen. John DeGoes said in a video that the department’s 2020 (now expired) policy allowing 5-year shaving waivers did not give clinicians enough clarity on diagnosis by not differentiating between PFB and shaving irritation.

“They are 2 different things,” DeGoes said. “Ensuring a standardized approach to managing PFB is essential. And it is crucial that we provide consistent and effective care to our service members, enabling them to meet grooming standards while managing their condition.”

The new grooming policies leave many service members in an uncomfortable quandary: Keep the beard, run the risk of getting kicked out; keep shaving and put your skin and health at risk for complications; or receive laser treatment and have to deal with lack of beard hair after leaving the military.

Simply changing the rules isn’t enough. Candrice Heath, MD, told Federal Practitioner, “You need to always strike a balance. One of those points that’s always raised is about the facial equipment that's needed to protect during times of war.”

Heath called for more research funding to develop equipment, so people can have some facial hair if needed. “There is an opportunity to not just say, hey, this is an issue, but there's an opportunity for innovation here, to really think about it this problem in a different way, so that we are solution-focused.”

The US military has revised its grooming standards to remove medical exemptions for male facial hair, a policy change that may put careers at risk for thousands of service members. According to the updated guidelines, all soldiers must be clean-shaven on duty when in uniform or civilian clothes, with temporary exemptions for medical reasons and permanent exemptions for religious accommodations. 

The Army is the latest service branch to update its guidelines about beards: Soldiers with skin conditions will no longer be granted permanent medical waivers that allow them to avoid shaving. The Air Force and Space Force updated their guidance on grooming waivers in January, as did the Marine Corps in March. 

Defense Secretary Pete Hegseth, who ordered the guideline review, focused on grooming and appearance. In a Feb. 7 townhall with troops and department employees, he said, “It starts with the basic stuff, right? It’s grooming standards and uniform standards and training standards, fitness standards, all of that matters.”

Hegseth compared not enforcing grooming standards to the “broken windows” theory of policing: “I’m not saying if you violate grooming standards, you’re a criminal. The analogy is incomplete. But if you violate the small stuff and you allow it to happen, it creates a culture where the big stuff, you’re not held accountable for.”

The policy changes are particularly significant for soldiers who grow beards because they suffer from pseudofolliculitis barbae (PFB), an often-painful genetic condition that causes ingrown hairs. PFB produces flesh-colored or red follicular papules, which can be itchy, tender, and may bleed when shaved. Even if they heal, the lesions may lead to postinflammatory hyperpigmentation, scarring (including keloid scarring), and abscess. 

Although the updated standards affect all service members with beards, they draw ire from those who claim the rules disproportionately affect men of African descent. Up to 60% of Black men have PFB, according to the American Osteopathic College of Dermatology. According to the US Department of Defense (DoD) 2023 Demographics: Profile of the Military Community, service members who self-identify as Black or African American make up 17% of the total DoD military force (N = 2,034,426). Of 1,273,382 active-duty members, 18% are Black. Of 1,038,909 active-duty enlisted members, 20% are Black, and 9% of 234,473 active-duty officers are Black.

“Almost 65% of the US Air Force shaving waivers are held by Black men. And PFB is one of the most common reasons,” DanTasia Welch, MS, told Federal Practitioner. She, along with Richard P. Usatine, MD, and Candrice R. Heath, MD, wrote a recent review of the impact of PFB that was published in Federal Practitioner. 

“It is almost exclusively found in men of African descent,” Usatine said. “That just means if you have a policy that affects people with this condition, you are basically aiming that policy directly at Black men.”

“Pseudofolliculitis barbae, a lot of that just has to do with your shaving technique is what we’ve determined,” Steve Warren, an Army spokesman, told reporters in early July. “A vast majority of minority soldiers, African American soldiers, are within the standards all the time.” 

Usatine disagreed: “[PFB] is genetic, and whether you shave with or against the direction of the hairs, the problem is still there, and you can't just shave it away by ‘shaving correctly.’ They're going after one racial/ethnic group who has this problem, because almost everyone that has the problem is of African descent.”

The most effective management for PFB is to discontinue shaving. Grooming techniques and topical medications can be effective in treating mild-to-moderate cases of PFB, but more severe cases respond best to laser therapy. The Army, Navy, and Marine Corps advise laser therapy as a treatment option, but it has drawbacks. It is expensive and coded as a cosmetic procedure, and patients also may not have access to specialists experienced in performing the procedure in people with darker skin tones. Some patients may not want to permanently reduce the amount of hair that grows in the beard area for personal or religious reasons. 

A survey of Air Force members with 10,383 responses suggested that the men who had medical shaving waivers experienced longer times to promotion than those with no waiver. Most in the waiver group were Black or African American. 

The branches have handled the rule change in different ways. The Air Force, for example, which began tightening its standards on uniform and shaving waivers in January 2025, grants long-term shaving waivers only to airmen or guardians who have severe cases of PFB following consultation with medical practitioners. Air Force Surgeon General Lt. Gen. John DeGoes said in a video that the department’s 2020 (now expired) policy allowing 5-year shaving waivers did not give clinicians enough clarity on diagnosis by not differentiating between PFB and shaving irritation.

“They are 2 different things,” DeGoes said. “Ensuring a standardized approach to managing PFB is essential. And it is crucial that we provide consistent and effective care to our service members, enabling them to meet grooming standards while managing their condition.”

The new grooming policies leave many service members in an uncomfortable quandary: Keep the beard, run the risk of getting kicked out; keep shaving and put your skin and health at risk for complications; or receive laser treatment and have to deal with lack of beard hair after leaving the military.

Simply changing the rules isn’t enough. Candrice Heath, MD, told Federal Practitioner, “You need to always strike a balance. One of those points that’s always raised is about the facial equipment that's needed to protect during times of war.”

Heath called for more research funding to develop equipment, so people can have some facial hair if needed. “There is an opportunity to not just say, hey, this is an issue, but there's an opportunity for innovation here, to really think about it this problem in a different way, so that we are solution-focused.”

Helicobacter pylori (HP) eradication reduced the risk of gastric noncardia adenocarcinoma in five Scandinavian countries, a population-based study in Gastroenterology reported. Risk became virtually similar to the background population from 11 years after treatment onward.

HP infection of the stomach is the main established risk factor for this tumor, but not much was known about the impact of eradication on long-term risk, particularly in Western populations, noted investigators led by Jesper Lagengren, MD, a gastrointestinal surgeon and professor at the Karolinksa Institutet in Stockholm, Sweden. Research with longer follow-up has reported contradictory results.

The study cohort included all adults treated for HP from 1995 to 2019 in Denmark, Finland, Iceland, Norway, and Sweden. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated by comparing the gastric noncardia adenocarcinoma incidence in the study cohort with the incidence in the background population of the same age, sex, calendar period, and country.

The 659,592 treated participants were 54.3% women, 61.5% age 50 or younger, and had no serious comorbidities. They contributed to 5,480,873 person-years at risk with a mean follow-up of 8.3 years. Treatment consisted of a minimum one-week antibiotic regimen with two of amoxicillin, clarithromycin, or metronidazole, in combination with a proton pump inhibitor. This is the recommended regimen in the Nordic countries, where it achieves successful eradication in 90% of infected individuals.

Among these patients, 1311 developed gastric noncardia adenocarcinoma. Over as many as 24 years of follow-up, the SIR in treated HP patients was initially significantly higher than in the background population at 2.27 (95% confidence interval [CI], 2.10-2.44) at 1 to 5 years after treatment. By 6 to 10 years the SIR had dropped to 1.34 (1.21-1.48) and by 11 to 24 years it further fell to 1.11 (.98-1.27). In terms of observed vs expected cases, that translated to 702 vs 310 at 1 to 5 years, 374 vs 270 at 6 to 10 years, and 235 vs 211 from 11 to 24 years.

The results of the Nordic study align with systematic reviews from Asian populations indicating that eradication reduces the risk of gastric cancer, the authors said. 

They noted gastric HP infection is the most prevalent bacterial infection worldwide, found in approximately 50% of the global population but with striking geographical variations in prevalence and virulence. The highest prevalence (>80%) and virulence are found in countries with low socioeconomic status and sanitation standards such as regions in Africa and Western Asia. 

Gastric adenocarcinoma is the fourth-commonest cause of cancer-related death globally, leading to 660,000 deaths in 2022. 

Lagergren and colleagues cited the need for research to delineate high-risk individuals who would benefit rom HP screening and eradication.

This study was supported by the Sjoberg Foundation, Nordic Cancer Union, Stockholm County Council, and Stockholm Cancer Society. The authors had no conflicts of interest to disclose.

Helicobacter pylori (HP) eradication reduced the risk of gastric noncardia adenocarcinoma in five Scandinavian countries, a population-based study in Gastroenterology reported. Risk became virtually similar to the background population from 11 years after treatment onward.

HP infection of the stomach is the main established risk factor for this tumor, but not much was known about the impact of eradication on long-term risk, particularly in Western populations, noted investigators led by Jesper Lagengren, MD, a gastrointestinal surgeon and professor at the Karolinksa Institutet in Stockholm, Sweden. Research with longer follow-up has reported contradictory results.

The study cohort included all adults treated for HP from 1995 to 2019 in Denmark, Finland, Iceland, Norway, and Sweden. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated by comparing the gastric noncardia adenocarcinoma incidence in the study cohort with the incidence in the background population of the same age, sex, calendar period, and country.

The 659,592 treated participants were 54.3% women, 61.5% age 50 or younger, and had no serious comorbidities. They contributed to 5,480,873 person-years at risk with a mean follow-up of 8.3 years. Treatment consisted of a minimum one-week antibiotic regimen with two of amoxicillin, clarithromycin, or metronidazole, in combination with a proton pump inhibitor. This is the recommended regimen in the Nordic countries, where it achieves successful eradication in 90% of infected individuals.

Among these patients, 1311 developed gastric noncardia adenocarcinoma. Over as many as 24 years of follow-up, the SIR in treated HP patients was initially significantly higher than in the background population at 2.27 (95% confidence interval [CI], 2.10-2.44) at 1 to 5 years after treatment. By 6 to 10 years the SIR had dropped to 1.34 (1.21-1.48) and by 11 to 24 years it further fell to 1.11 (.98-1.27). In terms of observed vs expected cases, that translated to 702 vs 310 at 1 to 5 years, 374 vs 270 at 6 to 10 years, and 235 vs 211 from 11 to 24 years.

The results of the Nordic study align with systematic reviews from Asian populations indicating that eradication reduces the risk of gastric cancer, the authors said. 

They noted gastric HP infection is the most prevalent bacterial infection worldwide, found in approximately 50% of the global population but with striking geographical variations in prevalence and virulence. The highest prevalence (>80%) and virulence are found in countries with low socioeconomic status and sanitation standards such as regions in Africa and Western Asia. 

Gastric adenocarcinoma is the fourth-commonest cause of cancer-related death globally, leading to 660,000 deaths in 2022. 

Lagergren and colleagues cited the need for research to delineate high-risk individuals who would benefit rom HP screening and eradication.

This study was supported by the Sjoberg Foundation, Nordic Cancer Union, Stockholm County Council, and Stockholm Cancer Society. The authors had no conflicts of interest to disclose.

Helicobacter pylori (HP) eradication reduced the risk of gastric noncardia adenocarcinoma in five Scandinavian countries, a population-based study in Gastroenterology reported. Risk became virtually similar to the background population from 11 years after treatment onward.

HP infection of the stomach is the main established risk factor for this tumor, but not much was known about the impact of eradication on long-term risk, particularly in Western populations, noted investigators led by Jesper Lagengren, MD, a gastrointestinal surgeon and professor at the Karolinksa Institutet in Stockholm, Sweden. Research with longer follow-up has reported contradictory results.

The study cohort included all adults treated for HP from 1995 to 2019 in Denmark, Finland, Iceland, Norway, and Sweden. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated by comparing the gastric noncardia adenocarcinoma incidence in the study cohort with the incidence in the background population of the same age, sex, calendar period, and country.

The 659,592 treated participants were 54.3% women, 61.5% age 50 or younger, and had no serious comorbidities. They contributed to 5,480,873 person-years at risk with a mean follow-up of 8.3 years. Treatment consisted of a minimum one-week antibiotic regimen with two of amoxicillin, clarithromycin, or metronidazole, in combination with a proton pump inhibitor. This is the recommended regimen in the Nordic countries, where it achieves successful eradication in 90% of infected individuals.

Among these patients, 1311 developed gastric noncardia adenocarcinoma. Over as many as 24 years of follow-up, the SIR in treated HP patients was initially significantly higher than in the background population at 2.27 (95% confidence interval [CI], 2.10-2.44) at 1 to 5 years after treatment. By 6 to 10 years the SIR had dropped to 1.34 (1.21-1.48) and by 11 to 24 years it further fell to 1.11 (.98-1.27). In terms of observed vs expected cases, that translated to 702 vs 310 at 1 to 5 years, 374 vs 270 at 6 to 10 years, and 235 vs 211 from 11 to 24 years.

The results of the Nordic study align with systematic reviews from Asian populations indicating that eradication reduces the risk of gastric cancer, the authors said. 

They noted gastric HP infection is the most prevalent bacterial infection worldwide, found in approximately 50% of the global population but with striking geographical variations in prevalence and virulence. The highest prevalence (>80%) and virulence are found in countries with low socioeconomic status and sanitation standards such as regions in Africa and Western Asia. 

Gastric adenocarcinoma is the fourth-commonest cause of cancer-related death globally, leading to 660,000 deaths in 2022. 

Lagergren and colleagues cited the need for research to delineate high-risk individuals who would benefit rom HP screening and eradication.

This study was supported by the Sjoberg Foundation, Nordic Cancer Union, Stockholm County Council, and Stockholm Cancer Society. The authors had no conflicts of interest to disclose.

Exocrine pancreatic insufficiency (EPI) is a recognized condition in patients with underlying pancreatic disease. However, it is a disease state that requires a meticulous approach to diagnose, as misdiagnosis can lead to inappropriate testing and unnecessary treatment.

EPI has been defined as “a near total decline in the quantity and/or activity of endogenous pancreatic enzymes to a level that is inadequate to maintain normal digestive capacity leading to steatorrhea.”¹ It can lead to complications including malnutrition, micronutrient deficiencies, metabolic bone disease and have significant impact on quality of life. In this article, we will review the approach to diagnosis of EPI, differential diagnosis considerations, the approach to treatment of EPI, and screening for complications.
 

EPI Diagnosis

EPI results from ineffective or insufficient pancreatic digestive enzyme secretion. In 2021, a group of experts from the American Gastroenterological Association (AGA) and PancreasFest met and proposed a new mechanistic definition of EPI. This suggests that EPI is the failure of sufficient pancreatic enzymes to effectively reach the intestine in order to allow for optimal digestion of ingested nutrients, leading to downstream macronutrient and micronutrient deficiencies with symptoms of maldigestion including post-prandial abdominal pain, bloating, steatorrhea, loose stools, or weight loss.²

A more pragmatic definition by Khan, et al in 2022 utilized a staging system to distinguish exocrine pancreatic dysfunction (EDP) from EPI. As such EPD occurs when there is a decline in pancreatic function without impaired digestive capacity, while EPI requires digestive capacity impairment leading to objective steatorrhea (coefficient of fat absorption <93 %).³Differential Diagnosis: There are many factors that can impact normal digestion. In approaching EPI, symptoms are often the most common reason to test for disease state in the appropriate clinical context. There can be pancreatic causes of EPI and non-pancreatic (secondary) causes of EPI (see Figure 1), though the latter can be challenging to detect.

The most common parenchymal etiologies for EPI include chronic pancreatitis, recurrent acute pancreatitis, cystic fibrosis, pancreatic cancer or prior pancreatic resections. Non-pancreatic conditions that impact synchronous mixing of endogenous pancreatic enzymes with meals (i.e., Roux-en-Y gastric bypass, short bowel syndrome, delayed gastric emptying), mucosal barriers causing decrease endogenous pancreatic stimulation despite intact parenchyma, such as celiac disease, foregut Crohn’s disease, intraluminal inactivation of pancreatic enzymes (Zollinger-Ellison syndrome), and bile salts de-conjugation with small intestinal bacterial overgrowth (SIBO) can predispose to EPI.^4-6 The true prevalence of EPI is difficult to ascertain due to a variety of factors including challenges in diagnosis and misdiagnosis.

Some of the major challenges in the diagnosis and treatment of EPI is that the symptoms of EPI overlap with many other GI conditions including celiac disease, diabetes mellitus, SIBO, irritable bowel syndrome (IBS), bile acid diarrhea, and other functional GI syndromes. These non-pancreatic conditions can also be associated with falsely low FE-1. Hence, ordering FE-1 should be employed with caution when the pretest probability is low. Patients with EPI will generally have a significant response to pancreatic enzyme replacement therapy (PERT) if it is adequately dosed and a lack of response should prompt consideration of an alternative diagnosis. A framework to factors which contribute to EPI is outlined in Figure 2.

Symptoms Screening and Signs: Pancreatic enzymes output estimation is the most reliable indicator for pancreatic digestive capacity. However, EPI diagnosis requires a combination of symptoms screening, stool-based (indirect pancreatic function) testing or direct pancreatic function testing (PFT).

Although symptoms might not correlate with objective disease state, in screening for symptoms of steatorrhea or maldigestion, it is important to ask specific questions regarding bloating, abdominal pain, stool frequency, consistency, and quality. Screening questions should be specific and include question such as, “Is there oil in the toilet bowl or is the stool greasy/shiny?”, “Is the stool sticky and difficult to flush or wipe?”, “Is there malodorous flatus?” If patients screen positive for EPI symptoms and there is a high pre-test probability of EPI such as the presence of severe chronic pancreatitis or significant pancreatic resection (> 90% loss of pancreatic parenchyma), then cautious trial of PERT and assessment for treatment response can be considered without additional stool-based testing. However, this practice end points are unclear and mainly based on subjective response.

Patients with EPI are at increased risk for malnutrition and micronutrient deficiencies. While not required for the diagnosis, low levels of fat-soluble vitamins (vitamin AEDK) or other minerals (zinc, selenium, magnesium, phosphorus) can suggest issues with malabsorption. Once the diagnosis of EPI is made, micronutrient screening should occur annually.

Stool Based Testing: The gold standard clinical test for steatorrhea is measuring coefficient of fat absorption (CFA). With a normal range of 93% fat absorption, the test is performed on a 72-hours fecal fat collection kit. To ensure accurate results, a patient must adhere to a diet with a minimum of 100 grams of fat per day in the three days leading up to the test and during the duration of the test. Patients must also abstain from taking PERT during the duration of the test. This can be incredibly challenging for someone with underlying steatorrhea but can reliably distinguish between EPD and EPI.

A more commonly used stool test is fecal elastase (FE-1). While easier to perform, the test often results in many false positives and false negatives. FE-1 is an ELISA based test, which measures the concentration of the specific isoform CELA3 (chymotrypsin-like elastase family) in the stool sample. The test must be run on a solid stool sample as soft or liquid stool will dilute down elastase concentration falsely. One test advantage is that a patient can continue PERT if needed. FE-1 test measures the concentration of patients’ elastase and PERT is porcine derived. As such, there is no interaction between porcine lipase and human elastase in stool. FE-1 sensitivity and specificity are high for severe disease (<100 mcg/g) if the test is performed properly on patients with a high pretest probability. However, the sensitivity and specificity are poor in mild to moderate pancreatic disease and in the absence of known pancreatic disease.⁷

Our suggested approach to utilizing FE-1 test is to reserve it for patients with known severe chronic pancreatitis or prior pancreatic surgery in patients with symptoms. In patients without pancreatic disease who are at low risk of EPI, a positive FE-1 can lead to misdiagnosis, further diagnostic testing, and unnecessary treatment. Currently, there is no stool-based test that is accurate, reproducible, and reliable.

Direct Pancreatic Function testing: Secretin stimulated PFT is highly reliable in measuring ductal function with bicarbonate concentration. However, it cannot reliably estimate acinar function as both do not decline at the same rate, unless in severe pancreatic disease. A much more robust test should include cholecystokinin analog to measure pancreatic enzymes concentration. This test involves endoscopy, administration of secretin, and/or a cholecystokinin analog, and subsequent measurement of bicarbonate and digestive enzymes in the pancreatic juice. This test is not routinely offered as it is invasive, cumbersome, and difficult to repeat for reassessment of pancreatic function over time.⁸

Treatment

The primary goal of treatment is to improve symptoms and nutritional status of the patient. EPI treatment consists of PERT and nutritional counseling. In the United States, there are multiple FDA approved PERT preparations, which include Creon, Zenpep, Pancreaze, Pertzye, Viokase, and Relizorb. While dosing is dependent on lipase concentration, all PERT (aside from Relizorb) preparations have a combination of lipase, proteases, and amylase. All but Viokace and Relizorb are enteric-coated formulations.⁹

In patients with an inadequate response to enteric coated PERT, non-enteric coated PERT can be added as it may provide a more immediate effect than enteric coated formulations, specially if concern about rapid gut transit with inadequate mixing is raised. If a non-enteric formations is used, acid suppression should be added to prevent inactivation of the PERT. Relizorb is a cartridge system which delivers lipase directly to tube feeds. This cartridge is only utilized in patients receiving enteral nutrition and allows for treatment of EPI even when patients are unable to tolerate oral feeding.

PERT dosing is intended to at least compensate for 10% of the physiologically secreted amount of endogenous lipase after a normal meal (approximately 30,000 IU). Hence, dosing is primarily weight-based. In symptomatic adults, PERT dose of 500-1000 units/kg/meal and half of the amount with snacks is appropriate. Although higher doses of 1500-2000 units/kg/meal may be needed when there is significant steatorrhea, weight loss, or micronutrient deficiencies, PERT doses exceeding 2500 units/kg/meal are not recommended and warrant further investigation.¹⁰

Proper counseling is important to ensure compliance with pancreatin preparations. PERT will generally be effective in improving steatorrhea, weight loss, bowel movement frequency, and reversal of nutritional deficiencies, but it does not reliably help symptoms of bloating or abdominal pain. If a patient’s steatorrhea does not respond to PERT, then alternative diagnoses such as SIBO, or diarrhea-predominant IBS should be considered.

PERT must be taken with meals. There are studies that support split dosing as a more effective way of absorbing fat.¹¹ If PERT is ineffective or minimally effective, review of appropriate dosing and timing of PERT to a meal is recommended. Addition of acid suppression may be required to improve treatment efficacy, especially in patients with abnormal intestinal motility or prior pancreatic surgery as PERT is effective at a pH of 4.5. Cost, pill burden, and persistence of certain symptoms may impact adherence to PERT and thus pre-treatment counseling and close follow-up after initiation is important. This aids in assessment of patients’ response to therapy, ensure appropriate PERT administration, and identifying any barriers to therapy adherence.

Nutritional management of EPI consists of an assessment of nutritional status, diet, and lifestyle. An important component of nutritional management is the assessment of micronutrient deficiencies. Patients with a confirmed diagnosis of EPI should be screened for the following micronutrients annually: Vitamins (A, E, D, K, B12), folate, zinc, selenium, magnesium, and iron. Patients with chronic pancreatitis and EPI should also be screened for metabolic bone disease once every two years and for diabetes mellitus annually.^{4, 12}

Conclusion

EPI is a challenging diagnosis as many symptoms overlap with other GI conditions. Pancreas exocrine function is rich with significant reserve to allow for proper digestive capacity, yet EPI occurs when an individual’s pancreatic digestive enzymes are insufficient to meet their nutritional needs. In patients with high likelihood of having EPI, such as those with pre-existing pancreatic disease, diagnosing EPI combines clinical evidence based on subjective symptoms and stool-based testing to support a disease state.

Appropriate dosing and timing of PERT is critical to improve nutritional outcomes and improve certain symptoms of EPI. Failure of PERT requires evaluating for proper dosing/timing, and consideration of additional or alternative diagnosis. EPI morbidity can lead to significant impact on patients’ quality of life, but with counseling, proper PERT use, nutritional consequences can be mediated, and quality of life can improve.

Dr. Hernandez-Barco is based in the Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. Dr. Ashkar is based in the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Dr. Hernandez-Barco disclosed consulting for AMGEN and served as a scientific advisor for Nestle Health Science. She had project-related funding support or conflicts of interest to disclose. Dr. Ashkar disclosed consulting for AMGEN. He had no project-related funding support or conflicts of interest to disclose.

References

1. Othman MO, et al. Introduction and practical approach to exocrine pancreatic insufficiency for the practicing clinician. Int J Clin Pract. 2018 Feb. doi: 10.1111/ijcp.13066.

2. Whitcomb DC, et al. AGA-PancreasFest Joint Symposium on Exocrine Pancreatitic Insufficiency. Gastro Hep Adv. 2022 Nov. doi: 10.1016/j.gastha.2022.11.008.

3. Khan A, et al. Staging Exocrine Pancreatic Dysfunction. Pancreatology. 2022 Jan. doi: 10.1016/j.pan.2021.11.005.

4. Whitcomb DC, et al. AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatitis insufficiency: Expert Review. Gastroenterology. 2023 Nov. doi: 10.1053/j.gastro.2023.07.007.

5. Kunovský L, et al. Causes of Exocrine Pancreatic Insufficiency Other than Chronic Pancreatitis. J Clin Med. 2021 Dec. doi: 10.3390/jcm10245779.

6. Singh VK, et al. Less common etiologies of exocrine pancreatic insufficiency. World J Gastroenterol. 2017 Oct. doi: 10.3748/wjg.v23.i39.7059.

7. Lankisch PG, et al. Faecal elastase 1: not helpful in diagnosing chronic pancreatitis associated with mid to moderate exocrine pancreatic insufficiency. Gut. 1998 Apr. doi: 10.1136/gut.42.4.551.

8. Gardner TB, et al. ACG Clinical Guideline: Chronic Pancreatitis. Am J Gastroenterol. 2020 Mar. doi: 10.14309/ajg.0000000000000535.

9. Lewis DM, et al. Exocrine Pancreatic Insufficiency Dosing Guidelines for Pancreatic Enzyme Replacement Therapy Vary Widely Across Disease Types. Dig Dis Sci. 2024 Feb. doi: 10.1007/s10620-023-08184-w.

10. Borowitz DS, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995 Nov. doi: 10.1016/s0022-3476(95)70153-2.

11. Domínguez-Muñoz JE, et al. Effect of the Administration Schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther. 2005 Apr. doi: 10.1111/j.1365-2036.2005.02390.x.

12. Hart PA and Conwell DL. Chronic Pancreatitis: Managing a Difficult Disease. Am J Gastroenterol. 2020 Jan. doi: 10.14309/ajg.0000000000000421.

Exocrine pancreatic insufficiency (EPI) is a recognized condition in patients with underlying pancreatic disease. However, it is a disease state that requires a meticulous approach to diagnose, as misdiagnosis can lead to inappropriate testing and unnecessary treatment.

EPI has been defined as “a near total decline in the quantity and/or activity of endogenous pancreatic enzymes to a level that is inadequate to maintain normal digestive capacity leading to steatorrhea.”¹ It can lead to complications including malnutrition, micronutrient deficiencies, metabolic bone disease and have significant impact on quality of life. In this article, we will review the approach to diagnosis of EPI, differential diagnosis considerations, the approach to treatment of EPI, and screening for complications.
 

EPI Diagnosis

EPI results from ineffective or insufficient pancreatic digestive enzyme secretion. In 2021, a group of experts from the American Gastroenterological Association (AGA) and PancreasFest met and proposed a new mechanistic definition of EPI. This suggests that EPI is the failure of sufficient pancreatic enzymes to effectively reach the intestine in order to allow for optimal digestion of ingested nutrients, leading to downstream macronutrient and micronutrient deficiencies with symptoms of maldigestion including post-prandial abdominal pain, bloating, steatorrhea, loose stools, or weight loss.²

A more pragmatic definition by Khan, et al in 2022 utilized a staging system to distinguish exocrine pancreatic dysfunction (EDP) from EPI. As such EPD occurs when there is a decline in pancreatic function without impaired digestive capacity, while EPI requires digestive capacity impairment leading to objective steatorrhea (coefficient of fat absorption <93 %).³Differential Diagnosis: There are many factors that can impact normal digestion. In approaching EPI, symptoms are often the most common reason to test for disease state in the appropriate clinical context. There can be pancreatic causes of EPI and non-pancreatic (secondary) causes of EPI (see Figure 1), though the latter can be challenging to detect.

The most common parenchymal etiologies for EPI include chronic pancreatitis, recurrent acute pancreatitis, cystic fibrosis, pancreatic cancer or prior pancreatic resections. Non-pancreatic conditions that impact synchronous mixing of endogenous pancreatic enzymes with meals (i.e., Roux-en-Y gastric bypass, short bowel syndrome, delayed gastric emptying), mucosal barriers causing decrease endogenous pancreatic stimulation despite intact parenchyma, such as celiac disease, foregut Crohn’s disease, intraluminal inactivation of pancreatic enzymes (Zollinger-Ellison syndrome), and bile salts de-conjugation with small intestinal bacterial overgrowth (SIBO) can predispose to EPI.^4-6 The true prevalence of EPI is difficult to ascertain due to a variety of factors including challenges in diagnosis and misdiagnosis.

Some of the major challenges in the diagnosis and treatment of EPI is that the symptoms of EPI overlap with many other GI conditions including celiac disease, diabetes mellitus, SIBO, irritable bowel syndrome (IBS), bile acid diarrhea, and other functional GI syndromes. These non-pancreatic conditions can also be associated with falsely low FE-1. Hence, ordering FE-1 should be employed with caution when the pretest probability is low. Patients with EPI will generally have a significant response to pancreatic enzyme replacement therapy (PERT) if it is adequately dosed and a lack of response should prompt consideration of an alternative diagnosis. A framework to factors which contribute to EPI is outlined in Figure 2.

Symptoms Screening and Signs: Pancreatic enzymes output estimation is the most reliable indicator for pancreatic digestive capacity. However, EPI diagnosis requires a combination of symptoms screening, stool-based (indirect pancreatic function) testing or direct pancreatic function testing (PFT).

Although symptoms might not correlate with objective disease state, in screening for symptoms of steatorrhea or maldigestion, it is important to ask specific questions regarding bloating, abdominal pain, stool frequency, consistency, and quality. Screening questions should be specific and include question such as, “Is there oil in the toilet bowl or is the stool greasy/shiny?”, “Is the stool sticky and difficult to flush or wipe?”, “Is there malodorous flatus?” If patients screen positive for EPI symptoms and there is a high pre-test probability of EPI such as the presence of severe chronic pancreatitis or significant pancreatic resection (> 90% loss of pancreatic parenchyma), then cautious trial of PERT and assessment for treatment response can be considered without additional stool-based testing. However, this practice end points are unclear and mainly based on subjective response.

Patients with EPI are at increased risk for malnutrition and micronutrient deficiencies. While not required for the diagnosis, low levels of fat-soluble vitamins (vitamin AEDK) or other minerals (zinc, selenium, magnesium, phosphorus) can suggest issues with malabsorption. Once the diagnosis of EPI is made, micronutrient screening should occur annually.

Stool Based Testing: The gold standard clinical test for steatorrhea is measuring coefficient of fat absorption (CFA). With a normal range of 93% fat absorption, the test is performed on a 72-hours fecal fat collection kit. To ensure accurate results, a patient must adhere to a diet with a minimum of 100 grams of fat per day in the three days leading up to the test and during the duration of the test. Patients must also abstain from taking PERT during the duration of the test. This can be incredibly challenging for someone with underlying steatorrhea but can reliably distinguish between EPD and EPI.

A more commonly used stool test is fecal elastase (FE-1). While easier to perform, the test often results in many false positives and false negatives. FE-1 is an ELISA based test, which measures the concentration of the specific isoform CELA3 (chymotrypsin-like elastase family) in the stool sample. The test must be run on a solid stool sample as soft or liquid stool will dilute down elastase concentration falsely. One test advantage is that a patient can continue PERT if needed. FE-1 test measures the concentration of patients’ elastase and PERT is porcine derived. As such, there is no interaction between porcine lipase and human elastase in stool. FE-1 sensitivity and specificity are high for severe disease (<100 mcg/g) if the test is performed properly on patients with a high pretest probability. However, the sensitivity and specificity are poor in mild to moderate pancreatic disease and in the absence of known pancreatic disease.⁷

Our suggested approach to utilizing FE-1 test is to reserve it for patients with known severe chronic pancreatitis or prior pancreatic surgery in patients with symptoms. In patients without pancreatic disease who are at low risk of EPI, a positive FE-1 can lead to misdiagnosis, further diagnostic testing, and unnecessary treatment. Currently, there is no stool-based test that is accurate, reproducible, and reliable.

Direct Pancreatic Function testing: Secretin stimulated PFT is highly reliable in measuring ductal function with bicarbonate concentration. However, it cannot reliably estimate acinar function as both do not decline at the same rate, unless in severe pancreatic disease. A much more robust test should include cholecystokinin analog to measure pancreatic enzymes concentration. This test involves endoscopy, administration of secretin, and/or a cholecystokinin analog, and subsequent measurement of bicarbonate and digestive enzymes in the pancreatic juice. This test is not routinely offered as it is invasive, cumbersome, and difficult to repeat for reassessment of pancreatic function over time.⁸

Treatment

The primary goal of treatment is to improve symptoms and nutritional status of the patient. EPI treatment consists of PERT and nutritional counseling. In the United States, there are multiple FDA approved PERT preparations, which include Creon, Zenpep, Pancreaze, Pertzye, Viokase, and Relizorb. While dosing is dependent on lipase concentration, all PERT (aside from Relizorb) preparations have a combination of lipase, proteases, and amylase. All but Viokace and Relizorb are enteric-coated formulations.⁹

In patients with an inadequate response to enteric coated PERT, non-enteric coated PERT can be added as it may provide a more immediate effect than enteric coated formulations, specially if concern about rapid gut transit with inadequate mixing is raised. If a non-enteric formations is used, acid suppression should be added to prevent inactivation of the PERT. Relizorb is a cartridge system which delivers lipase directly to tube feeds. This cartridge is only utilized in patients receiving enteral nutrition and allows for treatment of EPI even when patients are unable to tolerate oral feeding.

PERT dosing is intended to at least compensate for 10% of the physiologically secreted amount of endogenous lipase after a normal meal (approximately 30,000 IU). Hence, dosing is primarily weight-based. In symptomatic adults, PERT dose of 500-1000 units/kg/meal and half of the amount with snacks is appropriate. Although higher doses of 1500-2000 units/kg/meal may be needed when there is significant steatorrhea, weight loss, or micronutrient deficiencies, PERT doses exceeding 2500 units/kg/meal are not recommended and warrant further investigation.¹⁰

Proper counseling is important to ensure compliance with pancreatin preparations. PERT will generally be effective in improving steatorrhea, weight loss, bowel movement frequency, and reversal of nutritional deficiencies, but it does not reliably help symptoms of bloating or abdominal pain. If a patient’s steatorrhea does not respond to PERT, then alternative diagnoses such as SIBO, or diarrhea-predominant IBS should be considered.

PERT must be taken with meals. There are studies that support split dosing as a more effective way of absorbing fat.¹¹ If PERT is ineffective or minimally effective, review of appropriate dosing and timing of PERT to a meal is recommended. Addition of acid suppression may be required to improve treatment efficacy, especially in patients with abnormal intestinal motility or prior pancreatic surgery as PERT is effective at a pH of 4.5. Cost, pill burden, and persistence of certain symptoms may impact adherence to PERT and thus pre-treatment counseling and close follow-up after initiation is important. This aids in assessment of patients’ response to therapy, ensure appropriate PERT administration, and identifying any barriers to therapy adherence.

Nutritional management of EPI consists of an assessment of nutritional status, diet, and lifestyle. An important component of nutritional management is the assessment of micronutrient deficiencies. Patients with a confirmed diagnosis of EPI should be screened for the following micronutrients annually: Vitamins (A, E, D, K, B12), folate, zinc, selenium, magnesium, and iron. Patients with chronic pancreatitis and EPI should also be screened for metabolic bone disease once every two years and for diabetes mellitus annually.^{4, 12}

Conclusion

EPI is a challenging diagnosis as many symptoms overlap with other GI conditions. Pancreas exocrine function is rich with significant reserve to allow for proper digestive capacity, yet EPI occurs when an individual’s pancreatic digestive enzymes are insufficient to meet their nutritional needs. In patients with high likelihood of having EPI, such as those with pre-existing pancreatic disease, diagnosing EPI combines clinical evidence based on subjective symptoms and stool-based testing to support a disease state.

Appropriate dosing and timing of PERT is critical to improve nutritional outcomes and improve certain symptoms of EPI. Failure of PERT requires evaluating for proper dosing/timing, and consideration of additional or alternative diagnosis. EPI morbidity can lead to significant impact on patients’ quality of life, but with counseling, proper PERT use, nutritional consequences can be mediated, and quality of life can improve.

Dr. Hernandez-Barco is based in the Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. Dr. Ashkar is based in the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Dr. Hernandez-Barco disclosed consulting for AMGEN and served as a scientific advisor for Nestle Health Science. She had project-related funding support or conflicts of interest to disclose. Dr. Ashkar disclosed consulting for AMGEN. He had no project-related funding support or conflicts of interest to disclose.

References

1. Othman MO, et al. Introduction and practical approach to exocrine pancreatic insufficiency for the practicing clinician. Int J Clin Pract. 2018 Feb. doi: 10.1111/ijcp.13066.

2. Whitcomb DC, et al. AGA-PancreasFest Joint Symposium on Exocrine Pancreatitic Insufficiency. Gastro Hep Adv. 2022 Nov. doi: 10.1016/j.gastha.2022.11.008.

3. Khan A, et al. Staging Exocrine Pancreatic Dysfunction. Pancreatology. 2022 Jan. doi: 10.1016/j.pan.2021.11.005.

4. Whitcomb DC, et al. AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatitis insufficiency: Expert Review. Gastroenterology. 2023 Nov. doi: 10.1053/j.gastro.2023.07.007.

5. Kunovský L, et al. Causes of Exocrine Pancreatic Insufficiency Other than Chronic Pancreatitis. J Clin Med. 2021 Dec. doi: 10.3390/jcm10245779.

6. Singh VK, et al. Less common etiologies of exocrine pancreatic insufficiency. World J Gastroenterol. 2017 Oct. doi: 10.3748/wjg.v23.i39.7059.

7. Lankisch PG, et al. Faecal elastase 1: not helpful in diagnosing chronic pancreatitis associated with mid to moderate exocrine pancreatic insufficiency. Gut. 1998 Apr. doi: 10.1136/gut.42.4.551.

8. Gardner TB, et al. ACG Clinical Guideline: Chronic Pancreatitis. Am J Gastroenterol. 2020 Mar. doi: 10.14309/ajg.0000000000000535.

9. Lewis DM, et al. Exocrine Pancreatic Insufficiency Dosing Guidelines for Pancreatic Enzyme Replacement Therapy Vary Widely Across Disease Types. Dig Dis Sci. 2024 Feb. doi: 10.1007/s10620-023-08184-w.

10. Borowitz DS, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995 Nov. doi: 10.1016/s0022-3476(95)70153-2.

11. Domínguez-Muñoz JE, et al. Effect of the Administration Schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther. 2005 Apr. doi: 10.1111/j.1365-2036.2005.02390.x.

12. Hart PA and Conwell DL. Chronic Pancreatitis: Managing a Difficult Disease. Am J Gastroenterol. 2020 Jan. doi: 10.14309/ajg.0000000000000421.

Exocrine pancreatic insufficiency (EPI) is a recognized condition in patients with underlying pancreatic disease. However, it is a disease state that requires a meticulous approach to diagnose, as misdiagnosis can lead to inappropriate testing and unnecessary treatment.

EPI has been defined as “a near total decline in the quantity and/or activity of endogenous pancreatic enzymes to a level that is inadequate to maintain normal digestive capacity leading to steatorrhea.”¹ It can lead to complications including malnutrition, micronutrient deficiencies, metabolic bone disease and have significant impact on quality of life. In this article, we will review the approach to diagnosis of EPI, differential diagnosis considerations, the approach to treatment of EPI, and screening for complications.
 

EPI Diagnosis

EPI results from ineffective or insufficient pancreatic digestive enzyme secretion. In 2021, a group of experts from the American Gastroenterological Association (AGA) and PancreasFest met and proposed a new mechanistic definition of EPI. This suggests that EPI is the failure of sufficient pancreatic enzymes to effectively reach the intestine in order to allow for optimal digestion of ingested nutrients, leading to downstream macronutrient and micronutrient deficiencies with symptoms of maldigestion including post-prandial abdominal pain, bloating, steatorrhea, loose stools, or weight loss.²

A more pragmatic definition by Khan, et al in 2022 utilized a staging system to distinguish exocrine pancreatic dysfunction (EDP) from EPI. As such EPD occurs when there is a decline in pancreatic function without impaired digestive capacity, while EPI requires digestive capacity impairment leading to objective steatorrhea (coefficient of fat absorption <93 %).³Differential Diagnosis: There are many factors that can impact normal digestion. In approaching EPI, symptoms are often the most common reason to test for disease state in the appropriate clinical context. There can be pancreatic causes of EPI and non-pancreatic (secondary) causes of EPI (see Figure 1), though the latter can be challenging to detect.

The most common parenchymal etiologies for EPI include chronic pancreatitis, recurrent acute pancreatitis, cystic fibrosis, pancreatic cancer or prior pancreatic resections. Non-pancreatic conditions that impact synchronous mixing of endogenous pancreatic enzymes with meals (i.e., Roux-en-Y gastric bypass, short bowel syndrome, delayed gastric emptying), mucosal barriers causing decrease endogenous pancreatic stimulation despite intact parenchyma, such as celiac disease, foregut Crohn’s disease, intraluminal inactivation of pancreatic enzymes (Zollinger-Ellison syndrome), and bile salts de-conjugation with small intestinal bacterial overgrowth (SIBO) can predispose to EPI.^4-6 The true prevalence of EPI is difficult to ascertain due to a variety of factors including challenges in diagnosis and misdiagnosis.

Some of the major challenges in the diagnosis and treatment of EPI is that the symptoms of EPI overlap with many other GI conditions including celiac disease, diabetes mellitus, SIBO, irritable bowel syndrome (IBS), bile acid diarrhea, and other functional GI syndromes. These non-pancreatic conditions can also be associated with falsely low FE-1. Hence, ordering FE-1 should be employed with caution when the pretest probability is low. Patients with EPI will generally have a significant response to pancreatic enzyme replacement therapy (PERT) if it is adequately dosed and a lack of response should prompt consideration of an alternative diagnosis. A framework to factors which contribute to EPI is outlined in Figure 2.

Symptoms Screening and Signs: Pancreatic enzymes output estimation is the most reliable indicator for pancreatic digestive capacity. However, EPI diagnosis requires a combination of symptoms screening, stool-based (indirect pancreatic function) testing or direct pancreatic function testing (PFT).

Although symptoms might not correlate with objective disease state, in screening for symptoms of steatorrhea or maldigestion, it is important to ask specific questions regarding bloating, abdominal pain, stool frequency, consistency, and quality. Screening questions should be specific and include question such as, “Is there oil in the toilet bowl or is the stool greasy/shiny?”, “Is the stool sticky and difficult to flush or wipe?”, “Is there malodorous flatus?” If patients screen positive for EPI symptoms and there is a high pre-test probability of EPI such as the presence of severe chronic pancreatitis or significant pancreatic resection (> 90% loss of pancreatic parenchyma), then cautious trial of PERT and assessment for treatment response can be considered without additional stool-based testing. However, this practice end points are unclear and mainly based on subjective response.

Patients with EPI are at increased risk for malnutrition and micronutrient deficiencies. While not required for the diagnosis, low levels of fat-soluble vitamins (vitamin AEDK) or other minerals (zinc, selenium, magnesium, phosphorus) can suggest issues with malabsorption. Once the diagnosis of EPI is made, micronutrient screening should occur annually.

Stool Based Testing: The gold standard clinical test for steatorrhea is measuring coefficient of fat absorption (CFA). With a normal range of 93% fat absorption, the test is performed on a 72-hours fecal fat collection kit. To ensure accurate results, a patient must adhere to a diet with a minimum of 100 grams of fat per day in the three days leading up to the test and during the duration of the test. Patients must also abstain from taking PERT during the duration of the test. This can be incredibly challenging for someone with underlying steatorrhea but can reliably distinguish between EPD and EPI.

A more commonly used stool test is fecal elastase (FE-1). While easier to perform, the test often results in many false positives and false negatives. FE-1 is an ELISA based test, which measures the concentration of the specific isoform CELA3 (chymotrypsin-like elastase family) in the stool sample. The test must be run on a solid stool sample as soft or liquid stool will dilute down elastase concentration falsely. One test advantage is that a patient can continue PERT if needed. FE-1 test measures the concentration of patients’ elastase and PERT is porcine derived. As such, there is no interaction between porcine lipase and human elastase in stool. FE-1 sensitivity and specificity are high for severe disease (<100 mcg/g) if the test is performed properly on patients with a high pretest probability. However, the sensitivity and specificity are poor in mild to moderate pancreatic disease and in the absence of known pancreatic disease.⁷

Our suggested approach to utilizing FE-1 test is to reserve it for patients with known severe chronic pancreatitis or prior pancreatic surgery in patients with symptoms. In patients without pancreatic disease who are at low risk of EPI, a positive FE-1 can lead to misdiagnosis, further diagnostic testing, and unnecessary treatment. Currently, there is no stool-based test that is accurate, reproducible, and reliable.

Direct Pancreatic Function testing: Secretin stimulated PFT is highly reliable in measuring ductal function with bicarbonate concentration. However, it cannot reliably estimate acinar function as both do not decline at the same rate, unless in severe pancreatic disease. A much more robust test should include cholecystokinin analog to measure pancreatic enzymes concentration. This test involves endoscopy, administration of secretin, and/or a cholecystokinin analog, and subsequent measurement of bicarbonate and digestive enzymes in the pancreatic juice. This test is not routinely offered as it is invasive, cumbersome, and difficult to repeat for reassessment of pancreatic function over time.⁸

Treatment

The primary goal of treatment is to improve symptoms and nutritional status of the patient. EPI treatment consists of PERT and nutritional counseling. In the United States, there are multiple FDA approved PERT preparations, which include Creon, Zenpep, Pancreaze, Pertzye, Viokase, and Relizorb. While dosing is dependent on lipase concentration, all PERT (aside from Relizorb) preparations have a combination of lipase, proteases, and amylase. All but Viokace and Relizorb are enteric-coated formulations.⁹

In patients with an inadequate response to enteric coated PERT, non-enteric coated PERT can be added as it may provide a more immediate effect than enteric coated formulations, specially if concern about rapid gut transit with inadequate mixing is raised. If a non-enteric formations is used, acid suppression should be added to prevent inactivation of the PERT. Relizorb is a cartridge system which delivers lipase directly to tube feeds. This cartridge is only utilized in patients receiving enteral nutrition and allows for treatment of EPI even when patients are unable to tolerate oral feeding.

PERT dosing is intended to at least compensate for 10% of the physiologically secreted amount of endogenous lipase after a normal meal (approximately 30,000 IU). Hence, dosing is primarily weight-based. In symptomatic adults, PERT dose of 500-1000 units/kg/meal and half of the amount with snacks is appropriate. Although higher doses of 1500-2000 units/kg/meal may be needed when there is significant steatorrhea, weight loss, or micronutrient deficiencies, PERT doses exceeding 2500 units/kg/meal are not recommended and warrant further investigation.¹⁰

Proper counseling is important to ensure compliance with pancreatin preparations. PERT will generally be effective in improving steatorrhea, weight loss, bowel movement frequency, and reversal of nutritional deficiencies, but it does not reliably help symptoms of bloating or abdominal pain. If a patient’s steatorrhea does not respond to PERT, then alternative diagnoses such as SIBO, or diarrhea-predominant IBS should be considered.

PERT must be taken with meals. There are studies that support split dosing as a more effective way of absorbing fat.¹¹ If PERT is ineffective or minimally effective, review of appropriate dosing and timing of PERT to a meal is recommended. Addition of acid suppression may be required to improve treatment efficacy, especially in patients with abnormal intestinal motility or prior pancreatic surgery as PERT is effective at a pH of 4.5. Cost, pill burden, and persistence of certain symptoms may impact adherence to PERT and thus pre-treatment counseling and close follow-up after initiation is important. This aids in assessment of patients’ response to therapy, ensure appropriate PERT administration, and identifying any barriers to therapy adherence.

Nutritional management of EPI consists of an assessment of nutritional status, diet, and lifestyle. An important component of nutritional management is the assessment of micronutrient deficiencies. Patients with a confirmed diagnosis of EPI should be screened for the following micronutrients annually: Vitamins (A, E, D, K, B12), folate, zinc, selenium, magnesium, and iron. Patients with chronic pancreatitis and EPI should also be screened for metabolic bone disease once every two years and for diabetes mellitus annually.^{4, 12}

Conclusion

EPI is a challenging diagnosis as many symptoms overlap with other GI conditions. Pancreas exocrine function is rich with significant reserve to allow for proper digestive capacity, yet EPI occurs when an individual’s pancreatic digestive enzymes are insufficient to meet their nutritional needs. In patients with high likelihood of having EPI, such as those with pre-existing pancreatic disease, diagnosing EPI combines clinical evidence based on subjective symptoms and stool-based testing to support a disease state.

Appropriate dosing and timing of PERT is critical to improve nutritional outcomes and improve certain symptoms of EPI. Failure of PERT requires evaluating for proper dosing/timing, and consideration of additional or alternative diagnosis. EPI morbidity can lead to significant impact on patients’ quality of life, but with counseling, proper PERT use, nutritional consequences can be mediated, and quality of life can improve.

Dr. Hernandez-Barco is based in the Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. Dr. Ashkar is based in the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Dr. Hernandez-Barco disclosed consulting for AMGEN and served as a scientific advisor for Nestle Health Science. She had project-related funding support or conflicts of interest to disclose. Dr. Ashkar disclosed consulting for AMGEN. He had no project-related funding support or conflicts of interest to disclose.

References

1. Othman MO, et al. Introduction and practical approach to exocrine pancreatic insufficiency for the practicing clinician. Int J Clin Pract. 2018 Feb. doi: 10.1111/ijcp.13066.

2. Whitcomb DC, et al. AGA-PancreasFest Joint Symposium on Exocrine Pancreatitic Insufficiency. Gastro Hep Adv. 2022 Nov. doi: 10.1016/j.gastha.2022.11.008.

3. Khan A, et al. Staging Exocrine Pancreatic Dysfunction. Pancreatology. 2022 Jan. doi: 10.1016/j.pan.2021.11.005.

4. Whitcomb DC, et al. AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatitis insufficiency: Expert Review. Gastroenterology. 2023 Nov. doi: 10.1053/j.gastro.2023.07.007.

5. Kunovský L, et al. Causes of Exocrine Pancreatic Insufficiency Other than Chronic Pancreatitis. J Clin Med. 2021 Dec. doi: 10.3390/jcm10245779.

6. Singh VK, et al. Less common etiologies of exocrine pancreatic insufficiency. World J Gastroenterol. 2017 Oct. doi: 10.3748/wjg.v23.i39.7059.

7. Lankisch PG, et al. Faecal elastase 1: not helpful in diagnosing chronic pancreatitis associated with mid to moderate exocrine pancreatic insufficiency. Gut. 1998 Apr. doi: 10.1136/gut.42.4.551.

8. Gardner TB, et al. ACG Clinical Guideline: Chronic Pancreatitis. Am J Gastroenterol. 2020 Mar. doi: 10.14309/ajg.0000000000000535.

9. Lewis DM, et al. Exocrine Pancreatic Insufficiency Dosing Guidelines for Pancreatic Enzyme Replacement Therapy Vary Widely Across Disease Types. Dig Dis Sci. 2024 Feb. doi: 10.1007/s10620-023-08184-w.

10. Borowitz DS, et al. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. Consensus Committee. J Pediatr. 1995 Nov. doi: 10.1016/s0022-3476(95)70153-2.

11. Domínguez-Muñoz JE, et al. Effect of the Administration Schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther. 2005 Apr. doi: 10.1111/j.1365-2036.2005.02390.x.

12. Hart PA and Conwell DL. Chronic Pancreatitis: Managing a Difficult Disease. Am J Gastroenterol. 2020 Jan. doi: 10.14309/ajg.0000000000000421.

The Psychopharmacologic Drugs Advisory Committee of the FDA is set to meet on July 18 to consider a supplemental new drug application for brexpiprazole (Rexulti, Otsuka Pharmaceutical Co., Ltd.), in combination with sertraline, for the treatment of adults with posttraumatic stress disorder (PTSD).

If approved, it would be the first new treatment for PTSD in more than 20 years.

“It is my hope that the FDA does approve this treatment for two related reasons — the data look positive and compelling, and there’s a tremendous unmet need in PTSD,” Roger McIntyre, MD, professor of psychiatry and pharmacology and head of the Mood Disorders Psychopharmacology Unit, University of Toronto, Toronto, Ontario, Canada, told this news organization.

 

What’s in the Treatment Toolbox Now?

PTSD is a “common, severe, and nonremitting condition,” McIntyre noted. According to the National Center for PTSD, the condition affects roughly 13 million adults in the US in any given year. This represents about 5% of the adult population.

PTSD can develop following exposure to traumatic events such as combat, assault, disasters, or severe accidents. Core symptoms of PTSD include intrusive memories and flashbacks, avoidance behaviors, negative alterations in mood and cognition, and hyperarousal.

Currently, the selective serotonin reuptake inhibitors (SSRI), sertraline and paroxetine, are the only FDA-approved medications for PTSD, and while these medications can be effective, many patients fail to achieve remission or discontinue treatment due to adverse effects or lack of response.

Other medications used off-label to treat PTSD — including prazosin, mirtazapine, atypical antipsychotics, and mood stabilizers — have shown variable efficacy. 

There has not been a new FDA-approved drug for PTSD in over two decades, underscoring the need for better therapeutic options, particularly for patients who do not fully respond to SSRI alone.

 

Why Brexpiprazole Plus Sertraline?

Brexpiprazole is an atypical antipsychotic currently approved as adjunctive treatment of major depressive disorder (MDD) in adults; treatment of schizophrenia in adults and adolescents aged 13 years or older; and treatment of agitation associated with Alzheimer’s dementia.

The combination of brexpiprazole and sertraline could address the limitations of SSRI alone by working synergistically to treat PTSD.

Sertraline increases serotonin levels in the brain to improve mood and reduce anxiety. Brexpiprazole has a complex mechanism of action involving multiple neurotransmitter systems, including but not limited to serotonin and dopamine.

Together, they may target different aspects of PTSD, potentially leading to a more comprehensive reduction in symptoms.

 

What Do the Phase 3 Data Show?

In a pivotal, double-blind, randomized controlled, phase 3 trial, brexpiprazole plus sertraline provided significantly greater relief of PTSD symptoms than sertraline plus placebo.

The results were published late last year in JAMA Psychiatry and reported by this news organization at that time.

The trial enrolled 416 adults (mean age, 37 years; 75% women) aged 18-65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of PTSD and symptoms for at least 6 months prior to screening.

At baseline, participants had a mean Clinician Administered PTSD Scale (CAPS-5) for DSM-5 total score of 38.4, indicating moderate to high severity PTSD. The average time from the index traumatic event was 4 years, and three fourths had no prior exposure to PTSD prescription medications.

Participants underwent a 1-week placebo run-in period followed by randomization to daily oral brexpiprazole 2-3 mg plus sertraline 150 mg or daily sertraline 150 mg plus placebo for 11 weeks.

At week 10, brexpiprazole plus sertraline demonstrated statistically significant greater improvement in the CAPS-5 total score (primary outcome) than sertraline plus placebo (mean change, -19.2 points vs -13.6 points; P < .001).

Brexpiprazole plus sertraline also led to statistically significant greater improvement on all key secondary and other efficacy endpoints, both clinician-reported and patient-reported, including measures of anxiety, depression, intrusive symptoms, hyperarousal, and overall functioning.

Combining an atypical antipsychotic with an antidepressant for PTSD “builds on what we’ve been doing in depression,” Elspeth Ritchie, MD, chair of Psychiatry, MedStar Washington Hospital Center, Washington, DC, noted in an interview with this news organization.

“We have found that a combination of a low-dose antipsychotic and an antidepressant is helpful for depression, so it makes sense that it will be helpful for PTSD. However, this has been mostly based on clinical decisions, without a heavy research background. Good science is always helpful to support those clinical decisions,” Ritchie told this news organization.

 

What About Safety?

In the phase 3 trial, brexpiprazole plus sertraline had a safety profile consistent with that of brexpiprazole in approved indications. The rate of discontinuation due to adverse events was low (3.9% for brexpiprazole plus sertraline vs 10.2% for sertraline plus placebo), indicating that most participants tolerated the brexpiprazole and sertraline combination treatment, the study team said.

In both treatment groups, the only treatment-emergent adverse event (TEAE) with incidence greater than 10% was nausea, a known adverse effect of sertraline treatment.

Weight gain was greater in participants receiving the combination. At the last visit, a weight gain of 7% or greater from week 1 was experienced by 8% of participants taking brexpiprazole with the sertraline group and 5% of those taking the sertraline plus placebo. Previous analyses in schizophrenia and MDD show that brexpiprazole is associated with moderate weight gain (+3 to 4 kg over 1 year).

The incidence of sedating TEAEs (a concern with some antipsychotics) was generally low, although fatigue (7% vs 4%) and somnolence (5% vs 3%) were more common with brexpiprazole plus sertraline than with sertraline alone.

There were no clinically meaningful between-group differences in changes in laboratory test parameters, vital signs, or ECG and participant-reported TEAEs related to suicidality.

 

Potential Concerns

As with any new drug application, several questions and issues are likely to be raised by the advisory committee. They could include whether the clinical benefit is substantial enough to warrant approval and how the observed effect sizes compare to existing approved therapies and evidence-based psychotherapies.

McIntyre told this news organization what’s particularly noteworthy is that the magnitude of the improvement in PTSD symptoms with brexpiprazole plus sertraline is greater than with sertraline alone. “That’s a very important statement. And this high level of efficacy was consistent on the secondary outcome measures, and the overall tolerability and safety seemed very acceptable,” he said.

What’s equally important, said McIntyre, is that most people with PTSD have depression and anxiety, and the brexpiprazole plus sertraline combination was more helpful than sertraline alone on the measures of anxiety and depression. “This is really important, especially in light of the fact that this medication [brexpiprazole] is already approved for adults living with major depressive disorder and inadequate response to antidepressants,” McIntyre said.

McIntyre added he suspects some questions the committee may have could relate to the extent to which it’s the case that brexpiprazole is effective in PTSD regardless of the antidepressant that is prescribed with it.

“There also will be the inevitable questions about the absence of long-term data which I think will need to be addressed given how chronic and relapse prone this condition is,” McIntyre said.

The committee may ask how trauma and PTSD will be screened in primary care and how outcomes related to this therapy will be evaluated in everyday clinical practice, McIntyre said.

Overall, McIntyre said brexpiprazole plus sertraline in PTSD is a “very positive” development for the field.

“PTSD is a terrible condition. It’s so darn common, and we just don’t have enough treatments for it. The data look good for my perspective. My fingers are crossed for the patients with PTSD and their families,” said McIntyre.

Ritchie reported having no relevant disclosures. McIntyre received speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and atai Life Sciences. McIntyre is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.

The Psychopharmacologic Drugs Advisory Committee of the FDA is set to meet on July 18 to consider a supplemental new drug application for brexpiprazole (Rexulti, Otsuka Pharmaceutical Co., Ltd.), in combination with sertraline, for the treatment of adults with posttraumatic stress disorder (PTSD).

If approved, it would be the first new treatment for PTSD in more than 20 years.

“It is my hope that the FDA does approve this treatment for two related reasons — the data look positive and compelling, and there’s a tremendous unmet need in PTSD,” Roger McIntyre, MD, professor of psychiatry and pharmacology and head of the Mood Disorders Psychopharmacology Unit, University of Toronto, Toronto, Ontario, Canada, told this news organization.

 

What’s in the Treatment Toolbox Now?

PTSD is a “common, severe, and nonremitting condition,” McIntyre noted. According to the National Center for PTSD, the condition affects roughly 13 million adults in the US in any given year. This represents about 5% of the adult population.

PTSD can develop following exposure to traumatic events such as combat, assault, disasters, or severe accidents. Core symptoms of PTSD include intrusive memories and flashbacks, avoidance behaviors, negative alterations in mood and cognition, and hyperarousal.

Currently, the selective serotonin reuptake inhibitors (SSRI), sertraline and paroxetine, are the only FDA-approved medications for PTSD, and while these medications can be effective, many patients fail to achieve remission or discontinue treatment due to adverse effects or lack of response.

Other medications used off-label to treat PTSD — including prazosin, mirtazapine, atypical antipsychotics, and mood stabilizers — have shown variable efficacy. 

There has not been a new FDA-approved drug for PTSD in over two decades, underscoring the need for better therapeutic options, particularly for patients who do not fully respond to SSRI alone.

 

Why Brexpiprazole Plus Sertraline?

Brexpiprazole is an atypical antipsychotic currently approved as adjunctive treatment of major depressive disorder (MDD) in adults; treatment of schizophrenia in adults and adolescents aged 13 years or older; and treatment of agitation associated with Alzheimer’s dementia.

The combination of brexpiprazole and sertraline could address the limitations of SSRI alone by working synergistically to treat PTSD.

Sertraline increases serotonin levels in the brain to improve mood and reduce anxiety. Brexpiprazole has a complex mechanism of action involving multiple neurotransmitter systems, including but not limited to serotonin and dopamine.

Together, they may target different aspects of PTSD, potentially leading to a more comprehensive reduction in symptoms.

 

What Do the Phase 3 Data Show?

In a pivotal, double-blind, randomized controlled, phase 3 trial, brexpiprazole plus sertraline provided significantly greater relief of PTSD symptoms than sertraline plus placebo.

The results were published late last year in JAMA Psychiatry and reported by this news organization at that time.

The trial enrolled 416 adults (mean age, 37 years; 75% women) aged 18-65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of PTSD and symptoms for at least 6 months prior to screening.

At baseline, participants had a mean Clinician Administered PTSD Scale (CAPS-5) for DSM-5 total score of 38.4, indicating moderate to high severity PTSD. The average time from the index traumatic event was 4 years, and three fourths had no prior exposure to PTSD prescription medications.

Participants underwent a 1-week placebo run-in period followed by randomization to daily oral brexpiprazole 2-3 mg plus sertraline 150 mg or daily sertraline 150 mg plus placebo for 11 weeks.

At week 10, brexpiprazole plus sertraline demonstrated statistically significant greater improvement in the CAPS-5 total score (primary outcome) than sertraline plus placebo (mean change, -19.2 points vs -13.6 points; P < .001).

Brexpiprazole plus sertraline also led to statistically significant greater improvement on all key secondary and other efficacy endpoints, both clinician-reported and patient-reported, including measures of anxiety, depression, intrusive symptoms, hyperarousal, and overall functioning.

Combining an atypical antipsychotic with an antidepressant for PTSD “builds on what we’ve been doing in depression,” Elspeth Ritchie, MD, chair of Psychiatry, MedStar Washington Hospital Center, Washington, DC, noted in an interview with this news organization.

“We have found that a combination of a low-dose antipsychotic and an antidepressant is helpful for depression, so it makes sense that it will be helpful for PTSD. However, this has been mostly based on clinical decisions, without a heavy research background. Good science is always helpful to support those clinical decisions,” Ritchie told this news organization.

 

What About Safety?

In the phase 3 trial, brexpiprazole plus sertraline had a safety profile consistent with that of brexpiprazole in approved indications. The rate of discontinuation due to adverse events was low (3.9% for brexpiprazole plus sertraline vs 10.2% for sertraline plus placebo), indicating that most participants tolerated the brexpiprazole and sertraline combination treatment, the study team said.

In both treatment groups, the only treatment-emergent adverse event (TEAE) with incidence greater than 10% was nausea, a known adverse effect of sertraline treatment.

Weight gain was greater in participants receiving the combination. At the last visit, a weight gain of 7% or greater from week 1 was experienced by 8% of participants taking brexpiprazole with the sertraline group and 5% of those taking the sertraline plus placebo. Previous analyses in schizophrenia and MDD show that brexpiprazole is associated with moderate weight gain (+3 to 4 kg over 1 year).

The incidence of sedating TEAEs (a concern with some antipsychotics) was generally low, although fatigue (7% vs 4%) and somnolence (5% vs 3%) were more common with brexpiprazole plus sertraline than with sertraline alone.

There were no clinically meaningful between-group differences in changes in laboratory test parameters, vital signs, or ECG and participant-reported TEAEs related to suicidality.

 

Potential Concerns

As with any new drug application, several questions and issues are likely to be raised by the advisory committee. They could include whether the clinical benefit is substantial enough to warrant approval and how the observed effect sizes compare to existing approved therapies and evidence-based psychotherapies.

McIntyre told this news organization what’s particularly noteworthy is that the magnitude of the improvement in PTSD symptoms with brexpiprazole plus sertraline is greater than with sertraline alone. “That’s a very important statement. And this high level of efficacy was consistent on the secondary outcome measures, and the overall tolerability and safety seemed very acceptable,” he said.

What’s equally important, said McIntyre, is that most people with PTSD have depression and anxiety, and the brexpiprazole plus sertraline combination was more helpful than sertraline alone on the measures of anxiety and depression. “This is really important, especially in light of the fact that this medication [brexpiprazole] is already approved for adults living with major depressive disorder and inadequate response to antidepressants,” McIntyre said.

McIntyre added he suspects some questions the committee may have could relate to the extent to which it’s the case that brexpiprazole is effective in PTSD regardless of the antidepressant that is prescribed with it.

“There also will be the inevitable questions about the absence of long-term data which I think will need to be addressed given how chronic and relapse prone this condition is,” McIntyre said.

The committee may ask how trauma and PTSD will be screened in primary care and how outcomes related to this therapy will be evaluated in everyday clinical practice, McIntyre said.

Overall, McIntyre said brexpiprazole plus sertraline in PTSD is a “very positive” development for the field.

“PTSD is a terrible condition. It’s so darn common, and we just don’t have enough treatments for it. The data look good for my perspective. My fingers are crossed for the patients with PTSD and their families,” said McIntyre.

Ritchie reported having no relevant disclosures. McIntyre received speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and atai Life Sciences. McIntyre is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.

The Psychopharmacologic Drugs Advisory Committee of the FDA is set to meet on July 18 to consider a supplemental new drug application for brexpiprazole (Rexulti, Otsuka Pharmaceutical Co., Ltd.), in combination with sertraline, for the treatment of adults with posttraumatic stress disorder (PTSD).

If approved, it would be the first new treatment for PTSD in more than 20 years.

“It is my hope that the FDA does approve this treatment for two related reasons — the data look positive and compelling, and there’s a tremendous unmet need in PTSD,” Roger McIntyre, MD, professor of psychiatry and pharmacology and head of the Mood Disorders Psychopharmacology Unit, University of Toronto, Toronto, Ontario, Canada, told this news organization.

 

What’s in the Treatment Toolbox Now?

PTSD is a “common, severe, and nonremitting condition,” McIntyre noted. According to the National Center for PTSD, the condition affects roughly 13 million adults in the US in any given year. This represents about 5% of the adult population.

PTSD can develop following exposure to traumatic events such as combat, assault, disasters, or severe accidents. Core symptoms of PTSD include intrusive memories and flashbacks, avoidance behaviors, negative alterations in mood and cognition, and hyperarousal.

Currently, the selective serotonin reuptake inhibitors (SSRI), sertraline and paroxetine, are the only FDA-approved medications for PTSD, and while these medications can be effective, many patients fail to achieve remission or discontinue treatment due to adverse effects or lack of response.

Other medications used off-label to treat PTSD — including prazosin, mirtazapine, atypical antipsychotics, and mood stabilizers — have shown variable efficacy. 

There has not been a new FDA-approved drug for PTSD in over two decades, underscoring the need for better therapeutic options, particularly for patients who do not fully respond to SSRI alone.

 

Why Brexpiprazole Plus Sertraline?

Brexpiprazole is an atypical antipsychotic currently approved as adjunctive treatment of major depressive disorder (MDD) in adults; treatment of schizophrenia in adults and adolescents aged 13 years or older; and treatment of agitation associated with Alzheimer’s dementia.

The combination of brexpiprazole and sertraline could address the limitations of SSRI alone by working synergistically to treat PTSD.

Sertraline increases serotonin levels in the brain to improve mood and reduce anxiety. Brexpiprazole has a complex mechanism of action involving multiple neurotransmitter systems, including but not limited to serotonin and dopamine.

Together, they may target different aspects of PTSD, potentially leading to a more comprehensive reduction in symptoms.

 

What Do the Phase 3 Data Show?

In a pivotal, double-blind, randomized controlled, phase 3 trial, brexpiprazole plus sertraline provided significantly greater relief of PTSD symptoms than sertraline plus placebo.

The results were published late last year in JAMA Psychiatry and reported by this news organization at that time.

The trial enrolled 416 adults (mean age, 37 years; 75% women) aged 18-65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of PTSD and symptoms for at least 6 months prior to screening.

At baseline, participants had a mean Clinician Administered PTSD Scale (CAPS-5) for DSM-5 total score of 38.4, indicating moderate to high severity PTSD. The average time from the index traumatic event was 4 years, and three fourths had no prior exposure to PTSD prescription medications.

Participants underwent a 1-week placebo run-in period followed by randomization to daily oral brexpiprazole 2-3 mg plus sertraline 150 mg or daily sertraline 150 mg plus placebo for 11 weeks.

At week 10, brexpiprazole plus sertraline demonstrated statistically significant greater improvement in the CAPS-5 total score (primary outcome) than sertraline plus placebo (mean change, -19.2 points vs -13.6 points; P < .001).

Brexpiprazole plus sertraline also led to statistically significant greater improvement on all key secondary and other efficacy endpoints, both clinician-reported and patient-reported, including measures of anxiety, depression, intrusive symptoms, hyperarousal, and overall functioning.

Combining an atypical antipsychotic with an antidepressant for PTSD “builds on what we’ve been doing in depression,” Elspeth Ritchie, MD, chair of Psychiatry, MedStar Washington Hospital Center, Washington, DC, noted in an interview with this news organization.

“We have found that a combination of a low-dose antipsychotic and an antidepressant is helpful for depression, so it makes sense that it will be helpful for PTSD. However, this has been mostly based on clinical decisions, without a heavy research background. Good science is always helpful to support those clinical decisions,” Ritchie told this news organization.

 

What About Safety?

In the phase 3 trial, brexpiprazole plus sertraline had a safety profile consistent with that of brexpiprazole in approved indications. The rate of discontinuation due to adverse events was low (3.9% for brexpiprazole plus sertraline vs 10.2% for sertraline plus placebo), indicating that most participants tolerated the brexpiprazole and sertraline combination treatment, the study team said.

In both treatment groups, the only treatment-emergent adverse event (TEAE) with incidence greater than 10% was nausea, a known adverse effect of sertraline treatment.

Weight gain was greater in participants receiving the combination. At the last visit, a weight gain of 7% or greater from week 1 was experienced by 8% of participants taking brexpiprazole with the sertraline group and 5% of those taking the sertraline plus placebo. Previous analyses in schizophrenia and MDD show that brexpiprazole is associated with moderate weight gain (+3 to 4 kg over 1 year).

The incidence of sedating TEAEs (a concern with some antipsychotics) was generally low, although fatigue (7% vs 4%) and somnolence (5% vs 3%) were more common with brexpiprazole plus sertraline than with sertraline alone.

There were no clinically meaningful between-group differences in changes in laboratory test parameters, vital signs, or ECG and participant-reported TEAEs related to suicidality.

 

Potential Concerns

As with any new drug application, several questions and issues are likely to be raised by the advisory committee. They could include whether the clinical benefit is substantial enough to warrant approval and how the observed effect sizes compare to existing approved therapies and evidence-based psychotherapies.

McIntyre told this news organization what’s particularly noteworthy is that the magnitude of the improvement in PTSD symptoms with brexpiprazole plus sertraline is greater than with sertraline alone. “That’s a very important statement. And this high level of efficacy was consistent on the secondary outcome measures, and the overall tolerability and safety seemed very acceptable,” he said.

What’s equally important, said McIntyre, is that most people with PTSD have depression and anxiety, and the brexpiprazole plus sertraline combination was more helpful than sertraline alone on the measures of anxiety and depression. “This is really important, especially in light of the fact that this medication [brexpiprazole] is already approved for adults living with major depressive disorder and inadequate response to antidepressants,” McIntyre said.

McIntyre added he suspects some questions the committee may have could relate to the extent to which it’s the case that brexpiprazole is effective in PTSD regardless of the antidepressant that is prescribed with it.

“There also will be the inevitable questions about the absence of long-term data which I think will need to be addressed given how chronic and relapse prone this condition is,” McIntyre said.

The committee may ask how trauma and PTSD will be screened in primary care and how outcomes related to this therapy will be evaluated in everyday clinical practice, McIntyre said.

Overall, McIntyre said brexpiprazole plus sertraline in PTSD is a “very positive” development for the field.

“PTSD is a terrible condition. It’s so darn common, and we just don’t have enough treatments for it. The data look good for my perspective. My fingers are crossed for the patients with PTSD and their families,” said McIntyre.

Ritchie reported having no relevant disclosures. McIntyre received speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, AbbVie, and atai Life Sciences. McIntyre is a CEO of Braxia Scientific Corp.

A version of this article first appeared on Medscape.com.