Microbiome studies should be correcting statistics to account for proton pump inhibitor (PPI) use, according to a leading expert.
After antibiotics, PPIs are the leading cause of microbiome variance in both research and general populations, and these alterations could have a range of consequences, reported Rinse K. Weersma, MD, PhD, of the University of Groningen (the Netherlands).
About 20% of people are taking a PPI, Dr. Weersma said at the annual Gut Microbiota for Health World Summit, noting that, in countries such as the United States and the United Kingdom, this figure may be higher.
“There’s chronic use of proton pump inhibitors in the population on a massive scale,” Dr. Weersma said.
To complicate matters, estimates suggest that 25%-70% of people who are taking PPIs have no appropriate indication. While this issue is partly because of increasing over-the-counter usage, physicians are also contributing to the problem by prescribing PPIs without adequate follow-up.
“The number of people using proton pump inhibitors is steadily increasing,” Dr. Weersma said. “The number of people getting them prescribed is relatively stable. The problem is, we never stop.”
According to Dr. Weersma, a growing body of research shows that PPI use may increase the risk of developing other conditions. Although many of these relationships are correlative, some are now widely accepted as causal. Most notable and clinically relevant, Dr. Weersma said, are enteric infections. Clostridioides difficile–associated diarrhea, for instance, is 65% more common among PPI users.
While the mechanisms behind this susceptibility to infection are uncertain, Dr. Weersma suggested that the most likely cause is “oralization” of the gut microbiome caused by loss of the acid barrier, which introduces upper gastrointestinal bacteria, or oral bacteria, into the lower intestines.
Perhaps more relevant to clinical trials, PPIs may also influence the safety and efficacy of drugs.
“There is a lot of interaction between the gut microbiome and a lot of drugs,” Dr. Weersma said at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility. “We really don’t know a lot about this at the moment.”
He went on to explain that bidirectional interactions between drugs and the microbiome may actually present clinical opportunities.
“This is a field that people currently call pharmacomicrobiomics,” Dr. Weersma said. “This is very intriguing, of course, because everyone knows about pharmacogenomics ... which lets you stratify your patients, but you cannot intervene; you cannot change your genetic background to increase efficacy or avoid toxicity. But in fact, with the microbiome, we could modulate the microbiome and improve bioavailability, for example.”
Conversely, Dr. Weersma pointed out that PPI use may be interfering with drug efficacy to a life-altering degree.
He cited a recent study by Chalabi and colleagues, which found that PPI use affected responses to immune checkpoint inhibitors (Ann Oncol. 2020 Jan 16. doi: 10.1016/j.annonc.2020.01.006). Among 169 patients with lung cancer who were treated with atezolizumab, overall survival was significantly lower in PPI users (9.6 vs. 14.5 months; P = .001).
A number of other clinical implications are also possible, Dr. Weersma said, although these require further investigation. For example, a 2019 study by Stark and colleagues suggested that childhood use of PPIs may increase obesity risk.
“[There are] no microbiome data here,” Dr. Weersma said, “but it makes you think.”
While considering the downsides of PPIs, Dr. Weersma also emphasized their importance in clinical practice. “[Proton pump inhibitors] are very great drugs. They are cheap, they are safe, they are very effective. So if you have evidence-based indications to use proton pump inhibitors, you should definitely use them and not stop them.”
Dr. Weersma called for responsible use of PPIs, and suggested that clinicians need to prepare for pushback from patients, who, after stopping PPIs, may experience a temporary resurgence of symptoms because of acid rebound.
“You have to make them aware [of acid rebound],” Dr. Weersma said. “Say: ‘Wait 2 or 3 weeks and this rebound is gone.’ We should say that way, way, way more often.”
But clinicians shouldn’t bear the burden of responsible usage alone, Dr. Weersma said.
“There’s a role for clinicians, patients, and regulatory bodies also, to think about the massive use of proton pump inhibitors now and in the future.”
In the discussion that followed the presentation, a summit attendee brought up the realities of clinical practice before PPIs, when patients frequently had gastrointestinal bleeding secondary to nonsteroidal anti-inflammatory use. In response, Dr. Weersma again emphasized that PPIs play a critical role for many patients. After once more encouraging responsible use, Dr. Weersma expressed concern about the risks involved in conveying his message; not only to the medical community, but also to the general public.
“This is a very difficult message [to deliver],” Dr. Weersma said. “In the Netherlands this was taken up by the media and the news, so my email inbox exploded. It’s difficult to get this nuance right.”
Dr. Weersma disclosed relationships with Takeda, Johnson & Johnson, Ferring, and others.