From the AGA Journals

Normal gut colonizer induces serotonergic system, appears to regulate behavior

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Gut microbes are needed for normal neurologic function

“Gut-brain axis” is a widely used term that refers to the idea that the functions of these two organs are linked by bidirectional communication. The gut plays host to a large community of microbes and increasing data suggest that metabolites generated by these microbes can alter nervous system function. Such findings raise the exciting possibility that microbes and/or their metabolites could be used to treat a variety of disorders that involve gut-brain axis dysfunction, from irritable bowel syndrome (IBS) to Parkinson’s disease. To realize this possibility, it will be essential to establish clear mechanistic links between microbes, their products, and effects on host physiology. This study by Engevik and colleagues represents an important advance, demonstrating how a single microbe that commonly colonizes the healthy human intestine, Bifidobacterium dentium, is sufficient to stimulate the gut to make serotonin, a powerful signaling molecule known to influence visceral sensitivity, gut motility, and mood.

Dr. Meenakshi Rao is a principal investigator at Boston Children's Hospital, division of gastroenterology, hepatology and nutrition, and assistant professor of pediatrics at Harvard Medical School

Dr. Meenakshi Rao

One key approach to understanding the effects of microbes on host function is to study germ-free mice, which are raised such that they are never exposed to microbes. Germ-free mice have a wide range of immune and neurologic deficits, highlighting how essential microbes are to host function. Previous work has shown that germ-free mice have diminished serotonin levels and abnormal behavior. Exposure to human microbiota could rescue some of these impairments but it was unclear which microbes or signals were essential. This study shows that supplementing germ-free mice with B. dentium is sufficient to stimulate the gut to ramp up serotonin production, alter gene expression in the brain, and rescue some behavioral deficits. Acetate, a short-chain fatty acid produced by B. dentium, was crucial for this phenomenon. This work not only identifies B. dentium as a promising candidate for therapeutic development, it also emphasizes the value of rigorous studies that probe functional interactions between microbes and the nervous system.

Meenakshi Rao, MD, PhD, is a principal investigator at Boston Children’s Hospital, division of gastroenterology, hepatology and nutrition, and assistant professor of pediatrics at Harvard Medical School. She has no conflicts relevant to this study. She receives research support from Boston Pharmaceuticals for unrelated work and has participated on a scientific advisory board for Takeda Pharmaceuticals.


 

FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY

Together, Bifidobacterium dentium and its acetate metabolite regulate key parts of the serotonergic system and are associated with “a functional change in adult behavior,” according to a report published in Cellular and Molecular Gastroenterology and Hepatology.

Human gut microbiota had been known to regulate serotonin (5-hydroxytryptamine) production by gut cells, but underlying mechanisms had been unclear. This study showed that a common bacterial colonizer of the healthy adult gut stimulates serotonin (5-hydroxytryptamine, or 5-HT) release from enterochromaffin cells in both mice (in vivo) and humans (in vitro), wrote Melinda A. Engevik, PhD, of Baylor College of Medicine, Houston, and associates. “B. dentium modulates the serotonergic system in both the intestine and the brain [, which] likely influences behavior, and suggests that supplementation with a single, carefully selected, bacterial strain may be able to partially rescue behavioral deficits induced by shifts in the intestinal microbiota,” they added.

In a prior study, B. dentium modulated sensory neurons in rats with visceral hypersensitivity. In mammals, serotonin is primarily produced and released by enterochromaffin cells in the gut. To discover whether acetate – a short-chain fatty acid metabolite of B. dentium and some other microbiota – induces this pathway, the researchers first confirmed that B. dentium itself lacks the gene pathway for 5-HT production, and that growth media inoculated with B. dentium do not subsequently contain 5-HT. Next, they treated adult germ-free mice with either sterile media, live B. dentium, heat-killed B. dentium, or live Bacteroides ovatus (another commensal gut microbe). Gram staining and fluorescence in situ hybridization (FISH) confirmed that live B. dentium colonized mouse ileum and colon. Mass spectrometry, immunostaining, and quantitative PCR showed that mice treated with live B. dentium, but not B. ovatus, had greater intestinal concentrations of acetate, 5-HT, 5-HT receptors (2a and 4), serotonin transporter, and the gene that encodes free fatty acid receptor 2 (FFAR2), through which acetate signals. Furthermore, “[i]ncreases in 5-HT were observed in enteroendocrine cells directly above enteric neurons,” the researchers said.

They also performed RNA in situ hybridization of mouse brain tissue, which showed significantly increased expression of 5-HT-receptor 2a in the B. dentium–treated compared with germ-free controls. Mice were caged with specified numbers of marbles so the researchers could find out if these changes also modified behavior. Those with complete gut microbiota buried an average of 25% of the marbles, B. dentium­–monocolonized mice buried 15%, and germ-free mice buried fewer marbles. Hence, even short-term monocolonization by a bacterium that acts on the serotonergic system might help normalize behavior, even later in life, the researchers said. They noted that B. dentium–treated and germ-free mice performed similarly on both balance beam and footprint tests, suggesting that treatment with B. dentium does not affect motor coordination.

In humans, enterochromaffin cells released more 5-HT when exposed to B. dentium or acetate. Taken together, the findings “highlight the importance of Bifidobacterium species, and specifically B. dentium, in the adult microbiome-gut-brain axis,” the researchers wrote. Probiotic strains such as Lactobacillus and Bifidobacterium species are thought to improve health by means of signaling pathways, including the serotonergic system, they noted. “Our findings support the modulation of the serotonergic system by a model gut microbe, B. dentium, and provide a potential mechanism by which select microbes and their metabolites can promote endogenous, localized 5-HT biosynthesis. We speculate this may be an important bridging signal in the microbiome-gut-brain axis.”

The National Institutes of Health, BioGaia AB, and the RNA In Situ Hybridization Core facility supported the work. Two coinvestigators disclosed ties to BioGaia AB, Seed, Biomica, Plexus Worldwide, Tenza, Mikrovia, Probiotech, and Takeda. Dr. Engevik and the other investigators reported having no conflicts of interest.

SOURCE: Engevik MA et al. Cell Molec Gastro Hepatol. 2021;11:221-48. doi: 10.1016/j.jcmgh.2020.08.002.

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