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Normal gut colonizer induces serotonergic system, appears to regulate behavior
Key clinical point: Bifidobacterium dentium, a normal colonizer of the healthy adult gut, modulates the gut and brain serotonergic system, which appears to influence behavior.
Major finding: Acetate produced by B. dentium stimulated serotonin production by mouse and human enterochromaffin cells. B. dentium increased serotonin receptor expression in the gut and brain and modified behavior in mice.
Data source: Gram staining, immunostaining, quantitative PCR, mass spectrometry, and RNA in situ hybridization of B. dentium, its metabolites, and mouse and human enteroids (specifically, enterochromaffin cells), and the marble and balance beam tests and footprint analysis in mice.
Disclosures: 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. The investigators reported having no conflicts of interest.
Engevik MA et al. Cell Molec Gastroenterol Hepatol. 2021;11:221-48. doi: 10.1016/j.jcmgh.2020.08.002.
“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.
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.