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Human‐derived Bifidobacterium dentium Metabolites Modulate the Mammalian Serotonergic System
Author(s) -
Engevik Melinda A.,
Luk Berkley,
Ihekweazu Faith D.,
Danhof Heather A.,
Chang-Graham Alexandra A.,
Haag Anthony A.,
Britton Robert A.,
Hyser Joseph M.,
Versalovic James A.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.02292
Subject(s) - enterochromaffin cell , serotonergic , chemistry , serotonin , griffonia simplicifolia , bifidobacterium , 5 ht receptor , microbiology and biotechnology , endocrinology , medicine , biochemistry , biology , lactobacillus , receptor , fermentation , lectin
Background Recent work has identified an essential role for the gut microbiota in regulating host‐derived serotonin (5‐hydroxytryptamine; 5‐HT) from enterochromaffin cells. Studies using germ‐free mice have revealed impaired 5‐HT levels and signaling in the absence of microbes. While it is known that addition of microbial communities to germ‐free mice restores 5‐HT levels, information on which microbes directly influence 5‐HT remains unknown. Commensal Bifidobacterium species produce acetate, a short chain fatty acid known to stimulate 5‐HT release in vitro . We hypothesize that B. dentium , a model Bifidobacterium species, secretes acetate and modulates the serotonergic system. Methods & Results Adult germ‐free mice were mono‐associated with acetate producing B. dentium , propionate producing Bacteroides ovatus , or heat killed B. dentium . Mass spectrometry of cecal and fecal samples revealed elevated levels of acetate in B. dentium mono‐associated mice and increased ileal, colonic, fecal and serum 5‐HT compared to all other groups. No increases in acetate or 5‐HT were observed in heat‐killed B. dentium or B. ovatus treated mice compared to germ‐free controls, as assessed by mass spec, immunostaining, and qPCR. Using mouse and human enteroids, we observed that addition of B. dentium metabolites and acetate stimulated release of 5‐HT in a dose‐dependent manner. Depletion of acetate in B. dentium secreted products reduced the amount of 5‐HT released from enteroids. We also confirmed our findings using a novel NGN3 over‐expression system in human enteroids, which increased the number of enterochromaffin cells. In addition to 5‐HT alterations, we found increased expression of 5‐HT receptors 2a and 4 in B. dentium mono‐associated mouse ileum and colon. RNA in situ hybridization revealed a similar increase in 5‐HT receptor 2a in the hippocampus of B. dentium treated mice compared to germ‐free controls. Functionally, live B. dentium modulated species typical behavior previously shown to be linked to 5‐HT receptor 2a. Conclusion Collectively, these data indicate that B. dentium , and the bacterial metabolite acetate, regulate key components of the serotonergic system.B. dentium colonizes the intestinal mucus layer (left) and it’s metabolites stimulate serotonin release in mouse organoids (right).