TY - JOUR
T1 - Human-Derived Bifidobacterium dentium Modulates the Mammalian Serotonergic System and Gut–Brain Axis
AU - Engevik, Melinda A.
AU - Luck, Berkley
AU - Visuthranukul, Chonnikant
AU - Ihekweazu, Faith D.
AU - Engevik, Amy C.
AU - Shi, Zhongcheng
AU - Danhof, Heather A.
AU - Chang-Graham, Alexandra L.
AU - Hall, Anne
AU - Endres, Bradley T.
AU - Haidacher, Sigmund J.
AU - Horvath, Thomas D.
AU - Haag, Anthony M.
AU - Devaraj, Sridevi
AU - Garey, Kevin W.
AU - Britton, Robert A.
AU - Hyser, Joseph M.
AU - Shroyer, Noah F.
AU - Versalovic, James
N1 - Publisher Copyright:
© 2020 The Authors
PY - 2021/1
Y1 - 2021/1
N2 - Background & Aims: The human gut microbiota can regulate production of serotonin (5-hydroxytryptamine [5-HT]) from enterochromaffin cells. However, the mechanisms underlying microbial-induced serotonin signaling are not well understood. Methods: Adult germ-free mice were treated with sterile media, live Bifidobacterium dentium, heat-killed B dentium, or live Bacteroides ovatus. Mouse and human enteroids were used to assess the effects of B dentium metabolites on 5-HT release from enterochromaffin cells. In vitro and in vivo short-chain fatty acids and 5-HT levels were assessed by mass spectrometry. Expression of tryptophan hydroxylase, short-chain fatty acid receptor free fatty acid receptor 2, 5-HT receptors, and the 5-HT re-uptake transporter (serotonin transporter) were assessed by quantitative polymerase chain reaction and immunostaining. RNA in situ hybridization assessed 5-HT–receptor expression in the brain, and 5-HT–receptor–dependent behavior was evaluated using the marble burying test. Results: B dentium mono-associated mice showed increased fecal acetate. This finding corresponded with increased intestinal 5-HT concentrations and increased expression of 5-HT receptors 2a, 4, and serotonin transporter. These effects were absent in B ovatus-treated mice. Application of acetate and B dentium–secreted products stimulated 5-HT release in mouse and human enteroids. In situ hybridization of brain tissue also showed significantly increased hippocampal expression of 5-HT–receptor 2a in B dentium–treated mice relative to germ-free controls. Functionally, B dentium colonization normalized species-typical repetitive and anxiety-like behaviors previously shown to be linked to 5-HT–receptor 2a. Conclusions: These data suggest that B dentium, and the bacterial metabolite acetate, are capable of regulating key components of the serotonergic system in multiple host tissues, and are associated with a functional change in adult behavior.
AB - Background & Aims: The human gut microbiota can regulate production of serotonin (5-hydroxytryptamine [5-HT]) from enterochromaffin cells. However, the mechanisms underlying microbial-induced serotonin signaling are not well understood. Methods: Adult germ-free mice were treated with sterile media, live Bifidobacterium dentium, heat-killed B dentium, or live Bacteroides ovatus. Mouse and human enteroids were used to assess the effects of B dentium metabolites on 5-HT release from enterochromaffin cells. In vitro and in vivo short-chain fatty acids and 5-HT levels were assessed by mass spectrometry. Expression of tryptophan hydroxylase, short-chain fatty acid receptor free fatty acid receptor 2, 5-HT receptors, and the 5-HT re-uptake transporter (serotonin transporter) were assessed by quantitative polymerase chain reaction and immunostaining. RNA in situ hybridization assessed 5-HT–receptor expression in the brain, and 5-HT–receptor–dependent behavior was evaluated using the marble burying test. Results: B dentium mono-associated mice showed increased fecal acetate. This finding corresponded with increased intestinal 5-HT concentrations and increased expression of 5-HT receptors 2a, 4, and serotonin transporter. These effects were absent in B ovatus-treated mice. Application of acetate and B dentium–secreted products stimulated 5-HT release in mouse and human enteroids. In situ hybridization of brain tissue also showed significantly increased hippocampal expression of 5-HT–receptor 2a in B dentium–treated mice relative to germ-free controls. Functionally, B dentium colonization normalized species-typical repetitive and anxiety-like behaviors previously shown to be linked to 5-HT–receptor 2a. Conclusions: These data suggest that B dentium, and the bacterial metabolite acetate, are capable of regulating key components of the serotonergic system in multiple host tissues, and are associated with a functional change in adult behavior.
KW - Bifidobacterium
KW - Enterochromaffin Cells
KW - Enteroids
KW - Free Fatty Acid Receptor (FFAR)2
KW - Organoids
KW - Probiotics
KW - Serotonin
KW - Serotonin Transporter
KW - Short-Chain Fatty Acids (SCFAs)
KW - Humans
KW - Behavior, Animal/physiology
KW - Models, Animal
KW - Brain-Gut Axis/physiology
KW - Cell Culture Techniques
KW - Host Microbial Interactions/physiology
KW - Bifidobacterium/isolation & purification
KW - Receptors, Serotonin/metabolism
KW - Enterochromaffin Cells/metabolism
KW - Animals
KW - Serotonin/metabolism
KW - Gastrointestinal Microbiome/physiology
KW - Germ-Free Life
KW - Intestinal Mucosa/metabolism
KW - Acetates/metabolism
KW - Mice
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UR - http://www.scopus.com/inward/citedby.url?scp=85096186149&partnerID=8YFLogxK
U2 - 10.1016/j.jcmgh.2020.08.002
DO - 10.1016/j.jcmgh.2020.08.002
M3 - Article
C2 - 32795610
AN - SCOPUS:85096186149
SN - 2352-345X
VL - 11
SP - 221
EP - 248
JO - CMGH
JF - CMGH
IS - 1
ER -