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 - Funding Information:
Funding This study was supported by National Institutes of Health grants T32DK007664-28 , K01 K123195-01 and the Global Probiotic Council 2019-19319 (M.A.E.). Trainee support was provided by National Institutes of Health grants F30DK112563 (A.C.G.) and F32AI136404 (H.A.D.). Also supported by K01DK121869 (A.C.E.). This work also was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (grant P30-DK-56338 to the Texas Medical Center Digestive Disease Center , Gastrointestinal Experimental Model Systems), National Institutes of Health National Institute of Allergy and Infectious Diseases grant U01AI124290 (K.W.G. and R.A.B.), R01DK103759 , National Institute of Allergy and Infectious Diseases R01AI123278 (R.A.B.), National Institutes of Health grant U01CA170930 (J.V.), and unrestricted research support from BioGaia AB (Stockholm, Sweden) (R.A.B. and J.V.). This project also was supported by the RNA In Situ Hybridization Core facility and funding from the National Institutes of Health shared equipment grant 1S10 OD016167 .
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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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 -