Human-Derived Bifidobacterium dentium Modulates the Mammalian Serotonergic System and Gut–Brain Axis

Melinda A. Engevik, Berkley Luck, Chonnikant Visuthranukul, Faith D. Ihekweazu, Amy C. Engevik, Zhongcheng Shi, Heather A. Danhof, Alexandra L. Chang-Graham, Anne Hall, Bradley T. Endres, Sigmund J. Haidacher, Thomas D. Horvath, Anthony M. Haag, Sridevi Devaraj, Kevin W. Garey, Robert A. Britton, Joseph M. Hyser, Noah F. Shroyer, James Versalovic

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)221-248
Number of pages28
Issue number1
StatePublished - Jan 2021


  • Bifidobacterium
  • Enterochromaffin Cells
  • Enteroids
  • Free Fatty Acid Receptor (FFAR)2
  • Organoids
  • Probiotics
  • Serotonin
  • Serotonin Transporter
  • Short-Chain Fatty Acids (SCFAs)
  • Humans
  • Behavior, Animal/physiology
  • Models, Animal
  • Brain-Gut Axis/physiology
  • Cell Culture Techniques
  • Host Microbial Interactions/physiology
  • Bifidobacterium/isolation & purification
  • Receptors, Serotonin/metabolism
  • Enterochromaffin Cells/metabolism
  • Animals
  • Serotonin/metabolism
  • Gastrointestinal Microbiome/physiology
  • Germ-Free Life
  • Intestinal Mucosa/metabolism
  • Acetates/metabolism
  • Mice

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology


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