Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion

Science. 2017 Aug 11;357(6351):570-575. doi: 10.1126/science.aam9949.

Abstract

Perturbation of the gut-associated microbial community may underlie many human illnesses, but the mechanisms that maintain homeostasis are poorly understood. We found that the depletion of butyrate-producing microbes by antibiotic treatment reduced epithelial signaling through the intracellular butyrate sensor peroxisome proliferator-activated receptor γ (PPAR-γ). Nitrate levels increased in the colonic lumen because epithelial expression of Nos2, the gene encoding inducible nitric oxide synthase, was elevated in the absence of PPAR-γ signaling. Microbiota-induced PPAR-γ signaling also limits the luminal bioavailability of oxygen by driving the energy metabolism of colonic epithelial cells (colonocytes) toward β-oxidation. Therefore, microbiota-activated PPAR-γ signaling is a homeostatic pathway that prevents a dysbiotic expansion of potentially pathogenic Escherichia and Salmonella by reducing the bioavailability of respiratory electron acceptors to Enterobacteriaceae in the lumen of the colon.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-like 4 Protein / genetics
  • Anilides / pharmacology
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Butyrates / metabolism
  • Caco-2 Cells
  • Clostridium / drug effects
  • Clostridium / metabolism
  • Colitis / metabolism
  • Colitis / microbiology
  • Colon / metabolism
  • Colon / microbiology
  • Dysbiosis / chemically induced
  • Dysbiosis / genetics
  • Dysbiosis / metabolism*
  • Dysbiosis / microbiology*
  • Enterobacteriaceae / metabolism
  • Enterobacteriaceae / pathogenicity*
  • Epithelial Cells / metabolism
  • Epithelial Cells / microbiology
  • Female
  • Gastrointestinal Microbiome*
  • Gene Expression
  • Homeostasis
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nitrates / metabolism
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism*
  • Oxidation-Reduction
  • PPAR gamma / antagonists & inhibitors
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • Signal Transduction
  • Streptomycin / pharmacology

Substances

  • 2-chloro-5-nitrobenzanilide
  • Angiopoietin-like 4 Protein
  • Anilides
  • Anti-Bacterial Agents
  • Butyrates
  • Nitrates
  • PPAR gamma
  • Nitric Oxide Synthase Type II
  • Streptomycin