Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion

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

Authors

Mariana X Byndloss¹, Erin E Olsan¹, Fabian Rivera-Chávez¹, Connor R Tiffany¹, Stephanie A Cevallos¹, Kristen L Lokken¹, Teresa P Torres¹, Austin J Byndloss¹, Franziska Faber¹, Yandong Gao², Yael Litvak¹, Christopher A Lopez¹, Gege Xu³, Eleonora Napoli⁴, Cecilia Giulivi⁴, Renée M Tsolis¹, Alexander Revzin², Carlito B Lebrilla³, Andreas J Bäumler⁵

Affiliations

¹ Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
² Department of Biomedical Engineering, College of Engineering, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
³ Department of Chemistry, College of Letters and Sciences, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
⁴ Department of Molecular Biosciences, School of Veterinary Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
⁵ Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA. ajbaumler@ucdavis.edu.

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 Protein 4 / 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 Protein 4
Anilides
Anti-Bacterial Agents
Butyrates
Nitrates
PPAR gamma
Nitric Oxide Synthase Type II
Streptomycin

Abstract

Publication types

MeSH terms

Substances

Grants and funding