Microbiota-activated PPAR-γ-signaling inhibits dysbiotic Enterobacteriaceae expansion

By M. Byndloss, Erin E. Olsan, Fabian Rivera-Chávez, Connor R. Tiffany, Stephanie A. Cevallos, Kristen L Lokken, Teresa P. Torres, Austin J Byndloss, F. Faber, Yandong Gao and 9 more. Science, 2017

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Healthy guts exclude oxygen Normally, the lumen of the colon lacks oxygen. Fastidiously anaerobic butyrate-producing bacteria thrive in the colon; by ablating these organisms, antibiotic treatment removes butyrate. Byndloss et al. discovered that loss of butyrate deranges metabolic signaling in gut cells (see the Perspective by Cani). This induces nitric oxidase to generate nitrate in the lumen and disables β-oxidation in epithelial cells that would otherwise mop up stray oxygen before it enters the colon. Simultaneously, regulatory T cells retreat, and inflammation is unchecked, which contributes yet more oxygen species to the colon. Then, facultative aerobic pathogens, such as Escherichia coli and Salmonella enterica, can take advantage of the altered environment and outgrow any antibiotic-crippled and benign anaerobes. Science, this issue p. 570; see also p. 548 Butyrate-producing microbes contribute to synergism between epithelial cell metabolism and immune response regulation to maintain gut heath. 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.

Subfields: Food Science, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/007a91b4eea3fddb47796127b1a5227fa5b3a0fa

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Citations in the corpus

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Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases (2019, background): “In addition, depletion of butyrate-producing bacteria by antibiotic treatment reduces the intracellular butyrate/PPARγ signaling, increasing iNOS and nitrate levels, favoring Enterobacteriaceae expansion (52).”
Human gut microbiome: hopes, threats and promises (2018, background): “57 58 Specifically, the authors used recent information suggesting that the extremely low quantity of oxygen present in the luminal content of the gut (ie, the anaerobic state) is a condition that is required to prevent the expansion of putative facultative anaerobic pathogens such as Salmonella or…”
Impact of antibiotics on the human microbiome and consequences for host health (2022, background): “A study reported that an antibiotic‐mediated decrease in butyrate‐producing bacteria resulted in reduced epithelial signaling through the intracellular butyrate sensor peroxisome proliferator‐activated receptor γ (Byndloss et al., 2017).”
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