HHS Public access Author manuscript Science. Author manuscript; available in PMC 2017 October 16 Published in final edited form as Science. 2017 August 11; 357(6351): 570-575. doi: 10. 1 126/science. aam9949 Microbiota-activated PPAR-y-signaling inhibits dysbiotic Enterobacteriaceae expansion Mariana X. Byndloss', Erin E. Olsan', Fabian Rivera-Chavezl, Connor R. Tiffany Stephanie A Cevallos, Kristen L Lokken, Teresa P. Torres, Austin J. ByndlossT Franziska Faber Yandong Gao2, Yael Litvak', Christopher A Lopez, Gege Xu3, Eleonora Napoli, Cecilia Giulivi, Renee M. Solis, Alexander Revzin, Carlito Lebrilla,and Andreas j Baumler 1, Department of Medical Microbiology and Immunology, School of Medicine, University of California at davis One shields Ave: Davis ca 95616. USA 2Department of Biomedical Engineering, College of Engineering, University of California at Davis One Shields Ave: Davis CA 95616 USA Department of Chemistry, College of Letters and Sciences, University of California at Davis, One Shields Ave: Davis CA 95616 USA Department of Molecular Biosciences, School of Veterinary Medicine, University of California at Davis. One Shields Ave: Davis CA 95616. USA Abstract Perturbation of the gut-associated microbial community may underlie many human illnesses, but the mechanisms that maintain homeostasis are poorly understood. We found depletion of butyrate- producing microbes by antibiotic treatment reduced epithelial signaling through the intracellular butyrate sensor PPAR-y. Nitrate levels increased in the colonic lumen because epithelial expression of Nos2, the gene encoding inducible nitric oxide synthase(iNOS)was elevated in the absence of PPAR-y-signaling. Microbiota-induced PPAR-y-signaling also limits the luminal bioavailability of oxygen by driving the energy metabolism of colonic epithelial cells (colonocytes)towards p-oxidation. Therefore, microbiota-activated PPAR-y-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 a balanced gut microbiota is characterized by the dominance of obligate anaerobic members of the phyla Firmicutes and Bacteroidetes, while an expansion of facultative anaerobic Enterobacteriaceae(phylum Proteobacteria)is a common marker of gut dysbiosis(1)(Fig S1). Obligate anaerobic bacteria prevent dysbiotic expansion of facultative anaerobic Enterobacteriaceae, in part, by limiting the generation of host-derived nitrate and oxygen(2 To whom correspondence should be addressed. ajbaumler( @ucdavis. edu. Materials and Methods Figs. SI to S6Microbiota-activated PPAR-γ-signaling inhibits dysbiotic Enterobacteriaceae expansion 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 Lebrilla3, and Andreas J. Bäumler1,* 1Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave; Davis CA 95616, USA 2Department of Biomedical Engineering, College of Engineering, University of California at Davis, One Shields Ave; Davis CA 95616, USA 3Department of Chemistry, College of Letters and Sciences, University of California at Davis, One Shields Ave; Davis CA 95616, USA 4Department of Molecular Biosciences, School of Veterinary Medicine, University of California at Davis, One Shields Ave; Davis CA 95616, USA Abstract Perturbation of the gut-associated microbial community may underlie many human illnesses, but the mechanisms that maintain homeostasis are poorly understood. We found depletion of butyrate￾producing microbes by antibiotic treatment reduced epithelial signaling through the intracellular butyrate sensor PPAR-γ. Nitrate levels increased in the colonic lumen because epithelial expression of Nos2, the gene encoding inducible nitric oxide synthase (iNOS) 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) towards 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. A balanced gut microbiota is characterized by the dominance of obligate anaerobic members of the phyla Firmicutes and Bacteroidetes, while an expansion of facultative anaerobic Enterobacteriaceae (phylum Proteobacteria) is a common marker of gut dysbiosis (1) (Fig. S1). Obligate anaerobic bacteria prevent dysbiotic expansion of facultative anaerobic Enterobacteriaceae, in part, by limiting the generation of host-derived nitrate and oxygen (2, *To whom correspondence should be addressed. ajbaumler@ucdavis.edu. Supplemental Materials: Materials and Methods Figs. S1 to S6 HHS Public Access Author manuscript Science. Author manuscript; available in PMC 2017 October 16. Published in final edited form as: Science. 2017 August 11; 357(6351): 570–575. doi:10.1126/science.aam9949. Author Manuscript Author Manuscript Author Manuscript Author Manuscript