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Research Article

Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion

Science
11 Aug 2017
Vol 357, Issue 6351
pp. 570-575

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

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.

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Supplementary Material

Summary

Materials and Methods
Figs. S1 to S7
References (2635)

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References and Notes

1
N. R. Shin, T. W. Whon, J. W. Bae, Proteobacteria: Microbial signature of dysbiosis in gut microbiota. Trends Biotechnol. 33, 496–503 (2015).
2
A. M. Spees, T. Wangdi, C. A. Lopez, D. D. Kingsbury, M. N. Xavier, S. E. Winter, R. M. Tsolis, A. J. Bäumler, Streptomycin-induced inflammation enhances Escherichia coli gut colonization through nitrate respiration. mBio 4, e00430-13 (2013).
3
F. Rivera-Chávez, L. F. Zhang, F. Faber, C. A. Lopez, M. X. Byndloss, E. E. Olsan, G. Xu, E. M. Velazquez, C. B. Lebrilla, S. E. Winter, A. J. Bäumler, Depletion of butyrate-producing Clostridia from the gut microbiota drives an aerobic luminal expansion of Salmonella. Cell Host Microbe 19, 443–454 (2016).
4
S. E. Winter, M. G. Winter, M. N. Xavier, P. Thiennimitr, V. Poon, A. M. Keestra, R. C. Laughlin, G. Gomez, J. Wu, S. D. Lawhon, I. E. Popova, S. J. Parikh, L. G. Adams, R. M. Tsolis, V. J. Stewart, A. J. Bäumler, Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 339, 708–711 (2013).
5
D. R. Donohoe, N. Garge, X. Zhang, W. Sun, T. M. O’Connell, M. K. Bunger, S. J. Bultman, The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab. 13, 517–526 (2011).
6
R. Marion-Letellier, M. Butler, P. Déchelotte, R. J. Playford, S. Ghosh, Comparison of cytokine modulation by natural peroxisome proliferator-activated receptor gamma ligands with synthetic ligands in intestinal-like Caco-2 cells and human dendritic cells—Potential for dietary modulation of peroxisome proliferator-activated receptor gamma in intestinal inflammation. Am. J. Clin. Nutr. 87, 939–948 (2008).
7
M. Lefebvre, B. Paulweber, L. Fajas, J. Woods, C. McCrary, J. F. Colombel, J. Najib, J. C. Fruchart, C. Datz, H. Vidal, P. Desreumaux, J. Auwerx, Peroxisome proliferator-activated receptor gamma is induced during differentiation of colon epithelium cells. J. Endocrinol. 162, 331–340 (1999).
8
S. Alex, K. Lange, T. Amolo, J. S. Grinstead, A. K. Haakonsson, E. Szalowska, A. Koppen, K. Mudde, D. Haenen, S. Al-Lahham, H. Roelofsen, R. Houtman, B. van der Burg, S. Mandrup, A. M. J. J. Bonvin, E. Kalkhoven, M. Müller, G. J. Hooiveld, S. Kersten, Short-chain fatty acids stimulate angiopoietin-like 4 synthesis in human colon adenocarcinoma cells by activating peroxisome proliferator-activated receptor γ. Mol. Cell. Biol. 33, 1303–1316 (2013).
9
M. Vital, A. C. Howe, J. M. Tiedje, Revealing the bacterial butyrate synthesis pathways by analyzing (meta)genomic data. mBio 5, e00889-14 (2014).
10
K. Atarashi, T. Tanoue, K. Oshima, W. Suda, Y. Nagano, H. Nishikawa, S. Fukuda, T. Saito, S. Narushima, K. Hase, S. Kim, J. V. Fritz, P. Wilmes, S. Ueha, K. Matsushima, H. Ohno, B. Olle, S. Sakaguchi, T. Taniguchi, H. Morita, M. Hattori, K. Honda, Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).
11
C. J. Kelly, L. Zheng, E. L. Campbell, B. Saeedi, C. C. Scholz, A. J. Bayless, K. E. Wilson, L. E. Glover, D. J. Kominsky, A. Magnuson, T. L. Weir, S. F. Ehrentraut, C. Pickel, K. A. Kuhn, J. M. Lanis, V. Nguyen, C. T. Taylor, S. P. Colgan, Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe 17, 662–671 (2015).
12
G. T. Furuta, J. R. Turner, C. T. Taylor, R. M. Hershberg, K. Comerford, S. Narravula, D. K. Podolsky, S. P. Colgan, Hypoxia-inducible factor 1-dependent induction of intestinal trefoil factor protects barrier function during hypoxia. J. Exp. Med. 193, 1027–1034 (2001).
13
M. N. Xavier, M. G. Winter, A. M. Spees, A. B. den Hartigh, K. Nguyen, C. M. Roux, T. M. A. Silva, V. L. Atluri, T. Kerrinnes, A. M. Keestra, D. M. Monack, P. A. Luciw, R. A. Eigenheer, A. J. Bäumler, R. L. Santos, R. M. Tsolis, PPARγ-mediated increase in glucose availability sustains chronic Brucella abortus infection in alternatively activated macrophages. Cell Host Microbe 14, 159–170 (2013).
14
N. Terada, N. Ohno, S. Saitoh, S. Ohno, Immunohistochemical detection of hypoxia in mouse liver tissues treated with pimonidazole using “in vivo cryotechnique”. Histochem. Cell Biol. 128, 253–261 (2007).
15
S. Kizaka-Kondoh, H. Konse-Nagasawa, Significance of nitroimidazole compounds and hypoxia-inducible factor-1 for imaging tumor hypoxia. Cancer Sci. 100, 1366–1373 (2009).
16
K. M. Maslowski, A. T. Vieira, A. Ng, J. Kranich, F. Sierro, D. Yu, H. C. Schilter, M. S. Rolph, F. Mackay, D. Artis, R. J. Xavier, M. M. Teixeira, C. R. Mackay, Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286 (2009).
17
A. L. Millard, P. M. Mertes, D. Ittelet, F. Villard, P. Jeannesson, J. Bernard, Butyrate affects differentiation, maturation and function of human monocyte-derived dendritic cells and macrophages. Clin. Exp. Immunol. 130, 245–255 (2002).
18
B. Wang, A. Morinobu, M. Horiuchi, J. Liu, S. Kumagai, Butyrate inhibits functional differentiation of human monocyte-derived dendritic cells. Cell. Immunol. 253, 54–58 (2008).
19
P. V. Chang, L. Hao, S. Offermanns, R. Medzhitov, The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc. Natl. Acad. Sci. U.S.A. 111, 2247–2252 (2014).
20
K. Atarashi, T. Tanoue, T. Shima, A. Imaoka, T. Kuwahara, Y. Momose, G. Cheng, S. Yamasaki, T. Saito, Y. Ohba, T. Taniguchi, K. Takeda, S. Hori, I. I. Ivanov, Y. Umesaki, K. Itoh, K. Honda, Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).
21
N. Arpaia, C. Campbell, X. Fan, S. Dikiy, J. van der Veeken, P. deRoos, H. Liu, J. R. Cross, K. Pfeffer, P. J. Coffer, A. Y. Rudensky, Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).
22
Y. Furusawa, Y. Obata, S. Fukuda, T. A. Endo, G. Nakato, D. Takahashi, Y. Nakanishi, C. Uetake, K. Kato, T. Kato, M. Takahashi, N. N. Fukuda, S. Murakami, E. Miyauchi, S. Hino, K. Atarashi, S. Onawa, Y. Fujimura, T. Lockett, J. M. Clarke, D. L. Topping, M. Tomita, S. Hori, O. Ohara, T. Morita, H. Koseki, J. Kikuchi, K. Honda, K. Hase, H. Ohno, Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).
23
P. M. Smith, M. R. Howitt, N. Panikov, M. Michaud, C. A. Gallini, M. Bohlooly-Y, J. N. Glickman, W. S. Garrett, The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).
24
N. Singh, A. Gurav, S. Sivaprakasam, E. Brady, R. Padia, H. Shi, M. Thangaraju, P. D. Prasad, S. Manicassamy, D. H. Munn, J. R. Lee, S. Offermanns, V. Ganapathy, Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128–139 (2014).
25
L. Peyrin-Biroulet, J. Beisner, G. Wang, S. Nuding, S. T. Oommen, D. Kelly, E. Parmentier-Decrucq, R. Dessein, E. Merour, P. Chavatte, T. Grandjean, A. Bressenot, P. Desreumaux, J.-F. Colombel, B. Desvergne, E. F. Stange, J. Wehkamp, M. Chamaillard, Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon. Proc. Natl. Acad. Sci. U.S.A. 107, 8772–8777 (2010).
26
S. Narushima, Y. Sugiura, K. Oshima, K. Atarashi, M. Hattori, M. Suematsu, K. Honda, Characterization of the 17 strains of regulatory T cell-inducing human-derived Clostridia. Gut Microbes 5, 333–339 (2014).
27
J. Behnsen, S. Jellbauer, C. P. Wong, R. A. Edwards, M. D. George, W. Ouyang, M. Raffatellu, The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria. Immunity 40, 262–273 (2014).
28
Y. Y. Setiady, J. A. Coccia, P. U. Park, In vivo depletion of CD4+FOXP3+ Treg cells by the PC61 anti-CD25 monoclonal antibody is mediated by FcγRIII+ phagocytes. Eur. J. Immunol. 40, 780–786 (2010).
29
A. Barrientos, In vivo and in organello assessment of OXPHOS activities. Methods 26, 307–316 (2002).
30
F. Rivera-Chávez, C. A. Lopez, L. F. Zhang, L. García-Pastor, A. Chávez-Arroyo, K. L. Lokken, R. M. Tsolis, S. E. Winter, A. J. Bäumler, Energy taxis toward host-derived nitrate supports a Salmonella pathogenicity island 1-independent mechanism of invasion. mBio 7, e00960-16 (2016).
31
P. J. McMurdie, S. Holmes, phyloseq: An R package for reproducible interactive analysis and graphics of microbiome census data. PLOS ONE 8, e61217 (2013).
32
P. Louis, H. J. Flint, Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiol. Lett. 294, 1–8 (2009).
33
Y. N. Xia, G. M. Whitesides, Soft lithography. Annu. Rev. Mater. Sci. 28, 153–184 (1998).
34
Y. Gao, D. Majumdar, B. Jovanovic, C. Shaifer, P. C. Lin, A. Zijlstra, D. J. Webb, D. Li, A versatile valve-enabled microfluidic cell co-culture platform and demonstration of its applications to neurobiology and cancer biology. Biomed. Microdevices 13, 539–548 (2011).
35
A. M. Keestra, I. Godinez, M. N. Xavier, M. G. Winter, S. E. Winter, R. M. Tsolis, A. J. Bäumler, Early MyD88-dependent induction of interleukin-17A expression during Salmonella colitis. Infect. Immun. 79, 3131–3140 (2011).

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Published In

Science
Volume 357 | Issue 6351
11 August 2017

Submission history

Received: 15 February 2017
Accepted: 22 June 2017
Published in print: 11 August 2017

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Acknowledgments

We acknowledge the Host-Microbe Systems Biology Core (HMSB Core) at the University of California at Davis School of Medicine for expert technical assistance with microbiota sequence analysis. The data reported in the manuscript are tabulated in the main paper and the supplementary materials. M.X.B. and A.J.Bä. filed invention report number 0577501-16-0038 at iEdison.gov for a treatment to prevent postantibiotic expansion of Enterobacteriaceae. This work was supported by Public Health Service grants AI060555 (S.A.C.), TR001861 (E.E.O.), AI112241 (C.A.L.), DK087307 (C.G.), AI109799 (R.M.T.), AI112258 (R.M.T.), AI112949 (A.J.Bä. and R.M.T.), AI096528 (A.J.Bä.), AI112445 (A.J.Bä.), AI112949 (A.J.Bä.), and AI114922 (A.J.Bä.). K.L.L. was supported by an American Heart Association Predoctoral Fellowship (15PRE21420011).

Authors

Affiliations

Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Fabian Rivera-Chávez
Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Connor R. Tiffany
Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Department of Biomedical Engineering, College of Engineering, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Department of Chemistry, College of Letters and Sciences, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Eleonora Napoli
Department of Molecular Biosciences, School of Veterinary Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Cecilia Giulivi
Department of Molecular Biosciences, School of Veterinary Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Department of Biomedical Engineering, College of Engineering, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Department of Chemistry, College of Letters and Sciences, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.

Funding Information

National Institutes of Health: award302317, AI114922
National Institutes of Health: award302318, AI112949
National Institutes of Health: award302319, AI112445
National Institutes of Health: award302320, AI096528
National Institutes of Health: award317045, AI060555 TR001861 OD010931 DK087307
National Institutes of Health: award302329, AI112258, AI109799, AI112949
National Institutes of Health: award302328, AI114922, AI112949, AI112445, AI096528, AI112949

Notes

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Corresponding author. Email: [email protected]

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