High-fat diet modifies the PPAR-γ pathway leading to disruption of microbial and physiological ecosystem in murine small intestine

Contributed by Philippe J. Sansonetti, August 1, 2016 (sent for review February 28, 2016; reviewed by Fredrik Bäckhed, Lora V. Hooper, and Peter Turnbaugh)
September 16, 2016
113 (40) E5934-E5943

Significance

Our study aimed at exploring the intersection of high-fat diet, mucosal immune defenses, and microbiota. It remains unclear how diet imbalance toward excessive fat intake leads to secondary pathological effects on host physiology through the microbiota. We show that a short period of consumption of high-fat diet alters the small-intestinal defenses and that the biochemistry of the ileum is drastically modified, leading to physiological changes close to that observed in cystic fibrosis. We identified peroxisome proliferator-activated receptor-γ as major regulator of mucosal defenses upon exposure to fat excess. As a result, our work provides a fundamental understanding of the underlying cause of severe chronic disorders associated with Western diet.

Abstract

Diet is among the most important factors contributing to intestinal homeostasis, and basic functions performed by the small intestine need to be tightly preserved to maintain health. Little is known about the direct impact of high-fat (HF) diet on small-intestinal mucosal defenses and spatial distribution of the microbiota during the early phase of its administration. We observed that only 30 d after HF diet initiation, the intervillous zone of the ileum—which is usually described as free of bacteria—became occupied by a dense microbiota. In addition to affecting its spatial distribution, HF diet also drastically affected microbiota composition with a profile characterized by the expansion of Firmicutes (appearance of Erysipelotrichi), Proteobacteria (Desulfovibrionales) and Verrucomicrobia, and decrease of Bacteroidetes (family S24-7) and Candidatus arthromitus. A decrease in antimicrobial peptide expression was predominantly observed in the ileum where bacterial density appeared highest. In addition, HF diet increased intestinal permeability and decreased cystic fibrosis transmembrane conductance regulator (Cftr) and the Na-K-2Cl cotransporter 1 (Nkcc1) gene and protein expressions, leading to a decrease in ileal secretion of chloride, likely responsible for massive alteration in mucus phenotype. This complex phenotype triggered by HF diet at the interface between the microbiota and the mucosal surface was reversed when the diet was switched back to standard composition or when mice were treated for 1 wk with rosiglitazone, a specific agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ). Moreover, weaker expression of antimicrobial peptide-encoding genes and intervillous bacterial colonization were observed in Ppar-γ–deficient mice, highlighting the major role of lipids in modulation of mucosal immune defenses.

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Data Availability

Data deposition: The 16S rRNA gene sequence data have been deposited into the NCBI Sequence Read Archive database, www.ncbi.nlm.nih.gov/sra (BioProject accession nos. PRJNA306818 and PRJNA340242).

Acknowledgments

We thank Laurence Motreff for her help with the Illumina libraries preparation and the MiSeq run; Eeswari Paramalingam for animal handling and tissue preparation; Jacques Ravel for editing the manuscript; and Nathalie Bechon for her contribution during her fellowship. J.T. was in part funded by the Contrat Jeune Scientifique from the Institut National de la Recherche Agronomique (Jouy-en-Josas, France). This work was supported in part by the Société Française de Nutrition; the Fondation des Treilles created by Anne Gruner Schlumberger (www.les-treilles.com); the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence “Integrative Biology of Emerging Infectious Diseases” (Grant ANR-10-LABX-62-IBEID); the European Research Council Advanced Grants 339579-DECRYPT (to P.J.S.); a Start-Up Grant from the Lee Kong Chian School of Medicine, Nanyang Technological University; and the 7th EU program TORNADO.

Supporting Information

Supporting Information (PDF)
Supporting Information
pnas.1612559113.sd01.xlsx

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 113 | No. 40
October 4, 2016
PubMed: 27638207

Classifications

Data Availability

Data deposition: The 16S rRNA gene sequence data have been deposited into the NCBI Sequence Read Archive database, www.ncbi.nlm.nih.gov/sra (BioProject accession nos. PRJNA306818 and PRJNA340242).

Submission history

Published online: September 16, 2016
Published in issue: October 4, 2016

Keywords

  1. high-fat diet
  2. microbiota
  3. antimicrobial peptides
  4. PPAR-γ
  5. CFTR

Acknowledgments

We thank Laurence Motreff for her help with the Illumina libraries preparation and the MiSeq run; Eeswari Paramalingam for animal handling and tissue preparation; Jacques Ravel for editing the manuscript; and Nathalie Bechon for her contribution during her fellowship. J.T. was in part funded by the Contrat Jeune Scientifique from the Institut National de la Recherche Agronomique (Jouy-en-Josas, France). This work was supported in part by the Société Française de Nutrition; the Fondation des Treilles created by Anne Gruner Schlumberger (www.les-treilles.com); the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence “Integrative Biology of Emerging Infectious Diseases” (Grant ANR-10-LABX-62-IBEID); the European Research Council Advanced Grants 339579-DECRYPT (to P.J.S.); a Start-Up Grant from the Lee Kong Chian School of Medicine, Nanyang Technological University; and the 7th EU program TORNADO.

Authors

Affiliations

Julie Tomas
Unité de Pathogénie Microbienne Moléculaire, INSERM Unit U1202, Institut Pasteur, 75724 Paris Cedex 15, France;
Institut National de la Recherche Agronomique, UMR 1319 MICALIS, F-78350 Jouy-en-Josas, France;
AgroParisTech, UMR 1319 MICALIS, F-78350 Jouy-en-Josas, France;
Céline Mulet
Unité de Pathogénie Microbienne Moléculaire, INSERM Unit U1202, Institut Pasteur, 75724 Paris Cedex 15, France;
Azadeh Saffarian
Unité de Pathogénie Microbienne Moléculaire, INSERM Unit U1202, Institut Pasteur, 75724 Paris Cedex 15, France;
Jean-Baptiste Cavin
INSERM UMRS 1149, Centre de Recherche sur l’inflammation, Unité de Formation et de Recherche de Medecine Paris Diderot, F-75018 Paris, France;
Robert Ducroc
INSERM UMRS 1149, Centre de Recherche sur l’inflammation, Unité de Formation et de Recherche de Medecine Paris Diderot, F-75018 Paris, France;
Béatrice Regnault
Plate-forme de Génotypage des Eucaryotes, Biomics Pole, Centre d’Innovation et Recherche Technologique, Institut Pasteur, Paris F-75015, France;
Chek Kun Tan
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore;
Kalina Duszka
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore;
Rémy Burcelin
Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048 F-31432 Toulouse, France;
Université Paul Sabatier, F-31432 Toulouse, France;
Walter Wahli
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore;
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland;
Philippe J. Sansonetti1 [email protected]
Unité de Pathogénie Microbienne Moléculaire, INSERM Unit U1202, Institut Pasteur, 75724 Paris Cedex 15, France;
Chaire de Microbiologie et Maladies Infectieuses, Collège de France, 75005 Paris, France
Thierry Pédron
Unité de Pathogénie Microbienne Moléculaire, INSERM Unit U1202, Institut Pasteur, 75724 Paris Cedex 15, France;

Notes

1
To whom correspondence should be addressed. Email: [email protected].
Author contributions: J.T., P.J.S., and T.P. designed research; J.T., C.M., J.-B.C., R.D., B.R., C.K.T., K.D., and T.P. performed research; J.T., A.S., J.-B.C., R.D., R.B., W.W., and T.P. analyzed data; and J.T., P.J.S., and T.P. wrote the paper.
Reviewers: F.B., University of Gothenburg; L.V.H., The University of Texas Southwestern; and P.T., University of California, San Francisco.

Competing Interests

The authors declare no conflict of interest.

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    High-fat diet modifies the PPAR-γ pathway leading to disruption of microbial and physiological ecosystem in murine small intestine
    Proceedings of the National Academy of Sciences
    • Vol. 113
    • No. 40
    • pp. 11053-E5992

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