Dataset Information

Microbiota-activated PPAR-? signaling inhibits dysbiotic Enterobacteriaceae expansion.

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 ? (PPAR-?). 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-? signaling. Microbiota-induced PPAR-? signaling also limits the luminal bioavailability of oxygen by driving the energy metabolism of colonic epithelial cells (colonocytes) toward ?-oxidation. Therefore, microbiota-activated PPAR-? 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.

SUBMITTER: Byndloss MX

PROVIDER: S-EPMC5642957 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Byndloss Mariana X MX Olsan Erin E EE Rivera-Chávez Fabian F Tiffany Connor R CR Cevallos Stephanie A SA Lokken Kristen L KL Torres Teresa P TP Byndloss Austin J AJ Faber Franziska F Gao Yandong Y Litvak Yael Y Lopez Christopher A CA Xu Gege G Napoli Eleonora E Giulivi Cecilia C Tsolis Renée M RM Revzin Alexander A Lebrilla Carlito B CB Bäumler Andreas J AJ

Science (New York, N.Y.) 20170801 6351

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 <i>Nos2</i>, the gene encoding inducible nitric oxide ...[more]

PMID: 28798125

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Project description:Stromal Derived Factor-1? (SDF-1?) and its cognate receptor CXCR4 play a key role in mediating breast cancer cell invasion and metastasis. Therefore, drugs able to inhibit CXCR4 activation may add critical tools to reduce tumor progression, especially in the most aggressive form of the breast cancer disease. Peroxisome Proliferator-Activated Receptor (PPAR) ?, a member of the nuclear receptor superfamily, has been found to downregulate CXCR4 gene expression in different cancer cells, however the molecular mechanism underlying this effect is not fully understood. Here, we identified a novel PPAR?-mediated mechanism that negatively regulates CXCR4 expression in both epithelial and stromal breast cancer cells. We found that ligand-activated PPAR? downregulated CXCR4 transcriptional activity through the recruitment of the silencing mediator of retinoid and thyroid hormone receptor (SMRT) corepressor onto a newly identified PPAR response element (PPRE) within the CXCR4 promoter in breast cancer cell lines. As a consequence, the PPAR? agonist rosiglitazone (BRL) significantly inhibited cell migration and invasion and this effect was PPAR?-mediated, since it was reversed in the presence of the PPAR? antagonist GW9662. According to the ability of cancer-associated fibroblasts (CAFs), the most abundant component of breast cancer stroma, to secrete high levels of SDF-1?, BRL reduced migratory promoting activities induced by conditioned media (CM) derived from CAFs and affected CXCR4 downstream signaling pathways activated by CAF-CM. In addition, CAFs exposed to BRL showed a decreased expression of CXCR4, a reduced motility and invasion along with a phenotype characterized by an altered morphology. Collectively, our findings provide novel insights into the role of PPAR? in inhibiting breast cancer progression and further highlight the utility of PPAR? ligands for future therapies aimed at targeting both cancer and surrounding stromal cells in breast cancer patients.

Dataset Information

Microbiota-activated PPAR-? signaling inhibits dysbiotic Enterobacteriaceae expansion.

Publications

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

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