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Cell. 2015 Dec 3;163(6):1428-43. doi: 10.1016/j.cell.2015.10.048.

Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling.

Author information

1
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
2
Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
3
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel; Ben Gurion University of the Negev, Beer Sheva 8410501, Israel.
4
The Grand Israel National Center for Personalized Medicine (G-INCPM), Weizmann Institute of Science, Rehovot 76100, Israel.
5
Institute of Innate Immunity, University of Bonn, Bonn 53127, Germany; Department of Medicine, University of Massachusetts, Worcester, MA 01605, USA.
6
Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel.
7
Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Digestive Center, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel.
8
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
9
Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: eran.segal@weizmann.ac.il.
10
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: eran.elinav@weizmann.ac.il.

Abstract

Host-microbiome co-evolution drives homeostasis and disease susceptibility, yet regulatory principles governing the integrated intestinal host-commensal microenvironment remain obscure. While inflammasome signaling participates in these interactions, its activators and microbiome-modulating mechanisms are unknown. Here, we demonstrate that the microbiota-associated metabolites taurine, histamine, and spermine shape the host-microbiome interface by co-modulating NLRP6 inflammasome signaling, epithelial IL-18 secretion, and downstream anti-microbial peptide (AMP) profiles. Distortion of this balanced AMP landscape by inflammasome deficiency drives dysbiosis development. Upon fecal transfer, colitis-inducing microbiota hijacks this microenvironment-orchestrating machinery through metabolite-mediated inflammasome suppression, leading to distorted AMP balance favoring its preferential colonization. Restoration of the metabolite-inflammasome-AMP axis reinstates a normal microbiota and ameliorates colitis. Together, we identify microbial modulators of the NLRP6 inflammasome and highlight mechanisms by which microbiome-host interactions cooperatively drive microbial community stability through metabolite-mediated innate immune modulation. Therefore, targeted "postbiotic" metabolomic intervention may restore a normal microenvironment as treatment or prevention of dysbiosis-driven diseases.

PMID:
26638072
PMCID:
PMC5665753
DOI:
10.1016/j.cell.2015.10.048
[Indexed for MEDLINE]
Free PMC Article

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