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

Maayan Levy | Zendy; Christoph A. Thaiss | Zendy; David Zeevi | Zendy; Lenka Dohnalová | Zendy; Gili Zilberman-Schapira | Zendy; Jemal Ali Mahdi | Zendy; Eyal David | Zendy; Alon Savidor | Zendy; Tal Korem | Zendy; Yonatan Herzig | Zendy; Meirav PevsnerFischer | Zendy; Hagit Shapiro | Zendy; Anette Christ | Zendy; Alon Harmelin | Zendy; Zamir Halpern | Zendy; Eicke Latz | Zendy; Richard A. Flavell | Zendy; Ido Amit | Zendy; Eran Segal | Zendy; Eran Elinav | Zendy

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

Author(s) -

Maayan Levy,

Christoph A. Thaiss,

David Zeevi,

Lenka Dohnalová,

Gili Zilberman-Schapira,

Jemal Ali Mahdi,

Eyal David,

Alon Savidor,

Tal Korem,

Yonatan Herzig,

Meirav PevsnerFischer,

Hagit Shapiro,

Anette Christ,

Alon Harmelin,

Zamir Halpern,

Eicke Latz,

Richard A. Flavell,

Ido Amit,

Eran Segal,

Eran Elinav

Publication year - 2015

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2015.10.048

Subject(s) - biology , inflammasome , signal transduction , microbiology and biotechnology , inflammation , immunology

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.

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