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

Levy, Maayan, Thaiss, Christoph A., Zeevi, David, Dohnalová, Lenka, Zilberman-Schapira, Gili, Mahdi, Jemal Ali, David, Eyal, Savidor, Alon, Korem, Tal, Herzig, Yonatan, Pevsner-Fischer, Meirav, Shapiro, Hagit, Christ, Anette, Harmelin, Alon, Halpern, Zamir, Latz, Eicke, Flavell, Richard A., Amit, Ido, Segal, Eran, Elinav, Eran
Cell 2015 v.163 pp. 1428-1443
adenosine monophosphate, antimicrobial peptides, coevolution, colitis, disease resistance, epithelium, histamine, homeostasis, interleukin-18, landscapes, metabolites, metabolomics, microbial communities, microorganisms, secretion, spermine, taurine
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.