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

• Published in: Cell Vol. 163; no. 6; pp. 1428 - 1443
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.12.2015
• Subjects: Animals; Antimicrobial Cationic Peptides; antimicrobial peptides; coevolution; colitis; Colitis - chemically induced; Colitis - drug therapy; Colon - immunology; Colon - metabolism; Colon - microbiology; disease susceptibility; dysbiosis; Dysbiosis - metabolism; epithelium; Germ-Free Life; histamine; homeostasis; immunomodulation; inflammasomes; Inflammasomes - immunology; Inflammatory Bowel Diseases - chemically induced; Inflammatory Bowel Diseases - drug therapy; interleukin-18; Interleukin-18 - immunology; intestines; landscapes; metabolites; metabolomics; Mice; Mice, Inbred C57BL; microbial communities; Microbiota; microorganisms; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; secretion; Signal Transduction; spermine; taurine; Taurine - administration & dosage
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2015.10.048

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. [Display omitted] •Microbiota-modulated metabolites regulate NLRP6 inflammasome and intestinal IL-18•Inflammasome-derived IL-18 orchestrates colonic anti-microbial peptide expression•Inflammasome modulation by metabolites enables dysbiotic community transfer•Integrated metabolite signaling determines the severity of intestinal inflammation Microbiota-associated metabolites shape the host-microbiome interface by modulating NLRP6 inflammasome signaling, epithelial IL-18 secretion, and the generation of downstream anti-microbial peptides. This axis, therefore, determines both host indigenous microbiome profiles and the susceptibility to intestinal inflammation.