title: Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling.
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.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Maayan
authors.initials: M
authors.lastname: Levy
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Thaiss
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Zeevi
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Lenka
authors.initials: L
authors.lastname: Dohnalová
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Gili
authors.initials: G
authors.lastname: Zilberman-Schapira
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel; Ben Gurion University of the Negev, Beer Sheva 8410501, Israel.
authors.forename: Jemal Ali
authors.initials: JA
authors.lastname: Mahdi
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Eyal
authors.initials: E
authors.lastname: David
authors.affiliation: The Grand Israel National Center for Personalized Medicine (G-INCPM), Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Savidor
authors.affiliation: 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.
authors.forename: Tal
authors.initials: T
authors.lastname: Korem
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yonatan
authors.initials: Y
authors.lastname: Herzig
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Meirav
authors.initials: M
authors.lastname: Pevsner-Fischer
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Hagit
authors.initials: H
authors.lastname: Shapiro
authors.affiliation: Institute of Innate Immunity, University of Bonn, Bonn 53127, Germany; Department of Medicine, University of Massachusetts, Worcester, MA 01605, USA.
authors.forename: Anette
authors.initials: A
authors.lastname: Christ
authors.affiliation: Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Harmelin
authors.affiliation: 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.
authors.forename: Zamir
authors.initials: Z
authors.lastname: Halpern
authors.affiliation: Institute of Innate Immunity, University of Bonn, Bonn 53127, Germany; Department of Medicine, University of Massachusetts, Worcester, MA 01605, USA.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.affiliation: 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.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ido
authors.initials: I
authors.lastname: Amit
authors.affiliation: 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.
authors.forename: Eran
authors.initials: E
authors.lastname: Segal
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address: eran.elinav@weizmann.ac.il.
authors.forename: Eran
authors.initials: E
authors.lastname: Elinav
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy; D003106:Colon / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D064806:Dysbiosis / Q000378:metabolism; D005856:Germ-Free Life; D058847:Inflammasomes / Q000276:immunology*; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy; D020382:Interleukin-18 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013654:Taurine / Q000008:administration & dosage
chemical_list: D023181:Antimicrobial Cationic Peptides; D058847:Inflammasomes; D020382:Interleukin-18; C559901:Nod-like receptor pyrin domain-containing protein 6, mouse; D011956:Receptors, Cell Surface; D013654:Taurine