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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Summary 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.

Original languageEnglish
Pages (from-to)1428-1443
Number of pages16
JournalCell
Volume163
Issue number6
DOIs
StatePublished - 3 Dec 2015

Funding

FundersFunder number
Benoziyo Endowment Fund for the Advancement of Science
Crown Endowment Fund for Immunological Research
German-Israel Binational Foundation
John L. and Vera Schwartz
Lydia Hershkovich
Yael and Rami Ungar, Israel
National Cancer InstituteP30CA016359
National Institute of Diabetes and Digestive and Kidney DiseasesP30DK034989
Alcon Foundation
Achelis Foundation
Leona M. and Harry B. Helmsley Charitable Trust
Foulkes Foundation
European Research Council
Minerva Foundation
Israel Science Foundation
Centre National de la Recherche Scientifique
Ministry of Science and Technology, Israel
Rising Tide Foundation

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