Journal
CELL
Volume 163, Issue 6, Pages 1428-1443Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.10.048
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Funding
- Boehringer Ingelheim Fonds
- Ministry of Science, Technology, and Space, Israel
- Foulkes Foundation
- European Research Council (ERC)
- Israel Science Foundation (ISF)
- Yael and Rami Ungar, Israel
- Leona M. and Harry B. Helmsley Charitable Trust
- Gurwin Family Fund for Scientific Research
- Crown Endowment Fund for Immunological Research
- estate of Jack Gitlitz
- estate of Lydia Hershkovich
- Benoziyo Endowment Fund for the Advancement of Science
- Adelis Foundation
- French National Centre for Scientific Research (CNRS)
- European Research Council
- German-Israel Binational Foundation
- Israel Science Foundation
- Minerva Foundation
- Rising Tide Foundation
- Alon Foundation
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Host-microbiome co-evolution drives homeostasis and disease susceptibility, yet regulatory principles governing the integrated intestinal hostcommensal 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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