TY - JOUR
T1 - Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling
AU - Levy, Maayan
AU - Thaiss, Christoph A.
AU - Zeevi, David
AU - Dohnalová, Lenka
AU - Zilberman-Schapira, Gili
AU - Mahdi, Jemal Ali
AU - David, Eyal
AU - Savidor, Alon
AU - Korem, Tal
AU - Herzig, Yonatan
AU - Pevsner-Fischer, Meirav
AU - Shapiro, Hagit
AU - Christ, Anette
AU - Harmelin, Alon
AU - Halpern, Zamir
AU - Latz, Eicke
AU - Flavell, Richard A.
AU - Amit, Ido
AU - Segal, Eran
AU - Elinav, Eran
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/12/3
Y1 - 2015/12/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84949255269&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2015.10.048
DO - 10.1016/j.cell.2015.10.048
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C2 - 26638072
AN - SCOPUS:84949255269
SN - 0092-8674
VL - 163
SP - 1428
EP - 1443
JO - Cell
JF - Cell
IS - 6
ER -