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

被引：914

作者：

Levy, Maayan ^{[1
]}

Thaiss, Christoph A. ^{[1
]}

Zeevi, David ^{[2
,3
]}

Dohnalova, Lenka ^{[1
]}

Zilberman-Schapira, Gili ^{[1
]}

Mahdi, Jemal Ali ^{[1
,4
]}

David, Eyal ^{[1
]}

Savidor, Alon ^{[5
]}

Korem, Tal ^{[2
,3
]}

Herzig, Yonatan ^{[1
]}

Pevsner-Fischer, Meirav ^{[1
]}

Shapiro, Hagit ^{[1
]}

Christ, Anette ^{[6
,7
]}

Harmelin, Alon ^{[8
,10
]}

Halpern, Zamir ^{[9
]}

Latz, Eicke ^{[6
,7
]}

Flavell, Richard A. ^{[11
,12
]}

Amit, Ido ^{[1
]}

Segal, Eran ^{[2
,3
]}

Elinav, Eran ^{[1
]}

机构：

[1] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel

[2] Weizmann Inst Sci, Dept Comp Sci & Appl Math, IL-76100 Rehovot, Israel

[3] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel

[4] Ben Gurion Univ Negev, IL-8410501 Beer Sheva, Israel

[5] Weizmann Inst Sci, Grand Israel Natl Ctr Personalized Med G INCPM, IL-76100 Rehovot, Israel

[6] Univ Bonn, Inst Innate Immun, D-53127 Bonn, Germany

[7] Univ Massachusetts, Dept Med, Worcester, MA 01605 USA

[8] Weizmann Inst Sci, Dept Vet Resources, IL-76100 Rehovot, Israel

[9] Tel Aviv Univ, Res Ctr Digest Tract & Liver Dis, Tel Aviv Sourasky Med Ctr, Sackler Fac Med, IL-69978 Tel Aviv, Israel

[10] Tel Aviv Sourasky Med Ctr, Digest Ctr, IL-64239 Tel Aviv, Israel

[11] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA

[12] Yale Univ, Sch Med, Dept Immunobiol, New Haven, CT 06520 USA

来源：

CELL | 2015年 / 163卷 / 06期

基金：

以色列科学基金会; 欧洲研究理事会;

关键词：

IMMUNE-SYSTEM; GASTROINTESTINAL-TRACT; DIETARY TAURINE; GUT MICROBIOME; COLITIS; MICE; TUMORIGENESIS; INTERFACE; EXPANSION; OBESITY;

D O I：

10.1016/j.cell.2015.10.048

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：1428 / 1443

页数：16

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