Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling.
Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling.
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DOI：
10.1016/j.cell.2015.10.048
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发表时间：
2015-12-03
期刊：
影响因子：
64.5
通讯作者：
Elinav E
中科院分区：
文献类型：
--
作者：
Levy M;Thaiss CA;Zeevi D;Dohnalová L;Zilberman-Schapira G;Mahdi JA;David E;Savidor A;Korem T;Herzig Y;Pevsner-Fischer M;Shapiro H;Christ A;Harmelin A;Halpern Z;Latz E;Flavell RA;Amit I;Segal E;Elinav E
宿主-微生物组的共同进化驱动了体内平衡和疾病易感性，但管理整合的肠道宿主-微生物微环境的调节原则仍然不清楚。虽然炎症体信号参与这些相互作用，但其激活剂和微生物组调节机制尚不清楚。在这里，我们证明了微生物群相关代谢物牛磺酸，组胺和精胺通过共同调节NLRP 6炎性体信号传导，上皮IL-18分泌和下游抗菌肽（AMP）谱来塑造宿主-微生物组界面。炎性小体缺乏导致的这种AMP平衡景观的扭曲驱动了生态失调的发展。在粪便转移后，结肠炎诱导微生物群通过代谢物介导的炎性小体抑制劫持这种微环境协调机制，导致AMP平衡扭曲，有利于其优先定植。代谢物-炎性体-AMP轴的恢复恢复正常的微生物群并改善结肠炎。总之，我们确定了NLRP 6炎性体的微生物调节剂，并强调了微生物组-宿主相互作用通过代谢物介导的先天免疫调节协同驱动微生物群落稳定性的机制。因此，有针对性的“后生物”代谢组学干预可以恢复正常的微环境，作为治疗或预防生态失调驱动的疾病。
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.
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影响因子：
30.5
作者：
通讯作者：
--
影响因子：
64.8
作者：
Devkota, Suzanne;Wang, Yunwei;Musch, Mark W.;Leone, Vanessa;Fehlner-Peach, Hannah;Nadimpalli, Anuradha;Antonopoulos, Dionysios A.;Jabri, Bana;Chang, Eugene B.
通讯作者：
Chang, Eugene B.
影响因子：
9.8
作者：
Stecher, Barbel;Robbiani, Riccardo;Walker, Alan W;Westendorf, Astrid M;Barthel, Manja;Kremer, Marcus;Chaffron, Samuel;Macpherson, Andrew J;Buer, Jan;Parkhill, Julian;Dougan, Gordon;von Mering, Christian;Hardt, Wolf-Dietrich
通讯作者：
Hardt, Wolf-Dietrich
DOI：
10.1007/978-0-387-75681-3_27
发表时间：
2009-01-01
期刊：
TAURINE 7
影响因子：
--
作者：
Shimizu, Makoto;Zhao, Zhaohui;Satsu, Hideo
通讯作者：
Satsu, Hideo
影响因子：
64.5
作者：
Garrett, Wendy S.;Lord, Graham M.;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.