Fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of IL-17 expression.
Fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of IL-17 expression.
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DOI：
10.1080/19490976.2021.1987780
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发表时间：
2021-01
期刊：
影响因子：
12.2
通讯作者：
Garrett WS
中科院分区：
文献类型：
--
作者：
Brennan CA;Clay SL;Lavoie SL;Bae S;Lang JK;Fonseca-Pereira D;Rosinski KG;Ou N;Glickman JN;Garrett WS
结直肠癌（CRC）相关的微生物群创造了促肿瘤的肠道环境，并在肿瘤微环境中形成免疫反应。然而，在口腔中发现的与结直肠癌组织相关的核梭杆菌等肿瘤微生物如何影响肿瘤发生的这些不同方面，很难分析。本研究发现，在ApcMin/+小鼠的新生期接种核核F.菌株Fn7-1绕过了阻止其在肠道定植的技术障碍，在肿瘤形成之前驱动结肠Il17a的表达，并增强了肠道肿瘤的发生。通过使用最小复杂性微生物群（改变的Schaedler菌群）定殖的非生物小鼠，我们观察到肠道Fn7-1定殖增加了结肠Th17细胞频率及其IL-17A和IL-17F的表达，同时增加了结肠固有层Il23p19的表达。由于Fn7-1在我们的模型中稳定地定殖在肠道中，我们假设微生物代谢物，特别是短链脂肪酸（SCFA），如我们所证明的那样，在培养和肠道中大量产生，可能介导其在体内的部分免疫调节作用。为了支持这一假设，我们发现Fn7-1在缺乏SCFA受体FFAR2的情况下不会改变RORγt+ CD4+T细胞频率。综上所述，我们的工作表明，核梭菌通过以FFAR2依赖的方式塑造Th17反应来影响肠道免疫，尽管需要进一步的研究来阐明FFAR2的精确和多方面的作用。另一种肿瘤微生物——产肠毒素的脆弱拟杆菌（Bacteroides fragilis）也有可能增加肠道Th17反应，这突出了一种保守的途径，可能靶向减缓肿瘤微生物介导的CRC。
The colorectal cancer (CRC)-associated microbiota creates a pro-tumorigenic intestinal milieu and shapes immune responses within the tumor microenvironment. However, how oncomicrobes – like Fusobacterium nucleatum, found in the oral cavity and associated with CRC tissues– affect these distinct aspects of tumorigenesis is difficult to parse. Herein, we found that neonatal inoculation of ApcMin/+ mice with F. nucleatum strain Fn7-1 circumvents technical barriers preventing its intestinal colonization, drives colonic Il17a expression prior to tumor formation, and potentiates intestinal tumorigenesis. Using gnotobiotic mice colonized with a minimal complexity microbiota (the altered Schaedler’s flora), we observed that intestinal Fn7-1 colonization increases colonic Th17 cell frequency and their IL-17A and IL-17F expression, along with a concurrent increase in colonic lamina propria Il23p19 expression. As Fn7-1 stably colonizes the intestinal tract in our models, we posited that microbial metabolites, specifically short-chain fatty acids (SCFA) that F. nucleatum abundantly produces in culture and, as we demonstrate, in the intestinal tract, might mediate part of its immunomodulatory effects in vivo. Supporting this hypothesis, we found that Fn7-1 did not alter RORγt+ CD4+T cell frequency in the absence of the SCFA receptor FFAR2. Taken together, our work suggests that F. nucleatum influences intestinal immunity by shaping Th17 responses in an FFAR2-dependent manner, although further studies are necessary to clarify the precise and multifaceted roles of FFAR2. The potential to increase intestinal Th17 responses is shared by another oncomicrobe, enterotoxigenic Bacteroides fragilis, highlighting a conserved pathway that could potentially be targeted to slow oncomicrobe-mediated CRC.
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gnotobiotic小鼠模型表明，饮食纤维以微生物群和丁酸酯依赖性方式预防结肠直肠肿瘤发生。
影响因子：
28.2
作者：
Donohoe DR;Holley D;Collins LB;Montgomery SA;Whitmore AC;Hillhouse A;Curry KP;Renner SW;Greenwalt A;Ryan EP;Godfrey V;Heise MT;Threadgill DS;Han A;Swenberg JA;Threadgill DW;Bultman SJ
通讯作者：
Bultman SJ
影响因子：
6.4
作者：
Engevik MA;Danhof HA;Ruan W;Engevik AC;Chang-Graham AL;Engevik KA;Shi Z;Zhao Y;Brand CK;Krystofiak ES;Venable S;Liu X;Hirschi KD;Hyser JM;Spinler JK;Britton RA;Versalovic J
通讯作者：
Versalovic J
影响因子：
32.4
作者：
Chun, Eunyoung;Lavoie, Sydney;Garrett, Wendy S.
通讯作者：
Garrett, Wendy S.
影响因子：
7
作者：
Castellarin, Mauro;Warren, Rene L.;Holt, Robert A.
通讯作者：
Holt, Robert A.
影响因子：
11.2
作者：
Housseau F;Wu S;Wick EC;Fan H;Wu X;Llosa NJ;Smith KN;Tam A;Ganguly S;Wanyiri JW;Iyadorai T;Malik AA;Roslani AC;Vadivelu JS;Van Meerbeke S;Huso DL;Pardoll DM;Sears CL
通讯作者：
Sears CL