@article{cca343258d27411f9c868ca26f150de8,
title = "Microbiota maintain colonic homeostasis by activating TLR2/MyD88/PI3K signaling in IL-10-producing regulatory B cells",
abstract = "Resident microbiota activates regulatory cells that modulate intestinal inflammation and promote and maintain intestinal homeostasis. IL-10 is a key mediator of immune regulatory function. Our studies describe the functional importance and mechanisms by which gut microbiota and specific microbial components influence the development of intestinal IL-10-producing B cells. Using fecal transplant into germ-free (GF) Il10+/EGFP reporter and Il10-/- mice, we demonstrated that microbiota from specific pathogen-free mice primarily stimulated IL-10-producing colon-specific B cells and T regulatory 1 cells in ex-GF mice. IL-10 in turn downregulated microbiota-activated mucosal inflammatory cytokines. TLR2 and -9 ligands and enteric bacterial lysates preferentially induced IL-10 production and the regulatory capacity of intestinal B cells. Analysis of Il10+/EGFP mice crossed with additional gene-deficient strains and B cell cotransfer studies demonstrated that microbiota-induced IL-10-producing intestinal B cells ameliorated chronic T cell-mediated colitis in a TLR2-, MyD88-, and PI3K-dependent fashion. In vitro studies implicated downstream signaling of PI3Kp110δ and AKT. These studies demonstrated that resident enteric bacteria activated intestinal IL-10-producing B cells through TLR2, MyD88, and PI3K pathways. These B cells reduced colonic T cell activation and maintained mucosal homeostasis in response to intestinal microbiota.",
author = "Yoshiyuki Mishima and Akihiko Oka and Bo Liu and Herzog, {Jeremy W.} and Eun, {Chang Soo} and Fan, {Ting Jia} and Emily Bulik-Sullivan and Carroll, {Ian M.} and Hansen, {Jonathan J.} and Liang Chen and Wilson, {Justin E.} and Fisher, {Nancy C.} and Ting, {Jenny P.Y.} and Tomonori Nochi and Angela Wahl and {Victor Garcia}, J. and Karp, {Christopher L.} and {Balfour Sartor}, R.",
note = "Funding Information: These studies were supported by NIH grants P01 DK094779, R01 DK53347, P40 OD010995, and P30 DK34987 (to RBS); R01 CA156330 (to JPYT); R01 AI123010 (to AW); and R01 AI111899, AI140799, and MH108179 (to JVG); and by Crohn's and Colitis Foundation Microbiome Initiative and Gnotobiotic Facility grants (both to RBS) and Research Fellowship Award (to YM and AO). JEW was supported by a postdoctoral fellowship from the American Cancer Society (PF-13-401-01-TBE). The UNC Flow Cytometry Core is supported in part by Cancer Center Core Support Grant P30 CA016086 to the UNC Lineberger Comprehensive Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The views expressed herein do not necessarily represent the views of the Bill & Melinda Gates Foundation. The authors acknowledge the editorial assistance of Richard Youngblood of the UNC Translational and Clinical Sciences Institute. Funding Information: JEW was supported by a postdoctoral fellowship from the American Cancer Society (PF-13-401-01-TBE). The UNC Flow Cytometry Core is supported in part by Cancer Center Core Support Grant P30 CA016086 to the UNC Lineberger Comprehensive Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The views expressed herein do not necessarily represent the views of the Bill & Melinda Gates Foundation. The authors acknowledge the editorial assistance of Richard Youngblood of the UNC Translational and Clinical Sciences Institute. Funding Information: These studies were supported by NIH grants P01 DK094779, R01 DK53347, P40 OD010995, and P30 DK34987 (to RBS); R01 CA156330 (to JPYT); R01 AI123010 (to AW); and R01 AI111899, AI140799, and MH108179 (to JVG); and by Crohn{\textquoteright}s and Colitis Foundation Microbiome Initiative and Gnotobiotic Facility grants (both to RBS) and Research Fellowship Award (to YM and AO). Publisher Copyright: {\textcopyright} 2019, American Society for Clinical Investigation.",
year = "2019",
month = sep,
day = "3",
doi = "10.1172/JCI93820",
language = "English (US)",
volume = "129",
pages = "3702--3716",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "9",
}