@article{f3980697c9764465b8044c63537fb35c,
title = "Western diet induces Paneth cell defects through microbiome alterations and farnesoid X receptor and type I interferon activation",
abstract = "Intestinal Paneth cells modulate innate immunity and infection. In Crohn's disease, genetic mutations together with environmental triggers can disable Paneth cell function. Here, we find that a western diet (WD) similarly leads to Paneth cell dysfunction through mechanisms dependent on the microbiome and farnesoid X receptor (FXR) and type I interferon (IFN) signaling. Analysis of multiple human cohorts suggests that obesity is associated with Paneth cell dysfunction. In mouse models, consumption of a WD for as little as 4 weeks led to Paneth cell dysfunction. WD consumption in conjunction with Clostridium spp. increased the secondary bile acid deoxycholic acid levels in the ileum, which in turn inhibited Paneth cell function. The process required excess signaling of both FXR and IFN within intestinal epithelial cells. Our findings provide a mechanistic link between poor diet and inhibition of gut innate immunity and uncover an effect of FXR activation in gut inflammation.",
keywords = "cell-intrinsic, high fat diet, metabolism, microbiota, myeloid cells, obesity, organoids, transcriptomics",
author = "Liu, {Ta Chiang} and Kern, {Justin T.} and Umang Jain and Sonnek, {Naomi M.} and Shanshan Xiong and Simpson, {Katherine F.} and VanDussen, {Kelli L.} and Winkler, {Emma S.} and Talin Haritunians and Atika Malique and Qiuhe Lu and Yo Sasaki and Chad Storer and Diamond, {Michael S.} and Head, {Richard D.} and McGovern, {Dermot P.B.} and Stappenbeck, {Thaddeus S.}",
note = "Funding Information: The study was supported by NIH grant U01DK062413 and a grant from Helmsley Charitable Trust ( 2014PGIBD010 ). T.C.L. was supported by NIH grants R01 DK125296 and R01 DK124274 . K.L.V. was supported by NIH grant DK109081 . M.S.D. was supported by NIH grants R01 AI143673 , R01 AI127513 , and R01 AI123348 . We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The Center is partially supported by NCI Cancer Center support grant # P30 CA91842 to the Siteman Cancer Center and by ICTS /CTSA grant# UL1TR002345 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The study was also supported in part by Digestive Disease Research Core Center at Washington University by grant P30DK052574 from the NIH. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. The authors also appreciate Drs. Ashly Steed and Megan Baldridge for sharing reagents. Funding Information: The study was supported by NIH grant U01DK062413 and a grant from Helmsley Charitable Trust (2014PGIBD010). T.C.L. was supported by NIH grants R01 DK125296 and R01 DK124274. K.L.V. was supported by NIH grant DK109081. M.S.D. was supported by NIH grants R01 AI143673, R01 AI127513, and R01 AI123348. We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The Center is partially supported by NCI Cancer Center support grant #P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA grant# UL1TR002345 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The study was also supported in part by Digestive Disease Research Core Center at Washington University by grant P30DK052574 from the NIH. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. The authors also appreciate Drs. Ashly Steed and Megan Baldridge for sharing reagents. T.-C.L. and T.S.S. conceptualized and supervised the study. T.-C.L. designed the study. J.T.K. U.J. N.M.S. S.X. K.F.S. K.L.V. and E.S.W. performed experiments. Q.L. and D.P.B.M. provided materials. T.-C.L. E.S.W. M.S.D. Y.S. C.S. and R.D.H. analyzed data. T.-C.L. D.P.B.M. M.S.D. and T.S.S. provided funding. T.-C.L. and T.S.S. wrote the manuscript. All co-authors edited and approved the manuscript. T.-C.L. received research funding from Pfizer on Paneth cell phenotype in IBD, and advises Interline. R.D.H. and C.S. may receive royalty income based on the CompBio technology developed by R.D.H. and licensed by Washington University to PercayAI. T. Stappenbeck advises Janssen, Boehringer Ingelheim (Ingelheim, Germany), Kallyope, Takada, and Roche. All other authors declare no relevant competing interests. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jun,
day = "9",
doi = "10.1016/j.chom.2021.04.004",
language = "English",
volume = "29",
pages = "988--1001.e6",
journal = "Cell Host and Microbe",
issn = "1931-3128",
number = "6",
}