@article{e0c88704dbaf4a76b695f0525bb593db,
title = "Diet Diurnally Regulates Small Intestinal Microbiome-Epithelial-Immune Homeostasis and Enteritis",
abstract = "Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10+ lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions.",
keywords = "Crohn disease, HFD, IBD, IL-10, MHC class II, SFB, circadian clock, epithelial cell, high-fat diet, inflammatory bowel disease, interleukin-10, major histocompatibility complex, microbiome, segmented filamentous bacteria, small intestine",
author = "Timur Tuganbaev and Uria Mor and Stavros Bashiardes and Timur Liwinski and Nobs, {Samuel Philip} and Avner Leshem and Mally Dori-Bachash and Thaiss, {Christoph A.} and Pinker, {Elisha Y.} and Karina Ratiner and Lorenz Adlung and Sara Federici and Christian Kleimeyer and Claudia Moresi and Takahiro Yamada and Yotam Cohen and Xiao Zhang and Hassan Massalha and Efi Massasa and Yael Kuperman and Koni, {Pandelakis A.} and Alon Harmelin and Nan Gao and Shalev Itzkovitz and Kenya Honda and Hagit Shapiro and Eran Elinav",
note = "Funding Information: We thank the members of the E.E. lab for discussions and apologize to authors whose work was not included due to space constraints. We thank Idit Shachar and Yifat Merbl, Weizmann Institute of Science, for suggestions. We thank Carmit Bar-Nathan for assistance with animal work; Steffen Jung, Weizmann Institute of Science, for providing MHC class II fl/fl mice; and Jeremiah Faith, Mount Sinai School of Medicine, for generously providing GF Rag -/- mice. We thank Maria Eizner of Eizner Design for graphical design support. T.L. is funded as postdoctoral fellow by the German Research Foundation (DFG, 420943353 ). S.P.N. is funded by an EMBO Long term Fellowship ATF 767-2017 . E.E. is supported by Y. and R. Ungar , the Abisch Frenkel Foundation for the Promotion of Life Science s, the Gurwin Family Fund for Scientific Research , the Leona M. and Harry B. Helmsley Charitable Trust , the Crown Endowment Fund for Immunological Research , the Else Kroener Fresenius Foundation , the estate of J. Gitlitz , the estate of L. Hershkovich , the Benoziyo Endowment Fund for the Advancement of Science , the Adelis Foundation , J.L. and V. Schwartz , A. and G. Markovitz , A. and C. Adelson , the French National Center for Scientific Research (CNRS), D.L. Schwarz , The V.R. Schwartz Research Fellow Chair , L. Steinberg , J.N. Halpern , A. Edelheit , and by grants funded by the European Research Council , a Marie Curie Integration grant, the German-Israeli Foundation for Scientific Research and Development , the Israel Science Foundation , the Helmholtz Foundation , and the European Foundation for the Study of Diabetes . E.E. is a senior fellow, Canadian Institute of Advanced Research (CIFAR) and an international scholar, Howard Hughes Medical Institute (HHMI). Funding Information: We thank the members of the E.E. lab for discussions and apologize to authors whose work was not included due to space constraints. We thank Idit Shachar and Yifat Merbl, Weizmann Institute of Science, for suggestions. We thank Carmit Bar-Nathan for assistance with animal work; Steffen Jung, Weizmann Institute of Science, for providing MHC class IIfl/fl mice; and Jeremiah Faith, Mount Sinai School of Medicine, for generously providing GF Rag-/- mice. We thank Maria Eizner of Eizner Design for graphical design support. T.L. is funded as postdoctoral fellow by the German Research Foundation (DFG, 420943353). S.P.N. is funded by an EMBO Long term Fellowship ATF 767-2017. E.E. is supported by Y. and R. Ungar, the Abisch Frenkel Foundation for the Promotion of Life Sciences, the Gurwin Family Fund for Scientific Research, the Leona M. and Harry B. Helmsley Charitable Trust, the Crown Endowment Fund for Immunological Research, the Else Kroener Fresenius Foundation, the estate of J. Gitlitz, the estate of L. Hershkovich, the Benoziyo Endowment Fund for the Advancement of Science, the Adelis Foundation, J.L. and V. Schwartz, A. and G. Markovitz, A. and C. Adelson, the French National Center for Scientific Research (CNRS), D.L. Schwarz, The V.R. Schwartz Research Fellow Chair, L. Steinberg, J.N. Halpern, A. Edelheit, and by grants funded by the European Research Council, a Marie Curie Integration grant, the German-Israeli Foundation for Scientific Research and Development, the Israel Science Foundation, the Helmholtz Foundation, and the European Foundation for the Study of Diabetes. E.E. is a senior fellow, Canadian Institute of Advanced Research (CIFAR) and an international scholar, Howard Hughes Medical Institute (HHMI). T.T. H.S. and E.E. conceived the study; designed, performed, and interpreted the experiments; and wrote the manuscript. U.M. headed and performed all computational analyses and pipeline development and equally contributed to the study. S.P.N. H.S. and K.R. independently reproduced key experiments of the study. T.L. L.K.A. Y.C. and H.M. performed bioinformatics and statistical analysis. S.B. A.L. E.Y.P. S.F. C.K. C.M. Y.K. M.D.-B. C.A.T. T.Y. X.Z. and H.S. helped with experiments. H.M. and E.M. performed smFISH. P.A.K. A.H. N.G. S.I. and K.H. provided essential tools and insights. E.E. is a consultant to DayTwo and BiomX. None of the topics related to this work involve these or other commercial entities. None of the other authors have any financial or non-financial competing interest. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = sep,
day = "17",
doi = "10.1016/j.cell.2020.08.027",
language = "English",
volume = "182",
pages = "1441--1459.e21",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",
}