The Crohn's disease polymorphism, ATG16L1 T300A, alters the gut microbiota and enhances the local Th1/Th17 response.

Autor:	Lavoie S; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, United States.; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, United States., Conway KL; Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, United States., Lassen KG; Broad Institute of Harvard and MIT, Cambridge, United States.; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, United States., Jijon HB; Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, United States., Pan H; Joslin Diabetes Center, Boston, United States., Chun E; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, United States.; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, United States., Michaud M; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, United States.; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, United States., Lang JK; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, United States.; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, United States., Gallini Comeau CA; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, United States.; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, United States., Dreyfuss JM; Joslin Diabetes Center, Boston, United States., Glickman JN; Department of Pathology, Harvard Medical School, Boston, United States.; Beth Israel Deaconess Medical Center, Boston, United States., Vlamakis H; Broad Institute of Harvard and MIT, Cambridge, United States., Ananthakrishnan A; Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, United States., Kostic A; Joslin Diabetes Center, Boston, United States.; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States., Garrett WS; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, United States.; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, United States.; Broad Institute of Harvard and MIT, Cambridge, United States.; Department and Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, United States., Xavier RJ; Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, United States.; Broad Institute of Harvard and MIT, Cambridge, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2019 Jan 22; Vol. 8. Date of Electronic Publication: 2019 Jan 22.
DOI:	10.7554/eLife.39982
Abstrakt:	Inflammatory bowel disease (IBD) is driven by dysfunction between host genetics, the microbiota, and immune system. Knowledge gaps remain regarding how IBD genetic risk loci drive gut microbiota changes. The Crohn's disease risk allele ATG16L1 T300A results in abnormal Paneth cells due to decreased selective autophagy, increased cytokine release, and decreased intracellular bacterial clearance. To unravel the effects of ATG16L1 T300A on the microbiota and immune system, we employed a gnotobiotic model using human fecal transfers into ATG16L1 T300A knock-in mice. We observed increases in Bacteroides ovatus and Th1 and Th17 cells in ATG16L1 T300A mice. Association of altered Schaedler flora mice with B. ovatus specifically increased Th17 cells selectively in ATG16L1 T300A knock-in mice. Changes occur before disease onset, suggesting that ATG16L1 T300A contributes to dysbiosis and immune infiltration prior to disease symptoms. Our work provides insight for future studies on IBD subtypes, IBD patient treatment and diagnostics. Competing Interests: SL, KC, KL, HJ, HP, EC, MM, JL, CG, JD, JG, HV, AA, AK, RX No competing interests declared, WG Senior editor, eLife (© 2019, Lavoie et al.)
Databáze:	MEDLINE
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