期刊
NATURE IMMUNOLOGY
卷 18, 期 5, 页码 541-551出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.3690
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- US National Institute of Health (National Cancer Institute) [RO1-CA156330]
- US National Institute of Health (National Institute of Diabetes and Digestive and Kidney Diseases) [P01 DK094779, P30 DK034987, F32-DK088417-01, F32-DK098916]
- US National Institute of Health (National Institute of Allergy and Infectious Disease) [U19-AI067798, R37 AI029564, U19 AI090871]
- US National Institute of Health (Office of the Director) [P40 OD010995]
- American Cancer Society [PF-13-401-01-TBE]
- Crohn's and Colitis Foundation of America
- National Multiple Sclerosis Society [FG 1968-A-1]
Inflammatory bowel diseases involve the dynamic interaction of host genetics, the microbiome and inflammatory responses. Here we found lower expression of NLRP12 (which encodes a negative regulator of innate immunity) in human ulcerative colitis, by comparing monozygotic twins and other patient cohorts. In parallel, Nlrp12 deficiency in mice caused increased basal colonic inflammation, which led to a less-diverse microbiome and loss of protective gut commensal strains (of the family Lachnospiraceae) and a greater abundance of colitogenic strains (of the family Erysipelotrichaceae). Dysbiosis and susceptibility to colitis associated with Nlrp12 deficency were reversed equally by treatment with antibodies targeting inflammatory cytokines and by the administration of beneficial commensal Lachnospiraceae isolates. Fecal transplants from mice reared in specific-pathogen-free conditions into germ-free Nlrp12-deficient mice showed that NLRP12 and the microbiome each contributed to immunological signaling that culminated in colon inflammation. These findings reveal a feed-forward loop in which NLRP12 promotes specific commensals that can reverse gut inflammation, while cytokine blockade during NLRP12 deficiency can reverse dysbiosis.
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