NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth

Liang Chen, Justin E. Wilson, Mark J. Koenigsknecht, Wei Chun Chou, Stephanie A. Montgomery, Agnieszka D. Truax, W. June Brickey, Christopher D. Packey, Nitsan Maharshak, Glenn K. Matsushima, Scott E. Plevy, Vincent B. Young, R. Balfour Sartor, Jenny P.Y. Ting*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

206 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)541-551
Number of pages11
JournalNature Immunology
Volume18
Issue number5
DOIs
StatePublished - 18 Apr 2017

Funding

FundersFunder number
US National Institute of Health
National Institutes of HealthRO1-CA156330, F32-DK098916, P30 DK034987, U19 AI090871, F32-DK088417-01, P01 DK094779, U19-AI067798
National Institutes of Health
American Cancer SocietyPF-13-401-01-TBE
American Cancer Society
National Institute of Allergy and Infectious DiseasesR37AI029564, P40 OD010995
National Institute of Allergy and Infectious Diseases
National Multiple Sclerosis SocietyFG 1968-A-1
National Multiple Sclerosis Society
Crohn's and Colitis Foundation of America

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