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Nat Commun. 2018 Sep 13;9(1):3728. doi: 10.1038/s41467-018-06125-0.

NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease.

Author information

1
Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
2
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
3
Gut Health, QIMR Berghofer Medical Research Institute, Brisbane, 4029, QLD, Australia.
4
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06519, USA.
5
Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, 3584 CL, The Netherlands.
6
Medical Genomics, QIMR Berghofer Medical Research Institute, Brisbane, 4029, QLD, Australia.
7
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
8
Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
9
Statistics Division, QIMR Berghofer Medical Research Institute, Brisbane, 4029, QLD, Australia.
10
Olivia Newton-John Cancer Research Institute, School of Cancer Medicine, La Trobe University, Heidelberg, VIC, 3084, Australia.
11
Systems Biology and Personalized Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
12
Department of Food Science and Nutrition, Nara Women's University, Nara, 6308506, Japan.
13
Department of Microbiology, The Moyne Institute of Preventative Medicine, School of Genetics and Microbiology, Trinity College Dublin, Dublin 2, Ireland.
14
Metabolomics Australia, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, VIC, 3010, Australia.
15
Department of Biochemistry and Molecular Biology, Parkville, VIC, 3010, Australia.
16
Howard Hughes Medical Institute, Yale University, New Haven, CT, 06510, USA.
17
Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
18
ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
19
Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, 3800, VIC, Australia.
20
Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, 3010, Australia.
21
Bioinformatics and Cancer Genomics Lab, Peter MacCallum Cancer Centre, Melbourne, VIC, 3002, Australia.
22
Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, 4029, QLD, Australia.
23
University of Queensland School of Medicine, Brisbane, 4029, QLD, Australia.
24
Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. masters@wehi.edu.au.
25
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia. masters@wehi.edu.au.

Abstract

Anti-microbial signaling pathways are normally triggered by innate immune receptors when detecting pathogenic microbes to provide protective immunity. Here we show that the inflammasome sensor Nlrp1 aggravates DSS-induced experimental mouse colitis by limiting beneficial, butyrate-producing Clostridiales in the gut. The colitis-protective effects of Nlrp1 deficiency are thus reversed by vancomycin treatment, but recapitulated with butyrate supplementation in wild-type mice. Moreover, an activating mutation in Nlrp1a increases IL-18 and IFNγ production, and decreases colonic butyrate to exacerbate colitis. We also show that, in patients with ulcerative colitis, increased NLRP1 in inflamed regions of the colon is associated with increased IFN-γ. In this context, NLRP1, IL-18 or IFN-γ expression negatively correlates with the abundance of Clostridiales in human rectal mucosal biopsies. Our data identify the NLRP1 inflammasome to be a key negative regulator of protective, butyrate-producing commensals, which therefore promotes inflammatory bowel disease.

PMID:
30214011
PMCID:
PMC6137172
DOI:
10.1038/s41467-018-06125-0
[Indexed for MEDLINE]
Free PMC Article

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