NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease

Hazel Tye, Chien Hsiung Yu, Lisa A. Simms, Marcel R. de Zoete, Man Lyang Kim, Martha Zakrzewski, Jocelyn S. Penington, Cassandra R. Harapas, Fernando Souza-Fonseca-Guimaraes, Leesa F. Wockner, Adele Preaudet, Lisa A. Mielke, Stephen A. Wilcox, Yasunori Ogura, Sinead C. Corr, Komal Kanojia, Konstantinos A. Kouremenos, David P. De Souza, Malcolm J. McConville, Richard A. Flavell & 6 others Motti Gerlic, Benjamin T. Kile, Anthony T. Papenfuss, Tracy L. Putoczki, Graham L. Radford-Smith, Seth L. Masters

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article number3728
Number of pages11
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 13 Sep 2018

Keywords

  • antimicrobial responses
  • inflammasome
  • interleukins
  • NOD-like receptors

Cite this

Tye, H., Yu, C. H., Simms, L. A., de Zoete, M. R., Kim, M. L., Zakrzewski, M., ... Masters, S. L. (2018). NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease. Nature Communications, 9(1), [3728]. https://doi.org/10.1038/s41467-018-06125-0
Tye, Hazel ; Yu, Chien Hsiung ; Simms, Lisa A. ; de Zoete, Marcel R. ; Kim, Man Lyang ; Zakrzewski, Martha ; Penington, Jocelyn S. ; Harapas, Cassandra R. ; Souza-Fonseca-Guimaraes, Fernando ; Wockner, Leesa F. ; Preaudet, Adele ; Mielke, Lisa A. ; Wilcox, Stephen A. ; Ogura, Yasunori ; Corr, Sinead C. ; Kanojia, Komal ; Kouremenos, Konstantinos A. ; De Souza, David P. ; McConville, Malcolm J. ; Flavell, Richard A. ; Gerlic, Motti ; Kile, Benjamin T. ; Papenfuss, Anthony T. ; Putoczki, Tracy L. ; Radford-Smith, Graham L. ; Masters, Seth L. / NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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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.",
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Tye, H, Yu, CH, Simms, LA, de Zoete, MR, Kim, ML, Zakrzewski, M, Penington, JS, Harapas, CR, Souza-Fonseca-Guimaraes, F, Wockner, LF, Preaudet, A, Mielke, LA, Wilcox, SA, Ogura, Y, Corr, SC, Kanojia, K, Kouremenos, KA, De Souza, DP, McConville, MJ, Flavell, RA, Gerlic, M, Kile, BT, Papenfuss, AT, Putoczki, TL, Radford-Smith, GL & Masters, SL 2018, 'NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease' Nature Communications, vol. 9, no. 1, 3728. https://doi.org/10.1038/s41467-018-06125-0

NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease. / Tye, Hazel; Yu, Chien Hsiung; Simms, Lisa A.; de Zoete, Marcel R.; Kim, Man Lyang; Zakrzewski, Martha; Penington, Jocelyn S.; Harapas, Cassandra R.; Souza-Fonseca-Guimaraes, Fernando; Wockner, Leesa F.; Preaudet, Adele; Mielke, Lisa A.; Wilcox, Stephen A.; Ogura, Yasunori; Corr, Sinead C.; Kanojia, Komal; Kouremenos, Konstantinos A.; De Souza, David P.; McConville, Malcolm J.; Flavell, Richard A.; Gerlic, Motti; Kile, Benjamin T.; Papenfuss, Anthony T.; Putoczki, Tracy L.; Radford-Smith, Graham L.; Masters, Seth L.

In: Nature Communications, Vol. 9, No. 1, 3728, 13.09.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease

AU - Tye, Hazel

AU - Yu, Chien Hsiung

AU - Simms, Lisa A.

AU - de Zoete, Marcel R.

AU - Kim, Man Lyang

AU - Zakrzewski, Martha

AU - Penington, Jocelyn S.

AU - Harapas, Cassandra R.

AU - Souza-Fonseca-Guimaraes, Fernando

AU - Wockner, Leesa F.

AU - Preaudet, Adele

AU - Mielke, Lisa A.

AU - Wilcox, Stephen A.

AU - Ogura, Yasunori

AU - Corr, Sinead C.

AU - Kanojia, Komal

AU - Kouremenos, Konstantinos A.

AU - De Souza, David P.

AU - McConville, Malcolm J.

AU - Flavell, Richard A.

AU - Gerlic, Motti

AU - Kile, Benjamin T.

AU - Papenfuss, Anthony T.

AU - Putoczki, Tracy L.

AU - Radford-Smith, Graham L.

AU - Masters, Seth L.

PY - 2018/9/13

Y1 - 2018/9/13

N2 - 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.

AB - 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.

KW - antimicrobial responses

KW - inflammasome

KW - interleukins

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