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; Motti Gerlic; Benjamin T Kile; Anthony T Papenfuss; Tracy L Putoczki; Graham L Radford-Smith; Seth L Masters

doi:10.1038/s41467-018-06125-0

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 FlavellMotti Gerlic, Benjamin T Kile, Anthony T Papenfuss, Tracy L Putoczki, Graham L Radford-Smith, Seth L Masters

Research output: Contribution to journal › Article › Academic › peer-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 language	English
Article number	3728
Pages (from-to)	3728
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06125-0
Publication status	Published - 1 Dec 2018
Externally published	Yes

Keywords

Adaptor Proteins, Signal Transducing/genetics
Animals
Apoptosis Regulatory Proteins/genetics
Butyrates/metabolism
Clostridiales
Colitis/metabolism
Colon/pathology
Female
Gastrointestinal Microbiome
Gene Deletion
Humans
Inflammasomes
Inflammatory Bowel Diseases/drug therapy
Interferon-gamma/metabolism
Interleukin-18/metabolism
Intestinal Mucosa/metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Rectum/metabolism
Signal Transduction
T-Lymphocytes/cytology
Vancomycin/pharmacology

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10.1038/s41467-018-06125-0

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Tye, H., Yu, C.-H., Simms, L. A., de Zoete, M. R., Kim, M. L., Zakrzewski, M., Penington, J. S., Harapas, C. R., Souza-Fonseca-Guimaraes, F., Wockner, L. F., Preaudet, A., Mielke, L. A., Wilcox, S. A., Ogura, Y., Corr, S. C., Kanojia, K., Kouremenos, K. A., De Souza, D. P., McConville, M. J., ... Masters, S. L. (2018). NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease. Nature Communications, 9(1), 3728. Article 3728. https://doi.org/10.1038/s41467-018-06125-0

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title = "NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease",

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.",

keywords = "Adaptor Proteins, Signal Transducing/genetics, Animals, Apoptosis Regulatory Proteins/genetics, Butyrates/metabolism, Clostridiales, Colitis/metabolism, Colon/pathology, Female, Gastrointestinal Microbiome, Gene Deletion, Humans, Inflammasomes, Inflammatory Bowel Diseases/drug therapy, Interferon-gamma/metabolism, Interleukin-18/metabolism, Intestinal Mucosa/metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Rectum/metabolism, Signal Transduction, T-Lymphocytes/cytology, Vancomycin/pharmacology",

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

year = "2018",

month = dec,

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doi = "10.1038/s41467-018-06125-0",

language = "English",

volume = "9",

pages = "3728",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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Tye, H, Yu, C-H, 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, pp. 3728. https://doi.org/10.1038/s41467-018-06125-0

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 - 2018/12/1

Y1 - 2018/12/1

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 - Adaptor Proteins, Signal Transducing/genetics

KW - Animals

KW - Apoptosis Regulatory Proteins/genetics

KW - Butyrates/metabolism

KW - Clostridiales

KW - Colitis/metabolism

KW - Colon/pathology

KW - Female

KW - Gastrointestinal Microbiome

KW - Gene Deletion

KW - Humans

KW - Inflammasomes

KW - Inflammatory Bowel Diseases/drug therapy

KW - Interferon-gamma/metabolism

KW - Interleukin-18/metabolism

KW - Intestinal Mucosa/metabolism

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Rectum/metabolism

KW - Signal Transduction

KW - T-Lymphocytes/cytology

KW - Vancomycin/pharmacology

UR - https://www.scopus.com/pages/publications/85053325072

U2 - 10.1038/s41467-018-06125-0

DO - 10.1038/s41467-018-06125-0

M3 - Article

C2 - 30214011

SN - 2041-1723

VL - 9

SP - 3728

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3728

ER -

NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease

Abstract

Keywords

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