Cargando…

Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease

Host-microbial cross-talk plays a crucial role in maintenance of gut homeostasis. However, how microbiota-derived metabolites, e.g., butyrate, regulate functions of neutrophils in the pathogenesis of inflammatory bowel disease (IBD) remains elusive. We sought to investigate the effects of butyrate o...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Gengfeng, Lin, Jian, Zhang, Cui, Gao, Han, Lu, Huiying, Gao, Xiang, Zhu, Ruixin, Li, Zhitao, Li, Mingsong, Liu, Zhanju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437544/
https://www.ncbi.nlm.nih.gov/pubmed/34494943
http://dx.doi.org/10.1080/19490976.2021.1968257
_version_ 1783752179240140800
author Li, Gengfeng
Lin, Jian
Zhang, Cui
Gao, Han
Lu, Huiying
Gao, Xiang
Zhu, Ruixin
Li, Zhitao
Li, Mingsong
Liu, Zhanju
author_facet Li, Gengfeng
Lin, Jian
Zhang, Cui
Gao, Han
Lu, Huiying
Gao, Xiang
Zhu, Ruixin
Li, Zhitao
Li, Mingsong
Liu, Zhanju
author_sort Li, Gengfeng
collection PubMed
description Host-microbial cross-talk plays a crucial role in maintenance of gut homeostasis. However, how microbiota-derived metabolites, e.g., butyrate, regulate functions of neutrophils in the pathogenesis of inflammatory bowel disease (IBD) remains elusive. We sought to investigate the effects of butyrate on IBD neutrophils and elucidate the therapeutic potential in regulating mucosal inflammation. Peripheral neutrophils were isolated from IBD patients and healthy donors, and profiles of proinflammatory cytokines and chemokines were determined by qRT-PCR and ELISA, respectively. The migration and release of neutrophil extracellular traps (NETs) were studied by a Transwell model and immunofluorescence, respectively. The in vivo role of butyrate in regulating IBD neutrophils was evaluated in a DSS-induced colitis model in mice. We found that butyrate significantly inhibited IBD neutrophils to produce proinflammatory cytokines, chemokines, and calprotectins. Blockade of GPCR signaling with pertussis toxin (PTX) did not interfere the effects whereas pan-histone deacetylase (HDAC) inhibitor, trichostatin A (TSA) effectively mimicked the role of butyrate. Furthermore, in vitro studies confirmed that butyrate suppressed neutrophil migration and formation of NETs from both CD and UC patients. RNA sequencing analysis revealed that the immunomodulatory effects of butyrate on IBD neutrophils were involved in leukocyte activation, regulation of innate immune response and response to oxidative stress. Consistently, oral administration of butyrate markedly ameliorated mucosal inflammation in DSS-induced murine colitis through inhibition of neutrophil-associated immune responses such as proinflammatory mediators and NET formation. Our data thus reveal that butyrate constrains neutrophil functions and may serve as a novel therapeutic potential in the treatment of IBD.
format Online
Article
Text
id pubmed-8437544
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Taylor & Francis
record_format MEDLINE/PubMed
spelling pubmed-84375442021-09-14 Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease Li, Gengfeng Lin, Jian Zhang, Cui Gao, Han Lu, Huiying Gao, Xiang Zhu, Ruixin Li, Zhitao Li, Mingsong Liu, Zhanju Gut Microbes Research Paper Host-microbial cross-talk plays a crucial role in maintenance of gut homeostasis. However, how microbiota-derived metabolites, e.g., butyrate, regulate functions of neutrophils in the pathogenesis of inflammatory bowel disease (IBD) remains elusive. We sought to investigate the effects of butyrate on IBD neutrophils and elucidate the therapeutic potential in regulating mucosal inflammation. Peripheral neutrophils were isolated from IBD patients and healthy donors, and profiles of proinflammatory cytokines and chemokines were determined by qRT-PCR and ELISA, respectively. The migration and release of neutrophil extracellular traps (NETs) were studied by a Transwell model and immunofluorescence, respectively. The in vivo role of butyrate in regulating IBD neutrophils was evaluated in a DSS-induced colitis model in mice. We found that butyrate significantly inhibited IBD neutrophils to produce proinflammatory cytokines, chemokines, and calprotectins. Blockade of GPCR signaling with pertussis toxin (PTX) did not interfere the effects whereas pan-histone deacetylase (HDAC) inhibitor, trichostatin A (TSA) effectively mimicked the role of butyrate. Furthermore, in vitro studies confirmed that butyrate suppressed neutrophil migration and formation of NETs from both CD and UC patients. RNA sequencing analysis revealed that the immunomodulatory effects of butyrate on IBD neutrophils were involved in leukocyte activation, regulation of innate immune response and response to oxidative stress. Consistently, oral administration of butyrate markedly ameliorated mucosal inflammation in DSS-induced murine colitis through inhibition of neutrophil-associated immune responses such as proinflammatory mediators and NET formation. Our data thus reveal that butyrate constrains neutrophil functions and may serve as a novel therapeutic potential in the treatment of IBD. Taylor & Francis 2021-09-08 /pmc/articles/PMC8437544/ /pubmed/34494943 http://dx.doi.org/10.1080/19490976.2021.1968257 Text en © 2021 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Paper
Li, Gengfeng
Lin, Jian
Zhang, Cui
Gao, Han
Lu, Huiying
Gao, Xiang
Zhu, Ruixin
Li, Zhitao
Li, Mingsong
Liu, Zhanju
Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease
title Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease
title_full Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease
title_fullStr Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease
title_full_unstemmed Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease
title_short Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease
title_sort microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437544/
https://www.ncbi.nlm.nih.gov/pubmed/34494943
http://dx.doi.org/10.1080/19490976.2021.1968257
work_keys_str_mv AT ligengfeng microbiotametabolitebutyrateconstrainsneutrophilfunctionsandamelioratesmucosalinflammationininflammatoryboweldisease
AT linjian microbiotametabolitebutyrateconstrainsneutrophilfunctionsandamelioratesmucosalinflammationininflammatoryboweldisease
AT zhangcui microbiotametabolitebutyrateconstrainsneutrophilfunctionsandamelioratesmucosalinflammationininflammatoryboweldisease
AT gaohan microbiotametabolitebutyrateconstrainsneutrophilfunctionsandamelioratesmucosalinflammationininflammatoryboweldisease
AT luhuiying microbiotametabolitebutyrateconstrainsneutrophilfunctionsandamelioratesmucosalinflammationininflammatoryboweldisease
AT gaoxiang microbiotametabolitebutyrateconstrainsneutrophilfunctionsandamelioratesmucosalinflammationininflammatoryboweldisease
AT zhuruixin microbiotametabolitebutyrateconstrainsneutrophilfunctionsandamelioratesmucosalinflammationininflammatoryboweldisease
AT lizhitao microbiotametabolitebutyrateconstrainsneutrophilfunctionsandamelioratesmucosalinflammationininflammatoryboweldisease
AT limingsong microbiotametabolitebutyrateconstrainsneutrophilfunctionsandamelioratesmucosalinflammationininflammatoryboweldisease
AT liuzhanju microbiotametabolitebutyrateconstrainsneutrophilfunctionsandamelioratesmucosalinflammationininflammatoryboweldisease