Ana Mendes-Frias, Maria C Vieira, Marta Araújo, Cláudio Duarte-Oliveira, Simon Feys, Consuelo Micheli, Joana Gaifem, Luís Gafeira Gonçalves, Nuno S Osório, Adhemar Longatto-Filho, António Gil Castro, Egídio Torrado, Cristina Cunha, Agostinho Carvalho, Iola F Duarte, Nuno A Silva, Fernando Rodrigues, Ricardo Silvestre
{"title":"Branched-Chain Amino Acids Exacerbate Colitis Progression by Lowering Colonic Fumarate Levels.","authors":"Ana Mendes-Frias, Maria C Vieira, Marta Araújo, Cláudio Duarte-Oliveira, Simon Feys, Consuelo Micheli, Joana Gaifem, Luís Gafeira Gonçalves, Nuno S Osório, Adhemar Longatto-Filho, António Gil Castro, Egídio Torrado, Cristina Cunha, Agostinho Carvalho, Iola F Duarte, Nuno A Silva, Fernando Rodrigues, Ricardo Silvestre","doi":"10.1093/ibd/izaf125","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Ulcerative colitis (UC) is a gastrointestinal inflammatory condition with an unclear etiology. Recent findings suggest that metabolites play a pivotal role in promoting intestinal health. We have previously observed a significant enrichment in colonic branched-chain amino acids (BCAAs) in resistant mice to colitis suggesting the potential role of these metabolites in UC development.</p><p><strong>Methods: </strong>C57BL6/J mice underwent a 20-day BCAA supplementation regimen, followed by induction of colitis using dextran sulfate sodium (DSS). Disease activity index (DAI), immune cell profiling, and histological and transcriptomic analysis were evaluated. 16S rRNA sequencing and metabolomic profiling of stool extracts were performed. Additionally, mice were treated with dimethyl fumarate (DMF) post-supplementation to explore therapeutic interventions.</p><p><strong>Results: </strong>BCAA supplementation exacerbated colitis severity in mice, as evidenced by worsened DAI, increased histological damage, and significant alterations in immune cell populations, including decreased type 3 innate lymphoid cells and increased Th17 and regulatory T cells. Microbiota analysis showed a shift toward a decreased abundance of Lactobacillus spp. and an increase in pathobionts. Metabolomic profiling indicated significantly reduced colonic fumarate levels and increased pro-inflammatory metabolites. DMF treatment attenuated BCAA-induced pro-inflammatory phenotype, improved disease outcomes, and modulated the immune response in a microbiome-dependent manner.</p><p><strong>Conclusions: </strong>BCAA supplementation exacerbates DSS-induced colitis in mice. This effect is mediated by detrimental changes in gut microbiota composition and metabolome. DMF treatment shows promise to mitigate these adverse effects, suggesting potential therapeutic avenues to manage BCAA-induced colitis exacerbation and reinforcing the role of microbiome in UC. These findings underscore the caution needed with the use of BCAAs during inflammatory conditions.</p>","PeriodicalId":13623,"journal":{"name":"Inflammatory Bowel Diseases","volume":" ","pages":""},"PeriodicalIF":4.3000,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Inflammatory Bowel Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/ibd/izaf125","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Ulcerative colitis (UC) is a gastrointestinal inflammatory condition with an unclear etiology. Recent findings suggest that metabolites play a pivotal role in promoting intestinal health. We have previously observed a significant enrichment in colonic branched-chain amino acids (BCAAs) in resistant mice to colitis suggesting the potential role of these metabolites in UC development.
Methods: C57BL6/J mice underwent a 20-day BCAA supplementation regimen, followed by induction of colitis using dextran sulfate sodium (DSS). Disease activity index (DAI), immune cell profiling, and histological and transcriptomic analysis were evaluated. 16S rRNA sequencing and metabolomic profiling of stool extracts were performed. Additionally, mice were treated with dimethyl fumarate (DMF) post-supplementation to explore therapeutic interventions.
Results: BCAA supplementation exacerbated colitis severity in mice, as evidenced by worsened DAI, increased histological damage, and significant alterations in immune cell populations, including decreased type 3 innate lymphoid cells and increased Th17 and regulatory T cells. Microbiota analysis showed a shift toward a decreased abundance of Lactobacillus spp. and an increase in pathobionts. Metabolomic profiling indicated significantly reduced colonic fumarate levels and increased pro-inflammatory metabolites. DMF treatment attenuated BCAA-induced pro-inflammatory phenotype, improved disease outcomes, and modulated the immune response in a microbiome-dependent manner.
Conclusions: BCAA supplementation exacerbates DSS-induced colitis in mice. This effect is mediated by detrimental changes in gut microbiota composition and metabolome. DMF treatment shows promise to mitigate these adverse effects, suggesting potential therapeutic avenues to manage BCAA-induced colitis exacerbation and reinforcing the role of microbiome in UC. These findings underscore the caution needed with the use of BCAAs during inflammatory conditions.
期刊介绍：
Inflammatory Bowel Diseases® supports the mission of the Crohn''s & Colitis Foundation by bringing the most impactful and cutting edge clinical topics and research findings related to inflammatory bowel diseases to clinicians and researchers working in IBD and related fields. The Journal is committed to publishing on innovative topics that influence the future of clinical care, treatment, and research.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
