Branched-Chain Amino Acids Exacerbate Colitis Progression by Lowering Colonic Fumarate Levels.

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.