Multiomics Analysis Reveals the Therapeutic Effect of GRAS Yeast-Derived 2'-Fucosyllactose in DSS-Induced Colitis

Ulcerative colitis (UC) is a complex, multifactorial inflammatory disease, in which the gut microbiota is believed to play a pivotal role in its pathogenesis. 2'-Fucosyllactose (2'-FL), a naturally occurring human milk oligosaccharide, possesses prebiotic, immunomodulatory, and microbiota-regulating properties. This study aimed to investigate the protective effects and underlying mechanisms of 2'-FL in a dextran sulfate sodium (DSS)-induced acute colitis mouse model using a multiomics integrative approach. 2'-FL administration significantly alleviated colitis symptoms, improved intestinal barrier function, and reduced the expression of pro-inflammatory cytokines. Transcriptomic analysis revealed that 2'-FL markedly suppressed the PI3K-Akt signaling pathway, as evidenced by gene set enrichment analysis and decreased protein levels of PI3K and Akt. Metabolomic profiling identified several upregulated beneficial metabolites, including alpha-tocopherolquinone, 3-methyladenine, and pentadecanoylcarnitine, which showed strong positive correlations with anti-inflammatory markers and inverse associations with inflammatory mediators. Additionally, 2'-FL significantly restored gut microbial diversity and mitigated the dysbiosis induced by DSS. These results support the therapeutic potential of 2'-FL as a viable prebiotic intervention for UC and demonstrate the power of multiomics integration in elucidating complex host -microbe interactions in inflammatory diseases.