Human-associated gut bacterial dysbiosis affects the anti-colitic activity of 3-DF and 3-HF

Dysbiosis, defined as an imbalance in the gut microbiota, disrupts the gut barrier and impairs host immune and metabolic responses, playing a critical role in the pathogenesis of inflammatory bowel disease (IBD). Dietary flavonoids have been explored as safer alternatives to conventional drugs, showing efficacy in alleviating inflammation and restoring barrier integrity in colitis models. However, whether their anti-colitic activity is preserved under human microbial dysbiosis remains unclear. Here, we investigated the impact of ulcerative colitis (UC)-associated microbiota on the efficacy of 3-deoxyflavonoids (3-DFs) and 3-hydroxyflavonoids (3-HFs), using a humanized interleukin (IL)-10^-/^- mouse model. Four near-isogenic lines (NILs) of corn, Lines A (lacking 3-DF or 3-HF), B (expressing only 3-DF), C (expressing only 3-HF), and D (expressing both 3-DF + 3-HF), were incorporated into experimental diets, alongside a purified control. Mice were colonized with fecal microbiota from UC patients and fed the respective diets. The effects of flavonoid-rich diets on distal colon inflammatory markers, tight-junction expression, and disease activity varied according to the microbial composition of the three UC donors. Higher concentrations of gut metabolites, including short-chain fatty acids (SCFAs) and bile acids, were associated with reduced inflammation and enhanced barrier function. Overall, the composition of dysbiotic human microbiota influenced the anti-colitic activity of dietary flavonoids. When protective effects were observed, diets containing 3-HF were more effective than those with only 3-DF. These findings highlight the need to account for individual microbial profiles when designing flavonoid-based dietary interventions for IBD.