Role of microbial dysbiosis on the anti-colitic activity of 3-deoxyflavonoids and 3-hydroxyflavonoids

Gut microbiota dysbiosis is a hallmark of inflammatory disorders such as ulcerative colitis (UC). Flavonoids, recognized for their anti-inflammatory and microbiota-modulatory properties, offer a safer alternative to conventional drugs. While gut microbiota play a critical role in flavonoid efficacy, most studies rely on murine-native microbiota, limiting insights into interactions with human-associated microbiota. This dissertation addresses this gap by investigating how human microbiota influence the anti-colitic effects of 3-deoxyflavonoids (3-DF) and 3-hydroxyflavonoids (3-HF).

In the first study, germ-free IL-10−/− mice were colonized with microbiota from healthy human donors and supplemented with diets enriched in 3-DF, 3-HF, or both. While pooling the data from different donors for each diet showed no significant effects on inflammatory markers or microbial diversity. Anthocyanin-containing diets (3-HF) improved gut barrier function. Importantly, 3-HF effects varied by donor microbiota, with significant benefits in specific recipients.

The second study used UC-associated microbiota to colonize mice. Flavonoids either ameliorated or aggravated colitis symptoms depending on the microbiota composition. Improvements in gut barrier function and inflammation positively correlated with short-chain fatty acid and bile acid levels.

In the third study, fecal supernatants (FS) were evaluated in vitro. FS from healthy microbiota attenuated NF-κB activation and maintained barrier integrity, while FS from UC-associated microbiota exacerbated inflammation and permeability. Temporal analysis revealed constrained modulation of dysbiotic microbiota compared to healthy microbiota.

These findings underscore the pivotal role of microbiota composition and health status in flavonoid activity. They lay the foundation for personalized dietary interventions targeting inflammation based on individual microbiota profiles.