Self-assembled Lentinus edodes ergosterol-amyloid fiber hydrogel for zebrafish enteritis mitigation: Role of intestinal flora regulation and metabolomic remodeling.

Abstract

Inflammatory bowel disease (IBD) necessitates the development of effective and safe therapeutic strategies derived from food sources. Ergosterol from Lentinus edodes (Shiitake) exhibits anti-colitic properties but is limited by its poor bioavailability. To address this, we engineered a novel self-assembled hydrogel (LEE-AFH) using Lentinus edodes ergosterol (LEE) and food-protein-derived amyloid fibrils (AF) as a colon-targeted delivery system. The LEE-AFH demonstrated enhanced stability and a controlled release profile for ergosterol in vitro. In a zebrafish model of dextran sulfate sodium (DSS)-induced colitis, LEE-AFH demonstrated superior efficacy over free ergosterol in alleviating intestinal damage, oxidative stress, and inflammation. The protective effect was mediated through the inhibition of the MyD88/TRAF6/NF-κB signaling pathway. Multi-omics analyses revealed that LEE-AFH administration resulted in a remarkable restoration of gut microbial homeostasis, characterized by the suppression of pro-inflammatory genera (e.g., Vibrio, Pseudomonas) and the enrichment of beneficial bacteria (e.g., Akkermansia, Gilliamella). Concurrently, host metabolism was reprogrammed, with significant regulation in key pathways, including one‑carbon pool by folate, arginine biosynthesis, and steroid biosynthesis. Correlation analysis further elucidated a tight microbiota-metabolite network underlying the therapeutic effects. These findings position LEE-AFH as a potent food-grade hydrogel platform for mitigating colitis, primarily through orchestrating the gut microbiota-metabolite axis, and offer novel insights into the application of food structure design for advanced nutritional interventions against IBD.