A Multi-Target Approach to Colitis: Ergothioneine Promotes Recovery by Restoring the Intestinal Barrier, Reducing Inflammation, and Remodeling the Microbiota.

Ergothioneine (EGT) is a naturally occurring sulfur-containing histidine derivative with antioxidant and anti-inflammatory properties. However, its protective role and potential mechanisms in intestinal inflammation remain insufficiently understood. The impact of EGT on colitis was assessed in the present study using two experimental systems: an LPS-induced inflammatory model in Caco-2 cells and a DSS-induced colitis model in mice. In vitro, Caco-2 cells were treated with LPS and different concentrations of EGT, followed by assessment of inflammatory cytokines and tight junction-related markers using ELISA, qRT-PCR, and immunofluorescence staining. In vivo, DSS-induced colitis mice received low-, medium-, or high-dose EGT, and disease activity, colon histopathology, serum inflammatory mediators, immunoglobulins, and gut microbiota composition were analyzed. EGT treatment attenuated LPS-induced inflammatory responses in Caco-2 cells and partially restored the expression and distribution of tight junction proteins, including ZO-1, Occludin, and Claudin-1. In DSS-induced colitis mice, EGT alleviated body weight loss, reduced disease activity index scores, improved colon shortening and histological injury, and decreased serum levels of TNF-α, IL-6, IL-1β, IgM, and IgA. Moreover, EGT partially reversed DSS-induced gut microbiota dysbiosis. Notably, high-dose EGT was associated with the enrichment of Lachnospiraceae NK4A136 group and Enterorhabdus, suggesting that these taxa may contribute to EGT-mediated microbiota remodeling. Collectively, these findings indicate that EGT may alleviate experimental colitis through coordinated regulation of intestinal barrier integrity, inflammatory responses, and gut microbiota composition, supporting its potential as a functional food ingredient for intestinal inflammatory disorders.