D-serine alleviates colitis by regulating intestinal α1,2-fucosylation

Colitis is often accompanied with reduced intestinal α1,2-fucosylation. D-serine has been reported to prevent chronic colitis and upregulate the α1,2-fucosylation levels of intestinal epithelial cells in vitro. However, the role of D-serine in acute colitis and whether α1,2-fucosylation regulation is involved in the process remains unclear. In this study, D-serine alleviated body weight loss, colon shortening, and intestinal barrier damage in mice with acute colitis. Additionally, D-serine helped maintain gut microbiota balance by increasing the abundance of beneficial bacteria, including Bifidobacterium, and decreasing the harmful bacteria, such as Escherichia. Shigella. Furthermore, untargeted metabolomics showed that D-serine can modify the metabolism of cecal microbiota by decreasing concentrations of colitis-associated metabolites. Nevertheless, inhibiting α1,2-fucosylation impaired D-serine-mediated alleviation of colitis, highlighting the importance of α1,2-fucosylation upregulation in this process. D-serine significantly increased the trans-epithelial resistance of normal colonic epithelial cells, which was impaired by α1,2-fucosylation inhibition. Additionally, D-serine enhanced α1,2-fucosylation of macrophages (RAW264.7 cells) and reduced the secretion of tumor necrosis factor-α. The higher expression of the serine uptake gene Slc3a5 in type 3 innate lymphoid cells (ILC3s) suggested that D-serine may regulate intestinal α1,2-fucosylation by affecting IL-22 secretion of ILC3s. Taken together, our study showed that D-serine alleviates acute colitis by regulating α1,2-fucosylation of intestinal epithelial cells and macrophages. These findings suggest that regulating intestinal α1,2-fucosylation could be a potential strategy for the treatment of colitis.