Inadequate Zinc Intake in Adolescents Aggravates Inflammatory Bowel Disease by Inhibiting Antibody Class Switch Recombination in Mucosal B Cells Through Intestinal Microbial‐Derived KMV

Zinc homeostatic imbalance in adolescents is associated with inflammatory bowel disease (IBD), but mechanisms underlying how inadequate zinc intake (IZI) regulates IBD remained incompletely understood. Here, we report that integrated multi‐omics with LiP‐SMap‐guided metabolite docking were performed to identify Hmces and 3‐methyl‐2‐oxovaleric acid (KMV) as a hub gene and metabolite, which were further verified in the UK Biobank and RCT study. In vivo and in vitro studies showed IZI caused KMV accumulation by impairing the ability of gut microbiota to degrade isoleucine. KMV reduced Hmces expression in mucosal‐activated B‐cells by depleting Sacm1L through direct binding modification effects. Decreased Sacm1L induced endoplasmic reticulum (ER) stress and further decreased p‐ATM and CTIP levels at the DNA damage site with inhibition of Hmces recruitment. This biological mechanism inhibits class switch recombination (CSR) from IgM to IgA, IgG in mucosal B‐cells, which makes adherent‐invasive Escherichia coli (AIEC) colonize the intestinal tract more easily and contributes to colitis development. Human studies showed Hmces expression among IBD patients decreased 7.5% and 13.7% in blood and intestinal tissue. Zinc supplementation decreased serum KMV and lipopolysaccharide levels, and reduced IBD risk. IZI impairs the ability of gut microbiota to degrade isoleucine, inducing KMV accumulation and inhibiting CSR in mucosal activated B‐cells via down‐regulating p‐ATM‐CTIP‐Hmces pathway, thus promoting AIEC colonization.