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Intestinal symbiotic bacteria play a key role in the regulation of immune tolerance in inflammatory bowel disease (IBD) hosts. However, the bacterial strains directly involved in this regulation and their related metabolites are largely unknown. We sought to investigate the effects of intestinal microbial metabolites on intestinal epithelium and to elucidate their therapeutic potential in regulating intestinal mucosal inflammation and immune homeostasis. Here, we used metagenomic data from Crohn's disease (CD) patients to analyze the composition of intestinal flora and identify metabolite profiles associated with disease behavior, and used the mouse model of dextran sodium sulfate (DSS)-induced colitis to characterize the therapeutic effects of the flora metabolite acetyl l -carnitine (ALC) on DSS-induced colitis. We found that intraperitoneal injection of ALC treatment could significantly alleviate the symptoms of DSS-induced colitis in mice, including prevention of weight loss, reduction in disease activity index (DAI) scores, increasing of colonic length, reduction in histological scores, and improvement in intestinal barrier function. Further, transcriptome sequencing analysis and gene silencing experiments revealed that the absence of CADM2 abolished the inhibitory effect of ALC on the TLR-MyD88 pathway in colonic epithelial cells, thereby reducing the release of inflammatory factors in colon epithelial cells. And we confirmed a significant downregulation of CADM2 expression in intestinal tissues of CD patients compared to healthy people in a population cohort. In addition, we also found that ALC increased the ratio of Treg cells in colon, and decreased the ratio of Th17 cells and macrophages, thereby improving the immune tolerance of the organism. The proposed study could be a potential approach for the treatment of CD. [Display omitted] • ALC can alleviate the inflammatory level of colon epithelial by up-regulating CADM2. • CADM2 down-regulates the expression of MyD88 in colonic epithelial cells. • ALC can change the proportion of immune cells in colon LPMC. [ABSTRACT FROM AUTHOR]