Multiomics reveals microbial metabolites as key actors in intestinal fibrosis in Crohn's disease

Intestinal fibrosis is the primary cause of disability in patients with Crohn's disease (CD), yet effective therapeutic strategies are currently lacking. Here, we report a multiomics analysis of gut microbiota and fecal/blood metabolites of 278 CD patients and 28 healthy controls, identifying characteristic alterations in gut microbiota (e.g., Lachnospiraceae, Ruminococcaceae, Muribaculaceae, Saccharimonadales) and metabolites (e.g., L-aspartic acid, glutamine, ethylmethylacetic acid) in moderate-severe intestinal fibrosis. By integrating multiomics data with magnetic resonance enterography features, putative links between microbial metabolites and intestinal fibrosis-associated morphological alterations were established. These potential associations were mediated by specific combinations of amino acids (e.g., L-aspartic acid), primary bile acids, and glutamine. Finally, we provided causal evidence that L-aspartic acid aggravated intestinal fibrosis both in vitro and in vivo. Overall, we offer a biologically plausible explanation for the hypothesis that gut microbiota and its metabolites promote intestinal fibrosis in CD while also identifying potential targets for therapeutic trials. The gut microbiota and its functional metabolites play crucial roles in the development of intestinal fibrosis in patients with Crohn's disease (CD).The severity of intestinal fibrosis was associated with alterations in the gut microbiota (e.g., ) and the fecal and blood metabolites (e.g., -aspartic acid).Specific microbes and their metabolites were associated with fibrosis-related luminal and extraluminal morphological alterations (i.e., stricture, penetration, effusion and comb sign).-aspartic acid, identified as a potential target, promoted the progression of intestinal fibrosis in vitro and in vivo.A machine learning-based classifier had been developed based on the combination of 11 microbial and metabolic predictors for distinguishing the severity of intestinal fibrosis in patients with CD. The gut microbiota and its functional metabolites play crucial roles in the development of intestinal fibrosis in patients with Crohn's disease (CD).