Abstract Mesenteric adipose tissue (MAT) in Crohn's disease (CD) is associated with transmural inflammation. Extended mesenteric excision can reduce surgical recurrence and improve long‐term outcomes, indicating that MAT plays an important role in the pathogenesis of CD. Bacterial translocation has been reported to occur in the MAT of patients with CD (CD‐MAT), but the mechanisms by which translocated bacteria lead to intestinal colitis remain unclear. Here it is shown that members of Enterobacteriaceae are highly enriched in CD‐MAT compared with non‐CD controls. Viable Klebsiella variicola in Enterobacteriaceae is isolated exclusively in CD‐MAT and can induce a pro‐inflammatory response in vitro and exacerbates colitis both in dextran sulfate sodium (DSS)‐induced colitis mice model and IL‐10−/− spontaneous colitis mice model. Mechanistically, active type VI secretion system (T6SS) is identified in the genome of K. variicola, which can impair the intestinal barrier by inhibiting the zonula occludens (ZO‐1) expression. Dysfunction of T6SS by CRISPR interference system alleviates the inhibitory effect of K. variicola on ZO‐1 expression and attenuated colitis in mice. Overall, these findings demonstrate that a novel colitis‐promoting bacteria exist in the mesenteric adipose tissue of CD, opening a new therapeutic avenue for colitis management.
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