Downregulation of MLL1 Promotes Intestinal Epithelial Barrier Repair Through Gata4/Bmp4 Activation to Ameliorate Crohn's Disease-Like Colitis in Mice

Abstract

The dysfunctional reconstitution of the intestinal barrier is pivotal in driving the initiation of inflammatory pathogenesis in Crohn's disease (CD), although the exact pathophysiology underlying this phenomenon has yet to be definitively characterised. This study aimed to investigate the role of the histone methyltransferase mixed lineage leukaemia 1 (MLL1) in the development of CD-like colitis and to elucidate the mechanism by which MLL1 promotes epithelial cell differentiation. Colonic tissue specimens from CD patients and TNBS-induced murine models were analysed to assess MLL1 expression dynamics. The functional impact of MLL1 on murine colitis modelling CD was systematically investigated through clinical symptom scoring, histopathological profiling and quantitative evaluation of intestinal barrier integrity. The role of MLL1 in promoting epithelial cell differentiation and repairing the intestinal barrier was investigated through immunofluorescence and western blotting. Additionally, potential mechanisms underlying the reparative effects of MLL1 on intestinal barrier function were explored. MLL1 expression was upregulated in colonic tissues from CD patients and TNBS-induced murine colitis models. In contrast, MLL1 suppression in the TNBS cohort attenuated mucosal inflammation and downregulated pro-inflammatory cytokine production (IL-1β, IL-6, TNF-α) within the colonic mucosa. Additionally, reduced MLL1 expression increased the differentiation capacity of intestinal epithelial cells, including goblet cells, absorptive cells and tuft cells, and promoted barrier function restoration in injured colons and lipopolysaccharide-stimulated colonic organoids. MLL1 downregulation activated the Gata4/Bmp4 signalling pathway, which may contribute to the reparative effects of MLL1 on intestinal barrier integrity. Downregulating MLL1 expression promotes intestinal epithelial cell differentiation by activating the Gata4/Bmp4 pathway. These findings elucidate a pathophysiological mechanism wherein MLL1 suppression potentiates intestinal barrier restoration, thereby attenuating colitis severity in murine models. The observed therapeutic efficacy positions MLL1 inhibition presents a novel strategy for CD management.

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