Morganella morganii-derived histamine impairs intestinal barrier function via HRH4 and aggravates colitis

Pro-inflammatory dietary patterns are associated with an increased risk of Crohn's disease (CD) and shifts in the gut microbiota. Our previous multi-omics analysis had identified the enrichment of Morganella morganii (M. morganii) in both patients with CD and individuals consuming pro-inflammatory diets. In this study, we aimed to investigate the role and potential mechanisms by which M. morganii contributes to intestinal inflammation.

Using murine models of colitis, mouse colon organoids, and epithelial cell systems, combined with metabolomic profiling and pharmacological interventions, we investigated the effects of M. morganii and its secreted metabolites on tight junction integrity and intestinal permeability.

M. morganii aggravated colitis severity and induced a remarkable increase in intestinal permeability with disruption of tight junction architecture, including reduced occludin and zonula occludens-1 (ZO-1) expression and ultrastructural damage. These effects were predominantly mediated by the secreted low-molecular-weight metabolites rather than by bacterial invasion. Metabolomic analysis of the <3-kDa fraction of M. morganii culture supernatant identified histamine as a key bioactive molecule. Histamine recapitulated barrier disruption and colitis exacerbation in vivo. Pharmacological studies suggested that histamine-induced injury is mediated mainly through the histamine receptor H4 (HRH4) and that the inhibition of histamine synthesis significantly restored barrier integrity and alleviated colitis.

These findings suggest a previously unrecognized pathway in which the diet-responsive pathobiont M. morganii may impair epithelial barrier integrity through histamine-HRH4 signaling. Targeting histamine synthesis and HRH4 may offer a potential therapeutic avenue worth further investigation.