Mertk-dependent immune regulation is required for the therapeutic effects of fecal microbiota transplantation in a mouse model of constipation-predominant irritable bowel syndrome.

BACKGROUND

Constipation-predominant irritable bowel syndrome (IBS-C) is a disorder of brain-gut axis dysfunction closely associated with gut microbiota dysbiosis and disruption of mucosal immune homeostasis. Fecal microbiota transplantation (FMT) has been shown to alleviate IBS symptoms; however, its underlying molecular mechanisms remain incompletely understood. MER proto-oncogene tyrosine kinase (Mertk), a member of the receptor tyrosine kinase family, plays an important role in macrophage polarization-related regulation and inflammation resolution.

OBJECTIVE

To investigate the role of Mertk-mediated immune regulation in FMT-induced improvement of IBS-C and its underlying mechanisms.

METHODS

IBS-C was induced in wild-type(WT) and Mertk conditional knockout(cKO) mice (Mertkflox/floxLyz2Cre/+) by ice-water gavage combined with tail-clamping stress, followed by FMT treatment. Defecation, fecal water content, intestinal transit, and visceral sensitivity were assessed. Colonic histopathology, macrophage polarization-related markers, inflammatory cytokines, tight junction proteins, AKT-GSK3β signaling, and gut microbiota composition were examined by HE staining, immunohistochemistry, qPCR, Western blotting, and 16S rRNA sequencing.

RESULTS

In WT IBS-C mice, FMT improved constipation-like symptoms, intestinal transit, and visceral hypersensitivity, reduced colonic inflammation, restored Occludin and Claudin-1 expression, decreased CD86 and IL-1β, increased CD206 and IL-10, and activated AKT-GSK3β signaling. These beneficial effects were markedly attenuated in Mertk-deficient mice. However, FMT similarly remodeled gut microbiota composition in both WT and Mertk-deficient mice.

CONCLUSION

FMT alleviates IBS-C partly through Mertk-dependent immune regulation and AKT-GSK3β activation. Gut microbiota remodeling alone is insufficient for full therapeutic efficacy in the absence of intact host Mertk signaling.