LRRK2 deficiency mitigates colitis progression by favoring resolution of inflammation and restoring homeostasis of gut microbiota.

Leucine rich-repeat kinase 2 (LRRK2) has been considered a susceptibility gene for ulcerative colitis (UC), and its protein abundance was enhanced in the peripheral blood mononuclear cells (PBMCs) from UC cohorts as compared to healthy volunteers. In preclinical models of colitis, Lrrk2 deficiency ameliorated dextran sodium sulfate (DSS)-induced colitis progression, whereas the processes were aggravated by R1441C mutation. While intestinal macrophages (MФs) from Lrrk2 knock-out (Lrrk2-/- ) mice exhibited a tendency to transit to alternatively activated MФs, R1441C MФs mutation facilitated the pro-inflammatory phenotype polarization, determined by RNA sequencing and qPCR. Moreover, we characterized their microbiota profiles and found that loss of Lrrk2 increased the bacterial richness and altered bacterial community structure, and this shift contributed to the alleviation of colitis development and progression. We proposed that Lrrk2 deficiency promotes M2 MФ transition and facilitates probiotics colonization, providing a protective role during colitis.