TREM2 promotes susceptibility to colitis through the induction of gut microbiota dysbiosis.

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) has been implicated in the pathogenesis of inflammatory bowel disease (IBD), yet its role in microbiota-mediated intestinal immune homeostasis remains incompletely defined. Here, we demonstrate that TREM2 expression is associated with exacerbated colonic inflammation in a murine model of DSS-induced colitis, disrupting epithelial integrity and microbial homeostasis. TREM2 transgenic (TG) mice developed more severe disease and mucosal injury, accompanied by marked dysbiosis characterized by the expansion of pro-inflammatory taxa (Firmicutes, Actinobacteria, Prevotella) and depletion of beneficial commensals (Lactobacillus, Bifidobacterium). This TREM2-driven dysbiotic and inflammatory state was associated with region-specific suppression of antimicrobial peptide (AMP) expression in the gut, elevated production of pro-inflammatory cytokines and reactive oxygen species (ROS), and a diminished frequency of IL-17A-producing Th17 cells in the colon. Conversely, TREM2 knockout (KO) mice preserved microbial composition, strengthened epithelial defenses, and attenuated inflammatory responses. Collectively, these findings establish TREM2 as a pivotal regulator of gut immune-microbial interactions and demonstrate its potential as a therapeutic target in IBD.