[Protective Effect and Mechanism of Lactobacillus Rhamnosus on Immune Checkpoint Inhibitors Related Colitis in Mice].

Objective: Modeling the immune-related adverse events (irAE) colitis in mice, and explore the protective effect and related mechanism of Lactobacillus rhamnosus GG (LGG) on irAE colitis. Methods: C57BL/6 mice were divided into dextran sodium sulfate (DSS) group (n=3), DSS+anti-programmed death receptor 1 (PD-1) group (n=4), DSS+anti-PD-1+anti-cytotoxic T lymphocyte associated protein 4 (CTLA-4) Group (n=4), DSS+anti-PD-1+anti-CTLA-4+LGG group (n=4), all were given corresponding drugs and probiotics intervention. The severity of colitis were assessed by weight loss, disease activity index (DAI), colon length, colon histopathological score. The inflammatory cytokines and T cell immunity of CD4+, CD8+, FoxP3+regulatory T cells (Treg), were detected by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical staining respectively. Results: Compared to DSS group, the Day 9 weight [(87.40±1.79)% vs (94.57±0.53)%, P<0.05], colon length [(5.33±0.27)cm vs (6.63±0.12)cm, P<0.05] were lower, and DAI score(2.66±0.24 vs 0.89±0.48), colon histopathological score (12.50±1.04 vs 5.67±0.33), tumor necrosis factor-α (TNF-α) (6.73±1.68 vs 0.91±0.40) (P<0.05), as well CD8+T cells (156.80±8.84 vs 89.00±6.66) and FoxP3+Treg cells (103.80±2.66 vs 48.33±3.18) (P<0.05) were higher in DSS+anti-PD-1+anti-CTLA-4 group. Compared to DSS+anti-PD-1+anti-CTLA-4 group, the DAI score(1.83±0.17 vs 2.66±0.24), colonic histopathology score (8.75±0.63 vs 12.50±1.04), TNF-α level (1.32±0.18 vs 6.73±1.68) (P<0.05) were lower; and CD8+T cells(97.75±3.75 vs 156.80±8.84, P<0.01) level was lower with higher FoxP3+Treg cells (126.00±8.33 vs 103.80±2.66, P=0.046) in DSS+anti-PD-1+anti-CTLA-4+LGG group. Conclusion: DSS combined with anti-PD-1 and anti-CTLA-4 can successfully modeling the irAE colitis in mice, LGG can reduce irAE colitis severity by regulating Treg cells.