irAE-colitis induced by CTLA-4 and PD-1 blocking were ameliorated by TNF blocking and modulation of gut microbial

Abstract

Immune-related adverse events, particularly colitis (irAE-colitis), are significant impediments to the advancement of immune checkpoint therapy. To address this, blocking TNF-α and modulating gut microbiota are effective strategies. However, their precise roles in irAE-colitis pathogenesis and potential reciprocal relationship remain unclear. An irAE-colitis model was established to evaluate the toxicity of DICB and the efficacy of Infliximab, validated through a tumor irAE-colitis mice model. Co-administration of Infliximab with DICB mitigates colitis and enhances efficacy. Analysis of fecal samples from mice reveals altered gut microbiota composition and function induced by irAE-colitis, restored by Infliximab. Notably, Bacteriodes abundance is significantly higher in irAE-colitis. Disruption of arachidonic acid and tyrosine metabolism, and steroid hormone biosynthesis is evident. Mechanistically, a regenerative feedback loop involving DICB, TNF-α and gut microbiota underlies irAE-colitis pathogenesis. In conclusion, Infliximab shows therapeutic effects against DICB toxicity, highlighting the unforeseen roles of gut microbiota and TNF-α in irAE-colitis.

Keywords

• DICB
• Infliximab
• irAE-colitis
• microbiome & metabolomics