Mycobacterium tuberculosis PPE2 protein-derived peptide ameliorates DSS-induced colitis by depleting mast cells

In the present study, we demonstrated that a synthetic peptide derived from the Mycobacterium tuberculosis PPE2 protein alleviates dextran sodium sulphate (DSS)-induced colitis in mice and markedly improves ulcerative colitis (UC) symptoms, as evidenced by improvement in body weight loss, disease activity index (DAI) score, colon length, and decrease in myeloperoxidase activity. PPE2-peptide treatment attenuated the induction of pro-inflammatory cytokines, enhanced the mRNA levels of tight junction proteins (Occludin, Claudin-1, and ZO-1), and prevented gut barrier function. PPE2 acts mainly by targeting the mast cells, as adoptive transfer of mast cells restored the symptoms of DSS-induced colitis in PPE2-treated mice. We further explored the development of a combination therapy aimed at targeting multiple pathways involved in inflammatory bowel disease (IBD) pathogenesis and showed that combination therapy of PPE2-peptide and mesalazine had better efficacy in improving UC symptoms. This study highlights a potential therapeutic strategy targeting fibroblast-mast cell crosstalk in IBD.