Targeting the endo-lysosomal autophagy pathway to treat inflammatory bowel diseases

Inflammatory bowel disease (IBD) is a serious public health problem in Western society with a continuing increase in incidence worldwide. Safe, targeted medicines for IBD are not yet available. Autophagy, a vital process implicated in normal cell homeostasis, provides a potential point of entry for the treatment of IBDs, as several autophagy-related genes are associated with IBD risk. We conducted a series of experiments in three distinct mouse models of colitis to test the effectiveness of therapeutic P140, a phosphopeptide that corrects autophagy dysfunctions in other autoimmune and inflammatory diseases. Colitis was experimentally induced in mice by administering dextran sodium sulfate and 2,4,6 trinitrobenzene sulfonic acid. Transgenic mice lacking both il-10 and iRhom2 -involved in tumor necrosis factor alpha secretion -were also used. In the three models investigated, P140 treatment attenuated the clinical and histological severity of colitis. Post-treatment, altered expression of several macroautophagy and chaperone-mediated autophagy markers, and of pro-inflammatory mediators was corrected. Our results demonstrate that therapeutic intervention with an autophagy modulator improves colitis in animal models. These findings highlight the potential of therapeutic peptide P140 for use in the treatment of IBD.

Automated summary

Inflammatory bowel disease (IBD) is a growing global health problem, and there is currently a lack of safe and targeted medicines for its treatment. This study investigated the potential use of a therapeutic peptide, P140, which corrects autophagy dysfunctions, in three mouse models of colitis. The results showed that P140 treatment attenuated the severity of colitis and corrected the expression of autophagy markers and pro-inflammatory mediators. These findings suggest that the autophagy modulator P140 holds promise for the treatment of IBD.