<b>p62 Protein-Based Gene Therapy Modulates the Immune Responses in Moderate DSS-induced Colitis in Mice</b>

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC), constitute chronic inflammatory ailments of the gastrointestinal tract (GIT). These inflammatory diseases result from many factors, including the host's immune response, gut microbiota, and genetic background. Probiotics, including recombinant probiotic strains producing and delivering therapeutic biomolecules to the host mucosal surfaces, could constitute a tool to help prevent and mitigate chronic intestinal inflammation. p62 is a human multifunctional adaptor protein involved in key cellular processes such as tissue homeostasis, inflammation, and cancer. It acts as a negative regulator of inflammasome complexes. It may thus be considered a good candidate for therapeutic use in inflammatory gastrointestinal diseases. The objective of the present study was to combine the intrinsic immunomodulatory properties of Lactococcus lactis NCDO2118 with its ability to deliver health-promoting molecules to enhance its protective and preventive effects in the context of ulcerative colitis. We thus cloned a cDNA encoding p62 into the pExu expression vector, which was used to transform L. lactis NCDO2118. As a result, no additional protective effect was observed regarding mice clinical parameters compared to the L. lactis NCDO2118 pExu:empty. However, the recombinant strain, expressing p62, increased the goblet cell counts and upregulated Muc2 gene expression in the colon in the context of colitis. Also, pro-inflammatory cytokines Tnf and Ifng were downregulated by L. lactis NCDO2118 pExu:p62 compared to L. lactis NCDO2118 pExu:empty and inflamed groups. This recombinant strain also decreased colonic myeloperoxidase enzyme (MPO) activity. No difference in the intestinal microbiota was observed between all treatments. Altogether, our results show that recombinant L. lactis NCDO2118 delivering p62 protein protected the intestinal mucosa and mitigated inflammatory damage caused by DSS. We thus suggest that p62 may constitute part of a therapeutic approach targeted against inflammation.