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BACKGROUND Inflammatory Bowel Disease (IBD) involves an interplay of gut microbiota, intestinal epithelium and immune responses. Recent data suggest that decreased mitochondrial gene function plays an active role in the pathophysiology of active colitis. Here, we test a novel agent (AuPhos) (Wempe et al., Abstract control ID: 3668199; Crohn’s and Colitis Congress, 2022) that mitigates disease severity in chronic colitis by enhancing mitochondrial function in the gut epithelium. METHODS The piroxicam-accelerated (Px) IL-10 KO mouse colitis model was used for testing a novel therapeutic (AuPhos) that increases mitochondrial function in intestinal epithelial cells (IEC). Mice were given Px feeding for 2 weeks (as in Lee et al Gastro, 2010) then treated with AuPhos (25mg/kg) or vehicle every 3d (n=15/group). Disease activity indices (DAI) were calculated (weight loss, diarrhea, and hematochezia) and fecal lipocalin-2 (LCN2) levels (d33-d55) while histological scoring was performed by a blinded GI pathologist (d56). Biopsy samples from consented IBD patients and normal controls were collected in PBS, and treated ex-vivo for 3h with vehicle or AuPhos (0.5uM) at 4oC. Effect of AuPhos on mRNA levels of mitochondrial complexes, cytokine, chemokine and stem cell markers in treated biopsies were examined using RT-qPCR. RESULTS Disease activity in Px-IL10 KO mice showed severe colonic inflammation at d48. AuPhos treatment decreased the DAI in Px-IL10 KO mice starting from d31, showing its potential to enhance intestinal wound healing. Histological investigation showed significantly decreased severity of colonic inflammation in AuPhos-treated Px-IL10 KO mice with reductions in overall colitis scores at Day-56 (*; p&amp;lt;0.05). AuPhos treatment also reduced numbers of ulcers and areas of crypt hyperplasia in Px-IL10 KO mice. Further, AuPhos treatment significantly reduced the fecal LCN2 levels at D33 (*; p&amp;lt;0.05), D40 (**; p&amp;lt;0.01) and D55 (*; p&amp;lt;0.05) compared to vehicle treated group. Rt-qPCR analysis of colonic tissue from AuPhos-treated Px-IL10 KO mice showed significant increase in mitochondrial COX1 mRNA compared to vehicle treated mice. Gene expression analysis of human colonic biopsies revealed significant increases in mitochondrial complex I genes (Ndufa1, Ndufa4, Ndufb6), complex IV gene (Cox5B), and stem cell markers (Lgr4, Lgr5, Lrig1), with corresponding decreases in pro-inflammatory markers (IL1β, MCP1, RankL). CONCLUSION These data suggest that AuPhos compound improves mitochondrial bioenergetics to prevent inflammation-associated barrier damage under chronic colitis conditions. We believe that AuPhos has an important therapeutic potential to improve ulcer healing and accelerate mucosal repair by restoring mitochondrial metabolism.

AUPHOS, A NOVEL THERAPEUTIC THAT IMPROVES MITOCHONDRIAL FUNCTION AND AMELIORATES CHRONIC COLITIS