Oral Omilancor Treatment Ameliorates Clostridioides difficile Infection During IBD Through Novel Immunoregulatory Mechanisms Mediated by LANCL2 Activation

Abstract Background Clostridioides difficile infection (CDI) is an opportunistic infection of the gastrointestinal tract, commonly associated with antibiotic administration, that afflicts almost 500 000 people yearly only in the United States. CDI incidence and recurrence is increased in inflammatory bowel disease (IBD) patients. Omilancor is an oral, once daily, first-in-class, gut-restricted, immunoregulatory therapeutic in clinical development for the treatment of IBD. Methods Acute and recurrent murine models of CDI and the dextran sulfate sodium–induced concomitant model of IBD and CDI were utilized to determine the therapeutic efficacy of oral omilancor. To evaluate the protective effects against C. difficile toxins, in vitro studies with T84 cells were also conducted. 16S sequencing was employed to characterize microbiome composition. Results Activation of the LANCL2 pathway by oral omilancor and its downstream host immunoregulatory changes decreased disease severity and inflammation in the acute and recurrence models of CDI and the concomitant model of IBD/CDI. Immunologically, omilancor treatment increased mucosal regulatory T cell and decreased pathogenic T helper 17 cell responses. These immunological changes resulted in increased abundance and diversity of tolerogenic gut commensal bacterial strains in omilancor-treated mice. Oral omilancor also resulted in accelerated C. difficile clearance in an antimicrobial-free manner. Furthermore, omilancor provided protection from toxin damage, while preventing the metabolic burst observed in intoxicated epithelial cells. Conclusions These data support the development of omilancor as a novel host-targeted, antimicrobial-free immunoregulatory therapeutic for the treatment of IBD patients with C. difficile–associated disease and pathology with the potential to address the unmet clinical needs of ulcerative colitis and Crohn’s disease patients with concomitant CDI.