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

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.

Omilancor is an oral, gut-restricted first-in-class immunoregulatory therapeutic for the treatment of inflammatory bowel disease (IBD). This study demonstrates for the first time that omilancor provides therapeutic efficacy in models of acute and recurrent Clostridioides difficile infection (CDI), and concomitant CDI and IBD, by increasing regulatory T cell function while suppressing effector responses, plus modulating gut microbiome composition and preserving epithelial barrier function.

Treating Autoimmune Diseases With LANCL2 Therapeutics: A Novel Immunoregulatory Mechanism for Patients With Ulcerative Colitis and Crohn's Disease.

Lanthionine synthetase C-like 2 (LANCL2) therapeutics have gained increasing recognition as a novel treatment modality for a wide range of autoimmune diseases. Genetic ablation of LANCL2 in mice results in severe inflammatory phenotypes in inflammatory bowel disease (IBD) and lupus. Pharmacological activation of LANCL2 provides therapeutic efficacy in mouse models of intestinal inflammation, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and psoriasis. Mechanistically, LANCL2 activation enhances regulatory CD4 + T cell (Treg) responses and downregulates effector responses in the gut. The stability and suppressive capacities of Treg cells are enhanced by LANCL2 activation through engagement of immunoregulatory mechanisms that favor mitochondrial metabolism and amplify IL-2/CD25 signaling. Omilancor, the most advanced LANCL2 immunoregulatory therapeutic in late-stage clinical development, is a phase 3 ready, first-in-class, gut-restricted, oral, once-daily, small-molecule therapeutic in clinical development for the treatment of UC and CD. In this review, we discuss this novel mechanism of mucosal immunoregulation and how LANCL2-targeting therapeutics could help address the unmet clinical needs of patients with autoimmune diseases, starting with IBD.

Oral LANCL2 therapeutics are a safe and effective treatment modality for the long-term management of autoimmune diseases, including UC and CD, without causing systemic immunosuppression. This review discusses in detail the immunoregulatory mechanisms of action of LANCL2 therapeutics. More specifically, the article describes how omilancor, a first-in-class, oral, once daily, gut-restricted LANCL2 therapeutic could help address the unmet clinical needs of patients with IBD and other immune-mediated diseases.

Modulation of colonic immunometabolic responses during Clostridioides difficile infection ameliorates disease severity and inflammation.

Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea, and its clinical symptoms can span from asymptomatic colonization to pseudomembranous colitis and even death. The current standard of care for CDI is antibiotic treatment to achieve bacterial clearance; however, 15 to 35% of patients experience recurrence after initial response to antibiotics. We have conducted a comprehensive, global colonic transcriptomics analysis of a 10-day study in mice to provide new insights on the local host response during CDI and identify novel host metabolic mechanisms with therapeutic potential. The analysis indicates major alterations of colonic gene expression kinetics at the acute infection stage, that are restored during the recovery phase. At the metabolic level, we observe a biphasic response pattern characterized by upregulated glycolytic metabolism during the peak of inflammation, while mitochondrial metabolism predominates during the recovery/healing stage. Inhibition of glycolysis via 2-Deoxy-D-glucose (2-DG) administration during CDI decreases disease severity, protects from mortality, and ameliorates colitis in vivo. Additionally, 2-DG also protects intestinal epithelial cells from C. difficile toxin damage, preventing loss of barrier integrity and secretion of proinflammatory mediators. These data postulate the pharmacological targeting of host immunometabolic pathways as novel treatment modalities for CDI.

Computational modeling of complex bioenergetic mechanisms that modulate CD4+ T cell effector and regulatory functions.

We built a computational model of complex mechanisms at the intersection of immunity and metabolism that regulate CD4+ T cell effector and regulatory functions by using coupled ordinary differential equations. The model provides an improved understanding of how CD4+ T cells are shaping the immune response during Clostridioides difficile infection (CDI), and how they may be targeted pharmacologically to produce a more robust regulatory (Treg) response, which is associated with improved disease outcomes during CDI and other diseases. LANCL2 activation during CDI decreased the effector response, increased regulatory response, and elicited metabolic changes that favored Treg. Interestingly, LANCL2 activation provided greater immune and metabolic modulation compared to the addition of exogenous IL-2. Additionally, we identified gluconeogenesis via PEPCK-M as potentially responsible for increased immunosuppressive behavior in Treg cells. The model can perturb immune signaling and metabolism within a CD4+ T cell and obtain clinically relevant outcomes that help identify novel drug targets for infectious, autoimmune, metabolic, and neurodegenerative diseases.