Comparative therapeutic efficacy and immunological mechanisms of LANCL2 therapeutics for treating recurrent Clostridioides difficile infection 2260935

Abstract

Abstract Introduction Omilancor is an oral, gut-restricted, LANCL2 agonist with proven therapeutic efficacy in acute and recurrent mouse models of Clostridioides difficile infection (CDI). While gut microbiome disruption is the underlying cause of CDI, paradoxically, the infection is treated with antibiotics that cause further gut microbiome imbalance leading to recurrence. Methods We conducted comparative studies of oral omilancor versus current treatments using a recurrent model of CDI. To induce recurrence, mice received a clindamycin injection 12 d post infection. Colonic bacterial burden was evaluated by culture. Colitis was evaluated by histopathology. Gut microbiome composition was evaluated through 16S sequencing. Results During recurrent CDI, omilancor showed non-inferiority to anti-TcdB and rectal fecal microbiome transplantation (FMT), displaying the greatest therapeutic efficacy. Mice treated with vancomycin had the worst outcome during the recurring phase with a 2.5-fold increase in disease severity scores compared to vehicle-treated mice. Oral omilancor outperformed all current treatments in inducing the fastest C. difficile clearance, which was linked to preservation of the gut microbiome diversity. Immunologically, activation of LANCL2 by oral omilancor decreases the expression of proinflammatory cytokines, including IL-17, and infiltration of inflammatory subsets, such as Th17 cells and neutrophils in the gut mucosa while increasing mucosal regulatory T cells (Treg). Conclusion Oral omilancor treatment outperforms current drugs used for treating recurrent CDI. Given omilancor’s placebo-like safety profile and its superior efficacy, LANCL2 therapeutics have the potential to become first-in-class immunoregulatory, antimicrobial-free, gut microbiome-preserving host-targeting treatment modalities for recurrent CDI. Funding Source N/a Topic Categories Mucosal and Regional Immunology (MUC)