Host metabolic reprogramming ameliorates disease severity and colitis during Clostridioides difficileinfection

Abstract

Abstract Clostridioides difficile is an anaerobic, opportunistic bacterium that can cause severe infections in the gastrointestinal tract upon disruption of gut microbiome. C. difficile infection (CDI) affects 450,000 people yearly only in the U.S. The high recurrence rates associated to antibiotic regimen, the current standard of care, highlight the need to investigate novel antimicrobial free therapeutic approaches for the treatment of CDI. Here, we have conducted a global transcriptomics analysis and metabolic computational modeling, using our developed M 2pipeline, of an in vivo murine 10-day time course study of CDI to identify novel host metabolic mechanisms with therapeutic potential. Our analysis has reported a biphasic modulation of colonic metabolism, characterized by increased glycolysis during the induction of effector responses, while mitochondrial metabolism is favored in the recovery phase of the infection, when regulatory and healing processes are predominant. Inhibition of glycolysis through administration of 2-Deoxy-D-glucose (2-DG) ameliorates diseases severity, protects from mortality, and reduces colitis in a mouse model of CDI. In vitro treatment with 2-DG, an inhibitor of glycolysis, in T-84 cells exposed to C. difficile toxins A and B protects epithelial barrier integrity and decreases secretion of inflammatory mediators. In conclusion, host immunometabolic reprogramming represents a promising novel antimicrobial-free therapeutic approach for CDI. Supported by a grant from DTRA (HDTRA1-20-1-0021)