Oxidative ornithine metabolism supports non-inflammatory C. difficile colonization

Area of Science:

• Microbiology
• Gastroenterology
• Infectious Diseases

Background:

• Clostridioides difficile (Cd) causes significant U.S. hospitalizations and deaths.
• Asymptomatic Cd colonization is common and poses a risk for infection and transmission.
• Understanding Cd persistence mechanisms is crucial for developing new therapies.

Purpose of the Study:

• To investigate the molecular mechanisms of Cd persistence in the gut.
• To differentiate inflammation-dependent and -independent transcriptional states of Cd.
• To identify metabolic pathways supporting Cd colonization in a non-inflammatory state.

Main Methods:

• Gut microbiome metatranscriptomic analysis in mice.
• RNA sequencing of Cd strains (wild-type and toxin-deficient mutants) in gnotobiotic mice.
• Untargeted and targeted metabolomics combined with bacterial and host genetics.

Main Results:

• Mice resistant to Cd infection showed increased arginine and ornithine metabolic pathway expression.
• A specific operon for oxidative ornithine degradation was upregulated in non-toxigenic Cd strains.
• Ornithine, from both diet and host, conferred a competitive advantage to Cd.

Conclusions:

• Cd persistence in a healthy gut is linked to ornithine metabolism.
• Dietary and host-derived ornithine supports Cd colonization.
• Targeting ornithine metabolism may offer novel therapeutic strategies against Cd.