Chua, M. J. | Search bioRxiv

bioRxiv2024

Mice colonized with the defined microbial community OMM19.1 are susceptible to C. difficile infection without prior antibiotic treatment.

Diverse gut microorganisms present in humans and mice are essential for the prevention of microbial pathogen colonization. However, antibiotic-induced dysbiosis of the gut microbiome reduces microbial diversity and allows C. difficile to colonize the intestine. The Oligo Mouse Microbiota 19.1 (OMM19.1) is a synthetic community that consists of bacteria that are taxonomically and functionally designed to mimic the specific pathogen-free (SPF) mouse gut microbiota. Here, we examined the susceptibility of OMM19.1 colonized mice to C. difficile infection at a range of infectious doses (103, 105, and 107 spores) without prior antibiotic treatment. We found that mice colonized with OMM19.1 were susceptible to C. difficile infection regardless of the dose. The clinical scores increased with increasing C. difficile dosage. Infection with C. difficile was correlated with a significant increase in Ligilactobacillus murinus and Escherichia coli, while the abundance of Bacteroides caecimuris, Akkermansia muciniphila, Extibacter muris, and Turicimonas muris significantly decreased following C. difficile infection. Our results demonstrate that the OMM19.1 community requires additional bacteria to enable colonization resistance.

microbiology↗

bioRxiv2023

The microbial metabolite Urolithin A reduces C. difficile toxin expression and repairs toxin-induced epithelial damage.

Clostridioides difficile is a gram-positive, anaerobic, spore-forming bacterium that is responsible for antibiotic-associated pseudomembranous colitis. Clostridioides difficile infection (CDI) symptoms can range from diarrhea to life-threatening colon damage. Toxins produced by C. difficile (TcdA and TcdB) cause intestinal epithelial injury and lead to severe gut barrier dysfunction, stem cell damage, and impaired regeneration of the gut epithelium. Current treatment options for intestinal repair are limited. In this study, we demonstrate that treatment with the microbial metabolite urolithin A (UroA) attenuates CDI-induced adverse effects on the colon epithelium in a preclinical model of CDI-induced colitis. Moreover, our analysis suggests that UroA treatment protects against C. difficile-induced inflammation, disruption of gut barrier integrity, and intestinal tight junction proteins in the colon of CDI mice. Importantly, UroA treatment significantly reduced the expression and release of toxins from C. difficile, without inducing bacterial cell death. These results indicate the direct regulatory effects of UroA on bacterial gene regulation. Overall, our findings reveal a novel aspect of UroA activities, as it appears to act at both the bacterial and host levels to protect against CDI-induced colitis pathogenesis. This research sheds light on a promising avenue for the development of novel treatments for C. difficile infection. ImportanceTherapy for C. difficile infections includes the use of antibiotics, immunosuppressors, and fecal microbiota transplantation (FMT). However, these treatments have several drawbacks, including the loss of colonization resistance, promotion of autoimmune disorders, and the potential for unknown pathogens in donor samples. To date, the potential benefits of microbial metabolites in CDI-induced colitis have not been fully investigated. Here, we report for the first time that the microbial metabolite Urolithin A has the potential to block toxin production from C. difficile and enhance gut barrier function to mitigate CDI-induced colitis.

microbiology↗