Turicibacter modifies intestinal infection severity by modulating intestinal metabolites

SUMMARY Diarrheal diseases are a leading cause of child mortality worldwide, causing approximately 800,000 deaths per year in children under five years of age, and prevalent morbidity in adults. For bacterial diarrheal infections, antibiotics are often the primary treatment; however, their heavy use disrupts beneficial microbial communities, which, in turn, exacerbates disease outcomes. A crucial approach to treat or prevent these infections involves restoring or modulating the gut microbiota with specific commensals that offer targeted protection against pathogens. Although fecal transplantation is one potential method, it is limited by the risk of transferring harmful pathogens to the recipients. Interestingly, commensal bacteria can influence the composition of intestinal metabolites, which may play a crucial role in either curbing or promoting pathogenicity. Therefore, manipulating these metabolites presents a promising therapeutic avenue to prevent severe diseases caused by intestinal pathogens. Research focused on identifying protective commensals and key metabolites is essential for developing effective prevention strategies against bacterial diarrheal diseases. In this application, we present compelling preliminary findings suggesting that the commensal Turicibacter sanguinis may protect against severe disease caused by the intestinal pathogen Citrobacter rodentium, an established model of attaching and effacing (A/E) bacterial infections in mice. While little is known about T. sanguinis, recent studies have shown that higher levels of this commensal correlate with healthier outcomes in children with diarrhea or acute gastroenteritis, hinting at a potential protective association against diarrheal diseases in humans. Consistent with these observations, our data show that severe disease from C. rodentium is linked to the absence of T. sanguinis and elevated intestinal levels of two specific metabolites: adenine and dioscoretine. Based on these findings, we hypothesize that adenine and dioscoretine create an intestinal environment conducive to severe C. rodentium infection, whereas T. sanguinis confers resistance by reducing these metabolites' abundance. Project Number: 1R21AI187749-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Wenhan Zhu | Institution: VANDERBILT UNIVERSITY MEDICAL CENTER, NASHVILLE, TN | Award Amount: $262,410 | Activity Code: R21 | Study Section: Interspecies Microbial Interactions and Infections Study Section[IMII] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI18774901A1