Turicibacter modifies intestinal infection severity by modulating intestinal metabolites

Diarrheal diseases are a leading cause of child mortality worldwide causing approximately 800000 deaths peryear in children under five years of age and prevalent morbidity in adults. For bacterial diarrheal infectionsantibiotics are often the primary treatment; however their heavy use disrupts beneficial microbial communitieswhich in turn exacerbates disease outcomes. A crucial approach to treat or prevent these infections involvesrestoring or modulating the gut microbiota with specific commensals that offer targeted protection againstpathogens. Although fecal transplantation is one potential method it is limited by the risk of transferring harmfulpathogens to the recipients. Interestingly commensal bacteria can influence the composition of intestinalmetabolites which may play a crucial role in either curbing or promoting pathogenicity. Therefore manipulatingthese metabolites presents a promising therapeutic avenue to prevent severe diseases caused by intestinalpathogens. Research focused on identifying protective commensals and key metabolites is essential fordeveloping effective prevention strategies against bacterial diarrheal diseases. In this application we presentcompelling preliminary findings suggesting that the commensal Turicibacter sanguinis may protect againstsevere disease caused by the intestinal pathogen Citrobacter rodentium an established model of attaching andeffacing (A/E) bacterial infections in mice. While little is known about T. sanguinis recent studies have shownthat higher levels of this commensal correlate with healthier outcomes in children with diarrhea or acutegastroenteritis hinting at a potential protective association against diarrheal diseases in humans. Consistent withthese observations our data show that severe disease from C. rodentium is linked to the absence of T. sanguinisand elevated intestinal levels of two specific metabolites: adenine and dioscoretine. Based on these findings wehypothesize that adenine and dioscoretine create an intestinal environment conducive to severe C. rodentiuminfection whereas T. sanguinis confers resistance by reducing these metabolites' abundance.