A8 PROLONGED FASTING ALTERS THE GUT MICROBIOME AND PROTECTS AGAINST SALMONELLA-INDUCED GUT INFLAMMATION

During periods of acute sickness, all animals including humans voluntarily decrease their food intake, a behavior known as “infection-induced anorexia”. Since infection-induced anorexia or fasting is highly conserved amongst mammals, we and others have proposed that it actually promotes host-defense. Several studies have demonstrated that fasting indeed attenuates disease during acute systemic infection or chronic inflammation. Since the Gastrointestinal tract is the first organ to be affected by food deprivation, we investigated if fasting alters the course of infection and/or ameliorates intestinal inflammation using a mouse model of S. typhimurium-induced colitis. We furthermore examined if fasting modifies the resident gut microbiota, and whether these modifications are instrumental to alter the course of S. typhimurium infection and colitis. S. typhimurium causes severe colitis in streptomycin pre-treated, orally infected mice as early as 12h post infection. C57BL/6 conventional as well as germfree mice were fed or fasted for 24h and orally infected with S. typhimurium, continuing the fast for another 6h to 24h. Additionally, C57BL/6 conventional mice were fed single macronutrients to gauge the effect of different nutrients on the infection. Pathology as well as Salmonella colonization, was assessed by histological and immunofluorescent staining and organ pathogen burden counts; inflammatory gene transcription was measured by qPCR. Microbiome profiling of intestinal contents was performed utilizing 16S rRNA sequencing. Fasting completely abrogated S. typhimurium infection and colitis in conventional C57BL/6 mice, whereas infection still proceeded, albeit in a reduced fashion in germfree mice in concert with minimal signs of inflammation. Microbiome profiles between fed and fasted groups differed greatly in terms of beta diversity with the fasting group showing a consistent increase in the genus Akkermansia. Feeding mice glucose alone was not sufficient to re-establish the infection, but preliminary results indicate that other macronutrients can partially restore Salmonella colonization. Taken together, our findings show that prolonged fasting dramatically protects the host against S. typhimurium infection, in part by altering the intestinal microbiome and increasing colonization resistance, likely by limiting nutrient availability for the pathogenic bacteria. Additionally our results indicate that food deprivation impairs Salmonella virulence and reduces its ability to promote an inflammatory environment independent of changes in the microbiome. CCC, CIHRNSERC

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