Sulfides in the gut mediate protection against gastrointestinal infection via alterations to local immunity and the microbiome

Abstract Sulfide is a gaseous molecule, which has toxic effects at high concentrations yet plays key roles in homeostasis throughout the body. Sulfides are produced endogenously by both host tissues and the bacterial cells of the gut microbiome, which results in the gut containing the highest concentrations of sulfide in the body. We sought to assess the role of the highly abundant sulfide molecule in gut immunity, microbiome homeostasis and resistance to enteric infections. Local sulfides can be depleted by the compound bismuth subsalicylate (BSS), a common anti-diarrheal medication, which acts locally by sequestering sulfides in the gut. Key gut commensals such as Lactobacillusand segmented filamentous bacteria, major mediators of gut immunity and resistance to pathogen colonization, were profoundly depleted following sulfide sequestration. Additionally, we observed significant downstream immune effects, specifically within the local immunity of the small intestine. Depletion of gut sulfides resulted in profound collapse of CD4 T cells, especially among Th1 cells in the lamina propria of the small intestine. Using a mouse model of SalmonellaTyphimurium, mice treated with BSS were extremely susceptible to infection, with a 5-log increase in fecal bacterial load at 24 hours post infection. These data reveal a central role for sulfides in gut homeostasis and prevention of enteric infection. Strategies to manage gut sulfide levels, including diet supplementation and microbiome engineering, could be a possible intervention to promote gut health. NIH Office of Dietary Supplements (Research Scholar Grant 2022)