Type 2 diabetes increases susceptibility to invasive Salmonella Typhimurium despite butyrate supplementation

Non-typhoidal Salmonella is a major cause of bacterial foodborne illness leading to acute gastroenteritis. In individuals with type 2 diabetes (T2D), Salmonella infection is more likely to cause life-threatening extraintestinal infections. The mechanism underlying this susceptibility remains unclear. In this study, 8-week-old TALLYHO mice were fed either a chow or high-fat diet (HFD, 45% fat) for 8 weeks to induce the T2D. As expected, HFD-fed mice gained more weight and developed diabetic-range blood glucose levels by 16 weeks of age. Next, mice from each diet group were orally infected with a fully virulent bioluminescent Salmonella Typhimurium to monitor infection spread by in-vivo imaging. Although both groups developed clinical signs of salmonellosis, Salmonella spread was accelerated and followed an unusual pattern in T2D mice compared with healthy animals. Additionally, hyperglycemia increased gut-derived lipopolysaccharide leakage into the bloodstream. Based on the link between T2D and altered levels of butyrate-producing bacteria in the gut, we analyzed the intestinal short-chain fatty acid (SCFA) profiles in the TALLYHO mice. As expected, intestinal SCFA concentrations, including butyrate, were lower in HFD mice than in chow-fed animals. Given butyrate’s role in gut health and its ability to downregulate Salmonella invasion genes, mice received oral butyrate supplementation. We found that butyrate supplementation reduced the extraintestinal spread of Salmonella in normoglycemic chow-fed animals. Unexpectedly, although butyrate improved intestinal health in hyperglycemic mice, it failed to decrease Salmonella spread in diabetic animals. Taken together, these findings provide novel insights into the pathogenesis of enteric salmonellosis in the context of T2D.