Hyperglycemia worsens gut bacterial infection through intestinal Wnt, but independent of endotoxemia or obesity

Obesity and diabetes are interlinked diseases, but it was unclear how obesity vs. diabetes modifies the risk and severity of gut bacterial infection. We aimed to determine how obesity or hyperglycemia, indicative of diabetes, altered metabolic endotoxemia and severity of enteric infection. Metabolic endotoxemia was determined using TLR4 activity reporter assay in serum from humans with obesity or diabetes, and from hyperglycemic <i>Akita</i>^+/- mice and genetically obese <i>ob/ob</i> mice. Diarrhea severity during <i>Escherichia coli</i> infection was determined in humans during a previous community outbreak. The enteropathogen <i>Citrobacter rodentium</i> was used to define the mechanisms of action that altered the severity of enteric infection in <i>ob/ob</i> and <i>Akita</i>^+/- mice. We found that elevated blood glucose, indicative of diabetes, was associated with increased occurrence and severity of diarrhea during an <i>E. coli</i> outbreak in humans. Metabolic endotoxemia occurred in a separate cohort of people with obesity who were normoglycemic or hyperglycemic, and in mice with either obesity or hyperglycemia. Hyperglycemia, not obesity, increased mortality during infection with the diarrhea-causing pathogen <i>C. rodentium</i> in mouse models of type 1 and type 2 diabetes. Common indicators of poor prognosis, such as gut pathology, systemic bacteraemia, or metabolic endotoxemia, did not predict worse outcomes during enteric infection in diabetic mice. Hyperglycemia activated intestinal Wnt/β-catenin and increased mortality, which could be reversed by blocking Wnt/β-catenin, lowering blood glucose, or restoring fluid balance during infection. The increased severity of infection via overactivation of intestinal Wnt/β-catenin during hyperglycemia may be a potential target for therapeutics.<b>NEW & NOTEWORTHY</b> We show that elevated blood glucose is associated with worse diarrhea during an <i>Escherichia coli</i> outbreak in humans. Obesity or hyperglycemia was sufficient to promote metabolic endotoxemia in humans and mice. Hyperglycemia promotes worse enteric infection outcomes independent of obesity. Finally, we showed that blocking of Wnt/β-catenin, lowering blood glucose, or restoring fluids improved enteric infection outcomes in hyperglycemic mice.