Diabetes and hyperglucosuria exacerbate the severity of urinary tract infection caused by uropathogenic E. coli in the mouse model
Abstract
ABSTRACT Diabetes and urinary tract infection (UTI) are major global public health problems. We investigated the effects of glucose on bacterial colonization and host response to UTI caused by uropathogenic Escherichia coli (UPEC) in a mouse model of type 2 diabetes mellitus (T2DM) of polygenic origin. Dapagliflozin was used to induce hyperglucosuria in diabetic and healthy adult mice before and during experimental UTI with UPEC. Glucose, bacterial load, cytokines, tissue damage scores, and myeloid cell composition during acute UTI were determined. A UPEC mutant lacking a gluconeogenesis pathway was constructed to test the role of glucose on pathogen fitness in human urine and during UTI in diabetic mice. A significant increase in UPEC load was observed in the urinary tract of hyperglucosuric diabetic mice with a higher incidence of systemic dissemination and a higher degree of cystitis and bladder neutrophil counts compared to vehicle-treated controls. We also observed higher bacterial titer in vehicle-treated diabetic mice compared to healthy mice. While there was a significant increase in tissue damage in diabetic, hyperglucosuric mice, the levels of TNF-α, IL-1β, and IL-6 in the urinary tract were similar across treatment groups and genotypes. Our in vitro and in vivo competition experiments highlight the importance of the gluconeogenesis pathway in UPEC for optimal fitness of the pathogen in both healthy and diabetic hosts. Collectively, our results indicate that both…
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