Hyperglucosuria induced by dapagliflozin augments bacterial colonization in the murine urinary tract

Abstract

AimTo test the effects of dapagliflozin‐induced hyperglucosuria on ascending bacterial urinary tract infection (UTI) in a mouse model.MethodsDapagliflozin or canagliflozin was used to induce hyperglucosuria in non‐diabetic adult female mice prior to transurethral inoculation with uropathogenic Escherichia coli (UPEC) or Klebsiella pneumoniae. Glucose, bacterial load, cytokines, neutrophil mobilization and inflammation during acute and chronic UTI were determined.ResultsSignificant increase in UPEC load was observed in the urinary tract of hyperglucosuric mice compared with controls. Dapagliflozin‐treated mice developed bacteraemia resulting in UPEC colonization of the spleen and liver at a higher frequency than controls. Chronic UTI in hyperglucosuric mice resulted in an increased incidence of renal abscesses. Histopathological evaluation revealed only modest increases in tissue damage in the urinary bladders and kidneys of dapagliflozin‐treated mice, despite a profound increase in bacterial load. There was poor neutrophil mobilization to the urine of hyperglucosuric mice. We also observed a delayed increase of IL‐1β in urine, and bladders, and IL‐6 in urine of hyperglucosuric mice. Experimental inoculation with K. pneumoniae also revealed higher bacterial burden in the urinary bladder, spleen and liver from dapagliflozin‐treated mice compared with controls.ConclusionCollectively, our results indicate that dapagliflozin‐induced hyperglucosuria in non‐diabetic female mice leads to increased susceptibility to severe UTI, and bacteraemia of urinary tract origin.

Vaginal Inoculation of Uropathogenic Escherichia coli during Estrus Leads to Genital and Renal Colonization

“…S1). Levels of these analytes in UPEC-instilled mice were compared to those in phosphate-buffered saline (PBS)-instilled or unmanipulated naive mice at the 1-day endpoint, as reported by us and others ( 27 – 29 ). There were no significant differences in the levels of these analytes as determined by a semiquantitative ELISA between groups at this early time point (Fig.…”

“…Urine and homogenates of the vagina, uterus, bladder, and kidneys were used to determine the abundances of myeloperoxidase (MPO), IL-1β, IL-6, and TNF-α, as we have recently described ( 28 , 59 ). Urine samples were normalized based on the creatinine content, and tissue samples were normalized to the weight of organs.…”

Systematic Review of Literature Examining Bacterial Urinary Tract Infections in Diabetes

“…In this regard, we exposed Gram positive GBS to human urine supplemented with 300 mg/dl glucose for 2 h and observed augmentation of virulence characteristics such as adherence to human bladder epithelium, hemolysis, and resistance to antimicrobial peptide LL-37, and a higher urinary burden of glycosuria-exposed GBS in a mouse model of ascending UTI [ 93 ]. The effects of glycosuria on UTI pathogenesis have also been studied by experimental induction of ascending UTI in SGLT2i-treated mice [ 94 , 95 ]. In dapagliflozin- or canagliflozin-treated CBA/J mice, transurethral inoculation with UPEC strain CFT073 or K. pneumoniae- KPPR1 significantly increased bladder and urine bacterial burden and resulted in higher bacterial dissemination to spleen at 24 hpi; this was attributed to significant reduction in the levels of proinflammatory cytokines IL-6, IL-1 β , and TNF α and neutrophil myeloperoxidase (MPO) in the urine of SGLT2i-treated mice [ 94 ].…”

Copper Resistance Promotes Fitness of Methicillin-Resistant Staphylococcus aureus during Urinary Tract Infection

“…Bladders and kidney sections were fixed in formalin prior to embedding in paraffin. Sections were stained with hematoxylin and eosin and evaluated in a blinded manner by a board-certified veterinary anatomic pathologist as described earlier ( 70 ). Criteria used for assessment include the presence of neutrophils, degree of inflammatory changes, presence of bacteria, and tissue damage.…”

“…Urine and homogenates of bladder and kidneys were used for determination of myeloperoxidase (MPO; ThermoScientific), IL-1β, IL-6, and TNF-α (R&D Systems). Assays were performed in duplicate and in accordance with the manufacturer’s instructions, as we have reported earlier ( 70 ).…”