Underlying Metabolic Syndrome Exacerbates Vibrio vulnificus-induced Acute Kidney Injury via Systemic Th17/Treg Dysregulation

Climate change has led to a rise in Vibrio vulnificus infections, while the global obesity epidemic has increased susceptibility to severe bacterial infections. Obesity and high‐fat diet (HFD) consumption promote systemic inflammation and immune dysregulation, which may exacerbate sepsis and its complications, including acute kidney injury (AKI). This study investigates the mechanistic role of HFD-induced metabolic dysfunction in V. vulnificus sepsis‐associated AKI. Adult C57BL/6J mice were placed on a standard CHOW diet or a 60% kcal HFD for six weeks prior to infection. V. vulnificus infection was induced via intragastric administration by oral gavage of 10⁸ CFU of V. vulnificus suspended in PBS. Kidney function was assessed, and kidney tissues were analyzed for markers of inflammation, oxidative stress and necrosis. Systemic Th17/Treg ratios were determined. In vitro, renal proximal tubular epithelial cells were treated with leptin and IL‐17A with/without an IL‐17 receptor antagonist to confirm the role of IL‐17 signaling renal epithelial cell pathology. A pro‐inflammatory Th17/Treg imbalance along with a marked increase in renal TLR4 activation, inflammation and necrosis was observed in the HFD +VV group. In vitro studies confirmed that IL‐17 and leptin synergistically activate the NF‐κB pathway, promoting inflammatory cytokine release. These findings indicate that HFD‐induced metabolic stress exacerbates V. vulnificus sepsis‐associated AKI. The interplay between IL‐17 signaling and leptin may further amplify renal injury, underscoring the need for targeted interventions. Strategies to modulate IL‐ 17 signaling and metabolic inflammation may offer novel therapeutic approaches to reduce AKI severity in obese individuals with bacterial sepsis.