Ceftriaxone administration reduces vascular calcification associated with experimental models of chronic kidney disease.

Abstract

Gut microbiota dysbiosis has been implicated in systemic inflammation, potentially exacerbating chronic kidney disease (CKD) and vascular calcification (VC). The effects of gut microbiota depletion on VC using antibiotics remain largely unknown. We investigated the role of microbiota depletion in chronic and acute experimental models of CKD and VC in Wistar rats. The chronic CKD model consisted of 5/6 nephrectomy (Nx), a moderate-phosphate diet (0.9 %), and intraperitoneal injections of calcitriol (25 ng/kg i.p every 48 h) for 30 days. For the following 15 days, dietary phosphate was increased to 1.2 %, and calcitriol at 40 ng/kg i.p every 48 h. In the acute VC model, a high-phosphate diet (1.2 %) and calcitriol (60 ng/kg every 48 h) were administered for 14 days after the Nx. In both models, half of the animals received oral ceftriaxone (ATB, 400 mg/kg/day) for seven days prior to Nx. Parameters related to mineral metabolism, kidney function, bone histomorphometry and mineralization, VC, calcification-related signaling pathways, uremic toxins, and fecal microbiota composition and functional inference were analysed. Antibiotic-treated rats showed significantly lower serum phosphate levels, reduced uremic toxins, and decreased VC with no effects on bone turnover. Colidextribacter and Escherichia-Shigella were positively correlated with serum phosphate levels. Interestingly, Ceftriaxone treatment reduced the abundance of such genera. Additionally, the abundance of Colidextribacter also correlated with calcium content in the thoracic aorta. In conclusion, microbiota depletion by ceftriaxone reduced hyperphosphatemia and VC in experimental CKD and VC models. These findings support the potential of targeting the gut microbiota as a novel strategy to mitigate mineral metabolism disturbances and VC in CKD.