The gut–kidney axis is regulated by astragaloside IV to inhibit cyclosporine A-induced nephrotoxicity

Introduction Chronic nephrotoxicity caused by CNIs (CICN) manifests clinically as chronic kidney disease (CKD). Astragaloside IV (AS-IV) plays a certain role in the treatment of CKD. This study aimed to verify the ameliorative effects of AS-IV on CICN and further explore the mechanisms underlying the modulation of the “gut–transcriptome–metabolome coexpression network” by AS-IV within the context of the “gut–kidney axis” to improve CICN. Methods Five groups of 40 mice were studied: a normal group (N, olive oil), a model group (M, CsA, 30 mg kg -−1  d −1 ), a low-dose AS-IV group (CsA + AS-IV, 30 mg kg −1  d −1 + 10 mg kg −1  d −1 ), a high-dose AS-IV group (CsA + AS-IV, 30 mg kg −1  d −1 + 20 mg kg −1  d −1 ), and a valsartan group (CsA + Val, 30 mg kg −1  d −1 + 10 mg kg −1  d −1 ). The gut microbiota, renal transcriptome, and urine metabolome were separately detected to construct a gut–transcriptome–metabolome coexpression network. The target species, target genes, and target metabolites of AS-IV were evaluated. Results CsA led to increased proteinuria and a deterioration of kidney function, accompanied by increased inflammation and oxidative stress, whereas AS-IV improved kidney damage. AS-IV inhibited intestinal permeability and disrupted the microbiota structure, increasing the abundance of Lactobacillus reuteri , Bifidobacterium animalis , Ignatzschineria indica , and Blautia glucerasea. Six coexpression pathways related to transcription and metabolism, including the citrate cycle , ascorbate and aldarate metabolism , proximal tubule bicarbonate reclamation , glycolysis/gluconeogenesis, ferroptosis, and drug metabolism–cytochrome P450 , were identified. Seven target metabolites of AS-IV were identified in the 6 pathways, including UDP-D-galacturonic acid, 2-phenylethanol glucuronide, dehydroascorbic acid, isopentenyl pyrophosphate, alpha-D-glucose, 3-carboxy-1-hydroxypropylthiamine diphosphate and citalopram aldehyde. Five target genes of AS-IV, Ugt1a2, Ugt1a9, Ugt1a5, Pck1, and Slc7a11, were also identified and predicted by NONMMUT144584.1, MSTRG.30357.1 and ENSMUST00000174821. Lactobacillus reuteri was highly correlated with renal function and the target genes and metabolites of AS-IV. The target genes and metabolites of AS-IV were further validated. AS-IV inhibited intestinal-derived urinary toxins and improved renal tissue apoptosis, lipid accumulation, collagen deposition, and mitochondrial damage. Conclusion AS-IV improved CICN through the coexpression of the gut–transcriptome–metabolome network. The six pathways related to energy metabolism driven by L. reuteri , including the citrate cycle , ascorbate and alderate metabolism , proximal tube bicarbonate metabolism , glycolysis/gluconeogenesis, ferroptosis, drug metabolism–cytochrome P450 , are important mechanisms.