Alpha-ketoglutarate alleviates chronic kidney disease via mitochondrial protection, gut microbiota, and metabolite remodeling.

Chronic kidney disease (CKD) is a significant global health challenge, yet no effective pharmacological interventions exist for it. Alpha-ketoglutarate (AKG) is widely utilized in food and nutritional supplements, demonstrating anti-inflammatory, antioxidant, and gut barrier-protective properties. However, the therapeutic potential and underlying mechanisms of AKG in CKD remain unclear. This study aimed to investigate the effects of AKG on CKD mice and its potential mechanism. Male specific-pathogen-free C57BL/6 mice were fed a control diet or 0.25% adenine diet and administered 0.9% saline (vehicle) or 0.9% saline containing 2% AKG for 28 days. Using a combination of transmission electron microscopy (TEM), 16S ribosomal ribonucleic acid (rRNA) gene sequencing, metabolomics, and bioinformatics approaches, this study investigated the underlying mechanisms by which AKG alleviated CKD. We found that AKG ameliorated renal injury in CKD mice, attenuating inflammatory responses and fibrotic progression. AKG administration effectively restored mitochondrial ultrastructural abnormalities and functional impairments in CKD models. Notably, AKG treatment restored gut microbiota β-diversity: specifically, it increased Bacteroidetes abundance while decreasing the Firmicutes/Bacteroidetes ratio. At the genus level, it reduced the abundances of Bacteroides and Dorea and increased those of AF12 and Alistipes. Metabolomic analysis identified AKG-mediated regulation of 17 CKD-associated metabolites (including aldosterone, bufalin, and n-acetylproline). Bioinformatic integration predicted a potential role for tripartite crosstalk among mitochondrial function, gut microbiota composition, and fecal-metabolite profiles, potentially orchestrated through the focal-adhesion kinase (FAK)-phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling axis. These findings suggested that the nephroprotective effects of AKG against CKD could be mediated through the coordinated interplay of mitochondrial homeostasis, gut microbiota remodeling, and metabolic reprogramming.