Int Immunopharmacol. 2026 Aug 10;187:117238. doi: 10.1016/j.intimp.2026.117238. Online ahead of print.
ABSTRACT
Chronic kidney disease (CKD) is increasingly recognised as a systemic disorder driven by interconnected disturbances in gut microbial balance, metabolic regulation and renal cellular stress responses rather than by isolated renal dysfunction alone. Current therapies mainly slow disease progression but do not fully address the molecular networks responsible for renal inflammation, fibrosis and cardiovascular complications. This review summarises evidence showing that CKD is associated with gut dysbiosis marked by depletion of short-chain fatty acids (SCFAs) producing bacteria and enrichment of proteolytic, uremic toxin-generating microbial populations. These alterations increase the production and systemic accumulation of gut-derived metabolites such as indoxyl sulphate (IS), p-cresyl sulphate (pCS) and trimethylamine-N-oxide (TMAO) while reducing protective metabolites such as SCFAs and secondary bile acids. Accumulated uremic toxins contribute to oxidative stress, endothelial dysfunction, nuclear factor kappa B (NF-κB) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation, mitochondrial injury and renal fibrotic remodelling. Autophagy is discussed as a central regulatory mechanism connecting microbial metabolites with renal cell injury. Dysregulation of AMPK-mTOR signalling, ULK1-Beclin-1 complex activity and PINK1-Parkin-dependent mitophagy impairs mitochondrial quality control, promotes redox imbalance and supports progressive tubular damage, podocyte injury and interstitial fibrosis. Metabolomics further provides a systems-level approach for identifying CKD associated metabolic signatures including amino acid imbalance, lipid dysregulation, mitochondrial energy defects and accumulation of gut-derived uremic solutes. By integrating these findings, this review proposes the microbiota-autophagy-metabolomics triad as a useful framework for understanding CKD progression. This model highlights how gut dysbiosis alters systemic metabolite profiles, how these metabolites regulate renal autophagic activity, and how impaired autophagy further promotes metabolic and inflammatory reprogramming. Targeting gut microbiota, microbial metabolites and autophagy-related pathways may therefore facilitate future biomarker development and precision-based therapeutic strategies for CKD management.
PMID:42574806 | DOI:10.1016/j.intimp.2026.117238