Analysis of Gut Microbiota Metabolites in Chronic Kidney Disease-Associated Pruritus Using Network Pharmacology and
Lingling Sun1, Yining He2, Min Jiang1
1First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Background:
Chronic kidney disease-associated pruritus (CKD-aP) remains a frequent and distressing symptom in patients with renal dysfunction, yet its biological mechanisms are still not well defined. Growing evidence suggests that gut microbiota-derived metabolites may participate in systemic inflammatory regulation, providing a potential entry point for exploring CKD-aP pathogenesis.
Objectives:
This study aimed to elucidate how gut microbial metabolites interact with host molecular targets involved in CKD-aP, and to identify candidate metabolites with therapeutic relevance through integrative bioinformatics approaches.
Materials And Methods:
Gut metabolite data were retrieved from the gutMGene database, and CKD-aP-related genes were collected from GeneCards, DisGeNET, and OMIM. Intersection targets were processed through STRING-based protein-protein interaction (PPI) analysis, followed by Gene Ontology and KEGG pathway enrichment using the DAVID platform. An integrated microbiota-substrate-metabolite-target (MSMT) network was constructed to visualize microbial-metabolic interactions. Key metabolites were subsequently examined by molecular docking to assess binding affinity with pivotal targets.
Results:
A total of 44 overlapping genes were identified between microbial metabolites and CKD-aP, among which IL6, AKT1, and PPARG were highlighted as major hub regulators. MSMT network analysis indicated strong associations among Lacticaseibacillus paracasei, tryptophan-related metabolites, and linoleic-acid-derived compounds in modulating CKD-aP. KEGG results emphasized pathways enriched in inflammatory and immune responses, including IL-17, C-type lectin receptor, and Toll-like receptor signaling. Docking simulations supported robust interactions for several metabolites, particularly 10-keto-12Z-octadecenoic acid with PPARG, Genipin with CASP3, and Urolithin A with CYP1A1.
Conclusion:
Our findings suggest that gut microbial metabolites may alleviate CKD-aP by targeting IL6, AKT1, and PPARG through inflammatory signaling pathways. Notably, 10-keto-12Z-octadecenoic acid from Lacticaseibacillus paracasei demonstrates strong binding affinity with PPARG, highlighting the potential of probiotic-derived metabolites as novel therapeutic strategies for managing pruritus in chronic kidney disease patients.