Gut microbiota-derived metabolites as potential therapeutic agents for intervertebral disc degeneration: insights...

Increasing evidence highlights the critical role of gut microbiota diversity in maintaining systemic homeostasis; however, the mechanisms by which microbiota-derived metabolites regulate host targets remain incompletely understood. Intervertebral disc degeneration (IDD) is strongly associated with chronic inflammation and metabolic dysregulation. This study employed a network pharmacology approach to elucidate metabolite-target interactions underlying the gut-disc axis.

Gut microbiota-derived metabolites were retrieved from the gutMGene database, and their potential targets were predicted using the Similarity Ensemble Approach and SwissTargetPrediction. IDD-related genes were collected from GeneCards and OMIM databases. Overlapping targets were identified to construct a protein-protein interaction (PPI) network and screen core genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using R software. A gut microbiota-metabolites-targets (G-M-T) network was established, followed by molecular docking to assess metabolite-target binding affinities.

Twenty-two overlapping targets were identified, among which nine key candidates were initially screened. Network analysis revealed IL6, TLR4, CXCL8, and JUN as core targets due to their high connectivity. Enrichment analyses indicated that these targets were mainly involved in inflammatory responses, oxidative stress, apoptosis, extracellular matrix metabolism, and IL-17- and lipid-related pathways. The G-M-T network highlighted butyrate, propionate, acetate, succinate, trimethylamine oxide, and 3-indolepropionic acid as core metabolites. Molecular docking suggested favorable binding affinities, with 3-indolepropionic acid exhibiting the strongest interactions.

Gut microbiota-derived metabolites, particularly 3-indolepropionic acid, may modulate IDD progression by targeting IL6, TLR4, CXCL8, and JUN through inflammation- and lipid-related pathways, providing mechanistic insights into the gut-disc axis.