Metabolite and lipid profiling of human vitreous reveals purine metabolic dysregulation and inflammatory lipid remodeling as the drivers of bacterial endophthalmitis.

Abstract

Bacterial endophthalmitis, an intraocular infection and inflammation, often progresses rapidly and leads to irreversible vision loss, especially in culture-negative cases where the diagnosis is delayed. We profiled infection-associated metabolomic and lipidomic alterations in the vitreous of patients with microbiological and clinically confirmed bacterial endophthalmitis to understand pathogenesis and identify distinct markers that drive infection and retinal injury. Untargeted metabolomic and lipidomic profiling of vitreous samples from affected patients and non-infectious retinal controls was performed using liquid chromatography coupled to tandem mass spectrometry. Metabolites and lipids with P-value < 0.05 were considered for further pathway-specific analysis. Metabolomic profiling distinctly segregated infected from control samples, revealing dysregulation in purine metabolism, amino acid turnover, polyamine synthesis, redox regulation, and vitamin pathways. Key metabolites, xanthine, hypoxanthine, spermine, seryl-valine, seryl-isoleucine, thymine, O-methyltyramine, and phenyltrimethylammonium, were significantly elevated. These elevations were accompanied by enhanced nucleotide degradation and increased proteolytic activity. Markers of immune activation and oxidative stress were concurrently upregulated, reflecting the broader biochemical disruption characteristic of bacterial endophthalmitis. Antioxidant seleno-L-methionine was downregulated, indicating redox imbalance. Purine, glutathione, vitamin B6, beta-alanine, and arginine-proline metabolism were broadly disrupted. Complementary lipidomics showed extensive vitreous remodeling. Alongside, fatty acids, bile acid derivatives, and membrane lipids were also dysregulated. Bacterial endophthalmitis triggers strong and consistent changes in metabolite and lipid profiles within vitreous, which reflect alterations in immune activation, oxidative stress, tissue breakdown, and metabolic reprogramming. The persistence of these biomolecular signatures in the vitreous highlights host response to infection and subsequent mechanistic elucidation of the specific drivers of retinal inflammation and progressive tissue damage.IMPORTANCEThe study highlights that bacterial endophthalmitis is not only driven by microbial burden but also by host metabolic and lipidomic reprogramming, transforming the understanding of disease pathogenesis. This study reveals metabolite-lipid networks in ocular infections, laying a critical foundation for precision medicine strategies in endophthalmitis management. Specifically, we found significant increases in key metabolites including xanthine, hypoxanthine, spermine, seryl-valine, seryl-isoleucine, thymine, O-methyltyramine, and phenyltrimethylammonium, together reflecting increased nucleotide degradation, proteolytic activity, and immune metabolic reprogramming. These molecular signatures not only provide deeper mechanistic insights into ocular infection but also provide potential biomarkers that could aid in diagnosis and monitoring of infection when conventional microbiological methods are inconclusive. The results highlight the clinical importance of metabolic profiling as a powerful tool to optimize visual outcomes, guide adjunctive therapeutic decisions, and enhance prognostic evaluation in patients affected by the condition.