Metabolomics in Corneal Diseases: A Narrative Review from Clinical Aspects

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TL;DR

This narrative review summarizes metabolomic studies in corneal diseases, including dry eye disease, keratoconus, diabetic corneas, and others. Metabolomic profiling of tears and corneal tissue reveals distinct metabolic signatures, such as oxidative stress markers and altered lipid metabolism, that may serve as biomarkers or therapeutic targets. The review highlights the potential of metabolomics for personalized diagnosis and treatment, while noting the need for standardized methods and larger studies.

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**Background:** Metabolomics is an emerging field that analyzes low-molecular-weight metabolites in biological systems, reflecting cellular activity and physiological status. In ophthalmology, metabolomics has been applied to study diseases such as diabetic retinopathy, age-related macular degeneration, glaucoma, and uveitis. For corneal diseases, metabolomic analysis of tears or aqueous humor can reveal biomarkers with greater sensitivity and specificity than plasma or serum. This narrative review aims to summarize the literature on metabolomics in corneal diseases, focusing on dry eye disease (DED), Sjogren's syndrome, contact lens wear, refractive surgery, keratoconus, and diabetic corneas.

**Methods:** The review is a narrative synthesis of published studies on metabolomics in corneal diseases. It describes two principal analytical modalities: nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). NMR is rapid, reproducible, and non-destructive but less sensitive than MS. MS is highly sensitive and can be coupled with separation techniques like liquid chromatography (LC-MS) or gas chromatography (GC-MS). The review covers targeted and non-targeted metabolomic approaches and includes studies using various sample sources (tears, corneal tissue, aqueous humor, serum, urine) and experimental models (in vitro, animal, human).

**Key Results:** The review presents findings from multiple studies: - **Dry Eye Disease (DED):** In a rat model, MALDI-MSI showed altered glycerophospholipid and phenylalanine metabolism, increased betaine (cytoprotective), and decreased arginine (anti-inflammatory) in DED. Serum eye drops (cord blood serum vs. peripheral blood serum) contained higher levels of choline, creatine, beta-hydroxybutyrate, and myo-inositol, which may alleviate DED. Oral supplementation with essential polyunsaturated fatty acids (EPUFAs) modified the tear metabolomic profile, increasing choline and acetylcholine. - **Sjogren's Syndrome:** A study using LC-MS identified nine tear metabolites that could distinguish primary Sjogren's syndrome from DED, including increased phospholipids and decreased dopamine and serine. - **Contact Lens Wear:** Lipidomic analysis showed that daily wear lenses had a lower ratio of unsaturated to saturated lipids (1:2 vs. 1:9) compared with continuous wear lenses. Prolonged wear increased free cholesterol and phospholipids in tears, and LC-MS of corneal lenticules revealed upregulation of inflammatory factors (arachidonic acid, linoleic acid) and short-chain organic acids, along with downregulation of neuroprotective metabolites (taurine, docosahexaenoic acid). - **Refractive Surgery:** After SMILE, older patients (41–50 years) had higher levels of inflammatory metabolites (uric acid, histidine, arachidonic acid) and lower levels of antioxidants (ascorbic acid, taurine, spermidine) compared with younger patients (18–30 years), correlating with slower corneal nerve recovery. - **Keratoconus:** In vitro studies showed elevated lactate/pyruvate ratios and decreased glutathione ratios in keratoconic cells, indicating oxidative stress. Corneal buttons from keratoconus patients had downregulated unsaturated fatty acids and gluconic acid (pentose phosphate pathway intermediate) only in keratoconus. Collagen crosslinking (CXL) increased antioxidants (GSH, ascorbic acid) and decreased pro-inflammatory metabolites (myo-inositol, histidine) in keratoconus corneas. Tear analysis after CXL showed increased N-acetyl-L-aspartic acid and decreased 3-OH butyric acid. - **Diabetic Corneas:** Tears from type 2 diabetes patients had higher levels of carnitine, nicotinic acid, sorbitol, and several amino acids (aspartic acid, glutamate, glutamine, methionine, serine, threonine, tyrosine, valine). Cadaver corneal analysis showed altered lipid metabolism (upregulated sphingosine and dihydrosphingosine) and dysregulated kynurenine metabolism in type 1 diabetes. In vitro 3D constructs demonstrated that corneal innervation influences metabolic pathways, with myo-inositol dysregulation linked to neuronal dysfunction.

**Clinical Implications:** Metabolomic profiling offers potential for personalized diagnosis and treatment of corneal diseases. Identified biomarkers may enable early detection, disease monitoring, and targeted therapies. For example, betaine and beta-hydroxybutyrate are being investigated as treatments for DED, and arginine supplementation may support collagen secretion in keratoconus. However, the review emphasizes the need for standardized techniques, larger sample sizes, and longer follow-up to validate these findings. Metabolomics holds promise for constructing a library of corneal metabolic signatures to improve understanding of pathogenesis and treatment efficacy.