Whole-body Omega-3 and Omega-6 fatty-acid reserves in healthy controls and fatal COVID-19: Evidence of systemic long-chain n-3 depletion.

BACKGROUND & AIMS: While circulating lipid biomarkers are widely used, little is known about the absolute tissue reserves of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) in humans or their availability during severe systemic illness. We therefore mapped absolute PUFA concentrations across major human tissues and examined whether fatal COVID-19 is associated with depletion of long-chain n-3 substrate pools. METHODS: Absolute fatty acid concentrations (mg/g wet tissue) were quantified across nine tissues (adipose tissue, brain, heart, lungs, liver, spleen, skeletal muscle, small intestine, and kidney) using gas chromatography with flame-ionization detection (GC-FID). Whole-body fatty-acid reserves were then estimated from tissue concentrations and organ weights. The cohort included sudden-death controls and patients with fatal COVID-19 pneumonia. RESULTS: Controls exhibited distinct organ-specific lipid signatures with high n-3 concentrations in adipose tissue and brain. In fatal COVID-19, we observed a coherent cross-organ reduction in long-chain n-3 substrate pools driven primarily by depletion of EPA and DPA. DHA showed tissue-specific preservation or relative elevation, most notably in brain, adipose tissue, and spleen. Adipose tissue, the primary reservoir, showed a severe imbalance characterized by an approximately 3.3-fold increase in the n-6/n-3 ratio (median 50.66 vs. 15.56; p = 0.004) and lower total n-3 content (0.93 vs. 2.76 mg/g; p = 0.004). Brain tissue displayed species-specific remodeling: EPA and DPA were lower in COVID-19, whereas DHA was relatively higher (EPA, 0.018 vs. 0.16 mg/g; p = 0.004). In the lungs, EPA was similarly depleted (0.015 vs. 0.34 mg/g; p = 0.004), and the myocardium shifted toward a pro-inflammatory profile with an elevated n-6/n-3 ratio (16.87 vs. 4.01; p = 0.004). Estimated whole-body n-3 reserves were lower in the COVID-19 group (41.7 g vs. 86.6 g). CONCLUSIONS: This study establishes a comprehensive quantitative human tissue map of absolute PUFA reserves and suggests that severe systemic illness, exemplified here by fatal COVID-19, is associated with coherent depletion of long-chain n-3 substrates across organs. These findings support the concept that tissue substrate availability may be a clinically relevant constraint on resolution signalling during acute metabolic stress.