Low, Intermediate, and High Glutamine Levels Are Progressively Associated with Increased Lymphopenia, a Diminished Inflammatory Response, and Higher Mortality in Internal Medicine Patients with Sepsis

Abstract

Background: The pathophysiological mechanisms underlying altered plasma glutamine concentrations in sepsis remain poorly understood. Identifying clinical, immunological, and metabolic correlates of glutamine fluctuations is crucial to advancing precision medicine, developing targeted therapies, and improving survival outcomes in septic patients. Methods: We enrolled 469 patients with sepsis and assessed inflammatory markers-including body temperature, white blood cell count, and C-reactive protein levels-upon admission to the internal medicine unit. Lymphocyte count and plasma concentrations of glutamine, glutamic acid, 5-oxoproline, phenylalanine, tyrosine, and leucine were measured using gas chromatography-mass spectrometry. Patients were stratified into three groups based on plasma glutamine levels. Mortality was recorded at 30 days and 6 months. Results: Low, intermediate, and high glutamine levels were observed in 46% (n = 217), 47% (n = 218), and 7% (n = 34) of patients, respectively. Patients with hyperglutaminemia exhibited significantly lower body temperature, white blood cell and lymphocyte counts, C-reactive protein levels, and glutamic acid-to-5-oxoproline ratio (a surrogate marker of glutathione availability), along with elevated phenylalanine levels, leucine levels, and tyrosine-to-phenylalanine ratio (all p < 0.01). Metabolic disruption and mortality increased progressively across glutamine level groups. Kaplan-Meier analysis demonstrated significantly higher mortality in patients with elevated glutamine levels at both 30 days (log-rank p = 0.03) and 6 months (log-rank p = 0.05). Conclusions: At baseline, increasing plasma glutamine levels are associated with progressively deeper lymphopenia, more pronounced metabolic derangement, and higher short- and long-term mortality in patients with sepsis.

Keywords: 5-oxoproline; glutamic acid; glutamine; leucine; phenylalanine/tyrosine; sepsis.

Figure 1

Kaplan–Meier curves of freedom from 6-month mortality for patients grouped according to glutamine levels. ABBREVIATIONS: Gln = glutamine and IMU = internal medicine unit. LEGEND: Low, intermediate, and high glutamine levels were defined as glutamine levels < 400 μmol/L, 400–700 μmol/L, and >700 μmol/L, respectively. Log-rank (30 days), p = 0.003; log rank (6 months), p = 0.005.