Sepsis is a severe condition causing widespread organ damage and failure, affecting multiple systems like cardiovascular, immune, and metabolic. Understanding of the mechanisms remains limited, hindering targeted treatments.
Metabolism, especially mitochondrial dysfunction, has emerged as a key factor in sepsis progression. Biomarkers like lactate are commonly used, though their prognostic value is debated. Metabolomics has identified mitochondrial metabolic signals linked to sepsis severity and outcomes. However, most studies are cross-sectional; longitudinal, organ-focused research is needed to clarify if metabolic changes cause or result from organ dysfunction. Since metabolic pathways are conserved across species, metabolism offers a valuable bridge for translational research.
A recent study analysed human and murine sepsis models to show that blood mitochondrial metabolic signals mirror organ metabolism disruptions and may provide targets for therapy. Two patient cohorts were studied: (1) a secondary analysis of septic shock patients from the placebo arm of a multicentre trial on L-carnitine, and (2) a new cohort of sepsis patients without shock, defined by SEPSIS-3 criteria, enrolled at the University of Michigan between 2018 and 2020 (excluding COVID-19 patients and those with serum lactate >2 mmol/L to exclude shock).
Metabolomics assays measured 55 energy-related metabolites, including acylcarnitines and those involved in glycolysis, the TCA cycle, and nucleotide metabolism. Several blood metabolites showed significant correlations with organ dysfunction, even after adjusting for age, sex, and BMI and correcting for multiple comparisons. In septic shock patients, acylcarnitines were the main metabolites linked to organ dysfunction, besides creatinine, correlating with kidney function. Combining data from both cohorts, blood markers related to L-carnitine (LC) metabolism (acetylcarnitine [C2] and the C2/LC ratio) were consistently associated with overall and specific organ failure scores (SOFA), independent of demographic factors.
To investigate sepsis-related metabolic changes at the organ level, metabolites were measured in kidney and liver tissues from septic (CLP), sham, and healthy mice. Early metabolic alterations appeared by 6 hours post-sepsis in both organs, with some changes persisting up to 48 hours. In kidneys, histidine and creatine changes lasted, while aspartate decline was transient; in the liver, most altered metabolites remained different from sham at 48 hours. Despite these metabolic shifts, blood markers of kidney and liver function (creatinine and bilirubin) were unchanged early on, and no liver apoptosis was detected; kidney apoptosis appeared only after 48 hours. Pathway analyses revealed distinct organ-specific metabolic disruptions due to sepsis.
Building on human data linking LC metabolites to organ dysfunction scores, researchers studied temporal changes in blood LC, acetylcarnitine (C2), and their ratio (C2/LC) in septic mice. Early in sepsis, LC metabolites were unchanged, but by 24–48 hours, blood LC declined while the C2/LC ratio rose, paralleling human findings. Several kidney and liver metabolites correlated with this blood ratio, indicating that blood signals reflect organ metabolic changes. The study focused on carnitine acetyltransferase (CAT), a mitochondrial enzyme regulating LC metabolism and energy substrate use. CAT activity rose early in both organs but normalised in the liver while progressively increasing in the kidney. In the kidney, changes indicated disrupted LC homeostasis and reduced energy balance and charge, unlike in the liver. These distinct metabolic alterations in kidney and liver occur early in sepsis, preceding clinical or pathological signs of organ dysfunction.
Thirteen metabolites that differed between septic and control mice in kidney and liver tissues were also found in human blood samples. After adjusting for age, sex, and BMI, several of these metabolites showed significant associations with overall, renal, and liver organ dysfunction scores in sepsis patients. Specifically, histidine, aspartate, glutamate, malate, and asparagine remained significantly linked with total SOFA scores, while histidine and glutamate were strongly associated with renal and liver SOFA scores, respectively. These results support a close connection between organ metabolism and physiological organ function during sepsis.
This study shows that many blood metabolites correlate with overall and organ-specific (kidney and liver) dysfunction scores. A key consistent finding is the disruption of LC homeostasis, measured by the blood acetylcarnitine/LC (C2/LC) ratio, which correlates with sepsis severity and organ metabolic changes. In mice, distinct metabolic pathway disruptions were observed early (within 6 hours) in kidney and liver tissues: kidney metabolism was mainly affected in alanine, aspartate, and glutamate pathways, while liver metabolism showed changes in aromatic amino acid metabolism. These metabolic shifts precede clinical or histological evidence of organ injury and likely reflect early alterations in organ energy demands during sepsis.
Organ-specific differences were noted: the liver maintained LC and energy metabolite balance better than the kidney. In the kidney, loss of LC homeostasis led to reduced energy balance and ATP charge, potentially impairing critical kidney functions like glucose and electrolyte transport. These findings highlight an early, preclinical metabolic crisis in sepsis-affected organs, offering a window for therapeutic intervention before irreversible injury occurs. The study underscores mitochondrial dysfunction and energy metabolism disruption as central features of sepsis pathophysiology.
In summary, sepsis-induced organ dysfunction is preceded by distinct metabolic changes reflected in blood metabolites, notably a disruption of LC homeostasis measured by the C2/LC ratio. These metabolic signatures align with each organ’s unique physiology and may reveal earlier, more relevant indicators of organ function than current clinical measures. This understanding opens new avenues for studying sepsis mechanisms and developing targeted therapies. Interventions that modify metabolism, such as nutritional approaches like ketogenic diets, could become part of strategies to prevent organ failure, complementing existing sepsis treatment guidelines.
Source: American Journal of Respiratory Cell and Molecular Biology
Image Credit: iStock
References:
McCann MR, Fry C, Maile MD et al. (2025) Early Sepsis Metabolic Changes in Kidney and Liver Precede Clinical Evidence of Organ Dysfunction. American Journal of Respiratory Cell and Molecular Biology.
