Researchers investigating the metabolic changes across affected organs in a large animal model of sepsis say they have identified both potential common and organ-specific metabolic alterations contributing to the disease process. Their study (“Identification of Metabolic Changes in Ileum, Jejunum, Skeletal Muscle, Liver, and Lung in a Continuous I.V. Pseudomonas aeruginosa Model of Sepsis Using Nontargeted Metabolomics Analysis”) appears in the American Journal of Pathology.
“Sepsis is a multiorgan disease affecting the ileum and jejunum (small intestine), liver, skeletal muscle, and lung clinically. The specific metabolic changes in the ileum, jejunum, liver, skeletal muscle, and lung have not previously been investigated. Live Pseudomonas aeruginosa, isolated from a patient, was given via i.v. catheter to pigs to induce severe sepsis. Eighteen hours later, ileum, jejunum, medial gastrocnemius skeletal muscle, liver, and lung were analyzed by nontargeted metabolomics analysis using gas chromatography/mass spectrometry,” the investigators wrote.
“The ileum and the liver demonstrated significant changes in metabolites involved in linoleic acid metabolism: the ileum and lung had significant changes in the metabolism of valine/leucine/isoleucine; the jejunum, skeletal muscle, and liver had significant changes in arginine/proline metabolism; and the skeletal muscle and lung had significant changes in aminoacyl-tRNA biosynthesis, as analyzed by pathway analysis. Pathway analysis also identified changes in metabolic pathways unique for different tissues, including changes in the citric acid cycle (jejunum), β-alanine metabolism (skeletal muscle), and purine metabolism (liver).
“These findings demonstrate both overlapping metabolic pathways affected in different tissues and those that are unique to others and provide insight into the metabolic changes in sepsis leading to organ dysfunction. This may allow therapeutic interventions that focus on multiple tissues or single tissues once the relationship of the altered metabolites/metabolism to the underlying pathogenesis of sepsis is determined.”
Lead investigator Monte S. Willis, MD, PhD, professor, Krannert Institute of Cardiology, Indiana University School of Medicine, describes sepsis as “an inter-organ network issue.”
“Part of the issue with improving sepsis outcomes is due to our limited understanding of the pathological process,” explained Willis. “While the metabolic crosstalk of organs is taught conceptually, we tend to think of diseases in an organ-specific manner. We need to go beyond treatments that just target symptoms. Our studies illustrate that a broader system view of disease is needed and that metabolic intermediates may be responsible regulators of sepsis and other diseases.”
In this study, pigs were infected with Pseudomonas aeruginosa. Individuals can become ill from eating P. aeruginosa-contaminated food or touching infected moist areas or improperly cleaned medical equipment. Eighteen hours after infection, investigators analyzed tissue samples from the pigs’ intestine, skeletal muscle, liver, and lungs to determine how specific metabolic pathways were affected across organs.
Researchers identified both common metabolic alterations and organ-specific changes in a wider range of metabolic processes than previously reported. Organ-specific deficits in metabolism were also identified, with potential therapeutic implications.
“The observed organ-specific metabolic alterations provide clues to previously unexplored mechanisms of disease, while common metabolic alterations illustrate a broader array of changes than previously reported in individual organ studies. These studies provide insight into the potential for cross-communication among tissues in system disease and how specific organ damage may require therapeutic interventions targeting metabolism,” noted first author Amro Ilaiwy, MD, of the Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Duke University Medical Center.
Willis and his co-investigators emphasize the need to understand disease processes as a network of communicating organs instead of focusing on an isolated organ. Given a basic acceptance of metabolic crosstalk in diseases such as diabetes, there is a basis for expanding these concepts into other complex diseases in other disciplines, such as skeletal muscle and the heart.
An estimated 1.7 million U.S. adults develop sepsis annually, resulting in almost 270,000 deaths. Sepsis produces complex hemodynamic and cellular changes including tissue damage and organ failure, leading to inadequate oxygen delivery to cells. Treatments generally target symptoms such as low blood pressure or the bacteria responsible for infection, but do not address the underlying pathophysiology that occurs in affected organs. Understanding the underlying pathophysiology occurring in affected organs has been a challenge.
Some scientists believe that progress may have been somewhat stymied by approaches that either focus too narrowly on individual organs or aim too broadly at detecting widespread metabolic changes.