Diet Alters Serum Metabolomic Profiling in the Mouse Model of Chronic Chagas Cardiomyopathy

Abstract

Chagas disease is caused by Trypanosoma cruzi which is endemic in Latin America. T. cruzi infection results in a latent infection with approximately a third of latently infected patients developing chronic Chagas cardiomyopathy (CCM). CCM is a common cause of cardiomyopathy in endemic regions and has a poor prognosis compared to other cardiomyopathies. The factors responsible for the transition from the asymptomatic indeterminate latent stage of infection to CCM are poorly understood. Our previous studies demonstrated that lipid metabolism and diet are important determinants of disease progression. In the present study, we analyzed various serum metabolomic biomarkers such as acylcarnitines, amino acids, biogenic amines, glycerophospholipids, and sphingolipids in murine models of CCM, where the mice specifically develop either left or right ventricular cardiomyopathy based on the diets fed during the indeterminate stage in a murine model of Chagas disease. Our data provide new insights into the metabolic changes that may predispose patients to CCM and biomarkers that may help predict the risk of developing cardiomyopathy from T. cruzi infection. Author Summary. Chronic Chagas cardiomyopathy (CCM) is a parasitic disease prevalent in Latin America. Currently, no effective drugs or vaccines are available to prevent or cure CCM. The factors involved in the disease severity and progression are poorly understood to design new therapeutic interventions. In order to rapidly identify Chagas patients with a higher risk to develop CCM, a new set of biomarkers specific to Chagas disease is needed. We performed serum metabolomic analyses in chronic T. cruzi-infected mice fed on different diets and identified cardiac ventricular-specific metabolite biomarkers that could define CCM severity. In this paper, we present the results of serum metabolomic analyses and discuss its correlations to the diet-induced metabolic regulations in the pathogenesis of CCM in a murine model of Chagas disease.

Alterations to the cardiac metabolome induced by chronicT. cruziinfection relate to the degree of cardiac pathology

“…T. cruzi infection has been previously found to alter levels of members of the phosphocholine metabolic family in the serum and heart. 30,32,36 Our observation of positive correlation between overall phosphocholines and phosphocholines in mass ranges m/z 400-499, 500-599 vs fibrosis and/or inflammation concurs with our observation of infection-induced elevation in phosphocholines in an independent chronic infection system. 32 Phosphocholines are key factors in metabolism of lipids, choline production, and membrane structure.…”

“…We and others previously identified perturbation in acylcarnitine metabolism induced by T. cruzi infection when comparing infected vs uninfected animals. [30][31][32][33]36 In the current study, we found alterations in cardiac tissue acylcarnitine metabolite abundances correlate to severity of cardiac inflammation and fibrosis, as well as serum levels of cardiac fibrosis biomarkers, with mid-chain acylcarnitines in particular negatively correlated with serum PDGF. These results complement previous findings and concur with our prior observation of reduced mid-chain acylcarnitines in the heart of C3H/HeJ mice chronically infected with two different T. cruzi strains, Sylvio X10/4 (DTU TcI) and CL (DTU TcVI).…”

Spatial metabolomics identifies localized chemical changes in heart tissue during chronic cardiac Chagas Disease

“…Prior analysis of hearts from acutely infected mice also showed that cardiac metabolite profiles reflected disease severity, with changes in cardiac acylcarnitines and glycerophosphocholines predictive of acute infection outcome [ 9 ]. Metabolomic analysis of chronic CD has been limited to serum and gastrointestinal tract samples [ 18 , 19 ]. Serum analysis demonstrated significant changes in amino acid and lipid metabolism, particularly acylcarnitines, sphingolipids, and glycerophospholipids [ 19 ].…”

“…Metabolomic analysis of chronic CD has been limited to serum and gastrointestinal tract samples [ 18 , 19 ]. Serum analysis demonstrated significant changes in amino acid and lipid metabolism, particularly acylcarnitines, sphingolipids, and glycerophospholipids [ 19 ]. Analysis of GI tract samples observed persistent metabolic perturbations in the oesophagus and large intestine in chronic CD, including infection-induced elevation of acylcarnitines, phosphatidylcholines and amino acid derivatives [ 18 ].…”

Fat tissue regulates the pathogenesis and severity of cardiomyopathy in murine chagas disease

“…T. cruzi infected mice that are treated with the ER stress inhibitor, 2-Aminopurine or the lipid biosynthesis inhibitor Betulin have a significant modulation in cardiomyopathy, mitochondrial stress, and ER stress during chronic infection [4]. Cardiac lipid levels are regulated by many intrinsic and external factors including genetics, diet, and metabolic status [5]. High-fat diet differentially regulates cardiac parasite load, lipid accumulation, and pathology and survival rate during acute and chronic T. cruzi infection in mice and this effect is dependent on the observed body fat mass [6].…”