Early-life enteric infection and enteropathy markers are associated with changes in adipokine, apolipoprotein and cytokine profiles later in childhood consistent with those of an adverse cardiometabolic disease risk profile in a Peruvian birth cohort

Abstract

Background: Metabolic syndrome is a cluster of risk factors for cardiovascular disease thought to afflict over a billion people worldwide and is increasingly being identified in younger age groups and socio-economically disadvantaged settings in the global south. Enteropathogen exposure and environmental enteropathy in infancy may lead to metabolic syndrome by disrupting the metabolic profile in a way that is detectable in cardiometabolic markers later in childhood. Methods: 217 subjects previously enrolled in a birth cohort in Amazonian Peru were followed up annually from ages 2 to 5 years. Blood samples collected in later childhood were analyzed for a panel of 37 cardiometabolic biomarkers, including adipokines, apolipoproteins, cytokines, and other analytes. These were matched to extant early-life markers of enteropathy ascertained between birth and 2 years of age and multivariate and multivariable regression models were fitted to test for associations adjusting for confounders. Results: Fecal and urinary markers of intestinal permeability and inflammation (myeloperoxidase, lactulose and mannitol) measured from birth to 2 years of age were independently associated with later serum concentrations of soluble CD40-ligand, a proinflammatory cytokine correlated with adverse metabolic outcomes. Fecal myeloperoxidase was also strongly, directly associated with later levels of the anti-inflammatory adipocytokine omentin-1. Cumulative enteric protozoa exposure before 2 years of age showed stronger associations with later cardiometabolic markers than enteric viruses and bacteria and overall diarrheal episodes. Conclusion: Early-life markers of enteric infection and enteropathy were associated with numerous changes in adipokine, apolipoprotein and cytokine profiles later in childhood consistent with those of an adverse cardiometabolic disease risk profile in this Peruvian birth cohort. Markers of intestinal permeability and inflammation measured in urine (lactulose, mannitol) and stool (MPO, protozoal infections) during infancy, may predict disruptions to cytokine and adipocytokine production in later childhood that are precursors to metabolic syndrome in adulthood. Chronic enteric infections, such as by protozoan pathogens, may be more important drivers of these changes than symptomatic diarrhea or growth faltering.