Urinary N-methylnicotinamide and β-aminoisobutyric acid predict catch-up growth in undernourished Brazilian children

Abstract

Enteric infections, enteropathy and undernutrition in early childhood are preventable risk factors for child deaths, impaired neurodevelopment, and later life metabolic diseases. However, the mechanisms linking these exposures and outcomes remain to be elucidated, as do biomarkers for identifying children at risk. By examining the urinary metabolic phenotypes of nourished and undernourished children participating in a case-control study in Semi-Arid Brazil, we identified key differences with potential relevance to mechanisms, biomarkers and outcomes. Undernutrition was found to perturb several biochemical pathways, including choline and tryptophan metabolism, while also increasing the proteolytic activity of the gut microbiome. Furthermore, a metabolic adaptation was observed in the undernourished children to reduce energy expenditure, reflected by increased N-methylnicotinamide and reduced β-aminoisobutyric acid excretion. Interestingly, accelerated catch-up growth was observed in those undernourished children displaying a more robust metabolic adaptation several months earlier. Hence, urinary N-methylnicotinamide and β-aminoisobutyric acid represent promising biomarkers for predicting short-term growth outcomes in undernourished children and for identifying children destined for further growth shortfalls. These findings have important implications for understanding contributors to long-term sequelae of early undernutrition, including cognitive, growth, and metabolic functions.

Investigation of Variations in the Human Urine Metabolome amongst European Populations: An Exploratory Search for Biomarkers of People at Risk‐of‐Poverty

“…The major findings of this work, decreased urinary levels of citrate and hippurate among ROP populations, agree with a previous study where the concentration of these two metabolites were found to be decreased in the urine of Brazilian children suffering from undernourishment. In this study, urinary citrate was found to be negatively correlated with stunting, and hippurate urinary levels were positively correlated with nutritional parameters such as weight‐for‐age and weight‐for‐height.…”

Metabolic maturation in the first 2 years of life in resource-constrained settings and its association with postnatal growth

“…Complementary to these findings, urinary NMND, a biomarker of nicotinamide and NAD + (nicotinamide adenine dinucleotide) (TCA cycle cofactor) availability, also diminished with age in the study children. Consistent with this finding, we have previously observed urinary NMND to be positively associated with future growth in Brazilian children (8). Tryptophan is an essential amino acid that provides 90% of NAD + via the de novo synthesis pathway and is also important for growth in infants (10,21).…”

Protein- and zinc-deficient diets modulate the murine microbiome and metabolic phenotype

“…Because, choline was provided in all diets as choline bitartrate, the greater excretion of tartrate by the dPD-fed mice further supported this hypothesis. In addition, we recently reported a decrease in endogenous choline metabolism in undernourished children from Northeastern Brazil (4). Other microbial-mammalian cometabolites that were disrupted by the dPD diet included 2-hydroxyisobutyrate, hippurate, 4-hydroxyphenylacetate, m -hydroxyphenylpropionylsulfate, and cinnamate derivatives.…”