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.

Figure 1. Orthogonal projection to latent structures (OPLS) model identifying metabolic associations with measures of undernutrition.

Coefficients plot extracted from the OPLS model constructed from the urinary ¹H NMR profiles and corresponding (A) height-for-age z (HAZ)-scores (B) weight-for-age z (WAZ)-scores and (C) weight-for-height z (WHZ)-scores. 2HIB, 2-hydroxyisobutyric acid; 2-PY, N-methyl-2-pyridone-5-carboxamide; 3-IS, 3-indoxyl sulfate; 4-CS, 4-cresyl sulfate; DMA, dimethylamine; DMG, dimethylglycine; MG, methylguanidine; NAG, N acetylglycoprotein; NMNA, N-methylnicotinic acid; PAG, phenylacetylglutamine.

Figure 2. Summary of the metabolites associated with the OPLS models given by the correlation coefficient (R) with the response variable.

HAZ, height-for-age z-score; WAZ, weight-for-age z-score; WHZ, weight-for-height z-score; ΔHAZ, change in height-for-age z-score over two to five months. 2HIB, 2-hydroxyisobutyric acid; 2-PY, N-methyl-2-pyridone-5-carboxamide; 3-IS, 3-indoxyl-sulfate; 4-CS, 4-cresyl sulfate; BAIBA, β-aminoisobutyric acid; DMA, dimethylamine; DMG, dimethylglycine; MG, methylguanidine; NAG, N acetylglycoprotein; NMNA, N-methylnicotinic acid; NMND, N-methylnicotinamide; PAG, phenylacetylglutamine.

Figure 3. OPLS coefficients plot identifying metabolic predictors of growth in stunted children or those at risk of stunting.

Baseline urinary metabolic profiles of children with a baseline HAZ <−1 correlated with ΔHAZ measured two to five months later. 2-PY, N-methyl-2-pyridone-5-carboxamide; BAIBA, β-aminoisobutyric acid; NMNA, N-methylnicotinic acid; NMND, N-methylnicotinamide.

Figure 4. Metabolic pathways modulated by undernutrition.

Red solid arrows indicate pathways increased with undernutrition (negatively associated with HAZ, WAZ, WHZ) and green solid arrows indicate pathways decreased with undernutrition (positively associated with HAZ, WAZ, WHZ). Dashed green arrows indicate pathways and biological functions hypothesized to decrease as a result of these metabolic alterations. 3-IS, 3-indoxyl-sulfate; DMG, dimethylglycine; IDO, indoleamine 2,3-dioxygenase; NAD, nicotinamide adenine dinucleotide; NMND, N-methylnicotinamide; NNMT, nicotinamide N-methyltransferase; PC, phosphatidylcholine; SAH, S-adenosyl-L-homocysteine; SAMe, S-adenosyl-L-methionine; VLDL; very-low-density lipoproteins.