Severe acute malnutrition (SAM) contributes to the death of millions of children under age five annually. SAM is clinically classified as non-edematous SAM (NESAM) or the more severe edematous SAM (ESAM), which is more common in east-central Africa and the Caribbean. The reason some children develop ESAM while others develop NESAM remains unclear; however, recent studies have identified aberrant one-carbon metabolism (OCM) in ESAM relative to NESAM. Here, we assess genetic variants at 103 loci known to influence OCM, and determine their association with ESAM in 711 samples from Jamaica and Malawi. Seven OCM loci showed evidence of association across both populations, including five associated with homocysteine and folate metabolism (MTHFR, AHCYL1, PRICKLE2, GABBR2, and PLD2). Three SNPs in PLD2, PRICKLE2, and GABBR2, genotyped using cell-free DNA from serum metabolomic samples, supported causal effects on ESAM risk through homocysteine-related metabolites. Cumulatively, OCM-related variants showed more association with ESAM than expected by chance (z = 3.06), with differing effect magnitudes in the two populations. By leveraging chromosomelevel patterns of intracontinental African admixture, we demonstrate that OCM variant associations with ESAM occur on a shared east-African ancestral genetic background. Finally, using whole genome sequence data from eight African populations, we demonstrate that several OCM loci have outlier signatures of selection in multiple populations, including the ESAM-associated PLD2 locus. These findings strengthen support for aberrant OCM in ESAM pathogenesis, with implications for current interventions, and highlight the potential of cell-free DNA, intra-continental admixture, and population genetics in mapping disease risk.

The lack of diversity among human genetic studies has been well-documented in recent years, leading to multiple calls for increased representation of individuals from diverse ancestral groups. This ‘diversity gap’ is evident amongst reference databases derived from large-scale sequencing efforts, which are overwhelmingly populated by individuals of European ancestry. In fact, African populations represent <2% of all GWAS studies. Lack of representation leads to ambiguous genetic testing results and fails to capture unique admixture patterns and novel variants.

BACKGROUND:Bovine milk is a beneficial ingredient in teh treatment of malnutrition. OBJECTIVES:Our objectives were to determine the effect of dietary milk protein and milk carbohydrate on the intestinal permeability, fecal 16S rRNA gene configuration, and fecal metabolomics of children with moderate malnutrition. METHODS:This was a randomized, double-blind, controlled trial among 413 children with wasting in rural Sierra Leone who received 1 of the following 4 supplementary foods, which differed in sources of protein and carbohydrate: milk protein and milk carbohydrate (MPMC), milk protein and vegetable carbohydrate (MPVC), vegetable protein and milk carbohydrate (VPMC), or a control group consuming entirely vegetable-based food (VPVC). After 4 wk, urine and stool were collected from participants enrolled with mid-upper arm circumference of <12.1 cm. Urine was analyzed for lactulose excretion (%L). Stool samples were subjected to both 16S rRNA gene analysis to assess β-diversity and untargeted metabolomic abundance. RESULTS:Among the 386 children who completed permeability testing, the mean difference (95% CI) in %L excretion as compared with VPVC was 0.01 (-0.05, 0.07) for MPMC, 0.05 (-0.01, 0.11) for MPVC, and 0.01 (-0.05, 0.07) for VPMC. Of the 374 children who provided a stool sample that was analyzed, the β-diversity among bacterial taxa was similar between dietary groups (P > 0.05 for all comparisons). No significant differences between dietary groups were seen among the 20 most abundant bacterial taxa. Among the 5769 unique metabolomic features identified, greater flavonoid levels in VPVC were seen. CONCLUSIONS:Abnormal intestinal permeability do not improve with 4 wk of supplementary feeding. Fecal rRNA do not differ with consumption of different diets. This trial was registered at clinicaltrials.gov as NCT04216043.

This Viewpoint discusses food insecurity and the importance of choline-fortified food aid products.

Background Kwashiorkor is a childhood syndrome of edematous malnutrition. Its precise nutritional precipitants remain uncertain despite nine decades of study. Remarkably, kwashiorkor's disturbances resemble the effects of experimental diets that are deficient in one-carbon nutrients. This similarity suggests that kwashiorkor may represent a nutritionally mediated syndrome of acute one-carbon metabolism dysfunction. Here we report findings from a cross-sectional exploration of serum one-carbon metabolites in Malawian children. Methods Blood was collected from children aged 12-60 months before nutritional rehabilitation: kwashiorkor (N = 94), marasmic-kwashiorkor (N = 43) marasmus (N = 118), moderate acute malnutrition (N = 56) and controls (N = 46). Serum concentrations of 16 one-carbon metabolites were quantified using LC/MS techniques, and then compared across participant groups. Findings Twelve of 16 measured one-carbon metabolites differed significantly between participant groups. Measured outputs of one-carbon metabolism, asymmetric dimethylarginine (ADMA) and cysteine, were lower in marasmic-kwashiorkor (median mu mol/L (+/- SD): 0.549 (+/- 0.217) P = 0.00045 & 90 (+/- 40) P < 0.0001, respectively) and kwashiorkor (0.557 (+/- 0.195) P < 0.0001 & 115 (+/- 50) P < 0.0001), relative to marasmus (0.698 (+/- 0.212) 153 (+/- 42)). ADMA and cysteine were well correlated with methionine in both kwashiorkor and marasmic-kwashiorkor. Interpretation Kwashiorkor and marasmic-kwashiorkor were distinguished by evidence of one-carbon metabolism dysfunction. Correlative observations suggest that methionine deficiency drives this dysfunction, which is implicated in the syndrome's pathogenesis. The hypothesis that kwashiorkor can be prevented by fortifying low quality diets with methionine, along with nutrients that support efficient methionine use, such as choline, requires further investigation.Copyright (c) 2021 The Authors. Published by Elsevier B.V.

Edematous severe acute childhood malnutrition (edematous SAM or ESAM), which includes kwashiorkor, presents with more overt multi-organ dysfunction than non-edematous SAM (NESAM). Reduced concentrations and methyl-flux of methionine in 1-carbon metabolism have been reported in acute, but not recovered, ESAM, suggesting downstream DNA methylation changes could be relevant to differences in SAM pathogenesis. Here, we assess genome-wide DNA methylation in buccal cells of 309 SAM children using the 450 K microarray. Relative to NESAM, ESAM is characterized by multiple significantly hypomethylated loci, which is not observed among SAM-recovered adults. Gene expression and methylation show both positive and negative correlation, suggesting a complex transcriptional response to SAM. Hypomethylated loci link to disorders of nutrition and metabolism, including fatty liver and diabetes, and appear to be influenced by genetic variation. Our epigenetic findings provide a potential molecular link to reported aberrant 1-carbon metabolism in ESAM and support consideration of methyl-group supplementation in ESAM.

Hepatic steatosis is a hallmark feature of kwashiorkor malnutrition. However, the pathogenesis of hepatic steatosis in kwashiorkor is uncertain. Our objective was to develop a mouse model of childhood undernutrition in order to test the hypothesis that feeding a maize vegetable diet (MVD), like that consumed by children at risk for kwashiorkor, will cause hepatic steatosis which is prevented by supplementation with choline. A MVD was developed with locally sourced organic ingredients, and fed to weanling mice (n = 9) for 6 or 13 days. An additional group of mice (n = 4) were fed a choline supplemented MVD. Weight, body composition, and liver changes were compared to control mice (n = 10) at the beginning and end of the study. The MVD resulted in reduced weight gain and hepatic steatosis. Choline supplementation prevented hepatic steatosis and was associated with increased hepatic concentrations of the methyl donor betaine. Our findings show that (1) feeding a MVD to weanling mice rapidly induces hepatic steatosis, which is a hallmark disturbance of kwashiorkor; and that (2) hepatic steatosis associated with feeding a MVD is prevented by choline supplementation. These findings support the concept that insufficient choline intake may contribute to the pathogenesis of hepatic steatosis in kwashiorkor.

Resistant starch (RS) decreases intestinal inflammation in some settings. We tested the hypothesis that gut inflammation will be reduced with dietary supplementation with RS in rural Malawian children. Eighteen stunted 3–5-year-old children were supplemented with 8.5 g/day of RS type 2 for 4 weeks. The fecal samples were analyzed for the microbiota, the microbiome, short chain fatty acids, metabolome, and proteins indicative of inflammation before and after the intervention. Subjects served as their own controls.

Objective: This study tested the hypothesis that Malawian children at risk for zinc deficiency will have reduced endogenous fecal zinc (EFZ) and increased net absorbed zinc (NAZ) following the addition of high amylose maize resistant starch (RS) to their diet.Methods: This was a small controlled clinical trial to determine the effects of added dietary RS on zinc homeostasis among 17 stunted children, aged 3-5 years consuming a plant-based diet and at risk for perturbed zinc homeostasis. Dual zinc stable isotope studies were performed before and after 28 d of intervention with RS, so that each child served as their own control. The RS was incorporated into fried wheat flour dough and given under direct observation twice daily for 28 d. Changes in zinc homeostatic measures were compared using paired Student's t-tests and linear regression analysis.Results: Children had a mean height-for-age Z-score of -3.3, and consumed animal source foods <= twice per month. Their habitual diet contained a phytate:zinc molar ratio of 34:1. Children avidly consumed the RS without complaints. EFZ was 0.8 +/- 0.4 mg/d (mean +/- SD) both before and after the intervention. Fractional absorption of zinc was 0.38 +/- 0.08 and 0.35 +/- 0.06 before and after the RS intervention respectively. NAZ was 1.1 +/- 0.5 and 0.6 +/- 0.7 before and after the RS intervention. This reduction of NAZ corresponded with diminished dietary zinc intake on the study day following intervention with RS. Regression analysis indicated no change in zinc absorption relative to dietary intake as a result of the RS intervention.Conclusion: Consumption of RS did not improve zinc homeostasis in rural African children without zinc deficiency. RS was well tolerated in this setting. (C) 2015 Elsevier GmbH. All rights reserved.

Introduction: Previous research has shown that pediatric patients with cholestatic liver disease demonstrate significant increases in left ventricle wall thickness and left ventricular shortening fraction index. The risk of death due to the development of acute chronic liver failure (ACLF) while waiting for liver transplant (LT) necessitates optimal prioritization of patients listed for LT. Routine clinical assessment tools focus on readily obtained lab analyses. There is, however, little knowledge regarding the clinical relevance of cardiac changes in pediatric cirrhotic liver disease. The purpose of this investigation was to characterize cardiac geometric and functional parameters in children with biliary atresia (BA) who were listed for LT at a large tertiary care children’s hospital and to determine if there is a correlation with the development of ACLF. Methods: Medical records of 89 patients with BA listed for LT at Texas Children’s Hospital between 2001 and 2013 were reviewed. The ACLF group met UNOS criteria for status IB listing. Age-adjusted echocardiogram parameters at listing were analyzed for differences between patients who developed ACLF and those who did not. All statistical analyses were performed using R (version 2.15.2 2012). Results: Among 89 BA patients who were listed for LT between 2001 and 2013, 69 (78%) had echocardiograms from the time of listing available for review. Fifteen patients met criteria for ACLF, of whom 9 died. Median analysis demonstrated a difference between listing PELD scores and LV systolic mid-wall dimension z-scores for ACLF and non-ACLF patients (19.72 vs. 9.71 p<0.01 and 1.14 vs. 0.04 p<0.01, respectively). Other studied echocardiographic parameters did not demonstrate a clearly significant correlation. Conclusion: These findings again demonstrate the association of LV hypertrophic changes with cholestatic liver disease. Moreover, these findings are suggestive of a correlation between particular hypertrophic changes and the risk of ACLF. Although inherently limited by a small sample size and its retrospective approach, this is the first pediatric study that, to our knowledge, demonstrates a correlation between the cardiac structural changes associated with cirrhotic disease and an increased risk of clinical deterioration. Future investigation should focus on the nature of diastolic function in this same patient population.Table 1: Echocardiographic Parameters Among BA Patients Listed for LT

The Viabil® stent (Gore®, Flagstaff, AZ, USA) is a fully covered metal stent (FCMS) with a non-porous liner that provides a barrier to tissue ingrowth. Pediatric usage of this stent has not been reported. We have previously described the use of Viabil® for pancreatic pseudocysts in an adults. We present the use of this stent in a pediatric series of patients with pancreaticobiliary and gastrointestinal disease.

Background: Inflammatory bowel disease (IBD) is more common in countries with improved hygiene, suggesting that environmental exposures may be associated with its development. The primary objective of this study was to examine the association between self-reported childhood helminth infection and the development of IBD in South Africa.Methods: Unmatched case-control study. Logistic regression was used to model associations with IBD.Results: There were 88 patients with Crohn's disease (CD), 63 with ulcerative colitis (UC), and 219 control subjects. Of the 151, 93 (61.6%) IBD subjects (35 of 63 [55.6%] had UC and 58 of 88 [65.9%] had CD) reported childhood helminth exposure compared with 200 of 219 (91.3%) non-IBD subjects (P < 0.001). Helminth infection (adjusted odds ratio [AOR] = 0.2; 95% confidence interval [CI], 0.1 0.4), shared housing (AOR = 0.1; 95% CI, 0.04 0.4), and raw beef consumption (AOR = 0.2; 95% CI, 0.1-0.6) were protective, whereas urban dwelling (AOR = 4.2; 95% CI, 2.0-8.8) and parental tertiary education (AOR = 18.2; 95% CI, 3.2-103.7) were associated with CD. Helminth infection (AOR = 0.2; 95% CI, 0.1-0.6), mixed race (AOR = 0.1; 95% CI, 0.03-0.5), smoking (AOR = 0.2; 95% CI, 0.07-0.5), shared housing (AOR = 0.1; 95% CI, 0.01-0.4), and raw beef consumption (AOR = 0.1; 95% CI 0.04-0.5) were protective against UC, whereas parental tertiary education (AOR = 12.7; 95% CI, 1.0-157.4) was associated with UC.Conclusion: This study demonstrates a protective association of childhood helminth infection against the development of IBD and supports the "hygiene hypothesis" that improved living conditions may increase the incidence of IBD. Our epidemiologic conclusions provide support that helminths may have immunomodulatory effects which provides protection against the development of IBD later in life. (Inflamm Bowel Dis 2013;19:614-620)