Micronutrient supplements can promote disruptive protozoan and fungal communities in the developing infant gut.

Supplementation with micronutrients, including vitamins, iron and zinc, is a key strategy to alleviate child malnutrition. However, association of gastrointestinal disorders with iron has led to ongoing debate over their administration. To better understand their impact on gut microbiota, we analyse the bacterial, protozoal, fungal and helminth communities of stool samples collected from a subset of 80 children at 12 and 24 months of age, previously enrolled into a large cluster randomized controlled trial of micronutrient supplementation in Pakistan (ClinicalTrials.gov identifier NCT00705445). We show that while bacterial diversity is reduced in supplemented children, vitamins and iron (as well as residence in a rural setting) may promote colonization with distinct protozoa and mucormycetes, whereas the addition of zinc appears to ameliorate this effect. We suggest that the risks and benefits of micronutrient interventions may depend on eukaryotic communities, potentially exacerbated by exposure to a rural setting. Larger studies are needed to evaluate the clinical significance of these findings and their impact on health outcomes.

Treating high-risk moderate acute malnutrition using therapeutic food compared with nutrition counseling (Hi-MAM Study): a cluster-randomized controlled trial.

BACKGROUND: There is a lack of consensus on what is the most appropriate treatment of moderate acute malnutrition (MAM). OBJECTIVES: We aimed to determine if provision of ready-to-use-therapeutic food (RUTF) and antibiotics to "high-risk" MAM (HR-MAM) children in addition to nutritional counseling would result in higher recovery and less deterioration than nutrition counseling alone. METHODS: At the 11 intervention clinics, HR-MAM children were given RUTF and amoxicillin along with standard nutrition counseling, for 2-12 wk. All others received 6 wk of nutrition counseling alone. HR-MAM was defined as midupper arm circumference (MUAC) <11.9 cm, weight-for-age z score (WAZ) <-3.5, mother not the main caregiver, or a child <2 y old not being breastfed. Outcomes were compared using intention-to-treat analysis. RESULTS: Analysis included 573 children at the intervention sites and 714 children at the control sites. Of the intervention group, 317 (55%) were classified as HR-MAM. Short-term recovery was greater at the intervention sites [48% compared with 39% at week 12; risk difference (rd): 0.08; 95% CI: 0.03, 0.13]. The intervention group had lower risk of deteriorating to severe acute malnutrition (SAM) (18% compared with 24%; rd: -0.07; 95% CI: -0.11, -0.04), lower risk of dying (1.8% compared with 3.1%; rd: -0.02; 95% CI: -0.03, -0.00), and greater gains in MUAC and weight than did children at the control sites. However, by 24 wk, the risk of SAM was similar between the 2 arms (31% compared with 34%; rd: -0.03; 95% CI: -0.09, 0.02). Control group data identified recent illness, MUAC <12.0 cm, WAZ <-3, dropping anthropometry, age <12 mo, being a twin, and a history of previous SAM as risk factors for deterioration. CONCLUSIONS: Provision of RUTF and antibiotics to HR-MAM children improved short-term recovery and reduced short-term risk of deterioration. However, recovery rates were still suboptimal and differences were not sustained by 6 mo post enrollment.This trial was registered at clinicaltrials.gov as NCT03647150.

Plasma proteomics reveals markers of metabolic stress in HIV infected children with severe acute malnutrition.

HIV infection affects up to 30% of children presenting with severe acute malnutrition (SAM) in Africa and is associated with increased mortality. Children with SAM are treated similarly regardless of HIV status, although mechanisms of nutritional recovery in HIV and/or SAM are not well understood. We performed a secondary analysis of a clinical trial and plasma proteomics data among children with complicated SAM in Kenya and Malawi. Compared to children with SAM without HIV (n = 113), HIV-infected children (n = 54) had evidence (false discovery rate (FDR) corrected p < 0.05) of metabolic stress, including enriched pathways related to inflammation and lipid metabolism. Moreover, we observed reduced plasma levels of zinc-α-2-glycoprotein, butyrylcholinesterase, and increased levels of complement C2 resembling findings in metabolic syndrome, diabetes and other non-communicable diseases. HIV was also associated (FDR corrected p < 0.05) with higher plasma levels of inflammatory chemokines. Considering evidence of biomarkers of metabolic stress, it is of potential concern that our current treatment strategy for SAM regardless of HIV status involves a high-fat therapeutic diet. The results of this study suggest a need for clinical trials of therapeutic foods that meet the specific metabolic needs of children with HIV and SAM.

Long-term Exposure of Children to a Mixed Lipid Emulsion Is Less Hepatotoxic Than Soybean-based Lipid Emulsion.

Lipid emulsions have been associated with liver injury. Newer mixed emulsions (ML), such as SMOFlipid (Fresenius Kabi, Germany), are thought to be more hepatoprotective than soybean-based emulsions (SL), such as Intralipid (Baxter). Pediatric studies comparing long-term use between the 2 are limited. This study compares the severity of hepatic injury between a prospective cohort of hospitalized children on ML (n = 20) and a historical age- and diagnosis-matched cohort of hospitalized children on SL (n = 20). Median exposure to ML and SL were 10 versus 6 weeks (P = 0.030), respectively, at similar median lipid doses (2.2 vs 2.1 g ·â€Škg ·â€Šday). Using a generalized estimating equations approach, conjugated bilirubin trajectory was found to be lower in patients on ML compared with SL (P < 0.001), suggesting that prolonged exposure (≥4 weeks) to ML is associated with decreased liver injury compared with SL in hospitalized children.

Malnutrition-associated liver steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction.

BACKGROUND & AIMS: Severe malnutrition in young children is associated with signs of hepatic dysfunction such as steatosis and hypoalbuminemia, but its etiology is unknown. Peroxisomes and mitochondria play key roles in various hepatic metabolic functions including lipid metabolism and energy production. To investigate the involvement of these organelles in the mechanisms underlying malnutrition-induced hepatic dysfunction we developed a rat model of malnutrition. METHODS: Weanling rats were placed on a low protein or control diet (5% or 20% of calories from protein, respectively) for four weeks. Peroxisomal and mitochondrial structural features were characterized using immunofluorescence and electron microscopy. Mitochondrial function was assessed using high-resolution respirometry. A novel targeted quantitative proteomics method was applied to analyze 47 mitochondrial proteins involved in oxidative phosphorylation, tricarboxylic acid cycle and fatty acid ß-oxidation pathways. RESULTS: Low protein diet-fed rats developed hypoalbuminemia and hepatic steatosis, consistent with the human phenotype. Hepatic peroxisome content was decreased and metabolomic analysis indicated peroxisomal dysfunction. This was followed by changes in mitochondrial ultrastructure and increased mitochondrial content. Mitochondrial function was impaired due to multiple defects affecting respiratory chain complex I and IV, pyruvate uptake and several ß-oxidation enzymes, leading to strongly reduced hepatic ATP levels. Fenofibrate supplementation restored hepatic peroxisome abundance and increased mitochondrial ß-oxidation capacity, resulting in reduced steatosis and normalization of ATP and plasma albumin levels. CONCLUSIONS: Malnutrition leads to severe impairments in hepatic peroxisomal and mitochondrial function, and hepatic metabolic dysfunction. We discuss the potential future implications of our findings for the clinical management of malnourished children. LAY SUMMARY: Severe malnutrition in children is associated with metabolic disturbances that are poorly understood. In order to study this further, we developed a malnutrition animal model and found that severe malnutrition leads to an impaired function of liver mitochondria which are essential for energy production and a loss of peroxisomes, which are important for normal liver metabolic function.