Dataset Information

Transcriptomic analysis of enteropathy in Zambian children with severe acute malnutrition.

ABSTRACT:

Background

Children with severe acute malnutrition (SAM), with or without diarrhoea, often have enteropathy, but there are few molecular data to guide development of new therapies. We set out to determine whether SAM enteropathy is characterised by specific transcriptional changes which might improve understanding or help identify new treatments.

Methods

We collected intestinal biopsies from children with SAM and persistent diarrhoea. mRNA was extracted from biopsies, sequenced, and subjected to a progressive set of complementary analytical approaches: NOIseq, Gene Set Enrichment Analysis (GSEA), and correlation analysis of phenotypic data with gene expression.

Findings

Transcriptomic profiles were generated for biopsy sets from 27 children of both sexes, under 2?years of age, of whom one-third were HIV-infected. NOIseq analysis, constructed from phenotypic group extremes, revealed 66 differentially expressed genes (DEGs) out of 21,386 mapped to the reference genome. These DEGs include genes for mucins and mucus integrity, antimicrobial defence, nutrient absorption, C-X-C chemokines, proteases and anti-proteases. Phenotype - expression correlation analysis identified 1221 genes related to villus height, including increased cell cycling gene expression in more severe enteropathy. Amino acid transporters and ZIP zinc transporters were specifically increased in severe enteropathy, but transcripts for xenobiotic metabolising enzymes were reduced.

Interpretation

Transcriptomic analysis of this rare collection of intestinal biopsies identified multiple novel elements of pathology, including specific alterations in nutrient transporters. Changes in xenobiotic metabolism in the gut may alter drug disposition. Both NOIseq and GSEA identified gene clusters similar to those differentially expressed in pediatric Crohn's disease but to a much lesser degree than those identified in coeliac disease. FUND: Bill & Melinda Gates Foundation OPP1066118. The funding agency had no role in study design, data collection, data analysis, interpretation, or writing of the report.

SUBMITTER: Chama M

PROVIDER: S-EPMC6642221 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

Transcriptomic analysis of enteropathy in Zambian children with severe acute malnutrition.

Chama Mubanga M Amadi Beatrice C BC Chandwe Kanta K Zyambo Kanekwa K Besa Ellen E Shaikh Nurmohammad N Ndao I Malick IM Tarr Philip I PI Storer Chad C Head Richard R Kelly Paul P

EBioMedicine 20190620

<h4>Background</h4>Children with severe acute malnutrition (SAM), with or without diarrhoea, often have enteropathy, but there are few molecular data to guide development of new therapies. We set out to determine whether SAM enteropathy is characterised by specific transcriptional changes which might improve understanding or help identify new treatments.<h4>Methods</h4>We collected intestinal biopsies from children with SAM and persistent diarrhoea. mRNA was extracted from biopsies, sequenced, a ...[more]

PMID: 31229436

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Project description:BackgroundEnvironmental enteric dysfunction (EED) is widespread throughout the tropics and in children is associated with stunting and other adverse health outcomes. One of the hallmarks of EED is villus damage. In children with severe acute malnutrition (SAM) the severity of enteropathy is greater and short term mortality is high, but the metabolic consequences of enteropathy are unknown. Here, we characterize the urinary metabolic alterations associated with villus health, classic enteropathy biomarkers and anthropometric measurements in severely malnourished children in Zambia.Methods/principal findingsWe analysed 20 hospitalised children with acute malnutrition aged 6 to 23 months in Zambia. Small intestinal biopsies were assessed histologically (n = 15), anthropometric and gut function measurements were collected and the metabolic phenotypes were characterized by 1H nuclear magnetic resonance (NMR) spectroscopy. Endoscopy could not be performed on community controls children. Growth parameters were inversely correlated with enteropathy biomarkers (p = 0.011) and parameters of villus health were inversely correlated with translocation and permeability biomarkers (p = 0.000 and p = 0.015). Shorter villus height was associated with reduced abundance of metabolites related to gut microbial metabolism, energy and muscle metabolism (p = 0.034). Villus blunting was also related to increased sucrose excretion (p = 0.013).Conclusions/significanceIntestinal villus blunting is associated with several metabolic perturbations in hospitalized children with severe undernutrition. Such alterations include altered muscle metabolism, reinforcing the link between EED and growth faltering, and a disruption in the biochemical exchange between the gut microbiota and host. These findings extend our understanding on the downstream consequences of villus blunting and provide novel non-invasive biomarkers of enteropathy dysfunction. The major limitations of this study are the lack of comparative control group and gut microbiota characterization.

Project description:ObjectiveSevere acute malnutrition (SAM) is a major cause of mortality in children under 5 years and is associated with hepatic steatosis. Bile acids are synthesized in the liver and participate in dietary fat digestion, regulation of energy expenditure, and immune responses. The aim of this work was to investigate whether SAM is associated with clinically relevant changes in bile acid homeostasis.DesignAn initial discovery cohort with 5 healthy controls and 22 SAM-patients was used to identify altered bile acid homeostasis. A follow up cohort of 40 SAM-patients were then studied on admission and 3 days after clinical stabilization to assess recovery in bile acid metabolism. Recruited children were 6-60 months old and admitted for SAM in Malawi. Clinical characteristics, feces and blood were collected on admission and prior to discharge. Bile acids, 7α-hydroxy-4-cholesten-3-one (C4) and FGF-19 were quantified.ResultsOn admission, total serum bile acids were higher in children with SAM than in healthy controls and glycine-conjugates accounted for most of this accumulation with median and interquartile range (IQR) of 24.6 μmol/L [8.6-47.7] compared to 1.9 μmol/L [1.7-3.3] (p = 0.01) in controls. Total serum bile acid concentrations did not decrease prior to discharge. On admission, fecal conjugated bile acids were lower and secondary bile acids higher at admission compared to pre- discharge, suggesting increased bacterial conversion. FGF19 (Fibroblast growth factor 19), a marker of intestinal bile acid signaling, was higher on admission and was associated with decreased C4 concentrations as a marker of bile acid synthesis. Upon recovery, fecal calprotectin, a marker of intestinal inflammation, was lower.ConclusionSAM is associated with increased serum bile acid levels despite reduced synthesis rates. In SAM, there tends to be increased deconjugation of bile acids and conversion from primary to secondary bile acids, which may contribute to the development of liver disease.

Project description:BackgroundCurrent (1999) World Health Organization guidelines recommend giving routine antibiotics (AB) for all children with severe acute malnutrition (SAM), even if they have uncomplicated disease with no clinically obvious infections. We examined the evidence behind this recommendation.Methods and findingsOVID-MEDLINE, EMBASE, COCHRANE, GLOBAL-HEALTH, CINAHL, POPLINE, AFRICA-WIDE-NiPAD, and LILACS were searched for AB efficacy, bacterial resistance, and infection rates in SAM. Following PRISMA guidelines, a systematic review and meta-analysis were performed. Three randomised controlled trials (RCT), five Cochrane reviews, and 37 observational studies were identified. One cohort-study showed no increase in nutritional-cure and mortality in uncomplicated SAM where no AB were used. (p>0.05). However, an unpublished RCT in this setting did show mortality benefits. Another RCT did not show superiority of ceftriaxone over amoxicilllin for these same outcomes, but adressed SAM children with and without complications (p?=?0.27). Another RCT showed no difference between amoxicillin and cotrimoxazole efficacies for pneumonia in underweight, but not SAM. Our meta-analysis of 12 pooled susceptibility-studies for all types of bacterial isolates, including 2767 stricly SAM children, favoured amoxicillin over cotrimoxazole for susceptibility medians: 42% (IQR 27-55%) vs 22% (IQR 17-23%) and population-weighted-means 52.9% (range 23-57%) vs 35.4% (range 6.7-42%). Susceptibilities to second-line AB were better, above 80%. Prevalence of serious infections in SAM, pooled from 24 studies, ranged from 17% to 35.2%. No study infered any association of infection prevalence with AB regimens in SAM.ConclusionsThe evidence underlying current antibiotic recommendations for uncomplicated SAM is weak. Susceptibility-studies favour amoxicillin over cotrimoxazole. However, given that these antibiotics have side-effects, costs, and risks as well as benefits, their routine use needs urgent testing. With reliable monitoring, we believe that there is sufficient equipoise for placebo controlled RCTs, the only robust way to demonstrate true efficacy.

Project description:BackgroundChildren hospitalized with severe acute malnutrition (SAM) have poor long-term outcomes following discharge, with high rates of mortality, morbidity, and impaired neurodevelopment. There is currently minimal guidance on how to support children with SAM following discharge from inpatient treatment.ObjectivesThis systematic review and meta-analysis aimed to examine whether postdischarge interventions can improve outcomes in children recovering from complicated SAM.MethodsSystematic searches of 4 databases were undertaken to identify studies of interventions delivered completely or partially after hospital discharge in children aged 6-59 mo, following inpatient treatment of SAM. The main outcome of interest was mortality. Random-effects meta-analysis was undertaken where ≥2 studies were sufficiently similar in intervention and outcome.ResultsTen studies fulfilled the inclusion criteria, recruiting 39-1781 participants in 7 countries between 1975 and 2015. Studies evaluated provision of zinc (2 studies), probiotics or synbiotics (2 studies), antibiotics (1 study), pancreatic enzymes (1 study), and psychosocial stimulation (4 studies). Six studies had unclear or high risk of bias in ≥2 domains. Compared with standard care, pancreatic enzyme supplementation reduced inpatient mortality (37.8% compared with 18.6%, P < 0.05). In meta-analysis there was some evidence that prebiotics or synbiotics reduced mortality (RR: 0.72; 95% CI: 0.51, 1.00; P = 0.049). Psychosocial stimulation reduced mortality in meta-analysis of the 2 trials reporting deaths (RR: 0.36; 95% CI: 0.15, 0.87), and improved neurodevelopmental scores in ≥1 domain in all studies. There was no evidence that zinc reduced mortality in the single study reporting deaths. Antibiotics reduced infectious morbidity but did not reduce mortality.ConclusionsSeveral biological and psychosocial interventions show promise in improving outcomes in children following hospitalization for SAM and require further exploration in larger randomized mortality trials. This study was registered with PROSPERO as CRD42018111342 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=111342).

Dataset Information

Transcriptomic analysis of enteropathy in Zambian children with severe acute malnutrition.

Background

Methods

Findings

Interpretation

Publications

Transcriptomic analysis of enteropathy in Zambian children with severe acute malnutrition.

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