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Lactoferrin and lysozyme to reduce environmental enteric dysfunction and stunting in Malawian children: study protocol for a randomized controlled trial.

ABSTRACT: BACKGROUND:Chronic childhood malnutrition, as manifested by stunted linear growth, remains a persistent barrier to optimal child growth and societal development. Environmental enteric dysfunction (EED) is a significant underlying factor in the causal pathway to stunting, delayed cognitive development, and ultimately morbidity and mortality. Effective therapies against EED and stunting are lacking and further clinical trials are warranted to effectively identify and operationalize interventions. METHODS/DESIGN:A prospective randomized placebo-controlled parallel-group randomized controlled trial will be conducted to determine if a daily supplement of lactoferrin and lysozyme, two important proteins found in breast milk, can decrease the burden of EED and stunting in rural Malawian children aged 12-23 months old. The intervention and control groups will have a sample size of 86 subjects each. All field and laboratory researchers will be blinded to the assigned intervention group, as will the subjects and their caregivers. The percentage of ingested lactulose excreted in the urine (?%L) after 4 h will be used as the biomarker for EED and linear growth as the measure of chronic malnutrition (stunting). The primary outcomes of interest will be change in ?%L from baseline to 8 weeks and to 16 weeks. Intention-to-treat analyses will be used. DISCUSSION:A rigorous clinical trial design will be used to assess the biologically plausible use of lactoferrin and lysozyme as dietary supplements for children at high risk for EED. If proven effective, these safe proteins may serve to markedly reduce the burden of childhood malnutrition and improve survival. TRIAL REGISTRATION:Clinicaltrials.gov, NCT02925026 . Registered on 4 October 2016.

SUBMITTER: Cheng WD

PROVIDER: S-EPMC5674751 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Lactoferrin and lysozyme to reduce environmental enteric dysfunction and stunting in Malawian children: study protocol for a randomized controlled trial.

Cheng William D WD Wold Karl J KJ Benzoni Nicole S NS Thakwalakwa Chrissie C Maleta Kenneth M KM Manary Mark J MJ Trehan Indi I

Trials 20171106 1

<h4>Background</h4>Chronic childhood malnutrition, as manifested by stunted linear growth, remains a persistent barrier to optimal child growth and societal development. Environmental enteric dysfunction (EED) is a significant underlying factor in the causal pathway to stunting, delayed cognitive development, and ultimately morbidity and mortality. Effective therapies against EED and stunting are lacking and further clinical trials are warranted to effectively identify and operationalize interve ...[more]

PMID: 29110675

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Project description:BackgroundInterventions to decrease the burden of childhood malnutrition are urgently needed, as millions of children die annually owing to undernutrition and hundreds of millions more are left cognitively and physically stunted. Environmental enteric dysfunction (EED), a pervasive chronic subclinical inflammatory condition among children that develops when complementary foods are introduced, places them at high risk of stunting, malabsorption, and poor oral vaccine efficacy. Improved interventions to reduce the burden of EED and stunting are expected to markedly improve the nutritional status and survival of children throughout resource-limited settings.Methods/designWe will conduct, in parallel, two prospective randomized controlled clinical trials to determine whether common beans or cowpeas improve growth, ameliorate EED, and alter the intestinal microbiome during a high-risk period in the lives of rural Malawian children. Study 1 will enroll children at 6 months of age and randomize them to receive common beans, cowpeas, or a standard complementary food for 6 months. Anthropometry will be compared among the three groups; EED will be assessed using a dual-sugar absorption test and by quantifying human intestinal mRNA for inflammatory messages; and the intestinal microbiota will be characterized by deep sequencing of fecal DNA, to enumerate host microbial populations and their metabolic capacity. Study 2 will enroll children 12-23 months old and follow them for 12 months, with similar interventions and assessments as Study 1.DiscussionBy amalgamating the power of rigorous clinical trials and advanced biological analysis, we aim to elucidate the potential of two grain legumes to reduce stunting and EED in a high-risk population. Legumes have potential as an affordable and effective complementary food intervention, given their cultural acceptability, nutritional content, and agricultural feasibility in sub-Saharan Africa.Trial registrationClinicaltrials.gov NCT02472262 and NCT02472301 .

Project description:OBJECTIVES:Environmental enteric dysfunction (EED) may inhibit growth and development in low- and middle-income countries, but available assessment methodologies limit its study. In rural Bangladesh, we measured EED using the widely used lactulose mannitol ratio (L:M) test and a panel of intestinal and systemic health biomarkers to evaluate convergence among biomarkers and describe risk factors for EED. METHODS:In 539 18-month-old children finishing participation in a randomized food supplementation trial, serum, stool, and urine collected after lactulose and mannitol dosing were analyzed for biomarkers of intestinal absorption, inflammation, permeability and repair, and systemic inflammation. EED scores for each participant were developed using principal component analysis and partial least squares regression. Associations between scores and L:M and with child sociodemographic and health characteristics were evaluated using regression analysis. RESULTS:EED prevalence (L:M?>?0.07) was 39.0%; 60% had elevated acute phase proteins (C-reactive protein >5 mg/L or ?-1 acid glycoprotein >100 mg/dL). Correlations between intestinal biomarkers were low, with the highest between myeloperoxidase and ?-1 antitrypsin (r?=?0.33, P?<?0.01), and biomarker values did not differ by supplementation history. A 1-factor partial least squares model with L:M as the dependent variable explained only 8.6% of L:M variability. In adjusted models, L:M was associated with child sex and socioeconomic status index, whereas systemic inflammation was predicted mainly by recent illness, not EED. CONCLUSIONS:Impaired intestinal health is widespread in this setting of prevalent stunting, but a panel of serum and stool biomarkers demonstrated poor agreement with L:M. Etiologies of intestinal and systemic inflammation are likely numerous and complex in resource-poor settings, underscoring the need for a better case definition with corresponding diagnostic methods to further the study of EED.

Dataset Information

Lactoferrin and lysozyme to reduce environmental enteric dysfunction and stunting in Malawian children: study protocol for a randomized controlled trial.

Publications

Lactoferrin and lysozyme to reduce environmental enteric dysfunction and stunting in Malawian children: study protocol for a randomized controlled trial.

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