Selenium status in adults and children in Lusaka, Zambia.

Background: Selenium (Se) is a trace element found in many foodstuffs and critical for antioxidant and immune functions. Widespread Se deficiency has been noted in populations of some sub-Saharan African countries including Ethiopia and Malawi. As a first step towards developing a fuller understanding of problems with the availability of Se in the diet in Lusaka province, Zambia, we measured plasma Se in adults and children in this geographic area. Methods: Total plasma Se was measured using inductively coupled plasma optical emission spectrometry (ICP-OES) in several groups of adults recruited to various pre-existing studies, including those of high and low socioeconomic status (SES) and pregnant women, and children with a range of nutritional states (healthy, stunted or wasted). Results: A total of 660 plasma samples from 391 adults and 269 children were included. Adults had a median plasma Se concentration of 0.27 µmol/l (IQR 0.14-0.43). Concentrations consistent with deficiency (<0.63 µmol/l) were found in 83% of adults. Low SES was associated with low plasma Se among adults, [OR 0.1; 95% CI 0.1-0.3, p < 0.0001]. Among the children, 24% had plasma Se less than 0.41 µmol/l. There was a statistically significant positive correlation between plasma Se and age among children, Spearman's rho 0.47, p < 0.0001. Conclusions: These data suggest that Se deficiency is widespread in Lusaka province and could in part be related to socio-economic status. Supplementation or agronomic biofortification may therefore be needed.

Colostrum Therapy for Human Gastrointestinal Health and Disease.

There is increasing awareness that a broad range of gastrointestinal diseases, and some systemic diseases, are characterized by failure of the mucosal barrier. Bovine colostrum is a complex biological fluid replete with growth factors, nutrients, hormones, and paracrine factors which have a range of properties likely to contribute to mucosal healing in a wide range of infective, inflammatory, and injury conditions. In this review, we describe the anatomy and physiology of the intestinal barrier and how it may fail. We survey selected diseases in which disordered barrier function contributes to disease pathogenesis or progression, and review the evidence for or against efficacy of bovine colostrum in management. These disorders include enteropathy due to non-steroidal anti-inflammatory drugs (NSAIDs), inflammatory bowel disease (IBD), necrotizing enterocolitis, infectious diarrhea, intestinal failure, and damage due to cancer therapy. In animal models, bovine colostrum benefits NSAID enteropathy, IBD, and intestinal failure. In human trials, there is substantial evidence of efficacy of bovine colostrum in inflammatory bowel disease and in infectious diarrhea. Given the robust scientific rationale for using bovine colostrum as a promoter of mucosal healing, further work is needed to define its role in therapy.

Adaptation of the small intestine to microbial enteropathogens in Zambian children with stunting.

Environmental enteropathy is a major contributor to growth faltering in millions of children in Africa and South Asia. We carried out a longitudinal, observational and interventional study in Lusaka, Zambia, of 297 children with stunting (aged 2-17 months at recruitment) and 46 control children who had good growth (aged 1-5 months at recruitment). Control children contributed data only at baseline. Children were provided with nutritional supplementation of daily cornmeal-soy blend, an egg and a micronutrient sprinkle, and were followed up to 24 months of age. Children whose growth did not improve over 4-6 months of nutritional supplementation were classified as having non-responsive stunting. We monitored microbial translocation from the gut lumen to the bloodstream in the cohort with non-responsive stunting (n = 108) by measuring circulating lipopolysaccharide (LPS), LPS-binding protein and soluble CD14 at baseline and when non-response was declared. We found that microbial translocation decreased with increasing age, such that LPS declined in 81 (75%) of 108 children with non-responsive stunting, despite sustained pathogen pressure and ongoing intestinal epithelial damage. We used confocal laser endomicroscopy and found that mucosal leakiness also declined with age. However, expression of brush border enzyme, nutrient transporter and mucosal barrier genes in intestinal biopsies did not change with age or correlate with biomarkers of microbial translocation. We propose that environmental enteropathy arises through adaptation to pathogen-mediated epithelial damage. Although environmental enteropathy reduces microbial translocation, it does so at the cost of impaired growth. The reduced epithelial surface area imposed by villus blunting may explain these findings.

TAME trial: a multi-arm phase II randomised trial of four novel interventions for malnutrition enteropathy in Zambia and Zimbabwe - a study protocol.

INTRODUCTION: Severe acute malnutrition (SAM) in children in many countries still carries unacceptably high mortality, especially when complicated by secondary infection or metabolic derangements. New therapies are urgently needed and we have identified mucosal healing in the intestine as a potential target for novel treatment approaches. METHODS AND ANALYSIS: The TAME trial (Therapeutic Approaches for Malnutrition Enteropathy) will evaluate four novel treatments in an efficient multi-arm single-blind phase II design. In three hospitals in Zambia and Zimbabwe, 225 children with SAM will be randomised to one of these treatments or to standard care, once their inpatient treatment has reached the point of transition from stabilisation to increased nutritional intake. The four interventions are budesonide, bovine colostrum or N-acetyl glucosamine given orally or via nasogastric tube, or teduglutide given by subcutaneous injection. The primary endpoint will be a composite score of faecal inflammatory markers, and a range of secondary endpoints include clinical and laboratory endpoints. Treatments will be given daily for 14 days, and evaluation of the major endpoints will be at 14 to 18 days, with a final clinical evaluation at 28 days. In a subset of children in Zambia, endoscopic biopsies will be used to evaluate the effect of interventions in detail. ETHICS AND DISSEMINATION: The study has been approved by the University of Zambia Biomedical Research Ethics Committee (006-09-17, dated 9th July, 2018), and the Joint Research Ethics Committee of the University of Zimbabwe (24th July, 2019). Caregivers will provide written informed consent for each participant. Findings will be disseminated through peer-reviewed journals, conference presentations and to caregivers at face-to-face meetings. TRIAL REGISTRATION NUMBER: NCT03716115; Pre-results.

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

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.