Reduced infant rhesus macaque growth rates due to environmental enteric dysfunction and association with histopathology in the large intestine

Environmental enteric dysfunction is associated with malnutrition as well as infant growth stunting and has been classically defined by villous blunting, decreased crypt-to-villus ratio, and inflammation in the small intestine. Here, we characterized environmental enteric dysfunction among infant rhesus macaques that are naturally exposed to enteric pathogens commonly linked to human growth stunting. Remarkably, despite villous atrophy and histological abnormalities observed in the small intestine, poor growth trajectories and low serum tryptophan levels were correlated with increased histopathology in the large intestine. This work provides insight into the mechanisms underlying this disease and indicates that the large intestine may be an important target for therapeutic intervention.

Impact of maternal antibodies and microbiota development on the immunogenicity of oral rotavirus vaccine in African, Indian, and European infants

Identifying risk factors for impaired oral rotavirus vaccine (ORV) efficacy in low-income countries may lead to improvements in vaccine design and delivery. In this prospective cohort study, we measure maternal rotavirus antibodies, environmental enteric dysfunction (EED), and bacterial gut microbiota development among infants receiving two doses of Rotarix in India (n = 307), Malawi (n = 119), and the UK (n = 60), using standardised methods across cohorts. We observe ORV shedding and seroconversion rates to be significantly lower in Malawi and India than the UK. Maternal rotavirus-specific antibodies in serum and breastmilk are negatively correlated with ORV response in India and Malawi, mediated partly by a reduction in ORV shedding. In the UK, ORV shedding is not inhibited despite comparable maternal antibody levels to the other cohorts. In both India and Malawi, increased microbiota diversity is negatively correlated with ORV immunogenicity, suggesting that high early-life microbial exposure may contribute to impaired vaccine efficacy.

Serum Biomarkers of Environmental Enteric Dysfunction and Growth Perspective in Egyptian Children

BACKGROUND: Environmental enteric dysfunction (EED) is a chronic subclinical condition, contributed to limited sources and poor countries. EED pathology is concerned with small intestine structure and function, which affect the macronutrients and micronutrients absorption with consequent growth faltering. AIM: This study aimed to evaluate some serum biomarkers involved in EED and determine their association with stunting and faltering growth in children; zonulin, endotoxin core antibody (EndoCAb), high-sensitive C-reactive protein (hsCRP), alpha-1-acid glycoprotein (AGP), and tumor necrosis factor (TNF), serum iron, and Vitamins A and D. PATIENTS AND METHODS: This case–control study enrolled 105 children aged from 1 to 10 years old, having weight-for-age z-scores and height-for-age z-scores (WAZ or HAZ) ranging from −1.5 to −2. They were compared with control group consisted of 100 children having WAZ or HAZ > −1 of matched age and sex. Assessment of serum markers levels of enteric dysfunction (zonulin and EndoCAb), markers of systemic inflammation (Hs CRP and AGP), along with serum micronutrients (vitamin A, vitamin D and iron) in children with malnutrition in comparison to controls. RESULTS: There was a highly significant decrease as regarding the anthropometric measurements; weight, height, BMI, and arm circumference. Moreover, significant increase in serum zonulin, EndoCAb, HsCRP, and AGP and highly significant decrease of serum Vitamin D and iron in cases group as compared to control group. Height Z score showed negative correlation with zonulin, HsCRP, and AGP and positive correlation with Vitamin D. Weight Z score showed negative correlation with zonulin, HsCRP, and AGP and positive correlation with Vitamin D and Vitamin A. Regression analysis noted increase of zonulin and α1AGP as high associative markers with height Z score affection, however, increase of zonulin was high associative markers with weight Z score affection. CONCLUSION: Faltering growth is associated with elevated serum systemic markers of intestinal inflammation (HsCRP and α1AGP). EED may be a cause of faltering growth.

Association between intestinal bacterial carriage, biomarkers of environmental enteric dysfunction and stunting in rural Malawian children

BackgroundGut bacteria Bifidobacterium longum, Faecalibacterium prausnitzii, Dorea formicigenerans and Akkermansia muciniphila have been implicated in mediation of growth. We investigate the prevalence of these four species, levels of fecal biomarkers of environmental enteric dysfunction (EED) and association with stunting in rural Malawian children. Methods DNA and protein were extracted from fecal samples of 613 children (aged 1-59 months) at a baseline cross-sectional survey in the Mangochi district of Malawi conducted within the framework of the MORDOR (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance) trial. Intestinal carriage of bacteria was measured by PCR. Neopterin, myeloperoxidase and alpha-1 antitrypsin, biomarkers of EED, were measured by ELISA. Height-for-age Z (HAZ) score <-2 defined stunting. Tests of proportions and regression models were used to explore the relationship between bacterial carriage, EED and stunting.Results B. longum carriage in younger children was associated with elevated EED biomarkers. Two thirds of children had elevated NEO, 33% elevated MPO and 16% elevated AAT. Stunting was found in 38% of the children. No significant associations were found between EED biomarkers or intestinal bacteria carriage and stunting.

Nutritional deficiency recapitulates intestinal injury associated with environmental enteric dysfunction in patient-derived Organ Chips

Environmental Enteric Dysfunction (EED) is a chronic inflammatory condition of the intestine characterized by villus blunting, compromised intestinal barrier function, and reduced nutrient absorption. Here, we show that key genotypic and phenotypic features of EED-associated intestinal injury can be reconstituted in a human intestine-on-a-chip (Intestine Chip) microfluidic culture device lined by organoid-derived intestinal epithelial cells from EED patients and cultured in niacinamide- and tryptophan-deficient (-N/-T) medium. Exposure of EED Intestine Chips to -N/-T deficiencies resulted in transcriptional changes similar to those seen in clinical EED patient samples including congruent changes in six of the top ten upregulated genes. Exposure of EED Intestine Chips or chips lined by healthy intestinal epithelium (healthy Intestine Chips) to -N/-T medium resulted in severe villus blunting and barrier dysfunction, as well as impairment of fatty acid uptake and amino acid transport. EED Intestine Chips exhibited reduced secretion of cytokines at baseline, but their production was significantly upregulated compared to healthy Intestine Chips when exposed to -N/-T deficiencies. The human Intestine Chip model of EED-associated intestinal injury may be useful for analyzing the molecular, genetic, and nutritional basis of this disease and can serve as a preclinical model for testing potential EED therapeutics.

Fecal Markers of Environmental Enteric Dysfunction and their Relation to Faltering Growth in a Sample of Egyptian Children

BACKGROUND: Chronic malnutrition is a long-term health condition that has threatening effects on children’s health. Environmental enteric dysfunction (EED) is a subclinical disorder affecting the small intestine that may occur due to exposure to environmental pathogens and toxins. AIM: The present research was intended to detect the value of fecal biomarkers of intestinal epithelial damage alpha-1anti-trypsin (AAT) and intestinal inflammation Myeloperoxidase (MPO) and Neopetrin (NEO), also to quantify their association with faltering growth in stunted and underweight children. PATIENTS AND METHODS: This case–control study included 105 children with moderate malnutrition as a case group and 100 children of normal body weight and height as a control group. Quantification of fecal markers levels of intestinal permeability AAT and intestinal inflammation (NEO and MPO) along with serum micronutrients levels (iron and zinc) in children with malnutrition in comparison to controls. RESULTS: Fecal markers of intestinal permeability AAT and intestinal inflammation NEO had statistically significant higher levels in children with malnutrition, while serum micronutrients (iron and zinc) had statistically significant lower levels in children with malnutrition. CONCLUSION: Faltering growth is associated with elevated fecal markers of intestinal permeability AAT and intestinal inflammation NEO. EED may be a cause for faltering growth.

Host Fecal mRNAs Predicted Environmental Enteric Dysfunction among Children with Moderate Acute Malnutrition in Sierra Leone

Examining the role of environmental enteric dysfunction (EED) in child growth requires noninvasive, field-appropriate biomarkers. Alternatives to the traditionally used lactulose:mannitol (L:M) test have been explored, but few studies have compared the L:M test to host fecal mRNA transcripts. The objectives of this study were to examine whether 1) host fecal mRNA transcripts could predict presence and severity of EED, measured using the L:M test, and 2) EED modifies the effect of specialized nutritious foods (SNFs) on recovery from moderate acute malnutrition (MAM). This substudy was nested within a cluster randomized trial comparing four SNFs in the treatment of MAM among children 6 to 59 months in Sierra Leone. EED was assessed at enrollment using the L:M test and 15 host fecal mRNA transcripts on 522 children. Recovery from MAM was defined as achieving mid-upper arm circumference ≥ 12.5 cm within 12 weeks of supplementation. Random forest classification models were used to examine prediction of presence and severity of EED by host fecal mRNA transcripts. Logistic regression was used to test for effect modification by L:M test variables including % lactulose excreted (%L). Eight host fecal mRNA transcripts (AQP9, REG3A, IFI30, DECR1, BIRC3, SELL, PIK3AP1, DEFA6) identified EED (%L ≥ 0.2) and severe EED (%L ≥ 0.45) with high sensitivity and specificity. The L:M test variables did not modify the effect of SNFs on recovery from MAM. In this study, we found host fecal mRNA transcripts that could be biomarkers of EED but did not find EED to modify the effect of SNFs on MAM treatment.