Epithelial Abnormalities in the Small Intestine of Zambian Children With Stunting

Mulenga, Chola; Sviben, Sanja; Chandwe, Kanta; Amadi, Beatrice; Kayamba, Violet; Mudenda, Victor; Kelly, Paul

doi:10.3389/fmed.2022.849677

Cited by 9 publications

(9 citation statements)

References 54 publications

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“…The surface area of the intestine is hugely magnified by three levels of amplification: valvulae conniventes (folds visible to the naked eye), villi, and microvilli. In EE the villus surface area is reduced by villus blunting and fusion, and the microvilli are damaged (22). Consequently, we anticipated being able to detect this reduced surface area in Zambian adults from a community which we have shown in previous studies to have near-ubiquitous enteropathy (3, 27, 28) compared to British adults.…”

Section: Discussionmentioning

confidence: 91%

“…Nutrient digestion and absorption are important domains of small intestinal function and direct measurement may help in quantifying functionally important malabsorption. SI is an enterocyte-specific, brush-border enzyme that is maximally expressed as enterocytes mature and migrate to the top of the villus (21) and the villus blunting and microvillus damage observed in EE would suggest that SI is a good potential diagnostic target (18,22). Previous work in Zambian children has also demonstrated that gene expression of sucraseisomaltase is lower in stunted children (and markedly lower in severe acute malnutrition) compared with adults and expression of glucose transport enzymes (SLC5A1) appears to be upregulated in EE (23).…”

Section: Discussionmentioning

confidence: 99%

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13C-sucrose breath test for the non-invasive assessment of environmental enteropathy in Zambian adults

et al. 2022

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ObjectivesEnvironmental enteropathy (EE) is a subclinical disorder highly prevalent in tropical and disadvantaged populations and is thought to play a role in growth faltering in children, poor responses to oral vaccines, and micronutrient deficiencies. This study aims to evaluate the potential of a non-invasive breath test based on stable isotopes for evaluation of impaired digestion and absorption of sucrose in EE.MethodsWe optimized a 13C-sucrose breath test (13C-SBT) in 19 young adults in Glasgow, United Kingdom. In a further experiment (in 18 adults) we validated the 13C-SBT using Reducose, an intestinal glucosidase inhibitor. We then compared the 13C-SBT to intestinal mucosal morphometry, immunostaining for sucrose-isomaltase (SI) expression, and SI activity in 24 Zambian adults with EE.ResultsFully labeled sucrose (0.3 mg/kg) provided clear breath enrichment signals over 2–3 h in both British and Zambian adults, more than fivefold higher than naturally enriched sucrose. Reducose dramatically impaired 13C-sucrose digestion, reducing 4 h 13CO2 breath recovery by > 50%. Duodenal biopsies in Zambian adults confirmed the presence of EE, and SI immunostaining was present in 16/24 adults. The kinetics of 13CO2 evolution were consistently faster in participants with detectable SI immunostaining. Although sucrase activity was strongly correlated with villus height (r = 0.72; P < 0.05) after adjustment for age, sex and body mass index, there were no correlations between 13C-SBT and villus height or measured sucrase activity in pinch biopsies.ConclusionA 13C-SBT was developed which was easy to perform, generated clear enrichment of 13CO2 in breath samples, and clearly reports sucrase activity. Further work is needed to validate it and understand its applications in evaluating EE.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

13C-sucrose breath test for the non-invasive assessment of environmental enteropathy in Zambian adults

et al. 2022

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“…The suite of growth factors detected in children with SAM could reflect an attempt to restore normal barrier function or increase tissue growth ( 21 ). The extent of epithelial damage in SAM is marked ( 13 ), and can be directly visualised in the gut of adults with environmental enteropathy as plumes of effluxing fluorescein using confocal laser endomicroscopy ( 30 , 31 ). We posit that an inadequate growth factor response in the face of intestinal damage and persistent inflammation reflects a lack of epithelial repair, which permits further inflammatory damage and tissue remodelling, and ultimately drives mortality or poor growth recovery.…”

Section: Discussionmentioning

confidence: 99%

Inflammation and epithelial repair predict mortality, hospital readmission, and growth recovery in complicated severe acute malnutrition

Sturgeon,

Tome,

Dumbura

et al. 2024

Sci. Transl. Med.

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Severe acute malnutrition (SAM) is the most high-risk form of undernutrition, particularly when children require hospitalization for complications. Complicated SAM is a multisystem disease with high inpatient and postdischarge mortality, especially in children with comorbidities such as HIV; however, the underlying pathogenesis of complicated SAM is poorly understood. Targeted multiplex biomarker analysis in children hospitalized with SAM ( n = 264) was conducted on plasma samples, and inflammatory markers were assessed on stool samples taken at recruitment, discharge, and 12 to 24 and 48 weeks after discharge from three hospitals in Zimbabwe and Zambia. Compared with adequately nourished controls ( n = 173), we found that at baseline, complicated SAM was characterized by systemic, endothelial, and intestinal inflammation, which was exacerbated by HIV infection. This persisted over 48 weeks despite nutritional recovery and was associated with children’s outcomes. Baseline plasma concentrations of vascular endothelial growth factor, glucagon-like peptide-2, and intestinal fatty acid–binding protein were independently associated with lower mortality or hospital readmission over the following 48 weeks. Following principal components analysis of baseline biomarkers, higher scores of a component representing growth factors was associated with greater weight-for-height z score recovery and lower mortality or hospital readmission over the 48 weeks. Conversely, components representing higher gut and systemic inflammation were associated with higher mortality or hospital readmission. These findings highlight the interplay between inflammation, which damages tissues, and growth factors, which mediate endothelial and epithelial regeneration, and support further studies investigating interventions to reduce inflammation and promote epithelial repair as an approach to reducing mortality and improving nutritional recovery.

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“…Paneth cells may be implicated in the pathogenesis of EED. A recent study of small intestinal biopsies from Zambian children with EED complicated by growth stunting were found to have depleted Paneth cells and goblet cells compared with control (non-EED) biopsies [34 ▪ ]. The resulting impairment in secretory function may compromise intestinal barrier function, further perpetuating the intestinal inflammation characteristic of EED.…”

Section: Environmental Enteric Dysfunctionmentioning

confidence: 99%

Implications of Paneth cell dysfunction on gastrointestinal health and disease

Lee

Gulati

2022

Current Opinion in Gastroenterology

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Purpose of reviewPaneth cells are specialized, secretory epithelial cells located in the small intestine. Although their existence was first described in 1872, their precise role in the gut remained unclear for over a century. Over the past few decades, elegant studies have shown Paneth cells play a key role enhancing gut barrier function, as niche cells for the intestinal stem cell compartment and via secreting antimicrobial peptides to establish an antimicrobial barrier at the epithelial surface. This review describes what is known about Paneth cell biology from human and animal studies with a focus on their putative role in clinical gastrointestinal disease.Recent findingsRecent work has demonstrated important associations of dysfunctional Paneth cells with several gastrointestinal disorders. These include Crohn's disease, enteric infections, graft-versus-host disease, necrotizing enterocolitis, and environmental enteric dysfunction. Ongoing studies are examining precisely how Paneth cell biology is altered in these various disease states.SummaryBy understanding the mechanisms of Paneth cell regulation – and how these processes go awry in specific gastrointestinal diseases – we set the stage for using Paneth cells as biomarkers for disease progression and developing novel therapeutics that augment Paneth cell function to treat a spectrum of gastrointestinal disorders.

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Epithelial Abnormalities in the Small Intestine of Zambian Children With Stunting

Cited by 9 publications

References 54 publications

13C-sucrose breath test for the non-invasive assessment of environmental enteropathy in Zambian adults

13C-sucrose breath test for the non-invasive assessment of environmental enteropathy in Zambian adults

Inflammation and epithelial repair predict mortality, hospital readmission, and growth recovery in complicated severe acute malnutrition

Implications of Paneth cell dysfunction on gastrointestinal health and disease

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