Chronic T Cell-Mediated Enteropathy in Rural West African Children: Relationship with Nutritional Status and Small Bowel Function

Abstract

Previous studies from The Gambia have shown that poor childhood growth is resistant to all but the most intense nutritional intervention and highly dependent on small bowel permeability related to enteropathy. We thus aimed to characterize the mucosal inflammatory response in rural Gambian children in relation to intestinal permeability and nutritional status. Small bowel biopsies were taken from 38 rural Gambian children (age, 0.5-3 y) with a range of nutritional and clinical states (median weight z score, Ϫ4.6; range, 0.5 to Ϫ6.4), 75% of whom had diarrhea. Morphometry was performed with immunohistochemical analysis for a range of lineage and activation markers, including proinflammatory and regulatory cytokines, and related to current clinical status and gut permeability. Comparison was made with 19 age-matched U.K. controls. All Gambian children, regardless of nutritional status, had evidence of chronic cellmediated enteropathy with crypt hyperplasia, villous stunting, and high numbers of intraepithelial lymphocytes. CD25ϩ cells were 20-fold higher than in U.K. controls. Although small bowel architecture was independent of nutritional status, T cell numbers rose and B cell numbers fell with worsening nutrition, and mucosal cytokine production became biased toward a proinflammatory response, with progressive decrease of transforming growth factor-␤ expression. Tropical enteropathy predates the onset of marasmus and is characterized by a cell-mediated T H 1 response. Protein-energy malnutrition is associated with reduction of regulatory immune responses in the mucosal microenvironment, potentially impairing the mechanisms of oral tolerance. Children from The Gambia show a pattern of growth faltering typical of deprived areas of the developing world (1-4). Growth velocity falls from 4 mo onward, so by age 2, the mean weight-for-age lies 2 SD below U.K. standards (z score, Ϫ2). Previous studies from Keneba, rural Gambia, have identified biochemical and dietary deficiencies in these infants. Despite seemingly well-targeted nutritional intervention with macroand micronutrients, growth faltering continues (5-9). Massive dietary supplementation (twice recommended values for energy, 2.5 times for protein) produced short-term catch-up growth after gastroenteritis (5), but growth acceleration reached only the population mean, still 2 SD below the U.K., and reversed as soon as the child left the refeeding study (1, 8).The failure of dietary intervention to restore growth has led to search for other factors. Quantitatively the most important association identified is small bowel enteropathy (2, 4, 10), demonstrated by lactulose:mannitol (L:M) dual sugar permeability testing (11). This assesses both epithelial integrity (exclusion of lactulose entry through intercellular tight junctions) and absorptive capacity (passive absorption of mannitol) (12). During a 1-y period, increased L:M ratio accounted for 0031-3998/03/5403-0306 PEDIATRIC RESEARCH Vol. 54, No. 3, 2003 Copyright © 2003 Printed in U.S.A. ABSTRACT306

Reduced transforming growth factor‐β1‐producing T cells in the duodenal mucosa of children with food allergy

“…The density of duodenal TGF-g 1 + cells in rural Gambian infants is, indeed, up to ten times higher than in UK controls [25]. Clearly, there is important genetic predisposition to mucosal sensitization [4], and recent evidence suggests that reduced proinflammatory responses to bacterial lipopolysaccharide via NF-‹ B is important in both human and murine inflammatory Bowel disease (IBD), where tolerance is lost to enteric bacteria rather than dietary antigen [26,27].…”

Perturbed Zinc Homeostasis in Rural 3–5-y-Old Malawian Children Is Associated With Abnormalities in Intestinal Permeability Attributed to Tropical Enteropathy

“…and has been used to quantify the primary parameters that determine zinc homeostasis (3). Measurements of total dietary absorbed zinc (TAZ), endogenous fecal zinc (EFZ), and net zinc retention (NZR) have been made using this technique (3-6).Tropical enteropathy is a diffuse villous atrophy of the small bowel associated with inflammatory T cell infiltration (7,8). Tropical enteropathy is a chronic, subclinical condition of unknown etiology, distinguished from acute enteropathies associated with gastrointestinal infections.…”

“…Tropical enteropathy is a diffuse villous atrophy of the small bowel associated with inflammatory T cell infiltration (7,8). Tropical enteropathy is a chronic, subclinical condition of unknown etiology, distinguished from acute enteropathies associated with gastrointestinal infections.…”

“…The urinary lactulose-to-mannitol ratio (L:M) is a measure of gut absorptive capacity and intercellular permeability (12). Abnormal L:Ms are seen in association with histologic gut inflammation, reduced nutrient absorptive capacity, and growth faltering (7,9,10). Therefore, the dual sugar absorption test has been a noninvasive, surrogate test used to identify tropical enteropathy (11).…”

Probiotics, antibiotics and the immune responses to vaccines

“…Studies in Africa have shown that, in Gambian infants, increases in antibodies to the core lipopolysaccharide have been associated with gut translocation of Gram-negative bacteria and altered intestinal permeability measured by the lactose-mannitol urinary excretion test [45]. A chronic T-cell enteropathy has also been reported in Gambian infants resulting in a pro-inflammatory environment [42]. Although the importance of environmental enteropathy in undernutrition and poor growth is increasingly well described and the immunological effects of the condition are recognized, its role in the reduced efficacy of oral vaccines in a low-income setting is not defined.…”