Growth faltering of rural Gambian infants is associated with a chronic inflammatory enteropathy of the mucosa of the small intestine that may impair both digestive/absorptive and barrier functions. The aim of this study was to determine whether the enteropathy was associated with a compromised barrier function that allowed translocation of antigenic macromolecules from the gut lumen into the body, with subsequent systemic immunostimulation, resulting in growth retardation. Rural Gambian infants were studied longitudinally at regular intervals between 8 and 64 wk of age. On each study day, each child was medically examined, anthropometric measurements were made, a blood sample was taken and an intestinal permeability test performed. Evidence of chronic immunostimulation was provided by abnormally elevated white blood cell, lymphocyte and platelet counts, and frequently raised plasma concentration of C-reactive protein. Intestinal permeability was abnormal and associated with impaired growth (r = -0.41, P < 0.001). Plasma concentrations of endotoxin and immunoglobulin (Ig)G-endotoxin core antibody were also elevated and related to both growth (r = -0.30, P < 0.02; r = -0.64, P < 0.0001, respectively) and measures of mucosal enteropathy. Plasma IgG, IgA and IgM levels increased rapidly with age toward adult concentrations. Raised values were related to poor growth but also to measures of mucosal enteropathy and the endotoxin antibody titer. The interrelationships among these variables and growth suggested that they were all part of the same growth-retarding mechanism. These data are consistent with the hypothesis of translocation of immunogenic lumenal macromolecules across a compromised gut mucosa, leading to stimulation of systemic immune/inflammatory processes and subsequent growth impairment.

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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