Campbell, David Ian; (2001) Growth faltering in Gambian children under 15 months of age is associated with a chronic enteropathy leading to a breakdown of gut barrier function, and systemic inflammation. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Background: Gambian children have severe growth faltering in the first two years of life. Poor growth is strongly associated with an enteropathy, which exhibits abnormal lactulose and mannitol (L:M) permeability of the gastrointestinal tract. This thesis aimed to examine the following hypotheses relating to the enteropathy: 1. Impaired gut barrier function is related to poor growth in Gambian children (up to and beyond 2 years of age). 2. Impaired gut barrier function is persistent and associated with systemic inflammation. The final aim was to characterise the enteropathy and provide insights in to aetiology. Methods: Three groups of subjects were recruited. 1. Keneba longitudinal cohort, was designed to asses the impact of impaired gut barrier function (as assessed by the L:M permeability and plasma endotoxin levels) systemic inflammation (measured by acute phase reactants and plasma immunoglobulin levels), upon growth. Seventy-two children were included in this group and were recruited from 2 months of age and followed until they were 15 months of age. 2. Cross-sectional permeability survey. One hundred and sixty-two residents from the three MRC study villages, between 2-60+ years of age, were recruited. The natural history of enteropathy (measured by L:M permeability) and growth was examined in this group. 3. Hospital ward and clinic based patients with more severe malnutrition underwent endoscopic small bowel biopsy to investigate features and mechanisms of enteropathy. Forty children 6 months to 3 years old were studied. Children in the Keneba cohort were studied approximately every 2 months and changes in height and weight were recorded. At these same clinic visits L:M permeability (each sugar measured by automated enzymatic assay), plasma acute phase reactants (C-reactive protein measured by ELISA), plasma immunoglobulin subtypes (measured by automated turbidometry, Cobas Bio) and plasma endotoxin and endotoxin antibody were measured (by ELISA). Stool was collected for the identification of parasites and viruses that could cause enteropathy and also measured for faecal neopterin concentration (a marker of cell mediated inflammation, also measured by ELISA). The effect of enteropathy (measured by L:M permeability, or faecal neopterin) upon age corrected height and weight gain was studied by linear regression. Likewise the effect of enteropathy upon plasma endotoxin and plasma markers of inflammation was studied within each individual by linear regression. The overlapping effect of the different variables upon growth was studied using partial correlation modelling. Features of the enteropathy and possible mechanisms were studied using standard linear morphometry and peroxidase immunohistochemistry with standard methods for quantifying positively staining cell types including the use of no primary or cytokeratin control slides to correct for non-specific background staining. Results: L:M permeability was negatively associated with age corrected (height and weight) growth rates (P < 0.003, r = -0.46). Endotoxin core IgG was positively related to percentage recovery of lactulose (P <0.003, r = +0.36) and all plasma immunoglobulin subclasses (P < 0.0002, r > 0.47). Both plasma endotoxin antibody and immunoglobulin levels were related to age corrected height and weight growth rates (P < 0.0001, r > -0.63 and P < 0.006, r >0.33 respectively). Conclusions: 1. The data demonstrate that impaired gut barrier function is related to poor growth in Gambian children and, despite considerable improvement, persists up until 10 years of age. 2. The data suggests the translocation of endotoxin across the gut, provides a potential mechanism for systemic inflammation. 3. The enteropathy appears to be due to a cell mediated inflammatory reaction, which may be associated with a loss of oral tolerance in situations of severe malnutrition

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