Neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome

Abstract

The postnatal maturation of the gut, partially modulated by bacterial colonization, ends up in the establishment of an efficient barrier to luminal antigens and bacteria. The use of broad-spectrum antibiotics in pediatric practices alters the gut bacterial colonization and, consequently, may impair the maturation of the gut barrier function. To test this hypothesis, suckling Sprague-Dawley rats received a daily intragastric gavage of antibiotic (Clamoxyl; an amoxicillin-based commercial preparation) or saline solution from postnatal day 7 (d7) until d17 or d21. Luminal microbiota composition and global gene expression profile were analyzed on samples from small intestine and colon of each group. The treatment with Clamoxyl resulted in the almost-complete eradication of Lactobacillus in the whole intestine and in a drastic reduction of colonic total aerobic and anaerobic bacteria, in particular Enterobacteriacae and Enterococcus. The global gene expression analysis revealed that Clamoxyl affects the maturation process of 249 and 149 Affymetrix probe sets in the proximal and distal small intestine, respectively, and 163 probe sets in the colon. The expression of genes coding for Paneth cell products (defensins, matrilysin, and phospholipase A2) was significantly downregulated by the Clamoxyl treatment. A significant downregulation of major histocompatibility complex (MHC) class Ib and II genes, involved in antigen presentation, was also observed. Conversely, mast cell proteases expression was upregulated. These results suggest that early treatment with a largespectrum antibiotic deeply affects the gut barrier function at the suckling-weaning interface, a period during which the gut is challenged by an array of novel food-borne antigens. innate immunity; antigen presentation; mast cell THE GASTROINTESTINAL (GI) mucosa is in constant contact with a luminal environment that contains not only nutrients but also a huge array of potentially harmful microorganisms and toxins. A healthy GI mucosa is able to handle this massive collection of antigens and modulate the immune response according to the level of hazard related to each antigen. This capacity of the GI tract is defined as gut barrier function. In infants, the intestine remains immature and relatively permeable to antigens during the first weeks of life (3,18,50). Subsequently, the postnatal maturation of the mucosal barrier reduces drastically such transfer, so that in healthy adults, only small amounts of dietary antigens can reach the circulation (22). The maturation of the intestinal barrier is the consequence of morphological and functional changes of the mucosa, which occur under genetic and endocrine control (6). However, the onset of weaning and the impact of bacterial colonization have been shown to modulate this process (11, 28). The comparison of germ-free vs. conventional microbiota animals has brought interesting clues to further our understanding of the impact of the gut microbiota on the different mechanisms involved in the gut barrier function. In...

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