Leukocyte Antigens and Microbial Colonization 1 Interplay Between Human Leukocyte Antigen Genes and the Microbial Colonization Process of the Newborn Intestine

Coeliac disease (CD) development involves genetic (HLADQ2/DQ8) and environmental factors. Herein, the influence of the HLA-DQ genotype on the gut colonization process of breast-fed children was determined. Twenty newborns, with at least one first-degree relative with CD, were classified according to their HLA-DQ genotype into high, intermediate and low genetic risk groups, showing 24-28%, 7-8% and less than 1% probability to develop CD, respectively. Faecal microbiota was analysed at 7 days, 1 and 4 months of children’s age by fluorescence in situ hybridization. When considering all data, Bacteroides-Prevotella group proportions were higher (P<0.05) in the high than in the intermediate and low genetic risk groups. Gram-negative bacteria, E. coli, Streptococcus-Lactococcus, E. rectale-C. coccoides, sulphate-reducing bacteria, C. lituseburense and C. histolyticum group proportions were also significantly higher (P<0.05) in the high than in the low genetic risk group. Correlations between these bacterial groups and the genetic risk were also detected (P<0.05). In addition, the number and type of CD relative seemed to influence (P<0.050) these bacterial proportions in children at CD risk. At 4 months of age, similar relationships were established between the high genetic risk to develop CD and the proportions of Streptococcus-Lactococcus (P<0.05), E. rectale-C. coccoides (P<0.05), C. lituseburense (P<0.05), C. histolyticum (P<0.05), Bacteroides-Prevotella (P<0.10) groups and total Gram-negative bacteria (P<0.05). The results suggest a relationship between HLA-DQ genes and the gut microbial colonization process that could lead to a change in the way this disorder is investigated. Introduction Coeliac disease (CD) is the commonest immune-mediated enteropathy triggered by the ingestion of cereal gluten proteins in genetically susceptible individuals. CD is a chronic inflammatory disorder of the small intestinal mucosa caused by an abnormal Th1 immune response to ingested gluten (Rodrigo, 2006). The typical manifestation of CD is the malabsorption syndrome with chronic diarrhoea, weight loss, abdominal distension and impaired growth (Fasano and Catassi, 2005). CD can develop at any age, but it often manifests in early childhood between 6 and 24 months of age after the introduction of gluten in the diet (Fasano and Catassi, 2005). CD is strongly associated with the human leukocyte antigen (HLA) genes of the major histocompatibility complex (MHC) genomic region. Approximately 95 % of the patients are HLA-DQ2 or HLA-DQ8 positives; however, only a small percentage (20-50%) of those bearing high risk HLA haplotypes develop CD (Mearin et al., 2005). Studies with twins showed that in 25% of the cases one twin of the pair did not develop CD, supporting a role for environmental factors in the presentation of this disorder (Greco et al., 2002). In particular, the infant feeding pattern is thought to be involved in CD risk (Branski et al., 2006). Breast-feeding seems to exert a protective effect against CD development (Branski et al., 2006; Ivarsson et al., 2002), which may be related to its influence on the microbial colonization process of the newborn intestine (Sanz et al., 2008). The incidence of infections in early life, which may trigger a Th1 pro-inflammatory response and disrupt the gut microbial balance, has also been related to an increased risk of CD development (Ivarsson et al., 2003; Stene et al., 2006; Sanz et al., 2008). The microbiota rapidly colonizes the gut after birth and this process is influenced by a number of factors, including the heredity of the mother, the immediate living environment, the feeding practices, microbial infections, and the host’s genetics (Bjorkstén, 2006). The early stage of colonization is characterized by the presence of higher levels of facultative anaerobes (Enterobacteriaceae, Lactobacillus and Streptococcus) than anaerobic bacteria (e.g. Bifidobacterium, Bacteroides, Clostridium and Eubacterium), but these proportions are reversed within one *Corresponding author: Email: [email protected] Horizon Scientific Press. http://www.horizonpress.com Curr. Issues Mol. Biol. 12: 1-10. Online journal at http://www.cimb.org