Immunogenetic control of the intestinal microbiota

Abstract

All vertebrates contain a diverse collection of commensal, symbiotic and pathogenic microorganisms, such as bacteria, viruses and fungi, on their various body surfaces, and the ecological community of these microorganisms is referred to as the microbiota. Mucosal sites, such as the intestine, harbour the majority of microorganisms, and the human intestine contains the largest community of commensal and symbiotic bacteria. This intestinal community of bacteria is diverse, and there is a significant variability among individuals with respect to the composition of the intestinal microbiome. Both genetic and environmental factors can influence the diversity and composition of the intestinal bacteria with the predominant environmental factor being diet. So far, studies have shown that diet-dependent differences in the composition of intestinal bacteria can be classified into three groups, called enterotypes. Other environmental factors that can influence the composition include antibiotics, probiotics, smoking and drugs. Studies of monozygotic and dizygotic twins have proven that genetics plays a role. Recently, MHC II genes have been associated with specific microbial compositions in human infants and transgenic mice that express different HLA alleles. There is a growing list of genes/molecules that are involved with the sensing and monitoring of the intestinal lumen by the intestinal immune system that, when genetically altered, will significantly alter the composition of the intestinal microflora. The focus of this review will be on the genetic factors that influence the composition of the intestinal microflora.

Keywords: HLA; arthritis; immunogenetic; intestine; microbiome.

Figure 1

Genetic factors impact the intestinal microbiota. Mutations in host genes like MUC2, MyD88, IgA, NOD2, NLRP6 and TLR5 have a significant impact on the gut microbial composition and may determine the gut homeostasis or dysbiosis. The polymorphism in HLA genes determines the immune response to various proteins that are presented along the intestine, so impacting the colonizing bacteria. The intestinal immune system protects the host's exposure to pathogenic bacteria by stratification and compartmentalization. Environmental factors including diet and infections probably modulate the abundance of specific taxa within the microbial ecosystem. Expression of the intestinal peptide transporter PEPT 1 is modified by oestrogen, so providing sex-specific effects. The GPI-anchors are the major target of signalling via GPI-anchored proteins. The intestinal immune response monitors the taxa present in the gut through the expression of various pattern recognition receptors and Toll-like receptors by epithelial cells. Epithelial cells expressing HLA class II molecules can present bacterially derived products. In a genetically predisposed host, an infection or an event can lead to an expansion of pathogenic microbes or the disappearance of beneficial commensals resulting in dysbiosis and pro-inflammatory conditions in the gut. An inflammatory immune response in the gut can lead to a decreased expression of tight junction proteins, increased intestinal permeability, and subsequently compromised intestinal integrity. Increased permeability will result in the translocation of commensals and microbial products into the lamina propria where they are presented by antigen-presenting cells and enhance the pro-inflammatory response. A healthy and balanced microbiota leads to the generation of a balanced mucosal immune response while dysbiosis will cause the activation of T cells and the production of antibodies specific for microbial products that are found within the intestinal lumen. In the intestine, activated cells of the adaptive immune response will produce pro-inflammatory cytokines that can further activate the inflammatory cascade. The cells of the intestinal adaptive immune system can cause pathology outside the intestine. This may explain, in part, the association of genetic factors with various diseases. TLR, Toll-like receptor; PRR, pattern recognition receptor; GPI, glycophosphatidylinositol; PEPT1, peptide T 1; Muc, mucin.