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. 2015 Jun 3;145(3):313–322. doi: 10.1111/imm.12474

Immunogenetic control of the intestinal microbiota

Eric Marietta 1,*, Abdul Rishi 1,*, Veena Taneja 2,✉
PMCID: PMC4479531  PMID: 25913295

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: arthritis, intestine, immunogenetic, HLA, microbiome

The healthy intestinal microbiome

Microorganisms are present on all surfaces of the human body that are exposed to the environment. The human body contains 10 times more microbial cells than human cells.1 Of these surfaces, the gastrointestinal tract provides the largest mucosal surface that is constantly exposed to environmental factors, such as dietary proteins, bacteria,2 viruses3 and fungi.4 Bacteria make up the vast majority of the human intestinal microbiome5 with 1011–1012 bacteria in the colon, and 105–109 bacteria in the jejunum and ileum. The selective pressures and host physiological factors that determine the microbial composition of each site along the intestine remain largely unknown. The intestinal microbes have co-evolved with the host and share a symbiotic relation. It is known though, that colonization of the gut begins in utero and the composition is constantly changing during the first few years of life, a process that is dependent upon both environmental and dietary factors.6,7 By 3 years of age, the microbial composition becomes stable.7–10 In a healthy individual, Bacteroidetes and Firmicutes are the predominant phyla in the intestine11,12 and some of the most commonly found genera of intestinal bacteria in adults are Bifidobacterium, Lactobacillus, Bacteroides, Clostridium, Escherichia, Streptococcus and Ruminococcus.1 When comparing the intestinal microbiomes of healthy individuals at the species and genus level, one finds significant variability in the composition with each individual having unique composition, similar to that of a genetic fingerprint.1,5,8,13 The intestinal microbial composition is influenced by numerous factors including environment, diet, genetics, infections, age and hygiene. In part this is demonstrated by the fact that family members are more likely to share microbiota compared with unrelated individuals.14–16

Methods for determining variations in the intestinal microbiome have been improving. Previous methods were based on culturing, but the majority of the intestinal microbial population cannot be cultured by such methods. Recent technological advances in next-generation DNA sequencing and associated ‘-omics’ have allowed for the identification of the microbes that are difficult or impossible to culture. Despite such diversity though, each individual shares a symbiotic relationship with their intestinal microflora. This symbiotic relationship protects the host from colonization by pathogenic bacteria, helps the host harvest energy from indigestible food, and also provides nutrients from the host's diet for the intestinal bacteria. In addition, emerging studies suggest that the gut microbiota is also essential for immune homeostasis, the development of the gut-associated lymphoid tissue, the development of tolerance to autoantigens and shaping adaptive immune responses.17 There is growing knowledge about the impact that commensals have upon the human immune system in both health and disease. An initiative in 2007 by the National Institutes of Health sought to characterize the role of the human microbiome in affecting both health and various disease conditions.

Environmental factors and the microbiome

There is considerable evidence suggesting that the variability in the composition of the gut microbiota is affected by environmental factors.12,18 Diet is an important environmental factor that can serve as a source of nutrients for the bacteria that colonize the intestine and thereby affect the composition of the microbiota.12 Stool samples of healthy individuals analysed for 16s rDNA gene segments can be categorized into three enterotypes, depending upon their diet.19 A long-term diet of protein and a non-vegetarian diet with high protein are associated with higher Bacteroides, while a diet high in carbohydrates is associated with higher levels of Prevotella.15 Another study determined the impact of diet on bacterial diversity by analysing the intestinal microbiota in infants who were breast-fed or given formula milk. The results suggested that there were significant differences in intestinal bacterial diversity between the group that was breast-fed versus the group that was exclusively fed formula.20 Although breastfeeding favoured colonization of the gut with Clostridium leptum group, Bifidobacterium longum and Bifidobacterium breve, formula milk led to gut colonization with Escherichia coli, Bifidobacterium lactis, Clostridium coccoides–Eubacterium rectale and Bacteroides fragilis. In addition to diet, other environmental factors that influence the gut microbial composition include smoking, antibiotic use, drugs, probiotics, prebiotics and enteric infections.21,22

Sex-bias in the microbiome

Diet alone does not completely explain the differences in the composition of the intestinal microbiome of healthy individuals, and other strongly determining factors, such as sex, need also to be considered. A recent study conducted a multivariate analysis of the effect of sex and diet on the microbiota of two natural fish populations (three-spine stickleback and Eurasian perch) to determine if the interaction between genotype and environment controls the composition of the intestinal microbiome.23 Each species of fish consumes a mixture of insect larvae and zooplankton. However, within each species, individuals differ in their relative use of these two types of food. This forms a continuum ranging from only eating larvae, to consuming a mixed diet, and to only eating zooplankton.24 This study showed that both species of fish exhibited differences in the composition of the microbiome with respect to diet, only when sex was taken into consideration.23

Few studies have defined sex as a predictor of the gut microbial composition, but sex hormones and gender have been shown to influence the intestinal microbiome, though the exact mechanism is not understood.25,26 Humanized mice also showed sex-based differences in faecal microbial composition.27 The importance of sex-based differences in the microbiome was further elucidated in mouse models of autoimmune diseases where microbiota from females could drive autoimmunity in genetically susceptible mice.28,29

Genetic factors and the microbiome

The role of genetic factors in regulating microbial composition is suggested by trans-generational inheritance of the microbiome.30 In humans a host genetic effect on the microbiome has been studied by comparing monozygotic and dizygotic twins to determine the heritability of the microbiota.21 A recent study found that the concordance rate of pathogen carriage was significantly higher in monozygotic twins compared with dizygotic twins.20 In addition, comparisons of the faecal microbiota revealed a greater similarity among the microbiota of monozygotic twins than among those of dizygotic twins.31 This was confirmed with a larger set of 416 twin pairs.32,33 In contrast to these studies, another twin study that carried out metagenomics and 16S ribosomal RNA gene sequencing to characterize the faecal microbiome did not detect any heritable components.8,34 Further support for genetic factors affecting the composition of the intestinal microbiome comes from studies in humans where specific microbiota profiles were associated with subjects that had mutations at specific gene loci.35 Similar studies in mice have shown an association of genetic loci with shifts in the gut microbial diversity, suggesting that the host's genetic factors have a strong influence on the composition of the intestinal microbiome as well as its metabolic output.27,36,31,37,38

To determine the extent to which genetic factors play a role in controlling the gut microbiota, one study compared the intestinal microbial composition of in-bred C57BL/6 mice and the out-bred NMRI (Naval Medical Research Institute) mice (Table1).39,40 This was done using the amplification of the 16s rRNA gene followed by Denaturing Gradient Gel Electrophoresis (DGGE) analysis of faecal flora. This study determined that the intestinal microbiomes of inbred C57BL/6 mice were more similar to each other than those of out-bred NMRI mice (similarity index was 10% higher in in-bred C57BL/6 mice). This result was strongly supported by another study in which authors showed that the gut microbiotas of eight different recombinant in-bred mouse lines were impacted more strongly by the genetic background than gender (Table1).41 HLA genes coded in the MHC have also been shown to influence intestinal microbial composition20,27,42 as discussed in the Human Leucocyte Antigen section below.

Table 1.

Microbiota changes associated with various host genes in murine models

Genetic model Host gene effect on the microbiota References
Non-humanized mice
 IgA knockout IgG-mediated response to intestinal commensals showing activation of systemic immune system (ineffective compartmentalization); increased numbers of segmented filamentous bacteria 64,67,68
 TLR-5 knockout Associated with changes in intestinal microbiome Metabolic syndrome; immune response to vaccination, inactivated influenza vaccine and polio 70,71
 MyD88-knockout Inefficient response to pathogens, dysbiosis with respect to three bacterial families (Lactobacillaceae, Rikenellaceae and Porphyromonadaceae) and protection from type I diabetes 52,55
 NOD2-knockout Decreased production of α-defensins; increased numbers of Bacteroides, Firmicutes, and Bacillus, and decreased ability to remove Helicobacter hepaticus 58
 RELMB-knockout Rare lineages from Bacteroidetes, Proteobacteria and Firmicutes different compared with controls 80
 OB-knockout Abundance of Bacteroides compared with controls 83
 C57/BL6 Inbred versus NMRI outbred Higher similarity index of microbiota in inbred C57BL/6 mice compared with outbred NMRI mice 40
 MHC gene Genotype stronger determinant of microbiome than sex 41
Humanized mice
 α-Defensin-5 over-expression Resistance to challenge with Salmonella typhimurium; loss of segmented filamentous bacteria from the intestine as compared to controls 56,60
 HLA-DRB1*04 Dominance of Clostridium-like bacteria with low abundance of Porphyromonadaceae family and Bifidobacterium in the gut associated with T helper type 17 profile; loss of age- and sex-dependent gut microbiota 27,42
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Genes involved with stratification and compartmentalization

There is an increasing interest to define and understand the role of intestinal microbes in both health and disease. The interaction between the host and the resident intestinal microbes is symbiotic in healthy individuals, with the bacteria contributing to the metabolism of the diet of the host. In addition, bacteria found in healthy individuals (commensals) play a crucial role in maintaining homeostasis of the intestinal immune system while they derive the nutrients from the diet of the host. One method by which they maintain this homeostasis is by inhibiting the colonization of pathogenic bacteria. It is only in aberrant circumstances that commensals themselves become opportunistic, which results in inflammation and sepsis. The host's immune system, therefore, strives to limit this opportunistic invasion of the host's tissues by commensals, by a process called stratification and compartmentalization.17 Stratification refers to minimizing the exposure of microorganisms to the intestinal epithelium and compartmentalization refers to confining the microorganisms to within the intestinal wall, which prevents them from interacting with the systemic immune system.

Muc-2

One method by which the intestinal immune system achieves stratification is through the production of mucus. Intestinal mucus, which is composed of glycoproteins, is secreted by specialized cells (goblet cells) lining the intestinal epithelium. In the colon, the mucus layer is thick (∽150 µm) and double-layered. Although the outer layer has an abundance of microorganisms, the inner layer of mucus is remarkably resistant to penetration and prevents the microbiota from interacting with the lining of the epithelium.37 The production of intestinal mucus is regulated by the products of intestinal microbiome; germ-free mice have a highly attenuated mucus layer of the colon despite normal goblet cells, and the addition of bacterial lipopolysaccharide or peptidoglycan causes the release of intestinal mucus by the goblet cells.43 The role of the mucus layer in preventing disease in the intestine is exemplified by the fact that mice that lack a principal mucin gene (MUC-2) have an increased translocation of both commensal and pathogenic bacteria with increased permeability and bacterial adherence to the epithelial layer.44–46 As such, these MUC-2-deficient mice develop colitis spontaneously.47

MyD88

The two layers of mucus encountered in the colon, however, are not present in the small intestine.45 Stratification in the small intestine is achieved by the production of anti-microbial peptides (AMPs) by the Paneth cells, which are specialized cells at the base of the crypts of the small intestine. AMPs are essential for containing the bacteria and minimizing their contact with epithelial cells. Release of AMPs by Paneth cells is regulated by interleukin (IL)-22,48 the secretion of which is affected by the intestinal microbiome.49 This is exemplified by the fact that the expression of a specific AMP called Reg III γ was found to be decreased in germ-free mice.50 Reg III γ is an AMP that prevents the penetration of the small intestinal mucus layer by the microbiota and so limits the number of microorganisms that will make contact with the epithelial surface.51 While Reg III γ prevents the penetration of bacteria through the intestinal epithelium, it does not impact the composition of the intestinal microbiome. In contrast, α-defensins (described below) do impact the composition of the intestinal microbiome.

One way of regulating the production of Reg III γ is through the activation of the myeloid differentiation primary response gene 88 (MyD88) pathway as a result of the intestinal microbiome interacting with Paneth cells. Knocking out the MyD88 gene leads to a significant reduction in the production of Reg III γ, leading to an inefficient immune response to pathogens,52 including a failure to fight Listeria monocytogenes.53 Animals lacking T-cell-intrinsic MyD88 show dysbiosis and severe intestinal disease.54 The microbiome of MyD88-deficient mice is quantitatively different from controls with respect to three bacterial families (Lactobacillaceae, Rikenellaceae and Porphyromonadaceae; Table1).55

Nucleotide-binding oligomerization domain 2 and α-defensins

α-Defensins, which have been shown to control the composition of microbiota in the intestine,56 are released by paneth cells responding to microbiota, a process regulated by the nucleotide-binding oligomerization domain-2 (NOD2) receptor.57 NOD2-deficient mice also have an intestinal microbiome that is qualitatively and quantitatively different from control mice. They not only demonstrate significantly increased numbers of Bacteroides, Firmicutes and Bacillus, but also have a decreased ability to remove Helicobacter hepaticus, which is a pathogenic species of bacteria (Table1).58 In addition, mutations in NOD2 are among the strongest risk factors for the development of inflammatory bowel disease (Table2). Patients with NOD2 mutations show a significant dysbiosis, increased Actinobacteria and Proteobacteria, and a decrease in the levels of Clostridium groups IV and XIVa as compared to controls. (Table2).59

Table 2.

Genetic associations with human diseases and microbiota

Gene Disease Impact on the microbial composition References
HLA-DR/DQ Rheumatoid arthritis Increased presence of Prevotella copri and decreased umbers of Bacteroides in patients compared with controls 85
HLA-DQ Coeliac disease Decreased numbers of Bifidobacterium and increased numbers of Bacteroides; higher proportions of Firmicutes and Proteobacteria and lower proportions of Actinobacteria in DQ2 carrier infants compared with controls 86–89
MEFV Familial Mediterranean fever Loss of quantity and diversity of bacteria, and significant shifts in bacterial populations within the Bacteroidetes, Firmicutes and Proteobacteria phyla 77
NOD2/CARD15 Crohn's disease/Inflammatory bowel disease Increased Actinobacteria and Proteobacteria, and decreased Clostridium group XIVa and IV 59
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Studies in mice have further elucidated the role of α-defensins in health and disease. A recent study with transgenic mice that over-express human α-defensin-5 have a loss of segmented filamentous bacteria compared with control mice56 and are resistant to Salmonella typhimurium (Table1).60 In addition, mice deficient for an enzyme required for the cleavage and activation of α-defensins have a lower abundance of bacteria from the Bacteroidetes compared with wild-type mice.56 Although the exact mechanism by which α-defensin-5 controls the composition of the microbiota is unknown, various mechanisms have been suggested. One possible explanation is that α-defensin-5 acts directly on the luminal bacteria after diffusing through the mucus layer.17 Alternatively, α-defensin-5 may exert its antimicrobial activity on the bacteria located in the outer layers of mucus which serve as a reservoir for the bacteria located in the lumen of the intestine.17

NOD-like receptor family pyrin domain containing 6

In addition to the paneth cells of the small intestine, epithelial cells of the colon also control the composition of the microbiome. NOD-like receptor family pyrin domain containing 6 (NLRP6) is an intracellular protein expressed by intestinal epithelial cells and can associate with caspase-1 and thereby affect the activation of inflammasomes.61 Mice deficient in NLRP6 (NLRP6 knockout) have an alteration in their intestinal microbiome resulting in an increase in Prevotella and a decrease in Lactobacillus. The altered microbiome in NLRP6-deficient mice increases susceptibility to colitis (Table1).62 This increased susceptibility to colitis that results from NLRP6 deficiency is transmissible to wild-type mice, indicating that an altered microbiome plays a crucial role in the pathogenesis of colitis. Although the mechanism by which a deficiency in NLRP6 results in an altered microbiome is not completely understood, reduced interleukin-18 levels are observed in NLRP6-deficient mice, suggesting a significant role of interleukin-18 in downstream events of NLRP6.57

Immunoglobulin A in stratification and compartmentalization

Another method by which stratification is achieved is the production of IgA. Although microorganisms are confined to the lumen of the intestine, their extraordinary numbers allow for an occasional breach of the epithelial barrier. The majority of these breaches are intercepted by the mucosal macrophages, which engulf the microorganisms.63 In addition, the immune system samples these microorganisms to produce desired immune responses along the entire length of the intestine.64 In this context, the dendritic cells engulf the microorganisms and carry them to the gut-associated lymphoid tissue, rather than the systemic secondary lymphoid tissue (compartmentalization). The dendritic cells interact with the B cells residing in the gut-associated lymphoid tissue and direct the production of secretory IgA, which is distributed along the entire length of mucosal surfaces by the recirculation of activated B cells. Dendritic cells therefore play a critical role in differentiating between pathogenic and beneficial bacteria, and so are capable of stimulating both pro-inflammatory and regulatory T-cell responses with corresponding IgA response. In this context, the activated intestinal dendritic cells also play a significant role in the generation of induced regulatory T cells.65 Secretory IgA binds to luminal bacteria and can thereby prevent them from penetrating the intestinal epithelium.66 Mice engineered to lack IgA gene (IgA knockout) have increased numbers of segmented filamentous bacteria in the intestine (Table1).67 In addition, IgA-deficient mice produce IgG-mediated responses to intestinal bacteria, suggesting that their systemic immune system has been exposed to bacteria as a result of ineffective compartmentalization (Table1).66 In humans, patients with IgA deficiency have a higher incidence of inflammatory bowel disease,68 an autoimmune disorder that is associated with a significant alteration in the composition of intestinal microbiome.

Host genes associated with specific compositions of the intestinal microbiome

A number of genes of the host have been identified that have been associated with specific compositions of the intestinal microbiota. These genes may encode for proteins involved with detecting specific bacterial products, such as Toll-like receptor 5 (TLR5), or they may be genes that are associated with intestinal diseases with specific changes in the intestinal microbiome, such as the Mediterranean Fever gene. However, for many of these genes, it is still not clear how the encoded proteins affect the composition of the intestinal microbiome, such as the HLA molecules.

Toll-like receptors

Toll-like receptors are a family of proteins that recognize structurally conserved molecules of microbes and activate the innate immune system. Various TLRs bind a variety of microbial products; for example, TLR5 is a cell surface receptor with specificity for bacterial flagellin.69 Mice lacking TLR5 have an altered composition of intestinal microbiome and are predisposed to metabolic syndromes (insulin resistance, hyperlipidaemia and abnormal fat deposition in the body) (Table1).70 Interestingly, wild-type mice suffer from metabolic syndromes when they acquire the altered intestinal microbiome of the TLR5-deficient mice. Recent data suggest that TLR5 may also play a role in the development of an immune response to a vaccination (Table1).71 This study showed that mice lacking TLR5 developed reduced antibody titres to trivalent inactivated influenza vaccine and did not respond to the polio vaccine.71 It is thought that TLR5 mediates antibody responses to vaccines by its ability to sense bacterial flagellin. Two observations were reported in support of this idea.71 First, germ-free mice and antibiotic-treated mice developed reduced antibody titres following vaccination. Second, co-administration of flagellin with trivalent inactivated influenza vaccine resulted in restoration of the antibody response to vaccination in antibiotic-treated mice. It is important to note that the role of TLR5 in the immune response to vaccination is limited to those vaccines that do not contain an adjuvant; antibody responses to vaccines that contain an adjuvant were observed to be similar in both TLR5-deficient and wild-type mice.71

Another TLR, known as TLR4, is a natural ligand for lipopolysaccharide,56 which is an important component of the membranes of Gram-negative bacteria. Interestingly, TLR4 activation has been found to determine the severity of disease in animal models of inflammatory arthritis.72 It has also been found to be associated with the secretion of pro-inflammatory cytokines from the synovial tissue.73 Based on these observations, it has been suggested that TLR4 stimulation leads to activation of MyD88-dependent pathways, which control inflammatory gene expression and lead to induction of pro-inflammatory cytokines of the adaptive immune system.74 Similar to inflammatory arthritis, which is associated with activation of TLR4, a decreased expression of TLR2 (ligand for lipoteichoic acid that may be derived from bacteria) and an increased expression of TLR9 (which binds nucleic acids that may be derived from bacteria) has been observed in paediatric patients with coeliac disease.75

Mediterranean fever gene

The Mediterranean fever (MEFV) gene encodes a protein called pyrin that may be involved in the regulation of innate immunity.76 Mutations in this gene lead to an autoimmune disorder, Familial Mediterranean Fever, which is characterized by polyserositis and recurrent self-limiting episodes of fever and is associated with changes in the composition of the intestinal microbiome as compared with controls.76 These changes are characterized by a low diversity of bacteria, along with significant shifts in bacterial populations within the Bacteroidetes, Firmicutes and Proteobacteria phyla (Table2).77

Resistin-like molecule β

The Resistin-like molecule β (RELMB) is a colonic goblet cell-specific protein78 that is expressed in the gastrointestinal tract and that may be involved in innate responses to intestinal microbiota.79 It is also suggested to be involved in the regulation of the expression of Reg III γ.50 A study using RELMB-deficient mice showed a difference in the abundance of some rare lineages from the Bacteroidetes, Proteobacteria and Firmicutes in the intestine compared with wild-type mice when fed a high-fat diet (Table1).80

Obese gene

Leptin, a hormone encoded by the obese (OB) gene, is critical for appetite, energy expenditure and metabolism.81 Leptin is also involved in the regulation of immune cells and its deficiency is associated with a decreased protection against infections.82 The role of leptin in controlling the intestinal microbiome was shown by the disruption of the OB gene. Leptin-deficient mice not only are obese but also show changes in the intestinal microbiome characterized by an abundance of Bacteroides compared with controls (Table1).83

Human leucocyte antigen

The MHC encodes for the alleles of HLA class I and class II loci, which are the most polymorphic genes in humans. The class I and class II genes are the two major classes of the HLA loci that are involved in antigen presentation and clearance of infections. The polymorphism of HLA genes is attributed to the selective pressures of pathogens. Hence, the HLA alleles that generate a response against most pathogens by activating CD4+ T cells and producing cytokines, resulting in clearance of infections, have been preserved.84 However, certain class II molecules have been associated with inflammatory diseases. The association of dysbiosis with genetically predisposed diseases suggests a role of host genes in shaping the gut microbiota.

Evidence for the role of HLA genes in dysbiosis associated with inflammatory conditions in the gut which could contribute towards causation of disease came from the studies using humanized mice (Table1).27,42 Transgenic mice expressing rheumatoid arthritis-susceptible (HLA-DRB1*0401) and rheumatoid arthritis-resistant (HLA-DRB1*0402) genes were used to determine if HLA molecules and their interaction with the intestinal microbiome can be used to predict susceptibility to arthritis. Pyrosequencing of the bacterial 16S rRNA gene of the faecal microbiome showed that the intestinal microbiome of *0401 mice was dominated by Clostridium-like bacteria, whereas the intestines of *0402 mice showed an abundance of members of the Porphyromonadaceae family and Bifidobacteria. The intestinal microbial composition of *0401 mice did not show age- and sex-associated differences, which was in striking contrast to *0402 mice in which the intestinal microbiome showed dynamic changes with aging that were sex-dependent. The presence of Clostridia in *0401 mice was associated with pro-inflammatory conditions in the gut with higher levels of Th17 cytokines which, in all likelihood, contributed to the increased gut permeability observed in these mice. This study suggested that interaction between the genetic factors and the intestinal microbiome may influence the immune system of the host. Alternatively, it is possible that genetic factors control the immune system, which in turn determines the microbes that colonize the gut. The study suggested that the intestinal microbiome may be used as a potential biomarker for susceptibility to inflammatory arthritis. The observations in humanized mice were supported by a study of the faecal microbial composition in patients with new-onset rheumatoid arthritis and controls (Table2).85 The observations suggested a dysbiosis in patients with rheumatoid arthritis, who had an abundance of Prevotella copri and loss of Bacteroides, compared with controls. Surprisingly, the prevalence of P. copri in patients with chronic rheumatoid arthritis, who had been treated and who exhibited reduced disease activity, was similar to controls. Interestingly the relative abundance of P. copri inversely correlated with the presence of rheumatoid arthritis-associated HLA-DR alleles, suggesting a change in the gut microbiota before onset of clinical phenotype. These studies along with humanized mice suggest that MHC genes play a critical role in the colonization of gastrointestinal microbial flora and determining the pro-inflammatory conditions in the gut.

HLA-DQ2 is a strong genetic factor for susceptibility to develop coeliac disease, which has been associated with intestinal dysbiosis.86,87 A cohort of 20 newborns with high to low genetic risk of developing coeliac disease was tested for intestinal colonization to determine the association of colonization with genetic factors. The observations showed differences in the microbial diversity between infants with high-risk and low-risk genes, suggesting a relationship between HLA genes and gut microbial colonization.88 A recent study determined whether HLA-DQ2 (which is a strong genetic risk factor for coeliac disease ) is an independent risk factor for influencing the early intestinal microbiome in healthy infants with a family history of coeliac disease (Table2).89 Compared with low-risk infants (non-HLA-DQ2/8 carriers), high-risk infants (HLA-DQ2 carriers) had significantly higher proportions of Firmicutes and Proteobacteria and lower proportions of Actinobacteria, suggesting that specific disease-associated genes may select the early microbiota, which could contribute to increased susceptibility to the disease.89 Similarly, rats that express HLA-B27, an allele associated with ankylosing spondylitis and reactive arthritis, have an altered faecal microbiota compared with control rats.90

The precise mechanism by which HLA may affect the intestinal flora remains unknown. The MHC molecules contain domains exhibiting the typical immunoglobulin fold. Moreover, it is known that MHC plays a key role in immunity by presenting peptides to the T lymphocytes. Hence, the most obvious explanation is that HLA located within the MHC region could restrict colonization of the intestine by immune-mediated elimination or selection of certain bacterial species.34 However, very little information is available regarding the role of MHC in this process. Furthermore, the first step in the colonization is the adherence of the bacteria to the epithelial surface. MHC molecules exhibit the typical immunoglobulin fold and several immunoglobulin-binding proteins have been demonstrated on the bacterial surfaces. Indeed, one of these proteins (curli) has been shown to interact with the immunoglobulin-like domains of human class I MHC molecules.91 Hence, the other possible explanation could be that HLA controls the composition of the intestinal microbiome by affecting the adherence of certain bacterial species.38 The third possibility was shown by the Class II-mediated presentation of bacterial polysaccharides by dendritic cells in the gut in a process analogous to peptide presentation.92 The class II presentation of polysaccharides of Bacteroides fragilis leads to generation of an immunomodulatory regulatory response in the gut with implications in extra-intestinal disease in mice suggesting that an interaction between the host genotype and bacteria determine the immune response in the gut, which may regulate the microbial colonization.

Conclusions

The host's immune system works as an ecosystem manager and plays a critical role in controlling the microbial composition and diversity. Immune-related genetic factors of the host including HLA genes have a strong influence on the intestinal microbial composition. However, it remains unknown if HLA molecules control the composition of the microbiome by immune-mediated elimination or by directly affecting bacterial adhesion. HLA alleles are associated with predisposition to autoimmune diseases. Depending on the mutations in various genes, the local immune response in the intestine may be inflammatory in individuals genetically predisposed to inflammatory diseases. In addition, genetic traits such as sex and environmental factors like diet also exert an effect on the intestinal microbiome (Fig.1). An inflammatory immune response in the gut can lead to a change in the intestinal permeability and dysbiosis causing translocation of microbial products from the intestinal lumen. As such, any studies on the intestinal microbiome should take into consideration the effects of host's genetic factors and sex. Furthermore, interactions between these factors and the environment need to be taken into consideration when designing therapeutic strategies to correct dysbiosis associated with different disorders.

Figure 1.

Figure 1

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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,93 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.

Acknowledgments

The study was supported by grants from the Department of Defense, W81XWH-10-1-0257, and NIH AR30752.

Disclosures

All authors declare no competing interests.

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