Abstract
Humans and microbes have developed a symbiotic relationship over time, and alterations in this symbiotic relationship have been linked to several immune mediated diseases such as inflammatory bowel disease, type 1 diabetes and spondyloarthropathies. Improvements in sequencing technologies, coupled with a renaissance in 16S rRNA gene based community profiling, have enabled the characterization of microbiomes throughout the body including the gut. Improved characterization and understanding of the human gut microbiome means the gut flora is progressively being explored as a target for novel therapies including probiotics and faecal microbiota transplants. These innovative therapies are increasingly used for patients with debilitating conditions where conventional treatments have failed. This review discusses the current understanding of the interplay between host genetics and the gut microbiome in the pathogenesis of spondyloarthropathies, and how this may relate to potential therapies for these conditions.
Introduction
It has long been hypothesized that most human diseases arise because of interactions between host and environmental factors, including the microbiome. There are ten fold more bacteria in and on our bodies than the total of our own cells, with the human intestine containing ∼100 trillion bacteria. Our microbial communities are not passive bystanders, and we are only just beginning to appreciate the influence our microbial residents have on our overall health. Interrogation of our microbial communities using classical microbiology techniques offered a restricted view of these communities, allowing us to only see what we could grow in isolation. However, recent advances in sequencing technologies have greatly facilitated the systematic and comprehensive interrogation of the microbiome, and in turn, the elucidation of its role in human health and disease.
Dynamics of the gut microbiome
It is estimated that 29% of all microbes that live in and on the human body reside in the gut. The human gut microbiome contains a dynamic and vast array of microbes that are essential to health as well as providing important metabolic capabilities. Until recently, comprehensive studies of this type of microbial community has been difficult and limited due to classical analysis techniques , notably the limited capacity to profile bacterial populations using culture based methods. The application of molecular techniques, particularly sequencing, has shown the remarkable amount of diversity in the human gut, exceeding all previously held beliefs. Originally, the dominant species in the gut was thought to be Escherichia coli , as pathogen detection was the primary aim and normal flora was disregarded and considered inconsequential. Sequencing based methods have shown, in contrast to classical culture, a far greater diversity of bacteria living in our gut , and profiled them quantitatively with much greater accuracy. This has provided researchers with the tools required to examine microbial communities in health and in many diseases where it has been long suspected that the microbiome interacts with the host to causing disease. This has been of particular value in investigation of the gut’s role in metabolism, pathogen resistance, as well as the body’s immune response and role in driving immune-mediated diseases.
Studies comparing the gut microbiota of lean and obese twins have shed light on the importance of intestinal microbes and how a change in microbiome composition can affect food metabolism in the gut . Turnbaugh et al. showed that even with a similar genetic make-up, obese twins had substantial differences in the composition and diversity of their gut flora with a dominance of Gram-positive bacteria from the phylum Firmicutes, compared with discordant or lean twins . This shift in gut flora composition altered how food was broken down and metabolised in the gut, leading to increased body mass index, adiposity and obesity . This demonstrates that shifts in the intestinal microbiome have potential functional consequences on the health of the individual . To distinguish whether the changes observed in the human twins played a causative role in their obesity, faecal samples from four twin pairs were transplanted into germ free mice . The authors found that the Firmicutes phylum that dominated the microbial communities in the obese twin, lead to obesity in the germ-free mice. In contrast, Bacteroides dominated the microbial communities in the lean twin, and kept the germ-free mice lean.
Whilst it is not surprising that diet can change the intestinal microbial community, it is only in recent years that these changes have been shown to influence the tendency to develop inflammatory disease. Maslowski, Vieira et al., 2009 showed that a lower intake of fibre from complex plant polysaccharides adversely affects the makeup of the intestinal microbiota, which leads to less production of immunomodulatory products in particular short-chain fatty acids (SCFA) . These SCFA are produced by the phylum Bacteroidetes, so a shift in the flora from predominantly Bacteroidetes to Firmicutes due to a more western diet with less fibre, reduces the amount of SCFA secreted. The effect SCFA has on the immune response was investigated in a mouse strain deficient in single G protein–coupled receptor, GPR43 . Mice lacking GPR43 failed to suppress inflammation in models of colitis, arthritis and asthma, as did germ-free wild-type mice also lacking SCFA. Wild type mice raised in non-germ-free conditions were able to suppress inflammation. This suggests that diet-induced reduction in faecal SCFA leads to a reduced ability to suppress a variety of inflammatory conditions. Fascinatingly, genetic studies have now demonstrated association of multiple GPRs with human diseases, notably with ankylosing spondylitis (AS), providing evidence for a role of this mechanism in disease pathogenesis .
Dynamics of the gut microbiome
It is estimated that 29% of all microbes that live in and on the human body reside in the gut. The human gut microbiome contains a dynamic and vast array of microbes that are essential to health as well as providing important metabolic capabilities. Until recently, comprehensive studies of this type of microbial community has been difficult and limited due to classical analysis techniques , notably the limited capacity to profile bacterial populations using culture based methods. The application of molecular techniques, particularly sequencing, has shown the remarkable amount of diversity in the human gut, exceeding all previously held beliefs. Originally, the dominant species in the gut was thought to be Escherichia coli , as pathogen detection was the primary aim and normal flora was disregarded and considered inconsequential. Sequencing based methods have shown, in contrast to classical culture, a far greater diversity of bacteria living in our gut , and profiled them quantitatively with much greater accuracy. This has provided researchers with the tools required to examine microbial communities in health and in many diseases where it has been long suspected that the microbiome interacts with the host to causing disease. This has been of particular value in investigation of the gut’s role in metabolism, pathogen resistance, as well as the body’s immune response and role in driving immune-mediated diseases.
Studies comparing the gut microbiota of lean and obese twins have shed light on the importance of intestinal microbes and how a change in microbiome composition can affect food metabolism in the gut . Turnbaugh et al. showed that even with a similar genetic make-up, obese twins had substantial differences in the composition and diversity of their gut flora with a dominance of Gram-positive bacteria from the phylum Firmicutes, compared with discordant or lean twins . This shift in gut flora composition altered how food was broken down and metabolised in the gut, leading to increased body mass index, adiposity and obesity . This demonstrates that shifts in the intestinal microbiome have potential functional consequences on the health of the individual . To distinguish whether the changes observed in the human twins played a causative role in their obesity, faecal samples from four twin pairs were transplanted into germ free mice . The authors found that the Firmicutes phylum that dominated the microbial communities in the obese twin, lead to obesity in the germ-free mice. In contrast, Bacteroides dominated the microbial communities in the lean twin, and kept the germ-free mice lean.
Whilst it is not surprising that diet can change the intestinal microbial community, it is only in recent years that these changes have been shown to influence the tendency to develop inflammatory disease. Maslowski, Vieira et al., 2009 showed that a lower intake of fibre from complex plant polysaccharides adversely affects the makeup of the intestinal microbiota, which leads to less production of immunomodulatory products in particular short-chain fatty acids (SCFA) . These SCFA are produced by the phylum Bacteroidetes, so a shift in the flora from predominantly Bacteroidetes to Firmicutes due to a more western diet with less fibre, reduces the amount of SCFA secreted. The effect SCFA has on the immune response was investigated in a mouse strain deficient in single G protein–coupled receptor, GPR43 . Mice lacking GPR43 failed to suppress inflammation in models of colitis, arthritis and asthma, as did germ-free wild-type mice also lacking SCFA. Wild type mice raised in non-germ-free conditions were able to suppress inflammation. This suggests that diet-induced reduction in faecal SCFA leads to a reduced ability to suppress a variety of inflammatory conditions. Fascinatingly, genetic studies have now demonstrated association of multiple GPRs with human diseases, notably with ankylosing spondylitis (AS), providing evidence for a role of this mechanism in disease pathogenesis .
The normal microbiome
In order to investigate the role of the microbiome in disease, it is clearly essential to understand what constitutes a ‘normal’ microbiome and how it behaves. Two large studies interrogating and cataloguing microbiomes from various regions of the body in health and disease have been undertaken by the National Institutes of Health Human Microbiome Project in the USA and the European MetaHit project . The Human Microbiome Project was established for the purpose of identifying and cataloguing the human microbiome by sequencing samples from 242 individuals (129 males, 113 females) across five major body sites, including the mouth, skin, stool and vaginal tract. Samples were collected on multiple occasions with the aim of investigating within subject variation, between subject variation as well as microbiome variation over time. A total of 4788 specimens were sequenced with females sampled from 18 different habitats and males from 15 habitats . Diversity and abundance of each habitat’s signature microbes was found to vary greatly amongst the healthy subjects, with strong niche specialization found both within and between individuals, demonstrating the dynamic nature of the microbiome . Metagenomic carriage of metabolic pathways was found to be stable amongst individuals, despite the variation seen within community structure. When clinical metadata was present, ethnic background proved to be one of the strongest predictors of both pathways and microbes. This suggests that environmental factors such as diet, location/region and host genetics could play a role in sculpting the microbiome. These studies further define the range of structural and functional configurations that are present in normal microbial communities in a healthy population .
Enterotypes
The European MetaHit consortium combined published datasets from across the world and added 22 newly sequenced faecal metagenomes from four different European countries. They identified three robust clusters, termed ‘enterotypes’, that were not nation or continent specific. These enterotypes characterised the microbial phylogenetic variation as well as the function variation of the clusters at gene and functional class levels .
Each enterotype had a dominant bacterial genus: Enterotype 1 dominated by the genus Bacteroides ; enterotype 2 by Prevotella ; and enterotype 3 by Ruminococcus . The three enterotypes were also shown to be functionally different. For example enterotype 2, which is Prevotella dominant, also contains Desulfovibrio , which may act in synergy with Prevotella to degrade mucin glycoproteins present in the mucosal layer of the gut. It may be that different enterotypes are associated with diseases such as obesity and inflammatory bowel disease (IBD), rather than necessarily specific bacterial species, given their differing functional capacities. However, recent work suggests that the boundaries between the enterotypes are more vague than initially described. Multiple datasets including the Human Microbiome Project 16S rRNA gene sequence data and metagenomes with similar published data were interrogated for the existence of enterotypes across multiple body sites. However, many of the samples examined could not be fitted into discrete enterotypes, but rather that indicator species varied on continuous scales between individuals and even within individuals at different sites . Moreover, meta-analysis demonstrated that many of the methods used in the analysis of enterotypes, such as clustering approaches and distance metrics, affected the likelihood of identifying enterotypes in particular body habitats. This suggests enterotypes are not discrete but are continuous, and vary widely amongst and within individuals .
Homeostasis
Microbes and humans have evolved over time to live in symbiosis with each other. Many of these diverse communities carry out specific tasks that benefit the host, as well as the microorganisms ( Fig. 1 ). A balancing act between war and peace exists within the gut between resident microbial members of the gut and potentially pathogenic and non-pathogenic species. It is well documented that changes in the microbial composition in the gut by a pathogen, can elicit an innate immune responses . However, it is still unknown if a shift or dysbiosis in the gut flora has the capacity to elicit a similar response as an infection, as the gut tries to defend its self and restore homeostasis . Homeostasis of the normal flora in the gut microbiome is essential, and both the bacteria that inhabit the gut and the human immune system have developed strategies to regulate and protect it. Bacteria in the intestine employ several techniques to influence the gut microbiome, including competitive exclusion, biosurfactant production and modulation of tight junctions . Additionally, the gut has complex barrier and innate and adaptive immunological mechanisms in place which sense and interact with the normal gut microbiome and respond to disruptions in gut homeostasis or bacterial insults. Pathogenic bacterial infection can be detected by antigen presenting cells (APC), such as a dendritic cells, that activate naive T cells. Activated T H 17 and gut innate lymphoid cells may then be recruited and secrete cytokines such as IL-22, which promotes epithelial repair and secretion of antibacterial proteins. The T H 17 cells also secrete IL-17 that induces epithelial cells to recruit neutrophils . The epithelial cells lining the intestine can additionally respond themselves to a disturbance with Paneth cells in the small intestine known to secrete antimicrobial peptides that are like ‘antibiotics’ against a broad range of bacteria .
Influence of underlying host genetics on the intestinal microbiome
A key challenge in research into the role of the microbiome in immune-mediated diseases is determining whether host genetics directly influences changes in microbiome composition, or do so indirectly via the immune system. The extent that underlying host genetics influences intestinal microbial community composition in humans is unclear. Host gene deletions have been shown in animal models to cause shifts in microbiota composition . Moreover, a recent quantitative trait locus mapping study linked specific genetic polymorphisms with microbial abundances . These studies highlight the importance of underlying host genetics in community composition in animals. The role of host genetics is of interest in diseases such as IBD, where many of the genes associated with disease, such as IL23R , NOD2 , NOS2 , CARD9 , and FUT2 (which determines enteric IgA secretor status) are involved in handling, processing and response to microbes. Genetic studies in Crohn’s disease (CD), one of the two common forms of IBD, shows a marked over-representation of genes, such as NOD2 and TNFRSF18 , which are associated with an increased genetic risk of developing mycobacterial diseases, including leprosy and tuberculosis . There is significant overlap between the genetic risk of developing leprosy and CD, with seven of the eight known genetic variants associated with an increased risk of leprosy, including SLC11A1 , VDR and LGALS9 , also associated with an increase the risk of CD; compared with only two being associated with risk of any other immune-mediate disease. Combined with dramatic shifts in the gut microbiota composition associated with IBD , this strongly indicates a potential link between host genetics, the microbiome and the development of IBD.
The genetic influence over microbiome composition is further highlighted in a study of 416 monozygotic and dizygotic twin pairs investigating the heritability of the gut microbiome in obesity. The authors found that heritability of different taxa varied widely, with the most heritable taxon being the family Christensenellaceae (additive heritability 39%) . Taxa that showed significant heritability (>20%) were also more likely to be stable over time. The study showed that the family Christensenellaceae was central to a network of co-occurring heritable microbes associated with lean body mass index. Animal studies showed that the introduction of any of the members of the Christensenellaceae family had the capacity to protect the mice from weight gain . Even though the exact gene-microbe association with the Christensenellaceae family remains unknown, this study demonstrates that microbiome composition causatively associated with human disease is at least in part due to host genetics .
The microbiome in spondyloarthritis (SpA) and associated diseases
Ankylosing spondylitis
Intestinal microbial involvement has been suggested in the pathogenicity of AS for some time, although with the exception of AS associated to chronic reactive arthritis, a definite link has yet to be established . Few studies have directly investigated the hypothesis in gut or stool samples. One early study using denaturing gradient gel electrophoresis to profile the microbiome using faecal samples found no differences between AS cases and healthy controls . In contrast, microbial community profiling using 16S rRNA sequencing of terminal ileal (TI) biopsies from AS cases and healthy controls demonstrated that AS is associated with intestinal dysbiosis . The TI microbial communities of patients with AS differed significantly (P < 0.001) from those of healthy controls, driven by higher abundance of five families of bacteria Lachnospiraceae (P = 0.001), Ruminococcaceae (P = 0.012), Rikenellaceae (P = 0.004), Porphyromonadaceae (P = 0.001), and Bacteroidaceae (P = 0.001), and a decreases in abundance of two families Veilonellaceae (P = 0.01) and Prevotellaceae (P = 0.004) . The authors observed an increase in the diversity of the AS community without an overall change in microbial load, demonstrating that the dysbiosis seen in the AS gut is not due to an overgrowth or dominance of a particular specific microbe. Further investigations showed that correlations between these aforementioned families of bacteria were found to further shape the AS microbial signature. It was also found that these families of bacteria are present in all AS samples studied suggesting that they are not only driving the microbial signature, but they are at the core of the AS microbial signature. Increases in Prevotellaceae and decreases in Rikenellaceae have also recently been reported in the intestinal microbiome in the HLA-B27 transgenic rat model of SPA . Additionally in BALB/c ZAP-70 W163C -mutant (SKG) mice, the interaction between immunogenetic background and host microbiome has been demonstrated to influence SpA and Crohn’s-like disease outcomes. Both animal models suggests that underlying host genetics may play a role in sculpting the gut microbiome and disease progression and/or severity .
Many studies, largely using antibody tests, have suggested an increased carriage of Klebsiella species in AS patients, however this has not been universally supported . Several specific bacteria have been suggested to have a role in AS pathogenesis particularly Klebsiella pneumoniae and Bacteroides vulgatus although current studies using antibody tests have been unable to produce convincing evidence demonstrating increased infection with any specific triggering agent influencing AS development. K. pneumoniae and B. vulgatus have been of considerable focus for several reasons. Increased levels of B. vulgatus have linked to colitis in the HLA-B27 /β 2 microglobulin transgenic rats. When the HLA-B27 /β 2 microglobulin transgenic rats were raised in germ free conditions and subsequently colonised with an intestinal bacterial cocktail, the rats developed more severe colitis when increased amounts of B. vulgatus were present . Substantial research effort has been directed towards the possible involvement of K. pneumoniae . Early work examining the faeces of AS patients during active disease reported the presence of K. pneumoniae . Studies have also reported elevated levels of serum antibodies against K. pneumoniae in patient sera . Antigenic similarity has been noted between Klebsiella and HLA-B27, suggesting a role for molecular mimicry in driving AS-pathogenesis . In the sequencing study of AS TI samples however, no association between Klebsiella or any other members of the Enterobacteriaceae family of bacteria with AS was observed . This casts further doubt on the role of Klebsiella AS pathogenesis.
As well as specific bacteria triggering disease, it has also been speculated that antimicrobial reactivity can develop during intestinal inflammation. There have been a number of antibodies described over the years that have shown to have clinical significance in IBD. These include anti- Saccharomyces cerevisiae antibodies (ASCA), anti-I2 antibodies (which are associated with anti- Pseudomonas activity), perinuclear antineutrophil cytoplasmic antibodies (pANCA), anti- E. coli outer membrane porin C (anti-OmpC) antibodies, and anti-flagellin antibodies (anti-CBir1), . Given the overlap between IBD and AS, the prevalence of several of the above antimicrobial antibodies were examined in the serum of 80 AS patients and healthy controls . While there was no difference in the number of antibody positive results between AS patients and healthy controls, AS patients were more likely than healthy controls to have elevated levels of anti-I2 and ASCA antibodies. A recent study has shown of anti-CBir1 antibodies are elevated in patients with AS with IBD compared to patients who only have AS . Moreover, patients with AS had increased levels of anti-CBir1 antibodies when compared to healthy controls. This data suggests that AS patients may have increased exposure of the immune system to commensal bacteria, causing the antibody production. Increased levels of anti-CBir1 antibody in AS patients, compared to healthy controls, could be accounted for, at least in part, by microscopic gut inflammation even in the absence of clinical gastrointestinal symptoms . Whilst this observation requires further investigation, the development of anti-CBir1 antibodies in patients with AS raises the intriguing question of their pathophysiological significance with regards to commensal bacteria, and more specifically commensal bacteria with flagella.
Psoriasis and psoriatic arthritis
The microbiome is thought to play a significant role in psoriatic arthritis (PsA) and psoriasis (Ps), another SpA-related condition. It has long been suggested that streptococcal infection, especially throat infections, may trigger psoriasis in a genetically susceptible individual . Recent studies using 16S rRNA sequencing have found significant differences between the cutaneous microbiota of Ps cases and controls, and in Ps involved and control skin in Ps cases, with less Staphylococci and Propionibacteria observed in cases and in affected skin . Recently the gut microbiota in patients with both PsA and Ps was shown to be less diverse compared to healthy controls with a relative decrease in abundance of Coprococcus species. PsA patients were further characterised by a significant reduction in Akkermansia , Ruminococcus and Pseudobutyrivibrio not dissimilar to those previously described in IBD .
Dissecting microbiome and disease – cause and effect
Whether the changes noted in microbiome studies of immune-mediated diseases are a consequence of disease or are involved in disease development or persistence, remains unclear. This distinction may prove impossible to dissect in human studies, but there is considerable evidence animal studies to support a role for the microbiome in driving immune mediated diseases.
In the HLA-B27 rat model of AS, rats housed under germ free (GF) conditions did not develop disease , demonstrating that microbes in this model are important in disease penetrance. In contrast, in the New Zealand black (NZB) model of systemic lupus erythematosus (SLE), mice maintained under GF conditions produced higher levels of antinuclear antibodies and developed worse disease suggesting a protective role for commensal microbes.
Considering the IL-23 dependent IL-17/IL-22 cytokines, which are of relevance to AS, IBD and psoriasis in particular, there is strong evidence from murine studies to indicate that interaction between the gut microbiome and the host determines the overall level of activation of the immune cells producing these cytokines. Segmented filamentous bacteria (SFB) are commensal bacteria that induce IL-17 secretion particularly in mice. Mice lacking SFB have low levels of intestinal IL-17 and are susceptible to infection with pathogenic Citrobacter spp. Restoration of SFB in these mice increased the number of gut-resident IL-17-producing cells and enhanced resistance to infection . Further, using recolonization studies, investigators have recently demonstrated that in neonatal mice, commensal microbes influence iNKT cell intestinal infiltration and activation, establishing mucosal iNKT cell tolerance to later environmental exposures .
The mechanism by which the microbiome influences IL-17 producing cell activation is still being determined. Ivanov and colleagues demonstrated that serum amyloid A, produced in the terminal ileum, can induce T H 17 differentiation of CD4+ T-lymphocytes . It has also been shown that development of T H 17 lymphocytes in the intestine is stimulated by microbiota induced IL-1β but not IL-6 production . Colonisation with Clostridial species has been shown to stimulate intestinal TGF-β production, in turn increasing IL-10 + CTLA4 high Treg activation . Clostridial colonisation of neonatal mice reduced severity of induced colitis using DSS or oxazolone, and reduced serum IgE levels in adulthood. So it is likely that alterations to the gut microflora, or invasion of the gut by pathogenic bacteria, influence the balance of IL-17- and IL-22-producing cells, and other immune cells, influencing susceptibility to local and systemic immune mediated disease.
Dissecting out what is genetic influence on microbiome composition and what is environmental is inherently complicated. A recent study by Hildebrand et al., investigated exactly that across five common laboratory healthy mouse strains Balbc, FVB, B6, NOD and Swiss. They found that the gut microbiota differed according to genotype, caging and inter-individual variation . These factors contributed on average 19%, 31.7% and 45.5% respectively to the variance in the microbial composition. Genetic distance was also found to positively correlate to microbiota distance, indicating that strains that are more closely related genetically have more similar microbiota than distantly related strains. Microbiota composition was also correlated with inflammation marker calprotectin. Mice that displayed low microbial richness had higher levels of calprotectin but no obvious signs of inflammation suggesting low-grade inflammation. This study demonstrates the influence of genetic background on microbiota composition as well as the environmental influences albeit in a controlled setting. This work highlights the complexity of host-environment-microbiota interactions .
The above studies highlight that changes in the microbiome can lead to inflammation which may have far reaching effects, and demonstrate experimental approaches by which findings of metagenomic studies in mice and humans can be explored to successfully dissect the role of the microbiome in human immune mediated diseases.
Microbes as biomarkers and therapeutics
The intestinal microbiome is a dynamic and constantly changing environment . Whist the microbiome ebbs and flows with daily living , it overall remains reasonably stable for months, and possibly even years . However most of what we know regarding the make-up of the human gut microbiome and its stability, is based on single point in time stool studies and not mucosal biopsies . Several studies have shown that the microbiome profile from stool differs from the profile obtained from mucosal biopsy suggesting that stool, while the most accessible sample, is not optimal for studying gut microbiome composition, and may skew our understanding . Moreover, studies across mice and humans suggest that common aspects of a modern Western lifestyle including antibiotic use and high fat and fibre poor diets , can persistently alter commensal microbial communities. In turn, these microbial disturbances may increase susceptibility to pathogens , obesity and autoimmune disease . This makes dissecting cause and effect challenging given the significant environmental factors which can shape the microbiome as well as normal temporal variance; especially considering we have only been focusing on bacteria, not archea, viruses or fungi which also inhabit the intestinal tract.
The successful use of the gut microbiome as a biomarker and/or therapeutic target requires a more detailed understanding of factors that shape the community composition including age, diet, geographical location, gender as well as underlying host genetics. Investigations to date have largely focused on the bacterial composition of the microbiome, and so relatively little is known about the viruses and fungi that also inhabit the gut. Despite the considerable limitations in sequencing and functional annotation of the eukaryotic viruses present in the gastrointestinal tract, recent deep-sequencing efforts have revealed the existence of a complex enteric virome . A recent study revealed the beneficial role viruses may play a role in a healthy microbiome. Murine norovirus (MNV) infection of germ-free or antibiotic-treated mice rescued both intestinal morphology and lymphocyte function in the absence of overt inflammation and disease. This study demonstrated that eukaryotic viruses have the capacity to support intestinal homeostasis and shape mucosal immunity, similar to commensal bacteria . This work demonstrates how little we currently know and truly understand about the composition of a healthy intestinal microbiome. Much further research along these lines is required to improve our knowledge of the intestinal microbiome as well as well microbiome host interactions critical for overall health.
The gut microbiota is increasingly looked at as a target for novel therapies, including microbiome modulation with probiotics and faecal microbiota transplants (FMT). These novel therapies are being increasingly used to treat patients with debilitating Clostridium difficile infections, where conventional treatments and antibiotics have failed. The number and frequency of FMT is growing exponentially , and in response biobanks for stool have been created at Massachusetts General Hospital in Boston and Emory University Hospital in Atlanta, where ‘healthy’ stool is screened and stored for medical use in approved cases . A small trial comparing antibiotic treatment to FMT for C. difficile showed that FMT was more effective at resolving patient symptoms as antibiotics alone . The effectiveness of FMT caused the trial to be stopped early. Non-randomised studies of C. difficile treated with either antibiotics only or FMT have shown a typical success rate of about 90% . While the majority of testimonies surrounding FMT are positive, there are still many unknowns, with no published clinical trials in many conditions for which the treatment is being proposed and in some cases used. Screening of the donor faeces is currently not standardized and can be very basic. We all carry different combinations of bacteria, viruses and parasites at any given moment in time . While the particular microbial composition that has evolved in one person may not be harmful, transplanting it into another person with a different genetic makeup may also transplant potentially pathogenic microbes or combinations of microbes causing unexpected outcomes. Little long-term safety data exists for FMT recipients , however transient abdominal pain and bloating have been observed. Given the increasing evidence that the gut microbiome plays a role in metabolic diseases (such as obesity) and immune-mediated diseases at the least, it needs to be established whether FMT may inadvertently induce these diseases.
Research is underway in several laboratories, such as Openbiome ( http://www.openbiome.org/ ) in the US, working on patient screening procedures (for faeces) as well as overall FMT regulation, similar to the model used by the Red Cross for blood products . This is to ensure the microbes transplanted behave as we expect them to, as well as minimising unexpected consequences, with the goal of eventually not having to use a donor for the transplant at all, but tailoring the combination of synthetic microbes grown in the lab tailored to each individual patient . FMT is becoming more accepted as a valid treatment option for C. difficile infections and is currently being trialled for patients with CD . Though, the hope that manipulating the gut microbiome to treat diseases other than C. difficile infection is still speculative .
The role of the host genetics in shaping the intestinal microbial community composition is unclear. With recent work highlighting the importance of underlying host genetics in community composition , it raises the question: if underlying host genetics influences microbiome composition, is FMT in complex genetic diseases futile because the transplant will never permanently shift the intestinal flora? In diseases such as AS and CD, the expectation is that since the microbiome influences the immune system, transplanting the gut with healthy intestinal flora will lead to interactions with the immune system which create a less inflammatory environment reducing gut disease and providing overall improvement of symptoms and may be even disease. The caveat here is that many genes associated with AS and CD are involved in mucosal immunology and microbial processing, so underlying host genetics may eventually override the transplant.
16S taxonomy does not inform us about what microbes are active and what they are expressing , let alone if expression is in reaction to host gene transcription . To better understand how host and commensal microbes interact, we also need better tools to examine interaction at the transcriptomic level . Metagenomic analyses of the human intestine have previously identified genes and pathways involved in the transport and metabolism of simple carbohydrate substrates are enriched in the intestine microbiome and alterations in these pathways have been linked with obesity, suggesting their importance for the appropriate functioning of this microbial ecosystem. However, elucidation of the actual activity and metabolic role of individual microbial members within the intestinal microbiome is still limited. Many of the microbial transcriptomic studies have used stool , as the use of intestinal biopsies is still technically very difficult due to the shear amount of human material in samples. Examining host transcriptomics in the gut in combination with microbial transcriptions will further our understanding into how host genetics influences intestinal microbial community composition and function , which contributes to disease.
Finally, the pursuit to understand the pathogenesis of spondyloarthritis, enabling accurate and early diagnosis and effective treatment, requires better understanding of how underlying host genetics influences the immune system and the intestinal microbiome. In the next few years, it is expected that larger studies with matched genotype and microbiome data will elucidate how it is that genetic variants influence the immune response, which in turn shapes the gut microbiome, in such a way that causes or propagates disease. Microbial profiling of tissue or stool samples, either alone or in combination with genetic tests, may identify individuals at high risk of developing spondyloarthritis, enabling either preventative intervention or early diagnosis.
Related posts:
Role of genetics in infection-associated arthritis
Vasculitis related to viral and other microbial agents
Evolving spectrum of HIV-associated rheumatic syndromes
Arthropod-borne arthritides
Treatment considerations in patients with concomitant viral infection and autoimmune rheumatic diseases
Role of vaccinations and prophylaxis in rheumatic diseases
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
