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The microbiome and rheumatic diseases

Introduction

There is an extensive and diverse microbial community residing within the human body, the microbiota. Evidence that this community plays an important role in health and disease is ever increasing, although our understanding of the mechanisms behind this link remains limited. Studies have demonstrated that the microbiota present in various regions, including the gut, skin and the mouth, in individuals with rheumatic diseases differs from that of healthy controls. The nature of these differences is slowly becoming clearer, and studies are now beginning to reveal functional differences associated with these compositional differences. Further clarification of the differences in microbiota in various human diseases may lead to novel diagnostic, preventive and treatment approaches. This role of the microbiome in rheumatic disease is the focus of this themed collection, which comprises a selection of recent full-text articles and chapters from the Springer Nature portfolio.

General

How the microbiota shapes rheumatic diseases

This paper reviews the current understanding of the role of the human microbiome in maintenance of immune homeostasis, with a focus on changes in the microbiome in association with rheumatoid diseases.

Summary
  • There is growing evidence to suggest that the human microbiome, defined as “the collective genomes of the microorganisms (bacteria, bacteriophages, fungi, protozoa and viruses) that live inside and on the human body”, is involved in key activities associated with health and disease.
  • Constant signaling between microorganisms and the host occurs in the epithelium of the gut, with both the innate and adaptive immune systems able to respond to the microbiota.
  • Disruption of the host-microorganism equilibrium, termed dysbiosis, can lead to elevated host inflammation and to intestinal disorders.
  • The gut microbiome is involved in regulation of both intestinal and systemic immunity, and has been implicated in several inflammatory rheumatic diseases.
  • The skin microbiota also plays an important role – with changes in the balance of the composition of skin microbiota shown to be associated with the pathogenesis of psoriasis.
  • Evidence suggests that the lung might be an early site for rheumatoid arthritis-related autoimmunity, and that generation of this autoimmunity may be triggered or modulated by the presence of proinflammatory microbiota derived from periodontal tissue.
  • Two possible models are proposed to explain the relationship between the microbiota and the host, a linear/unidirectional model, in which a primary cause (such as an environmental trigger on a specific genetic background) starts a one-way process (such as influencing the local immune response in the intestinal tract) and a multidirectional model, whereby the interaction between the host, genetics, environmental factors, the microbiota and immunity is plastic, with a lack of balance associated with disease.
  • Restoration of microbiota homeostasis involves modulation of the various contributing factors. While modulation of genetic factors is complex, modulation of environmental factors, the immune response and targeting of the microbiota (using probiotics for example) are potential approaches to target the interplay between the host and the microorganisms, and may be a useful therapeutic approach for rheumatic diseases.

Van de Wiele T et al. Nat Rev Rheumatol 2016;12:398–411. doi:10.1038/nrrheum.2016.85

The microbiome: A revolution in treatment for rheumatic diseases?

This review discusses the possible role of the microbiome in rheumatic diseases, with a focus on mechanisms and therapeutic potential.

Summary
  • Palm and colleagues demonstrated in 2014 that patients with inflammatory bowel disease have more immunoglobulin A-coated bacteria in their bowel than healthy controls.
  • Research to establish if there are specific gut microbes or microbial products that may influence immune cell function is ongoing, with studies to date producing conflicting results; even studies of the same disease have implicated different bacteria.
  • The impact of the intestines on immune response reaches beyond the gut, as lymphocytes can migrate from within the gut to distant sites.
  • The gingival mucosa and the microbiome of the lungs have both been implicated as potentially involved in the pathogenesis of rheumatoid arthritis.
  • Human leukocyte antigen (HLA) molecules, implicated in most immune-mediated diseases, have been shown to be a genetic factor that shapes the microbiome.
  • Alterations in the microbiota have been reported in rheumatic diseases, including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and systemic sclerosis.
  • Manipulation of the microbiome as a therapeutic approach to inflammatory rheumatoid disorders is an attractive approach.

Rosenbaum JT, Asquith MJ. Curr Rheumatol Rep 2016;18:62. doi 10.1007/s11926-016-0614-8

Microbiota and chronic inflammatory arthritis: an interwoven link

This review outlines the role of the microbiota in the onset, severity and progression of inflammatory arthritis.

Summary
  • Evidence suggests that microbes and microbial-derived products can control epithelial and inflammatory cell function, and are thus key factors in the initiation and maintenance of disease.
  • The link between gut dysbiosis and joint pathology may be explained by translocation of intestinal microbes, due to increased permeability of the intestinal epithelium or increased exposure to microbial products.
  • Evidence for a role of the microbiota in disease comes from various pathologies, including spondyloarthritis and inflammatory bowel disease, with evidence suggesting these may arise from altered interactions between gut microbes and the mucosal immune system; the skin microbiota has also been implicated in diseases, including psoriasis.
  • Several studies have implicated gut dysbiosis in rheumatoid arthritis, but an even stronger relationship may exist between rheumatoid arthritis and altered oral microbiota. Notably, rheumatoid arthritis shares several immunological and morphological features with severe forms of periodontitis – with studies showing strong correlations between increased prevalence of periodontitis and rheumatoid arthritis disease severity.
  • Environmental factors that may influence the periodontal microbiome, such as smoking, diet and stress, have also been shown to impact rheumatoid arthritis.
  • Further research is needed to determine how changes in the gut microbiota due to environmental factors are associated with development of autoimmune arthritis, and what such changes may mean for prognosis.
  • While our knowledge of the role of the microbiome in autoimmune arthritis remains incomplete, there is enough evidence to include recommendations for smoking cessation and dietary interventions in disease management.

Diamanti AP, Rosado MM, Laganà B, D’Amelio R. J Transl Med 2016;14:233. doi 10.1186/s12967-016-0989-3

Rheumatoid arthritis

The lung microbiota in early rheumatoid arthritis and autoimmunity

In this study, bronchoalveolar lavage fluid was obtained from patients with rheumatoid arthritis, patients with lung sarcoidosis and from healthy control subjects to investigate differences in the lung microbiome of such patients.

Summary
  • Bronchoalveolar lavage (BAL) was obtained from patients with a rheumatoid arthritis symptom duration of < 1 year (n=20), newly diagnosed pulmonary sarcoidosis patients (n=10) and healthy controls (n=28) to characterise the composition of the microbiota.
  • Microbial α-diversity was significantly reduced in the BAL of both rheumatoid arthritis and sarcoidosis patients compared with healthy controls, and microbial β-diversity plots could differentiate between the lung microbiota of healthy controls and that of rheumatoid arthritis and sarcoidosis patients.
  • There was decreased diversity and richness of the microbiota in rheumatoid arthritis and sarcoidosis patients, compared with healthy controls, with marked similarities between these two groups.
  • The Paraprevotellaceae, Chryseobacterium, and Burkhordelia taxa, and the families Burkholderiaceae, Actinomycetaceae, and Spirochaetaceae within these taxa, were less frequently present in rheumatoid arthritis and sarcoidosis patients than in healthy controls.
  • Contrary to expectations, Porphyromonas spp. and Treponema spp., both associated with periodontitis, were far more frequent in healthy subjects.
  • Disease activity in rheumatoid arthritis was positively correlated with Micrococcus and Renibacterium at the genus level, and with various operational taxonomic units belonging to Pseudonocardia, Streptococcus, and Xanthomonadaceae. An association with the presence of erosive disease was seen for Pseudonocardia in rheumatoid arthritis BAL.
  • High-throughput sequencing revealed that lung microbial composition in patients with rheumatoid arthritis differs significantly from that of healthy controls, but has a high degree of similarity to that of patients with lung sarcoidosis.

Scher JU, Joshua V, Artacho A, et al. Microbiome 2016;4:60. doi 10.1186/s40168-016-0206-x

An expansion of rare lineage intestinal microbes characterizes rheumatoid arthritis

This study used fecal samples to investigate the gut microbial and metabolite profiles of patients with rheumatoid arthritis, compared with both first-degree relatives and with other healthy controls.

Summary
  • This study was conducted to determine the microbial and metabolite profile in patients with rheumatoid arthritis, compared with controls.
  • Microbial DNA was extracted from fecal samples taken from adults with rheumatoid arthritis (n=40), first-degree relatives of such patients (n=15) and other controls (n=17).
  • Patients with rheumatoid arthritis had a significant decrease in gut microbial diversity, and α-diversity showed decreased species richness with increased rheumatoid factor levels and disease duration.
  • Phylum level profiles were similar between rheumatoid arthritis patients and all controls, except for increases in Actinobacteria and its two genera Eggerthella and Actinomyces; the genus Eggerthella demonstrated the most significant association with rheumatoid arthritis.
  • In addition to the increase in abundance of rare microbial lineages in the rheumatoid arthritis patients, there was a decrease in abundant taxa, such as
    Faecalibacterium.
  • Prediction models suggested that Collinsella, Eggerthella, and Faecalibacterium differed between patients with rheumatoid arthritis and controls. High levels of Collinsella correlated with high levels of alpha-aminoadipic acid, asparagine and IL-17A production.
  • The metabolomic profile differed significantly between patients with rheumatoid arthritis and their first-degree relatives, suggesting only a small percentage of the differences in the metabolome in rheumatoid arthritis is explained by genetic and environmental factors.
  • Overall, data from this study suggest that the dysbiosis seen in patients with rheumatoid arthritis results from abundance of particularly rare microbial lineages, and that determining the functions of the microbial clades that are increased or decreased in rheumatoid arthritis is likely to be important for future therapeutic approaches.

Chen J, Wright K, Davis JM, et al. Genome Med 2016;8:43. doi:10.1186/s13073-016-0299-7

The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment

This study investigated the oral and gut microbiomes in patients with rheumatoid arthritis.

Summary
  • This study used metagenomic shotgun sequencing of fecal samples, dental samples and saliva samples from treatment-naive individuals with rheumatoid arthritis (n=77) and unrelated healthy controls (n=80), to investigate the gut and oral microbiome in rheumatoid arthritis.
  • Gut dysbiosis was evident in patients with rheumatoid arthritis, with increased Gram-positive bacteria and depleted Gram-negative bacteria, and gut dysbiosis was shown to be associated with clinical indices of disease.
  • Researchers also demonstrated that oral dysbiosis was present in patients with rheumatoid arthritis, with an association with clinical indices again shown.
  • There was some concordance observed between the gut and the oral microbiomes. Notably, Haemophilus spp. were found in reduced abundance in patients with rheumatoid arthritis in all three sites, and were negatively correlated with amounts of serum antibodies and c-reactive protein. In contrast, levels of Lactobacillus salivarius were higher in rheumatoid arthritis, particularly in very active disease, and levels of gut and salivary L. salivarius were positively correlated with IgG levels.
  • Treatment with disease-modifying antirheumatic drugs (DMARDs) modified the microbiome, improving the dysbiosis.
  • These results show both oral and gut dysbiosis in rheumatoid arthritis, and suggest that greater understanding may allow microbiome-assisted diagnosis, prognosis and treatment.

Zhang​​​​​​​ X et al. Nat Med 2015;21:895–905. doi:10.1038/nm.3914

Juvenile idiopathic arthritis

The human microbiome and juvenile idiopathic arthritis

This review examines the relationship between the microbiome and pathogenesis in juvenile idiopathic arthritis (JIA), with a focus on potential microbiome-associated mechanisms of disease development.

Summary
  • Evidence suggests that only 18% of the pathogenesis of JIA can be attributed to genetic factors, with the remaining likely to be, at least in part, explained by various environmental influences, such as infections agents.
  • Both the innate immune system and the adaptive immune system have been implicated in the pathogenesis of JIA.
  • The influence of the microbiome on the immune system occurs via a number of mechanisms, including influencing development of the intestinal mucosal barrier, through its role in the generation and maturation of gut-associated lymphoid tissue, and via a direction influence on the development of T cells (notably Th1 and Th17 cells). The microbiome also seems to influence the development of Tregs; Th1, T17 and Tregs are all assumed to play a role in the development of autoimmunity.
  • Mechanisms by which microbes may influence the immune system include molecular mimicry, bystander activation, and by altering host proteins.
  • Questions remain regarding whether the microbial dysbiosis is a cause of JIA or an effect of JIA, or a bystander effect.
  • A growing body of evidence suggests that exposure to antimicrobial agents may have long-term effects on the composition of the microbiota, and there is some evidence that diet may also play a role in the development of dysbiosis.
  • Improved understanding of the mechanisms by which the microbiome may influence the development of JIA may lead to novel treatment and prevention approaches in the future.

Verwoerd A, Ter Haar NM, de Roock S, Vastert SJ, Bogaert D. Pediatr Rheumatol. 2016;14:55. doi:10.1186/s12969-016-0114-4

Spondyloarthritis

Spondyloarthritis and the microbiome: New insights from an ancient hypothesis

This review investigates the role of the microbiome in the pathogenesis of spondyloarthritis, with a focus on enteropathic arthritis, reactive arthritis, ankylosing spondylitis and psoriatic arthritis.

Summary
  • Factors shown to be associated with the composition of the microbiome, after initial imprinting at birth, include aging, the external environment, stress, antibiotic use and infection, all of which may result in decreased microbiome diversity.
  • In enteropathic arthritis, the pathogenesis remains to be fully elucidated, but important animal studies have linked the development of both colitis and joint disease to the gut microbiome, and IL23R has been implicated as a susceptibility gene for both Crohn’s disease and psoriasis.
  • There are several theories to explain the pathogenesis of reactive arthritis, including an increase in intestinal permeability, allowing luminal agents to travel to other sites, interact with the host immune system and cause inflammation and synovitis. A second therapy involves molecular mimicry, in which antigens associated with infectious bacteria are similar to those of the host, but different enough to induce an immune response leading to a breakdown of autoantigen tolerance.
  • Animal studies suggest a role for the intestinal microbiome in the development of ankylosing spondylitis, for example, several studies have implicated the IL-23 pathway, suggesting that the gut microbiome promotes an IL-23-dependant pro-inflammatory response, ultimately resulting in enthesitis, arthritis, and axial osteoproliferation.
  • Only a few studies have investigated the role of the microbiome in psoriatic arthritis, but dysbiosis has been demonstrated.
  • Further investigation into the composition of the microbiome in spondyloarthritis may lead to improved outcomes.

Manasson J, Scher JU. Curr Rheumatol Rep 2015;17:10. doi:10.1007/s11926-014-0487-7

The intestinal microbiome, the immune system and spondyloarthropathy

This chapter reviews the physiological processes involved in maintenance of intestinal homeostasis including the role of the microbiome, and discusses the role of dysbiosis in several disease states.

Summary
  • The intestinal epithelial cells that line the human gastrointestinal tract form a physical barrier – the interaction between this barrier, intestinal microbes and local immune cells is essential for intestinal homeostasis, yet such interactions have been shown to contribute to disease pathogenesis.
  • Both innate immunity (dendritic cell secretion of cytokines and chemokines for example) and adaptive immunity (including IL-23-responsive cells, γδ T cells, natural killer T cells, and lymphoid tissue inducer-like cells) are involved in maintenance of intestinal homeostasis.
  • Murine studies indicate that the interaction between the host and the gut microbiome determines levels of activation of cytokine-producing immune cells.
  • One of the first steps towards targeting the microbiome for the treatment of disease is to define the normal microbiome – a process first started by the Human Microbiome Project. Information from such projects reveals that ethnic background is a strong influencing factor, suggesting that environmental factors such as diet, location/region and host genetics play a role in determining the composition of the microbiome.
  • The microbiome has been implicated in several immune-mediated diseases, including ankylosing spondylitis, rheumatoid arthritis, inflammatory bowel disease, psoriasis and psoriatic arthritis.
  • Use of the gut microbiome as a biomarker or therapeutic target requires greater understanding of factors influencing the composition of the microbiome, such as age, diet, geographical location, gender and host genetics.
  • Modulation of the intestinal microbiome is becoming increasingly looked to as a target for novel therapeutic approaches, and it is becomingly increasingly clear that more individually targeted treatment, rather than generalised approaches, are needed.

Costella M-E, Brown MA. In Mina-Osorio P (Ed) Next-generation therapies and technologies for immune-mediated inflammatory diseases, progress in inflammation research. 2017:145-165. doi:10.1007/978-3-319-42252-7_8

The microbiome and psoriatic arthritis

This review highlights the possible relationship between the microbiome and psoriatic arthritis through an examination of the literature and by looking at other immune-mediated inflammatory diseases.

Summary
  • There is limited evidence available regarding the relationship between the microbiome and psoriatic arthritis.
  • While bacteria are by far the most abundant microorganisms in the human intestine, the human fungal and yeast microbial community, termed the mycobiome, is becoming increasingly recognised as also being important for health.
  • The interaction between the microbiome and the immune system involves both the immune system influencing the composition of the microbiome and modulation of the immune system by the microbiome.
  • The skin microbiome has been implicated in the pathogenesis of psoriasis, and may also be involved in the etiopathogenesis of psoriatic arthritis.
  • There are connections between the joint and the skin, the joint and the gut and between the gut and the skin, with the microbiome the possible mediator of common inflammatory pathways seen in the immune-mediated diseases affecting the gut, joints and skin.
  • Modulation of the immune system, with immunosuppressive agents, is known to be effective in the treatment of the symptoms of psoriatic arthritis. A novel approach to modulation of the immune system is via modulation of the microbiome, using pre- and probiotics and fecal microbiota transplantation.

Eppinga H, Konstantinov SR, Peppelenbosch MP, Bing Thio, H. Curr Rheumatol Rep 2014;16:407. doi:10.1007/s11926-013-0407-2

The role of the skin and gut microbiome in psoriatic disease

This systematic review compared the microbiota of the skin and gut between patients with psoriasis and healthy controls.

Summary
  • There is currently no consensus regarding the composition of the psoriatic microbiome. This systematic review looks at studies conducted to date investigating the gut and/or skin microbiome in patients with psoriasis and psoriatic arthritis.
  • Studies of α-diversity – the variety in the microbial community in terms of evenness, species distribution and richness – revealed conflicting differences between healthy control skin, lesional skin and non-lesional skin in individuals with psoriasis. Results for β-diversity – a measure of the similarity of microbial communities – were also conflicting.
  • Although data on the composition of the microbiome in psoriatic skin are generally conflicting, 3 out of 4 studies revealed decreased relative abundance of Propionibacterium in psoriatic lesional skin and higher levels of Streptococcus.
  • While there are studies suggesting a potential role for cutaneous dysbiosis in the development of psoriasis, there are currently no studies of the skin microbiome in psoriatic arthritis.
  • Studies of the gut microbiome in psoriatic arthritis found a decrease in Actinobacteria, a phylum that includes Bifidobacterium species that have been shown to decrease intestinal inflammation, suppress autoimmunity and induce Tregs.
  • Perturbations in the balance of Firmicutes and Bacteroidetes were also observed in psoriasis and psoriatic arthritis. At the genus level, level, a decrease in Akkermansia and Ruminoccocus was found.
  • Improved understanding of the psoriatic microbiome may lead to development of novel therapeutic approaches to target this changing microbiota, including antibiotics, prebiotics, probiotics and fecal transplant therapy.

Yan D, Issa N, Afifi L, Jeon C, Chang H-W, Liao W. Curr Derm Rep 2017;6:94–103. doi:10.1007/s13671-017-0178-5

Fecal metabolomics in pediatric spondyloarthritis implicate decreased metabolic diversity and altered tryptophan metabolism as pathogenic factors

This study used fecal water metabolomics to identify mechanisms by which the altered microbiota in children with enthesitis-related arthritis might contribute to the pathogenesis of this disease.

Summary
  • Previous studies showing dysbiosis in the gut microbiota in enthesitis-related arthritis have not established a mechanism by which dysbiosis can lead to arthritis.
  • In this study, faecal water metabolomics was performed in children with enthesitis-related arthritis in two cohorts, one comprising 14 children with newly diagnosed arthritis, including five naïve to treatment, and cohort 2 comprising 10 children with more long-standing disease, and controls (n=19) to investigate the role of microbiome-associated alterations in metabolic pathways in enthesitis-related arthritis pathogenesis.
  • For cohort 1, of almost 1500 negatively charged ions, 154 were significantly less abundant and 1 more abundant in patients, and for positively charged ions, 107 were lower in patients and only 17 were higher than in controls; these yielded 21 and five metabolic pathways, respectively, under-represented in patients compared with controls.
  • For cohort 2, of approximately 1000 ions, 59 negatively charged ions and 71 positively charged ions occurred with less frequency in patients than controls, with only 0 and 5, respectively, occurring with greater frequency. The number of pathways represented was less than that for cohort 1, at four for negatively charged and nine for positively charged ions.
  • The pathway for tryptophan metabolism was represented by both negative and positive charged ions as being under-represented among patients in both cohorts.
  • 16s rDNA was used to evaluate organisms responsible for these differences, but at the taxonomic level there were no organisms that clearly stood out as being more abundant in controls.
  • The metabolomics data suggest that differences exist in the metabolism of tryptophan in children with enthesitis-related arthritis due to the gut microbiota.

Stoll ML et al. Genes Immun 2016;17:400–405. doi:10.1038/gene.2016.38

Lupus

The microbiome and systemic lupus erythematosus

This review examines the relationship between intestinal microbiota and autoimmunity, with a focus on lupus, looking at the effect of the intestinal microbiota on disease and its potential role in therapy.

Summary
  • The gut microbiota has been shown to change with pregnancy, aging, geographic location and dietary patterns, and evidence suggests that it may play a role in the metabolism of food and drugs and may influence human behaviour.
  • Allergies, autoimmune disorders and inflammatory diseases are all considered to arise from failure to control immune responses against self, microbiota-derived or environmental antigens.
  • Both experimental models and clinical models have demonstrated that the gut microbiota plays a role in the pathogenesis of systemic lupus erythematosus.
  • Evidence suggests that the immunological response to the microbiota in patients with systemic lupus erythematosus may involve increased lymphocyte activation and Th17 differentiation.
  • In patients with systemic lupus erythematosus the ratio of Firmicutes/Bacteroidetes has been shown to be significantly lower than in healthy matched controls, even for systemic lupus erythematosus patients in remission.
  • The composition of the microbiome may play a role in the development of several manifestations of lupus, with fluctuation of the composition of the microbiome, due to factors such as gender, genetics and the environment, associated with disease flares.
  • Available evidence supporting the intestinal dysbiosis theory of lupus pathogenesis suggests that the microbiota be considered as a novel target for therapy, manipulating the gut microbiome composition via dietary intervention strategies, and the use of antibiotics and probiotics, for example.

Katz-Agranov N, Zandman-Goddard GZ. Immunol Res 2017;65:432–437. doi:10.1007/s12026-017-8906-2

Osteoarthritis

Does lipopolysaccharide-mediated inflammation have a role in OA?

This paper outlines the inflammatory process involved in osteoarthritis, with a focus on the place of lipopolysaccharide in the pathogenesis of this inflammatory process.

Summary
  • Once considered a non-inflammatory condition, low-grade inflammation is now known to be prevalent in osteoarthritis.
  • One postulated mechanism for the inflammation seen in osteoarthritis involves lipopolysaccharides (outer membrane components of Gram-negative bacteria), which induce an immune response.
  • Several of the mechanisms involved in osteoarthritis pathogenesis overlap with the immune-activating function of the lipopolysaccharides – including activation of the innate immune system via TLR3 and its coreceptor MD-2, enhanced phagocytosis and cytotoxicity of macrophages, and activation of the complement cascade and the coagulation cascade.
  • Factors influencing the systemic concentration of lipopolysaccharides include impaired clearance, changes in gut microbiota, changes in gut permeability (as occurs in obesity), dietary factors, intestinal motility, intestinal levels of alkaline phosphatase, and exercise and HDL cholesterol levels.
  • The researchers hypothesise that lipopolysaccharides in the bloodstream play a role in a two-hit model of osteoarthritis pathogenesis. The first involves the lipopolysaccharides priming the proinflammatory innate immune response, with the second involving complementary mechanisms, such as joint injury and damage, which also activate the innate immune system.
  • Lipopolysaccharides may provide the common mechanism for the association between obesity, metabolic syndrome and osteoarthritis.
  • Therapies to reduce lipopolysaccharides could include a high-fibre diet, weight loss, exercise, antibiotics and microbiota transplant.
  • Measurement of circulating lipopolysaccharide levels may provide a means of detecting individuals at high risk of joint failure who could most benefit from therapies aimed at lowering these levels.

Huang Z & Kraus VB. Nat Rev Rheumatol 2016;12:123–129. doi:10.1038/nrrheum.2015.158

Gout

Intestinal microbiota distinguish gout patients from healthy humans

In this cross-sectional study, the intestinal microbiota of individuals with gout was compared with that of healthy controls.

Summary
  • Gout is an autoinflammatory condition characterized by the accumulation of uric acid in the blood due to disordered purine metabolism. In humans, uric acid is excreted primarily by the kidney, but the intestines also play an important role.
  • This cross-sectional study included 35 patients with gout and 33 healthy adults, as well as 15 further subjects (six with gout and nine healthy individuals) for model validation purposes.
  • Microbiota sequencing was performed using 16s rRNA gene pyrosequencing, with the functional profiles of microbiota characterised in a subset of patients using whole-metagenome shotgun sequencing.
  • A significant reduction was observed in α-diversity of intestinal microbiota from individuals with gout compared with healthy controls, and the intestinal microbiota were highly distinct in structure between the two groups.
  • Of 41 metagenomic species identified, 22 were enriched in healthy individuals, such as those representing Faecalibacterium prausnitzii, Clostridium butyrate-producing bacterium and Bifidobacterium pseudocatenulatum, with 19 enriched in gout patients, including Bacteroides spp.
  • Seventeen genera were associated with gout, with some, such as Bacteroides, Holdemania, and Anaerotruncus positively associated, and others, such as Faecalibacterium, Coprococcus and Ruminococcus negatively associated.
  • The researchers developed a model for microbiota-based diagnosis of gout using bacterial markers, finding that the accuracy of diagnosis using these markers had a predictive value of 88.9%, compared with 71.3% using blood uric acid levels.
  • The association shown in this study between gout and the composition of the microbiota suggests that it is important to include intestinal microbiota metabolism when examining diagnoses and mechanisms of gout.

Guo​​​​​​​ Z et al. Sci Rep 2016; 6: 20602. doi:10.1038/srep20602