Association of anti-TNF-α treatment with gut microbiota of patients with ankylosing spondylitis.

OBJECTIVE: Gut dysbiosis contributes to multiple autoimmune diseases, including ankylosing spondylitis, which is commonly treated with tumor necrosis factor (TNF)-α inhibitors (TNFis). Because host TNF-α levels are considered to interact with gut microbiota, we aimed to systematically investigate the microbiota profile of ankylosing spondylitis patients with anti-TNF-α-based treatment and identify potential key bacteria. METHODS: Fecal samples were collected from 11 healthy controls and 24 ankylosing spondylitis patients before/after anti-TNF-α treatment, the microbiota profiles of which were evaluated by 16S ribosomal DNA amplicon sequencing and subsequent bioinformatic analysis. RESULTS: Significantly different microbial compositions were observed in samples from ankylosing spondylitis patients compared with healthy controls, characterized by a lower abundance of short-chain fatty acid (SCFA)-producing bacteria. All patients exhibited a positive response after anti-TNF-α treatment, accompanied by a trend of restoration in the microbiota compositions and functional profile of ankylosing spondylitis patients to healthy controls. In particular, the abundance of SCFA-producing bacteria (e.g. Megamonsa and Lachnoclostridium ) was not only significantly lower in ankylosing spondylitis patients than in healthy controls and restored after anti-TNF-α treatment but also negatively correlated with disease severity (e.g. cor = -0.52, P = 8 × 10 -5 for Megamonsa ). In contrast, Bacilli and Haemophilus may contribute to ankylosing spondylitis onset and severity. CONCLUSIONS: Microbiota dysbiosis in ankylosing spondylitis patients can be restored after anti-TNF-α treatment, possibly by impacting SCFA-producing bacteria.

Comparison of the antibacterial activity of Australian Terminalia spp. extracts against Klebsiella pneumoniae: a potential treatment for ankylosing spondylitis.

Traditional medicines prepared using Terminalia species have been used globally to treat inflammation and pathogenic infections. Recent studies have demonstrated that multiple Asian and African Terminalia spp. inhibit bacterial triggers of some autoimmune inflammatory diseases, including ankylosing spondylitis. Despite this, the effects of Australian Terminalia spp. on a bacterial trigger of ankylosing spondylitis (K. pneumoniae) remain unexplored. Fifty-five extracts from five Australian Terminalia spp. were investigated for K. pneumoniae growth inhibitory activity. Methanolic, aqueous and ethyl acetate extracts of most species and plant parts inhibited K. pneumoniae growth, with varying potencies. Methanolic leaf extracts were generally the most potent bacterial growth inhibitors, with minimum inhibitory concentration (MIC) values of 66 µg/mL (T. ferdinandiana), 128 µg/mL (T. carpenteriae) and 83 µg/mL (T. petiolares). However, the aqueous leaf extract was the most potent T. grandiflora extract (MIC = 87 µg/mL). All T. catappa extracts displayed low growth inhibitory activity. The Terminalia spp. methanolic leaf extracts were examined by liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS). All contained a relative abundance of simple gallotannins (particularly gallic and chebulic acids), the flavonoid luteolin, as well as the monoterpenoids cineole and terpineol. Notably, all Terminalia spp. were non-toxic or of low toxicity in ALA and HDF toxicity assays, highlighting their potential for preventing the onset of ankylosing spondylitis and treating its symptoms once the disease is established, although this needs to be verified in in vivo systems.

Shotgun metagenomics reveals an enrichment of potentially cross-reactive bacterial epitopes in ankylosing spondylitis patients, as well as the effects of TNFi therapy upon microbiome composition.

OBJECTIVES: Diverse evidence including clinical, genetic and microbiome studies support a major role of the gut microbiome in the common immune-mediated arthropathy, ankylosing spondylitis (AS). We set out to (1) further define the key microbial characteristics driving disease, and (2) examine the effects of tumour necrosis factor-inhibitor (TNFi) therapy upon the microbiome. METHODS: The stools from a case-control cohort of 250 Han-Chinese subjects underwent shotgun metagenomic sequencing. All subjects were genotyped using the Illumina CoreExome SNP microarray. RESULTS: Previous reports of gut dysbiosis in AS were reconfirmed and several notable bacterial species and functional categories were differentially abundant. TNFi therapy was correlated with a restoration the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. Enrichment of bacterial peptides homologous to HLA-B27-presented epitopes was observed in the stools of patients with AS, suggesting that either HLA-B27 fails to clear these or that they are involved in driving HLA-B27-associated immune reactions. TNFi therapy largely restored the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. TNFi therapy of patients with AS was also associated with a reduction of potentially arthritogenic bacterial peptides, relative to untreated patients. CONCLUSION: These findings emphasise the key role that the gut microbiome plays in driving the pathogenesis of AS and highlight potential therapeutic and/or preventative targets.

The correlation between intestinal dysbiosis and the development of ankylosing spondylitis.

The pathogenesis and development of ankylosing spondylitis (AS) is concealed and complicated. In recent years, alterations in gut microbiota of AS patients have been largely investigated, although the underlying mechanisms remain unclear. This article reviews the recent studies on changes of gut microbiota in AS patients, and discusses the possible correlation between intestinal dysbiosis and AS development from aspects including genetic factor HLA-B27, mucosal immune responses and the depression accompanying AS.

Progress in our understanding of the pathogenesis of ankylosing spondylitis.

AS is a common rheumatic condition characterized by inflammation and new bone formation. The pathogenesis of AS is likely multifactorial and has not been fully elucidated to date. A major genetic role has been demonstrated. The strongest genetic association is with HLA B27. Numerous other associated genetic polymorphisms have been identified, including those affecting the type 17 immune pathway, although the precise link between genetics and pathogenesis remains unexplained. Several immunological alterations, together with recent therapeutic advances, support a central role for IL-23- and IL-17-producing immune cells in disease pathogenesis. Recently, perturbations of gut microbiota of AS patients have further catalysed research and offer potential for future therapeutic intervention. In this review we outline the genetic basis of AS and describe the current hypotheses for disease pathogenesis. We synthesize recent experimental research data and clinical studies to support a central role for the type 17/23 immune axis in AS.

The association of HLA-B27 and Klebsiella pneumoniae in ankylosing spondylitis: A systematic review.

Ankylosing spondylitis (AS) is a chronic inflammatory arthritis of unknown origin. Its autoimmune origin has been suggested but never proven. Several reports have implicated K. pneumoniae as a triggering or perpetuating factor in AS; and the HLA-B27 antigen has also been found in association with AS. But there is no satisfactory explanation of why the presence of HLA-B27 predisposes to AS and the precise role played by K. pneumoniae in the disease has not yet been clarified. However, various studies have shown that the results of molecular, immunological, and microbiological studies could establish the link between K. pneumoniae infections and HLA-B27 in the aetiopathogenesis of AS. In this review, we have examined the evidence linking the interaction between K. pneumoniae infections and HLA-B27 in AS, and tried to exploit the possible mechanisms by which K. pneumoniae infections might induce pathologic processes to develop novel diagnostic criteria. Finally, we have also summarized some dietary regimens that could be helpful in the therapeutic management of AS patients.

The evidence for microbiome manipulation in inflammatory arthritis.

The human body consists of millions of commensal bacteria (the microbiome), with the intestinal tract being the most prevalent site of colonization. This colonization process begins at birth, and despite numerous factors such as ageing, diet and drug use affecting the microbiome make-up, by adulthood the composition of the gut bacteria is relatively consistent across local populations. The recent advent of new scientific techniques has enabled us to explore how the microbiome affects health and, in particular, has shed light on the involvement of the microbiome in the pathogenesis of inflammatory disease. In this review we highlight the current evidence for microbiome manipulation in inflammatory arthritis in animal and human models and discuss potential therapeutics targeting the microbiome as treatment for these diseases.

Risk of Tuberculosis Reactivation in Patients with Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Receiving Non-Anti-TNF-Targeted Biologics.

Tuberculosis (TB) still represents an important issue for public health in underdeveloped countries, but the use of antitumor necrosis factor agents (anti-TNF) for the treatment of inflammatory rheumatic disorders has reopened the problem also in countries with low TB incidence, due to the increased risk of TB reactivation in subjects with latent tuberculosis infection (LTBI). Over the last 5 years, several non-anti-TNF-targeted biologics have been licensed for the treatment of rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. We reviewed the epidemiology of TB, the role of different cytokines and of the immune system cells involved in the immune response against TB infection, the methods to detect LTBI, and the risk of TB reactivation in patients exposed to non-anti-TNF-targeted biologics. Given the limited role exerted by the cytokines different from TNF, as expected, data from controlled trials, national registries of biologics, and postmarketing surveillance show that the risk of TB reactivation in patients receiving non-anti-TNF-targeted biologics is negligible, hence raising the question whether the screening procedures for LTBI would be necessary.

Inhibition of Klebsiella pneumoniae growth by selected Australian plants: natural approaches for the prevention and management of ankylosing spondylitis.

A wide variety of herbal remedies are used in traditional Australian medicine to treat inflammatory disorders, including autoimmune inflammatory diseases. One hundred and six extracts from 40 native Australian plant species traditionally used for the treatment of inflammation and/or to inhibit bacterial growth were investigated for their ability to inhibit the growth of a microbial trigger for ankylosing spondylitis (K. pneumoniae). Eighty-six of the extracts (81.1%) inhibited the growth of K. pneumoniae. The D. leichardtii, Eucalyptus spp., K. flavescens, Leptospermum spp., M. quinquenervia, Petalostigma spp., P. angustifolium, S. spinescens, S. australe, S. forte and Tasmannia spp. extracts were effective K. pneumoniae growth inhibitors, with MIC values generally <1000 µg/mL. The T. lanceolata peppercorn extracts were the most potent growth inhibitors, with MIC values as low as 16 µg/mL. These extracts were examined by non-biased GC-MS headspace analysis and comparison with a compound database. A notable feature was the high relative abundance of the sesquiterpenoids polygodial, guaiol and caryophyllene oxide, and the monoterpenoids linalool, cineole and α-terpineol in the T. lanceolata peppercorn methanolic and aqueous extracts. The extracts with the most potent K. pneumoniae inhibitory activity (including the T. lanceolata peppercorn extracts) were nontoxic in the Artemia nauplii bioassay. The lack of toxicity and the growth inhibitory activity of these extracts against K. pneumoniae indicate their potential for both preventing the onset of ankylosing spondylitis and minimising its symptoms once the disease is established.

The interaction between host genetics and the microbiome in the pathogenesis of spondyloarthropathies.

PURPOSE OF REVIEW: The intestinal microbiome is increasingly implicated in the pathogenesis of ankylosing spondylitis, reactive arthritis, and other diseases collectively known as the spondyloarthropathies (SpAs). In common with other complex inflammatory diseases, SpAs have both a strong genetic and environmental component. Recent genetic studies have highlighted host pathways that may intersect the host-microbiota interaction and offer novel paradigms to understand the pathophysiology of these diseases. RECENT FINDINGS: Genetic association studies have identified genes such as RUNX3, PTPEN2, and IL-33 as susceptibility loci for SpAs. Functional studies in humans have extended knowledge of established genetic risk factors for ankylosing spondylitis that include ERAP1, ERAP2, and interleukin-23R. Recent basic research has identified new mechanisms that regulate host immune responses to the microbiota that conceivably may be dysregulated in SpA. SUMMARY: Intestinal barrier function, deletional tolerance, Th17 signature response, and endoplasmic reticulum stress pathways have been recently linked to SpA. Dysregulated immune responses to the gut microbiota and an altered microbial community structure are shared features of SpA. Although the cause-effect dynamic of this relationship remains equivocal, it nonetheless has major implications for both intestinal and extra-intestinal pathology observed in SpA.

Patients with ankylosing spondylitis have been breast fed less often than healthy controls: a case-control retrospective study.

OBJECTIVE: Ankylosing spondylitis (AS) is a chronic inflammatory disease affecting the spine and pelvis of young adults. On the HLA-B27 genetic background, the occurrence of AS is influenced by the intestinal microbiota. The goal of our study was to test whether breast feeding, which influences microbiota, can prevent the development of AS. METHODS: First, 203 patients with HLA-B27-positive AS fulfilling the modified New York criteria were recruited in the Department of Rheumatology, Ste Marguerite hospital in Marseilles. A total of 293 healthy siblings were also recruited to make up a control group within the same families. Second, 280 healthy controls, and 100 patients with rheumatoid arthritis and their siblings were recruited. The data collected were age, gender, number of brothers and sisters, age at disease onset, type and duration of feeding (breast or bottle). RESULTS: Patients with AS had been breast fed less often than healthy controls. In families where children were breast fed, the patients with AS were less often breast fed than their healthy siblings (57% vs 72%), giving an OR for AS onset of 0.53 (95% CI (0.36 to 0.77), p value=0.0009). Breast feeding reduced familial prevalence of AS. The frequency of breast feeding was similar in the AS siblings and in the 280 unrelated controls. However, patients with AS were less often breast fed compared with the 280 unrelated controls (OR 0.6, 95% CI (0.42 to 0.89), p<0.01). CONCLUSIONS: Our study suggests a breastfeeding-induced protective effect on the occurrence of AS. To our knowledge, this is the first study of breastfeeding history in patients with AS.

A Possible Role of Intestinal Microbiota in the Pathogenesis of Ankylosing Spondylitis.

Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the sacroiliac joints and the spine, for which the pathogenesis is thought to be a result of the combination of host genetic factors and environmental triggers. However, the precise factors that determine one's susceptibility to AS remain to be unraveled. With 100 trillion bacteria residing in the mammalian gut having established a symbiotic relation with their host influencing many aspects of host metabolism, physiology, and immunity, a growing body of evidence suggests that intestinal microbiota may play an important role in AS. Several mechanisms have been suggested to explain the potential role of the microbiome in the etiology of AS, such as alterations of intestinal permeability, stimulation of immune responses, and molecular mimicry. In this review, the existing evidence for the involvement of the microbiome in AS pathogenesis was discussed and the potential of intestinal microbiome-targeting strategies in the prevention and treatment of AS was evaluated.

Gut microbes, immunity, and spondyloarthritis.

The last decade has witnessed an explosion of studies evaluating the impact of the human microbiota on a variety of disease states. The microbiota can impact diseases in multiple ways, including through abnormalities in the diversity and contents of the microbiota, as well as by acting as targets of immunologic dysregulation. Herein, evidence that the microbiota in spondyloarthritis is both altered and abnormally targeted by the immune system will be presented.

The intestinal microbiome in spondyloarthritis.

PURPOSE OF REVIEW: Microbial dysbiosis in the gut is emerging as a common component in various inflammatory disorders including spondyloarthritis (SpA). The depth of this influence has begun to be realized with next-generation sequencing of the gut microbiome providing unbiased assessment of previously uncharted bacterial populations. RECENT FINDINGS: Decreased numbers of Firmicutes, a major phyla of gut commensals, especially the species Faecalibacterium prausnitzii and Clostridium leptum have been found in various inflammatory disorders including SpA and inflammatory bowel disease (IBD), and could be an important link between SpA and gut inflammation. Multiple studies in ankylosing spondylitis, psoriatic arthritis, juvenile SpA, and animal models of SpA are revealing common bacterial associations among these diseases as well as IBD. SUMMARY: We are beginning to appreciate the complex relationship between the gut microbiome and host immune regulation and dysregulation in health and disease. Potentially important differences have been revealed in SpA, but cause and effect relationships remain far from established. Many critical questions remain to be answered before we can apply new knowledge to improve therapeutics in SpA.

Update on ankylosing spondylitis: current concepts in pathogenesis.

Ankylosing spondylitis is an insidiously progressive and debilitating form of arthritis involving the axial skeleton. The long delay in diagnosis and insufficient response to currently available therapeutics both advocate for a greater understanding of disease pathogenesis. Genome-wide association studies of this highly genetic disease have implicated specific immune pathways, including the interleukin (IL)-17/IL-23 pathway, control of nuclear factor kappa B (NF-κB) activation, amino acid trimming for major histocompatibility complex (MHC) antigen presentation, and other genes controlling CD8 and CD4 T cell subsets. The relevance of these pathways has borne out in animal and human subject studies, in particular, the response to novel therapeutic agents. Genetics and the findings of autoantibodies in ankylosing spondylitis revisit the question of autoimmune vs. autoinflammatory etiology. As environmental partners to genetics, recent attention has focused on the roles of microbiota and biomechanical stress in initiating and perpetuating inflammation. Herein, we review these current developments in the investigation of ankylosing spondylitis pathogenesis.

Spondyloarthritis and the microbiome: new insights from an ancient hypothesis.

The human microbiome, which represents the total collection of microorganisms (and their genes) inhabiting the human body, has increasingly been recognized as a potential key factor in the development of autoimmune disease. Multiple studies suggest that the microbiome has significant influence on immune homeostasis, while disruptions in local microbiome composition can result in a heightened systemic inflammatory response. The intestinal microbiome, in particular, harbors the densest assembly of bacteria and appears to influence the immune system in the context of inflammatory arthropathies. Although studies are still sparse, this review will examine the role of the microbiome in the pathogenesis of spondyloarthritis (SpA), particularly in enteropathic arthritis (EA), reactive arthritis (ReA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA).

Raised incidence of ankylosing spondylitis among Inuit populations could be due to high HLA-B27 association and starch consumption.

Ankylosing spondylitis (AS) is a chronic inflammatory arthritis mainly affecting the spinal joints. It would appear that the most likely causative agent in the development of AS is an environmental factor in the genetically susceptible, HLA-B27 positive, individuals. Extensive data from several countries support the notion that Klebsiella pneumonia bacteria are the most likely culprit in the causation of AS. These microbes possess antigens which resemble HLA-B27 and spinal collagens. Increased intake of high-starch diet is directly proportional to the gut-associated bacterial load, especially in the large intestine, and among these microbial agents, Klebsiella is considered as one of the main constituting components. Therefore, a low-starch diet intake alongside the currently used medical therapeutic modalities could be beneficial in the management of patients with early AS. It is suggested that a change in the dietary habits from high protein, low-starch marine components to the Westernized high-starch diet among the Inuit peoples of Alaska and Canada could be considered as one of the main contributing factors in the increased prevalence of AS during the last few decades within this genetically unmixed native population.

The potential of selected South African plants with anti-Klebsiella activity for the treatment and prevention of ankylosing spondylitis.

A wide variety of herbal remedies are used in traditional African medicine to treat inflammatory disorders, including some autoimmune diseases. Thirty-four extracts from 13 South African plant species traditionally used for the treatment of inflammation were investigated for their ability to control a microbial trigger for ankylosing spondylitis (Klebsiella pneumoniae). Twenty-six of the extracts (76.5%) inhibited the growth of K. pneumoniae. Methanol and water extracts of Ballota africana, Carpobrotus edulis leaves, Kigellia africana, Lippia javanica, Pelargonium fasiculata, Syzygium cordatum (including bark), Terminalia pruinoides and Terminalia sericea were effective K. pneumoniae inhibitors, with MIC values <1000 µg/ml. The roots of Tulbaghia violaceae and bark from Warburgia salutaris also demonstrated efficacy. The most potent extracts were examined by RP-HPLC and UV-Vis spectroscopy for the presence of resveratrol. Methanolic extracts of B. africana, C. edulis leaves, L. javanica, T. pruinoides and T. sericea, as well as aqueous B. africana, T. pruinoides and T. sericea extracts, displayed peaks with retention times and UV-Vis spectra consistent with the presence of resveratrol. Resveratrol was generally a minor component, indicating that resveratrol was not solely responsible for the anti-Klebsiella growth inhibitory properties. Plant extracts with K. pneumoniae inhibitory activity were either non-toxic, or of low toxicity in the Artemia (brine shrimp) nauplii bioassay. Their low toxicity and antibiotic bioactivity against K. pneumoniae indicate their potential for both preventing the onset of ankylosing spondylitis and minimising its symptoms once the disease is established.

Microbiome and probiotics: link to arthritis.

PURPOSE OF REVIEW: The gut microbiome plays an integral role in the development and maintenance of the host immune system. Expanding knowledge about this microbial microenvironment has raised the possibility of new treatments based on this knowledge. In this review, we describe the recent evidence of the impact of the gut microbiome on arthritis and possible novel therapeutic approaches to alter the gut flora. RECENT FINDINGS: Recent studies support the growing evidence of microbiome as a causative agent underlying certain rheumatic diseases like ankylosing spondylitis and rheumatoid arthritis. There is intriguing yet still inconclusive evidence to support the use of probiotics as a treatment for these diseases. SUMMARY: There is recently a new level of understanding how the microbiome interacts with the immune system. Gene-environment interaction is another important element that sets the stage for initiation of autoimmune disease, which calls for further investigation. Probiotics could be an appealing therapeutic strategy, but further interventional studies exploring the dynamic interaction of microbiome and probiotics are still needed.

Mycobacterial diseases developed during anti-tumour necrosis factor-α therapy.

Nontuberculous mycobacterial (NTM) disease and tuberculosis (TB) develop during anti-tumour necrosis factor (TNF)-α therapy. We compared clinical characteristics and outcomes between the two diseases. A total of 1165 patients were screened for TB and treated with TNF-α antagonists from July 2004 to July 2013 for the following conditions: inflammatory bowel disease (n = 422), rheumatoid arthritis (n = 320), and ankylosing spondylitis (n = 389). TB and NTM disease were diagnosed at baseline screening in four and three patients, respectively, and developed during anti-TNF-α therapy in 19 and six patients, respectively. The incidence rate of TB and NTM disease was 747.7 per 100 000 and 238.2 per 100 000 person-years, respectively. Patients with NTM disease were older, with a greater proportion of females. All cases of NTM disease involved the lung, with rheumatoid arthritis (83.3%) being the most frequent underlying disease. The most common radiological feature was consolidation in NTM disease, and honeycombing was present in two rheumatoid arthritis patients with NTM disease. The most common pathogen was Mycobacterium intracellulare (n = 3) followed by Mycobacterium avium (n = 2). Both the NTM and TB group showed favourable outcomes. The clinical characteristics differed between NTM disease and TB that developed on anti-TNF-α agents, but clinical outcomes were favourable in both diseases.