Gut microbiota dysbiosis in ankylosing spondylitis: a systematic review and meta-analysis.

Background: Ankylosing spondylitis (AS) is a connective tissue disease that primarily affects spinal joints, peripheral joints, and paravertebral soft tissues, leading to joint stiffness and spinal deformity. Growing evidence has implicated gut microbiota in the regulation of AS, though the underlying mechanisms remain poorly understood. Methods: We conducted a comprehensive search of PubMed, Embase, Web of Science, the Cochrane Library, MEDLINE, Wanfang Data, China Science and Technology Journal Database (VIP), and China National Knowledge Internet (CNKI) databases from the time the databases were created until 30 July 2023. To evaluate changes in α-diversity and the abundance of certain microbiota families in AS, standardized mean difference (SMD) and 95% confidence interval (CI) calculations were made. Meta-analyses were performed using STATA 12.0 and the quality of the literature was assessed by following systematic review guidelines. Results: This systematic review and meta-analysis included 47 studies, providing insights into the gut microbiota composition in patients with AS compared to healthy controls (HCs). Our findings indicate a significant reduction in gut microbial diversity in patients with AS, as evidenced by a decrease in both richness and evenness. Specifically, the Shannon index showed a moderate decrease (SMD = -0.27, 95% CI: -0.49, -0.04; P < 0.001), suggesting a less diverse microbial ecosystem in patients with AS. The Chao1 index further confirmed this trend, with a larger effect size (SMD = -0.44, 95% CI: -0.80, -0.07; P < 0.001), indicating a lower species richness. The Simpson index also reflected a significant reduction in evenness (SMD = -0.30, 95% CI: -0.53, -0.06; P < 0.001). Additionally, patients with AS who received anti-rheumatic combination treatment exhibited a more pronounced reduction in α-diversity compared to untreated patients, highlighting the potential impact of this treatment on gut microbiota balance. In terms of specific microbial families, we observed a significant decrease in the abundance of Bifidobacterium (SMD = -0.42, 95% CI: -2.37, 1.52; P < 0.001), which is known for its beneficial effects on gut health. Conversely, an increase in the abundance of Bacteroidetes was noted (SMD = 0.42, 95% CI: -0.93, 1.76; P < 0.001), suggesting a possible shift in the gut microbiota composition that may be associated with AS pathophysiology. Conclusion: Our analysis revealed changes in α-diversity and the relative abundance of specific bacteria in AS. This suggests that targeting the gut microbiota could provide new therapeutic opportunities for treating AS. Systematic review registration: https://www.crd.york.ac.uk./PROSPERO/, identifier CRD42023450028.

Gut microbiota and risk of ankylosing spondylitis.

OBJECTIVE: Observational studies have established a connection between gut microbiota and ankylosing spondylitis (AS) risk; however, whether the observed associations are causal remains unclear. Therefore, we conducted a two-sample Mendelian randomization (MR) analysis to assess the potential causal associations of gut microbiota with AS risk. METHODS: Instrumental variants of gut microbiota were obtained from the MiBioGen consortium (n = 18,340) and the Dutch Microbiome Project (n = 7738). The FinnGen consortium provided genetic association summary statistics for AS, encompassing 2860 cases and 270,964 controls. We used the inverse-variance weighted (IVW) method as the primary analysis, supplemented with the weighted median method, maximum likelihood-based method, MR pleiotropy residual sum and outlier test, and MR-Egger regression. In addition, we conducted a reverse MR analysis to assess the likelihood of reverse causality. RESULTS: After the Bonferroni correction, species Bacteroides vulgatus remained statistically significantly associated with AS risk (odds ratio (OR) 1.55, 95% confidence interval (CI) 1.22-1.95, P = 2.55 × 10-4). Suggestive evidence of associations of eleven bacterial traits with AS risk was also observed (P < 0.05 by IVW). Among them, eight were associated with an elevated AS risk (OR 1.37, 95% CI 1.07-1.74, P = 0.011 for phylum Verrucomicrobia; OR 1.31, 95% CI 1.03-1.65, P = 0.026 for class Verrucomicrobiae; OR 1.17, 95% CI 1.01-1.36, P = 0.035 for order Bacillales; OR 1.31, 95% CI 1.03-1.65, P = 0.026 for order Verrucomicrobiales; OR 1.43, 95% CI 1.13-1.82, P = 0.003 for family Alcaligenaceae; OR 1.31, 95% CI 1.03-1.65, P = 0.026 for family Verrucomicrobiaceae; OR 1.31, 95% CI 1.03-1.65, P = 0.026 for genus Akkermansia; OR 1.55, 95% CI 1.19-2.02, P = 0.001 for species Sutterella wadsworthensis). Three traits exhibited a negative association with AS risk (OR 0.68, 95% CI 0.53-0.88, P = 0.003 for genus Dialister; OR 0.84, 95% CI 0.72-0.97, P = 0.020 for genus Howardella; OR 0.75, 95% CI 0.59-0.97, P = 0.026 for genus Oscillospira). Consistent associations were observed when employing alternate MR methods. In the reverse MR, no statistically significant correlations were detected between AS and these bacterial traits. CONCLUSION: Our results revealed the associations of several gut bacterial traits with AS risk, suggesting a potential causal role of gut microbiota in AS development. Nevertheless, additional research is required to clarify the mechanisms by which these bacteria influence AS risk. Key Points • The association of gut microbiota with AS risk in observational studies is unclear. • This MR analysis revealed associations of 12 gut bacterial traits with AS risk.

Detection Ewingella americana from a patient with Andersson lesion in ankylosing spondylitis by metagenomic next-generation sequencing test: a case report.

BACKGROUND: Andersen's lesion (AL) is a rare complication of ankylosing spondylitis (AS), characterized by nonneoplastic bone destruction, typically manifested as bone destruction and sclerosis in the vertebral body and/or intervertebral disc area. At present, there is no consensus on the pathology and etiology of AL. Repeated trauma, inflammation in essence and part of the natural history of Ankylosing spondylitis itself are the most widely recognized theories of the etiology of AL. However, positive bacteria cultured in bone biopsy of Andersen's lesion (AL) in Ankylosing spondylitis patients are extremely rare. Herein, we report a rare case of detecting Ewingella americana from a patient with Andersson lesion in ankylosing spondylitis by Metagenomic Next-Generation Sequencing (mNGS) Test. CASE PRESENTATION: This case involved a 39-year-old male with a history of AS for 11 years, who developed AL (T11/12) in the thoracic vertebrae. After sufficient preoperative preparation, we successfully performed one-stage posterior approach corrective surgery and collected bone biopsies samples for examination. Cultured bacteria were not found, and pathological histology indicated infiltration of inflammatory cells. However, it is worth noting that we discovered a gram-negative bacterium, the Ewingella americana, through mNGS testing. Further histopathological examination suggests chronic inflammatory cell infiltration. After one-stage posterior approach corrective surgery, the patient's condition significantly improved. At the 6-month follow-up, the pain significantly decreased, and the patient returned to normal life. CONCLUSION: We detected Ewinia americana in the bone biopsies of Andersson lesion (AL) in ankylosing spondylitis patient by mNGS.

Causal relationship between gut microbiota and ankylosing spondylitis and potential mediating role of inflammatory cytokines: A mendelian randomization study.

Associations between gut microbiota and ankylosing spondylitis have been discovered in previous studies, but whether these associations reflect a causal relationship remains inconclusive. Aiming to reveal the bidirectional causal associations between gut microbiota and ankylosing spondylitis, we utilized publicly available genome wide association study summary data for 211 gut microbiota (GM) taxa and ankylosing spondylitis (AS) to conduct two sample mendelian randomization analyses. Mediation analysis was performed to explore mediating inflammatory cytokines. We found that genetically predicted higher abundance of Lactobacillaceae family, Rikenellaceae family and Howardella genus had suggestive associations with decreased risk of ankylosing spondylitis while genetic proxied higher abundance of Actinobacteria class and Ruminococcaceae_NK4A214_group genus was associated with increased risk of ankylosing spondylitis. IL23 and IFN-γ were potential mediating cytokines for GM dysbiosis, especially for Actinobacteria class, leading to AS. Our study provided a new exploration direction for the treatment of AS. Lactobacillaceae family, Rikenellaceae family, Howardella genus, Actinobacteria class and Ruminococcaceae_NK4A214_group genus are expected to become new therapeutic targets and monitoring indicators for AS.

Combined analysis of metabolomics and 16S rRNA sequencing for ankylosing spondylitis patients before and after secukinumab therapy.

OBJECTIVE: Alterations in gut microbiota have been implicated in the pathogenesis of ankylosing spondylitis (AS), but the underlying mechanisms remain elusive. This study aims to investigate changes in gut microbiota and metabolites in individuals with AS before and after treatment with secukinumab, to identify the biological characteristics specific to AS patients and investigate the potential biomarkers, for optimizing therapeutic strategies more effectively. METHODS: Fecal microbiome data were collected from 30 AS patients before and after secukinumab therapy and compared with data from 40 healthy controls (HC). Additionally, we analyzed the metabolic profile of both groups from plasma. RESULTS: Findings indicated that the treatment-induced changes in the composition of several crucial bacterial groups, including Megamonas, Prevotella_9, Faecalibacterium, Roseburia, Bacteroides, and Agathobacter. Post-treatment, these groups exhibited a distribution more akin to that of the healthy populations compared with their pretreatment status. We identified three gut microbial taxa, namely Prevotellaceae_bacterium_Marseille_P2831, Prevotella_buccae, and Elusimicrobiota, as potential biomarkers for diagnosing individuals at a higher risk of developing AS and assessing disease outcomes. Plasma metabolomics analysis revealed 479 distinct metabolites and highlighted three disrupted metabolic pathways. Integration of microbiome and metabolomics datasets demonstrated a significant degree of correlation, underscoring the impact of the microbiome on metabolic activity. CONCLUSION: Secukinumab can restore the balance of the gut microbiome and metabolites in AS patients, rendering them more similar to those found in the healthy population. The analysis of microbiome and metabolomics data have unveiled some candidate biomarkers capable of evaluating treatment efficacy.

Exploring the role of gut microbes in spondyloarthritis: Implications for pathogenesis and therapeutic strategies.

The gut microbiota plays a pivotal role in regulating host immunity, and dysregulation of this interaction is implicated in autoimmune and inflammatory diseases, including spondyloarthritis (SpA). This review explores microbial dysbiosis and altered metabolic function observed in various forms of SpA, such as ankylosing spondylitis (AS), psoriatic arthritis (PsA), acute anterior uveitis (AAU), and SpA-associated gut inflammation. Studies on animal models and clinical samples highlight the association between gut microbial dysbiosis, metabolic perturbations and immune dysregulation in SpA pathogenesis. These studies have received impetus through next-generation sequencing methods, which have enabled the characterization of gut microbial composition and function, and host gene expression. Microbial/metabolomic studies have revealed potential biomarkers and therapeutic targets, such as short-chain fatty acids, and tryptophan metabolites, offering insights into disease mechanisms and treatment approaches. Further studies on microbial function and its modulation of the immune response have uncovered molecular mechanisms underlying various SpA. Understanding the complex interplay between microbial community structure and function holds promise for improved diagnosis and management of SpA and other autoimmune disorders.

Gut microbiome and metabolome to discover pathogenic bacteria and probiotics in ankylosing spondylitis.

Objective: Previous research has partially revealed distinct gut microbiota in ankylosing spondylitis (AS). In this study, we performed non-targeted fecal metabolomics in AS in order to discover the microbiome-metabolome interface in AS. Based on prospective cohort studies, we further explored the impact of the tumor necrosis factor inhibitor (TNFi) on the gut microbiota and metabolites in AS. Methods: To further understand the gut microbiota and metabolites in AS, along with the influence of TNFi, we initiated a prospective cohort study. Fecal samples were collected from 29 patients with AS before and after TNFi therapy and 31 healthy controls. Metagenomic and metabolomic experiments were performed on the fecal samples; moreover, validation experiments were conducted based on the association between the microbiota and metabolites. Results: A total of 7,703 species were annotated using the metagenomic sequencing system and by profiling the microbial community taxonomic composition, while 50,046 metabolites were identified using metabolite profiling. Differential microbials and metabolites were discovered between patients with AS and healthy controls. Moreover, TNFi was confirmed to partially restore the gut microbiota and the metabolites. Multi-omics analysis of the microbiota and metabolites was performed to determine the associations between the differential microbes and metabolites, identifying compounds such as oxypurinol and biotin, which were correlated with the inhibition of the pathogenic bacteria Ruminococcus gnavus and the promotion of the probiotic bacteria Bacteroides uniformis. Through experimental studies, the relationship between microbes and metabolites was further confirmed, and the impact of these two types of microbes on the enterocytes and the inflammatory cytokine interleukin-18 (IL-18) was explored. Conclusion: In summary, multi-omics exploration elucidated the impact of TNFi on the gut microbiota and metabolites and proposed a novel therapeutic perspective: supplementation of compounds to inhibit potential pathogenic bacteria and to promote potential probiotics, therefore controlling inflammation in AS.

[Faecal microbiota study reveals specific dysbiosis in spondyloarthritis according to subtype, disease activity and treatment]. / Estudio de microbiota fecal revela disbiosis específica en espondiloartritis, según subtipo, actividad de la enfermedad y tratamiento.

OBJECTIVE: To compare the diversity and composition of the gastrointestinal microbiome of patients with SpA. METHODS: MiSeq sequencing of the V3-V4 region of the 16S ribosomal RNA gene was performed on DNA isolated from stool. Patients with concurrent SpA and IBD were excluded. Differences were assessed for richness and diversity indices by QIIME 2™. Differences between means >0,2% with a p-value<0,05 were assumed significant. Institutional Ethics Committee endorsement. RESULTS: 69 individuals included, 49 with SpA (ankylosing spondylitis-AS 72,9%, psoriatic arthritis-PsA 18,8%, reactive arthritis-ReA 8,3%) 5 positive controls-dysbiosis and 15 controls-eubiosis. Conventional treatment in 42,9%, anti-IL-17 16,3% and anti-TNF 40,8%. By subtype, statistically significant differences in favour of AS were found for the diversity indices. AS vs PsA there was a difference in favour of AS for Clostridium clostridioforme (p=0,002), Gemmiger formicilis (p=0,009), Roseburia inulivorans (p=0,008) and Lachnospira pectinoschiza. AS vs ReA there was a difference in favour of AS for L. pectinoschiza (p=0,009), Ruminococcus callidus (p=0.006), Clostridium ruminantium (p=0.031); G. formicilis (p=0,034). Diversity and richness showed differences in patients with high activity for Simpson's and Pielou's indices. In high activity, lower enrichment of Bacteroides eggerthii (p= 0,0003), C. ruminantium (p= 0,026) and Alistipes putredinis (p=0,035) was found. The number of ASV was higher in the anti-IL-17 vs conventional group (p=0.025) and a trend between anti-IL-17 vs anti-TNF (p=0.09). In anti-TNF there was a lower proportion for C. clostridioforme (p=0.023), G. formicilis (p=0.030) and R. callidus (p= 0.003). In anti IL-17, Alistipes indistinctus (p= 0.012) was decreased. CONCLUSIONS: There are differences in microbial diversity for SpA subtypes. The level of disease activity is plausible to influence the composition of the faecal microbiota. Anti-TNFα treatment may influence the microbiome environment favouring restoration of the gut microbiota, while anti-IL-17 may maintain an inflammatory environment.

OBJETIVO: Comparar la diversidad y composición del microbioma gastrointestinal de pacientes con EspA. MÉTODOS: La secuenciación MiSeq de la región V3-V4 del gen ARN ribosomal 16, se realizó en ADN aislado de heces. Se excluyeron pacientes con EspA y EII simultánea. Se evaluaron diferencias para los índices de riqueza y diversidad por medio de QIIME 2™. Las diferencias entre medias> 0,2%, con un valor de p< 0,05, se asumieron significativas. Aval del Comité de Ética Institucional. RESULTADOS: 69 individuos incluidos, 49 con EspA (espondilitis anquilosante-EA 72,9%, artritis psoriásica-APs 18,8%, artritis reactiva-ARe 8,3%), cinco controles positivos-disbiosis y 15 controles-eubiosis. El tratamiento convencional en 42,9%, anti-IL-17 16,3%, y anti-TNF 40,8%. Por subtipo-EasP, se encontraron diferencias estadísticamente significativas a favor de EA para los índices de diversidad. Entre EA vs APs, hubo diferencia a favor de EA para Clostridium clostridioforme (p=0,002), Gemmiger formicilis (p=0,009), Roseburia inulivorans (p=0,008) y Lachnospira pectinoschiza. Entre EA vs ARe hubo diferencia a favor de EA para L. pectinoschiza (p=0,009), Ruminococcus callidus (p = 0,006), Clostridium ruminantium (p=0,031); G. formicilis (p=0,034). La diversidad y riqueza mostraron diferencias en pacientes con alta actividad para los índices de Simpson y Pielou. En alta actividad, se encontró menor enriquecimiento de Bacteroides eggerthii (p=0,0003), C. ruminantium (p= 0,026) y Alistipes putredinis (p= 0,035). El número de ASV fue superior en el grupo de anti IL-17 vs convencional (p=0.025), y una tendencia entre anti IL-17 vs anti-TNF (p=0,09). En anti TNF hubo menor proporción para C. clostridioforme (p=0,023), G. formicilis (p=0,030) y R. callidus (p= 0,003). Y en anti IL-17, Alistipes indistinctus (p= 0,012), estuvo disminuida. CONCLUSIONES: Existen diferencias en la diversidad microbiana para los subtipos de EspA. El nivel de actividad de la enfermedad es plausible para influir en la composición de microbiota fecal. El tratamiento con anti-TNFα, puede influenciar el ambiente del microbioma favoreciendo la restauración de la microbiota intestinal, mientras los anti IL-17 podrían mantener un ambiente inflamatorio.

Investigating the Influence of ANTXR2 Gene Mutations on Protective Antigen Binding for Heightened Anthrax Resistance.

Bacillus anthracis is the bacterium responsible for causing the zoonotic disease called anthrax. The disease presents itself in different forms like gastrointestinal, inhalation, and cutaneous. Bacterial spores are tremendously adaptable, can persist for extended periods and occasionally endanger human health. The Anthrax Toxin Receptor-2 (ANTXR2) gene acts as membrane receptor and facilitates the entry of the anthrax toxin into host cells. Additionally, mutations in the ANTXR2 gene have been linked to various autoimmune diseases, including Hyaline Fibromatosis Syndrome (HFS), Ankylosing Spondylitis (AS), Juvenile Hyaline Fibromatosis (JHF), and Infantile Systemic Hyalinosis (ISH). This study delves into the genetic landscape of ANTXR2, aiming to comprehend its associations with diverse disorders, elucidate the impacts of its mutations, and pinpoint minimal non-pathogenic mutations capable of reducing the binding affinity of the ANTXR2 gene with the protective antigen. Recognizing the pivotal role of single-nucleotide polymorphisms (SNPs) in shaping genetic diversity, we conducted computational analyses to discern highly deleterious and tolerated non-synonymous SNPs (nsSNPs) in the ANTXR2 gene. The Mutpred2 server determined that the Arg465Trp alteration in the ANTXR2 gene leads to altered DNA binding (p = 0.22) with a probability of a deleterious mutation of 0.808; notably, among the identified deleterious SNPs, rs368288611 (Arg465Trp) stands out due to its significant impact on altering the DNA-binding ability of ANTXR2. We propose these SNPs as potential candidates for hypertension linked to the ANTXR2 gene, which is implicated in blood pressure regulation. Noteworthy among the tolerated substitutions is rs200536829 (Ala33Ser), recognized as less pathogenic; this highlights its potential as a valuable biomarker, potentially reducing side effects on the host while also reducing binding with the protective antigen protein. Investigating these SNPs holds the potential to correlate with several autoimmune disorders and mitigate the impact of anthrax disease in humans.

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.

Association between 9-month isoniazid prophylaxis of latent tuberculosis and severe hepatitis in patients treated with TNF inhibitors.

To investigate associations between isoniazid for latent tuberculosis and risk of severe hepatitis, affecting patients with rheumatoid arthritis or ankylosing spondylitis whose treatment includes tumor necrosis factor inhibitors. Our self-controlled case series study analyzed Taiwan's National Health Insurance Database from 2003 to 2015 to identify RA or AS patients, aged ≥ 20 years, receiving TNF inhibitors and a 9-month single isoniazid treatment. The outcome of interest was hospitalization due to severe hepatitis. We defined risk periods by isoniazid exposure (days): 1-28, 29-56, 57-84, 85-168, 169-252, and 253-280. To compare risk of severe hepatitis in exposed and non-exposed periods, we performed conditional Poisson regressions to generate incidence rate ratios (IRR) and 95% confidence intervals, with adjustment of patients' baseline covariates including age, sex, HBV, HCV and related medication. Of 54,267 RA patients and 137,889 AS patients identified between 2000 and 2015, 11,221 (20.7%) RA and 4,208 (3.1%) AS patients underwent TNFi therapy, with 722 (5%) receiving isoniazid for latent tuberculosis. We identified 31 incident cases (4.3%) of hospitalization due to severe hepatitis. Of these hospitalization events, 5 occurred in the exposed periods, 25 occurred in the INH unexposed periods, and 1 occurred in the pre-exposure period. Compared with non-exposure, the risk of severe hepatitis was higher in exposed periods (incidence rate ratio [IRR]: 5.1, 95% CI: 1.57-16.55), especially 57-84 days (IRR: 17.29, 95% CI: 3.11-96.25) and 85-168 days (IRR:10.55, 95% CI: 1.90-58.51). The INH related fatal hepatotoxicity was not identified in our study. Our findings suggest an association between risk of severe hepatitis and exposure to isoniazid in patients with RA or AS under TNFi therapy, particularly within the exposed period 57-168 days. A close monitoring of liver function is mandatory to minimize the risk, especially within the first 6 months after initiation of 9 months isoniazid.

Inflammasome Activation in Ankylosing Spondylitis Is Associated With Gut Dysbiosis.

OBJECTIVE: We undertook this study to evaluate the activation and functional relevance of inflammasome pathways in ankylosing spondylitis (AS) patients and rodent models and their relationship to dysbiosis. METHODS: An inflammasome pathway was evaluated in the gut and peripheral blood from 40 AS patients using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), flow cytometry, and confocal microscopy, and was compared to that of 20 healthy controls and 10 patients with Crohn's disease. Bacteria was visualized using silver stain in human samples, and antibiotics were administered to HLA-B27-transgenic rats. The NLRP3 inhibitor MCC950 was administered to SKG mice, and ileal and joint tissues were assessed by IHC analysis and real-time qRT-PCR. The role of inflammasome in modulating the interleukin-23 (IL-23)/IL-17 axis was studied ex vivo. RESULTS: Expression levels of Nlrp3, Nlrc4, and Aim2 were increased in the gut of HLA-B27-transgenic rats and reduced by antibiotic treatment (P < 0.05). In curdlan-treated SKG mice, NLRP3 blockade prevented ileitis and delayed arthritis onset (P < 0.05). Compared to healthy controls, AS patients demonstrated overexpression of NLRP3 (fold induction 2.33 versus 22.2; P < 0.001), NLRC4 (fold induction 1.90 versus 6.47; P < 0.001), AIM2 (fold induction 2.40 versus 20.8; P < 0.001), CASP1 (fold induction 2.53 versus 24.8; P < 0.001), IL1B (fold induction 1.07 versus 10.93; P < 0.001), and IL18 (fold induction 2.56 versus 15.67; P < 0.001) in the ileum, and caspase 1 activity was increased (P < 0.01). The score of adherent and invasive mucosa-associated bacteria was higher in AS (P < 0.01) and correlated with the expression of inflammasome components in peripheral blood mononuclear cells (P < 0.001). NLRP3 expression was associated with disease activity (the Ankylosing Spondylitis Disease Activity Score using the C-reactive protein level) (r2 = 0.28, P < 0.01) and with IL23A expression (r2 = 0.34, P < 0.001). In vitro, inflammasome activation in AS monocytes was paralleled by increased serum levels of IL-1ß and IL-18. Induction of IL23A, IL17A, and IL22 was IL-1ß-dependent. CONCLUSION: Inflammasome activation occurs in rodent models of AS and in AS patients, is associated with dysbiosis, and is involved in triggering ileitis in SKG mice. Inflammasomes drive type III cytokine production with an IL-1ß-dependent mechanism in AS patients.

The association between Candida infection and ankylosing spondylitis: a population-based matched cohort study.

AIMS: To explore whether newly diagnosed Candida infection increases the risk of developing ankylosing spondylitis (AS). METHODS AND MATERIALS: We investigated 61,550 patients with newly diagnosed Candida infection between 1997 and 2013 from the Taiwan National Health Insurance Research Datasets to conduct a population-based matched-cohort study. Controls were 61,550 subjects without Candida infection and propensity score matched with the Candida exposure cohort. The follow-up period was defined as month from the initial diagnosis of Candida infection (or nested index date for controls) to the date of AS, or 31 December 2013. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the occurrence of AS. RESULTS: The incidence rates of AS in the Candida group and comparison group were respectively 4.58 and 3.88 per 100,000 person-months. The adjusted HR (95% CI) of AS for the Candida group was 1.19 (0.99-1.44) compared to the control group after adjustment for age, gender and all covariates (95% CI = 1.77-2.27). However, an adjusted hazard ratio (aHR) of 1.77-fold (95% CI = 1.26-2.53) significant increase in the risk of developing AS was observed after 6 years of follow-up, when exposure to Candida was at baseline. The effect of Candida infection was significantly time varying (p value for interaction between follow-up period and Candida infection is .018). CONCLUSIONS: A risk of AS was found after Candida infection, and a year of follow-up acts as an effect modifier between the Candida infection and risk of AS. Key messages What is already known on this subject? Links between spondyloarthritis and fungal infections have been found in animal studies before. What does this study add? Our study demonstrated that Candida infection is an independent risk factor for developing ankylosing spondylitis in terms of gender, age and relevant variables and comorbidities. A risk of ankylosing spondylitis was found after Candida infection, and year of follow-up acts as an effect modifier between the Candida infection and risk of AS. Clinicians should be aware of possible Candida infection in managing patients with ankylosing spondylitis. Implications: Clinicians must pay greater attention to patients with newly diagnosed Candida infection. Specifically, they should conduct tests for ankylosing spondylitis. Further research is needed to examine if and how treatment of Candida infection alleviates symptoms of AS.

Consumption of Cooked Black Beans Stimulates a Cluster of Some Clostridia Class Bacteria Decreasing Inflammatory Response and Improving Insulin Sensitivity.

There is limited information on the effect of black beans (BB) as a source of protein and resistant starch on the intestinal microbiota. The purpose of the present work was to study the effect of cooked black beans with and without high fat and sugar (HF + S) in the diet on body composition, energy expenditure, gut microbiota, short-chain fatty acids, NF-κB, occluding and insulin signaling in a rat model and the area under the curve for glucose, insulin and incretins in healthy subjects. The consumption of BB reduced the percentage of body fat, the area under the curve of glucose, serum leptin, LPS, glucose and insulin concentrations and increased energy expenditure even in the presence of HF + S. These results could be mediated in part by modification of the gut microbiota, by increasing a cluster of bacteria in the Clostridia class, mainly R. bromii, C. eutactus, R. callidus, R. flavefaciens and B. pullicaecorum and by an increase in the concentration of fecal butyrate. In conclusion, the consumption of BB can be recommended to prevent insulin resistance and metabolic endotoxemia by modifying the gut microbiota. Finally, the groups fed BB showed lower abundance of hepatic FMO-3, even with a high-fat diet protecting against the production of TMAO and obesity.

Dynamic Variations in Gut Microbiota in Ankylosing Spondylitis Patients Treated with Anti-TNF-α for Six Months.

Ankylosing spondylitis (AS) is known as a microbiome-driven disease; however, the current understanding of microbiota dynamics in AS is limited. In the present study, we conducted a 16S rDNA sequence-based microbiota survey of 97 fecal samples from healthy subjects and AS patients at baseline, 1, 3 and 6 months after anti-TNF-α treatment to demonstrate the dynamic characteristic variations of gut microbiota in AS patients. The goal of this experiment is to explore the values of gut microbiota as biomarkers of disease activity and therapeutic responses to anti-TNF-α. We found that the relative abundance of microbiota in AS patients treated with anti-TNF-α differed at various time points and distinguished 4 groups: the higher and lower than healthy control (HC) level groups throughout the study and the unchanged and restored to HC levels groups. The characteristic increases of microbes in AS patients were f_Prevotellaceae and f_Actinomycetaceae In HC, the characteristic increase was f_Lachnospiraceae BASDAI positively correlated with the relative abundance of g_Escherichina-Shigella and g_Klebsiella, but negatively correlated with f_Lachnospiraraceae at baseline. (r=0.544, P=0.013, r=0.509, P=0.022 and r=-0.577, P=0.008, respectively). The beta-diversity of microbiota in AS at baseline was lower than HC at the same level (P<0.01) and restored to normal values one month after treatment. In conclusion, the variation of gut microbiota is dynamic. Therefore, some microbes can be used as indicators for monitoring disease activity and therapeutic responsiveness during treatment.

Effect of Gut Involvement in Patients with High Probability of Early Spondyloarthritis: Data from the DESIR Cohort.

OBJECTIVE: Inflammatory bowel disease (IBD) is a well-known extraarticular feature of spondyloarthritis (SpA). The aims of this study were to evaluate factors associated with IBD and incidence over 5 years of followup in the DESIR cohort. METHODS: DESIR is a prospective observational cohort of patients with recent-onset inflammatory back pain suggestive of axial SpA. All available variables in the database were compared between patients with and without IBD at baseline and 5 years, and occurrence over 5 years of followup, with uni- and then multivariable analysis. RESULTS: At baseline, of 708 patients, 35 had IBD (prevalence 4.94%, CI 95% 3.3-6.5). IBD was associated (multivariable) with history of uveitis, levels of Dickkopf-1, and tumor necrosis factor, but not with phenotypic presentation (peripheral arthritis, enthesitis, dactylitis, uveitis) or baseline serum levels of other cytokines. At 5 years, 480 patients were analyzed, 58 with IBD. IBD was associated (multivariable) with fulfillment of modified New York criteria, sick leave, Bath Ankylosing Spondylitis Disease Activity Index, and smoking. There was no association with magnetic resonance imaging scores, enthesitis, psoriasis, and bone mineral density. Twenty-three incident cases of IBD were recorded: estimated occurrence rate of 0.95/100 (95% CI 0.57-1.35) patient-years (PY). Incidence of IBD is associated (multivariable) with HLA-B27 (OR 0.36, 95% CI 0.22-0.59), fulfillment of modified New York criteria (OR 3.35, 95% CI 1.85-6.08), and familial history of IBD (OR 3.31, 95% CI 1.62-6.77). CONCLUSION: In early SpA, IBD occurs with an incidence of 1/100 PY, and is associated with poor outcome, familial history of IBD, absence of HLA-B27, and fulfillment of modified New York criteria.

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.

Metagenome-wide association study of the alterations in the intestinal microbiome composition of ankylosing spondylitis patients and the effect of traditional and herbal treatment.

Introduction. Ankylosing spondylitis (AS) is a systemic progressive disease with an unknown etiology that may be related to the gut microbiome. Therefore, a more thorough understanding of its pathogenesis is necessary for directing future therapy.Aim. We aimed to determine the differences in intestinal microbial composition between healthy individuals and patients with AS who received and who did not receive treatment interventions. In parallel, the pathology of AS in each patient was analysed to better understand the link between AS treatment and the intestinal microbiota of the patients.Methodology. Sixty-six faecal DNA samples, including 37 from healthy controls (HCs), 11 from patients with untreated AS (NM), 7 from patients treated with nonsteroidal anti-inflammatory drugs (e.g. celecoxib; WM) and 11 from patients treated with Chinese herbal medicine (CHM), such as the Bushen-Qiangdu-Zhilv decoction, were collected and used in the drug effect analysis. All samples were sequenced using Illumina HiSeq 4000 and the microbial composition was determined.Results. Four species were enriched in the patients with AS: Flavonifractor plautii, Oscillibacter, Parabacteroides distasonis and Bacteroides nordii (HC vs. NM, P<0.05); only F. plautii was found to be significantly changed in the NM-HC comparison. No additional species were found in the HC vs. CHM analysis, which indicated a beneficial effect of CHM in removing the other three strains. F. plautii was found to be significantly increased in the comparison between the HC and WM groups, along with four other species (Clostridium bolteae, Clostridiales bacterium 1_7_47FAA, C. asparagiforme and C. hathewayi). The patients with AS harboured more bacterial species associated with carbohydrate metabolism and glycan biosynthesis in their faeces. They also had bacterial profiles less able to biodegrade xenobiotics or synthesize and transport vitamins.Conclusion. The gut microbiota of the patients with AS varied from that of the HCs, and the treatment had an impact on this divergence. Our data provide insight that could guide improvements in AS treatment.