Dose-response relationship between alcohol drinking and gout risk: do subtypes of alcoholic beverages make a difference?

OBJECTIVE: Although previous studies have explored the association of drinking with gout risk, the dose-response relationship was uncertain and the evidence between subtypes of alcoholic beverages and gout risk was limited. METHODS: The weekly alcoholic beverage consumption in the United Kingdom Biobank (UKB) was collected and calculated. The Cox regression model was applied to assess the impact of alcohol drinking and its subtypes on gout risk by calculating the hazard ratio (HR) and 95% confidence interval (CI). Besides, the restricted cubic splines were used to estimate the dose-response relationship between alcoholic drinking and gout risk. To evaluate the robustness, we performed subgroup analysis across various demographic characteristics. RESULTS: During a mean follow-up period of 11.70 years, a total of 5,728 newly incident gout cases were diagnosed among 331,865 participants. We found that light alcohol drinking was linked to a slight decrease in gout incidence among females (HR, 0.78; 95% CI, 0.65 to 0.94, P=0.01), whereas it showed no significant association in males. Moreover, the dose-response relationship showed that light red wine and fortified wine could reduce the gout risk, while beer, champagne plus white wine and spirits promoted the gout risk at any dose. CONCLUSION: Our study suggested a J-shaped dose-response relationship of drinking with gout risk in females rather than males. For specific alcoholic beverages, light consumption of red wine and fortified wine was associated with reduced gout risk. These findings offer new insights into the roles of alcoholic beverages in gout, while further validation is warranted.

Association between combined exposure to ambient air pollutants, genetic risk, and incident gout risk: A prospective cohort study in the UK Biobank.

BACKGROUND: Limited research has been conducted on the association between long-term exposure to air pollutants and the incidence of gout. OBJECTIVES: This study aims to assess the individual and combined effects of prolonged exposure to five air pollutants (NO2, NOx, PM10, PMcoarse and PM2.52) on the incidence of gout among 458,884 initially gout-free participants enrolled in the UK Biobank. METHODS: Employing a land use regression model, we utilized an estimation method to ascertain the annual concentrations of the five air pollutants. Subsequently, we devised a weighted air pollution score to facilitate a comprehensive evaluation of exposure. The Cox proportional hazards model was utilized to investigate the association between ambient air pollution and gout risk. Interaction and stratification analyses were conducted to evaluate age, sex, BMI, and genetic predisposition as potential effect modifiers in the air pollution-gout relationship. Furthermore, mediation analyses were conducted to explore the potential involvement of biomarkers in mediating the association between air pollution and gout. RESULTS: Over a median follow-up time of 12.0 years, 7,927 cases of gout were diagnosed. Significant associations were observed between the risk of gout and a per IQR increase in NO2 (HR3: 1.05, 95 % CI4: 1.02-1.08, p = 0.003), NOx (HR: 1.04, 95 % CI: 1.01-1.06, p = 0.003), and PM2.5 (HR: 1.03, 95 % CI: 1.00-1.06, p = 0.030). Per IQR increase in the air pollution score was associated with an elevated risk of gout (p = 0.005). Stratified analysis revealed a significant correlation between the air pollution score and gout risk in participants ≥60 years (HR: 1.05, 95 % CI: 1.02-1.09, p = 0.005), but not in those <60 years (p = 0.793), indicating a significant interaction effect with age (p-interaction=0.009). Mediation analyses identified five serum biomarkers (SUA:15.87 %, VITD: 5.04 %, LDLD: 3.34 %, GGT: 1.90 %, AST: 1.56 %5) with potential mediation effects on this association. CONCLUSIONS: Long-term exposure to air pollutants, particularly among the elderly population, is associated with an increased risk of gout. The underlying mechanisms of these associations may involve the participation of five serum biomarkers.

TCMSSD: A comprehensive database focused on syndrome standardization.

BACKGROUD: Quantitative and standardized research on syndrome differentiation has always been at the forefront of modernizing Traditional Chinese Medicine (TCM) theory. However, the majority of existing databases primarily concentrate on the network pharmacology of herbal prescriptions, and there are limited databases specifically dedicated to TCM syndrome differentiation. PURPOSE: In response to this gap, we have developed the Traditional Chinese Medical Syndrome Standardization Database (TCMSSD, http://tcmssd.ratcm.cn). METHODS: TCMSSD is a comprehensive database that gathers data from various sources, including TCM literature such as TCM Syndrome Studies (Zhong Yi Zheng Hou Xue) and TCM Internal Medicine (Zhong Yi Nei Ke Xue) and various public databases such as TCMID and ETCM. In our study, we employ a deep learning approach to construct the knowledge graph and utilize the BM25 algorithm for syndrome prediction. RESULTS: The TCMSSD integrates the essence of TCM with the modern medical system, providing a comprehensive collection of information related to TCM. It includes 624 syndromes, 133,518 prescriptions, 8,073 diseases (including 1,843 TCM-specific diseases), 8,259 Chinese herbal medicines, 43,413 ingredients, 17,602 targets, and 8,182 drugs. By analyzing input data and comparing it with the patterns and characteristics recorded in the database, the syndrome prediction tool generates predictions based on established correlations and patterns. CONCLUSION: The TCMSSD fills the gap in existing databases by providing a comprehensive resource for quantitative and standardized research on TCM syndrome differentiation and laid the foundation for research on the biological basis of syndromes.

Metabolic Syndrome Is Associated With an Increased Risk of Rheumatoid Arthritis: A Prospective Cohort Study Including 369,065 Participants.

OBJECTIVE: To explore the associations between metabolic syndrome (MetS) and its individual components and the risk of rheumatoid arthritis (RA). METHODS: A total of 369,065 individuals were included in the present study based on the UK Biobank. Multivariable Cox proportional hazards regression models were applied to estimate the associations between MetS and its individual components and the risk of RA. Mediation analysis was performed to further assess the potential mediating role of C-reactive protein (CRP) in the relationship between MetS and RA. RESULTS: During a median follow-up period of 12.04 years, a total of 4901 incident RA cases were documented. MetS (hazard ratio [HR] 1.22, 95% CI 1.14-1.30) and 4 of its 5 components (elevated waist circumference [WC; HR 1.21, 95% CI 1.12-1.32], elevated triglyceride [TG] level [HR 1.12, 95% CI 1.05-1.19], reduced high-density lipoprotein cholesterol [HDL-C] level [HR 1.31, 95% CI 1.23-1.39], and hyperglycemia [HR 1.15, 95% CI 1.05-1.25]) were associated with an increased risk of RA. In addition, the risk of RA increased as the number of diagnosed MetS components increased, with the highest risk in participants with all 5 components. Mediation analysis showed that CRP might mediate the association between MetS and RA, accounting for 9.27% of the total effect. CONCLUSION: These findings indicated positive associations between MetS and 4 of its components (WC, TG, HDL-C, and hyperglycemia) and the risk of RA, highlighting the importance of MetS management in the prevention of RA.

Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis.

Systemic lupus erythematosus (SLE), a severe autoimmune disorder, is characterized by systemic inflammatory response, autoantibody accumulation and damage to organs. The dysregulation of double-negative (DN) T cells is considered as a crucial commander during SLE. Neddylation, a significant type of protein post-translational modification (PTM), has been well-proved to regulate T cell-mediated immune response. However, the function of neddylation in SLE is still unknown. Here, we reported that neddylation inactivation with MLN4924, a specific inhibitor of NEDD8-activating enzyme E1 (NAE1), or genetic abrogation of Ube2m in T cells decreased DN T cell accumulation and attenuated murine lupus development. Further investigations revealed that inactivation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in DN T cells, contributing to the apoptosis of the accumulated DN T cells in lupus mice. Then double knockout (KO) lupus-prone mice (Ube2m-/-Bim-/-lpr) were generated and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus progression. Our findings identified that neddylation inactivation promoted Bim-mediated DN T cell apoptosis and attenuated lupus progression. Clinically, we also found that in SLE patients, the proportion of DN T cells was raised and their apoptosis was reduced. Moreover, compared to healthy groups, SLE patients exhibited decreased Bim levels and elevated Cullin1 neddylation levels. Meantime, the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from SLE patients. Altogether, our findings provide the direct evidence about the function of neddylation during lupus, suggesting a promising therapeutic approach for this disease.

Fibromyalgia and risk of all-cause, specific mortality: A meta-analysis of observational studies.

OBJECTIVES: To evaluate the risk of all-cause, specific mortality among patients with fibromyalgia, which is a controversial topic. METHODS: We conducted a thorough search for cohort studies across the PubMed, Cochrane Library, and Embase databases, from their inception to 1 March 2023, using medical subject headings and relevant keywords. All data were meticulously analyzed using Stata statistical software version 16.0. The protocol was registered on PROSPERO (CRD42023402337). RESULTS: After analyzing seven cohort studies involving 152 933 individuals published between 2001 and 2020, we found no clear evidence linking fibromyalgia or widespread pain to all-cause mortality risk (odds ratio [OR] 1.11, 95% confidence interval [CI] 0.81-1.53; I2 = 82.6%, p = .505). However, our subgroup analysis revealed that the risk of suicide was significantly higher in fibromyalgia patients compared with non-fibromyalgia patients (OR 5.39, 95% CI 2.16-13.43; I2 = 69.9%, p < .05). CONCLUSIONS: Our research did not discover any proof indicating a link between fibromyalgia or widespread pain and all-cause mortality. However, it is worth noting that there may be a potential correlation between individuals with fibromyalgia or widespread pain and a higher likelihood of suicide. As we had a limited number of participants in our study, further research is necessary to thoroughly investigate the relationship between these factors.

Integrated network pharmacology and gut microbiome analysis to reveal the mechanism of Qu-Zhuo-Tong-Bi decoction against hyperuricemia and gout.

ETHNOPHARMACOLOGICAL RELEVANCE: Qu-zhuo-tong-bi decoction (QZTBD) is a classic Chinese herbal medicine that has shown therapeutic efficacy in clinical practice against hyperuricemia and gout. However, the potential mechanisms of QZTBD remain poorly investigated. AIM OF THE STUDY: To assess the therapeutic effects of QZTBD on hyperuricemia and gout and to reveal its mechanisms of action. MATERIALS AND METHODS: A Uox-KO mouse model of hyperuricemia and gout was established, and QZTBD was administered at a dosage of 18.0 g/kg/d. Throughout the experimental period, the effects of QZTBD on gout symptoms were monitored and analyzed. The integrated network pharmacology and gut microbiota analysis strategy was conducted to explore the mechanism of QZTBD in the treatment of hyperuricemia and gout. Targeted metabolomic analysis was performed to investigate the variation of amino acids and Spearman's rank correlation analysis was conducted to reveal the relationship between the discrepant bacterial genera and the altered amino acid. Flow cytometry was utilized to analysis the proportion of Th17 and Treg cells, and the production of pro-inflammatory cytokines was measured by ELISA. qRT-PCR and Western blot assay were applied to detect the expression of mRNA and protein respectively. Autodock vina 1.1.2 was used to evaluate the docking interactions. RESULTS: QZTBD treatment showed remarkable efficacy against hyperuricemia and gout with respect to attenuation of disease activity metrics through gut microbiome recovery and intestinal immune homeostasis. The administration of QZTBD significantly elevated the abundance of Allobaculum and Candidatus sacchairmonas, corrected the aberrant amino acid patterns, repaired the impaired intestinal barrier, restored the balance of Th17/Treg cells via PI3K-AKT-mTOR pathway, and reduced the levels of inflammatory cytokines such as IL-1ß, IL-6, TNF-α and IL-17. Fecal microbiota transplantation from QZTBD treated mice demonstrated convincing evidence of efficacy and mechanism of QZTBD. CONCLUSION: Taken together, our study explores the therapeutic mechanism of an effective herbal formula, QZTBD, for gout treatment through remodeling gut microbiome and regulating the differentiation of CD4+ T cells via PI3K-AKT-mTOR pathway.

Gut microbiota mediated the therapeutic efficiency of Simiao decoction in the treatment of gout arthritis mice.

BACKGROUND: Gut microbiota plays a significant role in the development and treatment of gouty arthritis. Simiao decoction has been shown to alleviate gouty arthritis by inhibiting inflammation, regulating NLRP3 inflammasome, and altering gut microbiota. However, there is no evidence to prove whether gut microbiota directly mediates the therapeutic efficiency of Simiao decoction in treating gout arthritis. METHODS: In this study, fecal microbiota transplantation (FMT) was used to transfer the gut microbiota of gout arthritis mice treated with Simiao decoction or allopurinol to blank gout arthritis mice, in order to investigate whether FMT had therapeutic effects on gout arthritis. RESULTS: Both Simiao decoction and allopurinol effectively reduced the levels of serum uric acid, liver XOD activity, foot thickness, serum IL-1ß, and G-CSF in gout arthritis mice. However, Simiao decoction also had additional benefits, including raising the pain threshold, reducing serum TNF-α and IL-6, alleviating gut inflammation, and repairing intestinal pathology, which were not observed with allopurinol treatment. Moreover, Simiao decoction had a greater impact on gut microbiota than allopurinol, as it was able to restore the abundance of phylum Proteobacteria and genus Helicobacter. After transplantation into gout arthritis mice, gut microbiota altered by Simiao decoction exhibited similar therapeutic effects to those of Simiao decoction, but gut microbiota altered by allopurinol showed no therapeutic effect. CONCLUSIONS: These findings demonstrates that Simiao decoction can alleviate gout arthritis symptoms by regulating gut microbiota.

Assessing the relationship between gut microbiota and irritable bowel syndrome: a two-sample Mendelian randomization analysis.

BACKGROUND: Growing evidence has suggested that gut microbiota is closely related to the risk of irritable bowel syndrome (IBS), but whether there is a causal effect remains unknown. We adopted a Mendelian randomization (MR) approach to evaluate the potential causal relationships between gut microbiota and the risk of IBS. METHODS: Genetic instrumental variables for gut microbiota were identified from a genome-wide association study (GWAS) of 18,340 participants. Summary statistics of IBS were drawn from a GWAS including 53,400 cases and 433,201 controls. We used the inverse-variance weighted (IVW) method as the primary analysis. To test the robustness of our results, we further performed the weighted-median method, MR-Egger regression, and MR pleiotropy residual sum and outlier test. Finally, reverse MR analysis was performed to evaluate the possibility of reverse causation. RESULTS: We identified suggestive associations between three bacterial traits and the risk of IBS (odds ratio (OR): 1.08; 95% confidence interval (CI): 1.02, 1.15; p = 0.011 for phylum Actinobacteria; OR: 0.95; 95% CI: 0.91, 1.00; p = 0.030 for genus Eisenbergiella and OR: 1.10; 95% CI: 1.03, 1.18; p = 0.005 for genus Flavonifractor). The results of sensitivity analyses for these bacterial traits were consistent. We did not find statistically significant associations between IBS and these three bacterial traits in the reverse MR analysis. CONCLUSIONS: Our systematic analyses provide evidence to support a potential causal relationship between several gut microbiota taxa and the risk of IBS. More studies are required to show how the gut microbiota affects the development of IBS.

Efficacy and safety of tofacitinib combined with methotrexate in the treatment of rheumatoid arthritis: A systematic review and meta-analysis.

Objective: To evaluate the efficacy and safety of tofacitinib in combination with methotrexate (MTX) versus MTX monotherapy in patients with active rheumatoid arthritis (RA). Methods: Trials were identified from four electronic databases: PubMed, Web of science, Cochrane Library and EMBASE from inception to April 2022. Two independent reviewers evaluated each database to scan the title, abstract and keywords of each record retrieved. Full articles were further assessed when the information suggested that the study was a randomized clinical trial (RCT) comparing tofacitinib combined with MTX vs. MTX monotherapy in patients with active RA. Data were extracted from the literature, and the methodological quality of the included literature were evaluated and screened by two reviewers independently. The results were analyzed using RevMan5.3 software. The full text of the studies and extracted data were reviewed independently according to PRISMA guidelines. The outcome indicators were ACR 20, ACR 50, ACR 70, Disease activity score 28 (DAS28), erythrocyte sedimentation Rate (ESR) and adverse events (AEs). Results: Of 1152 studies yielded by the search, 4 were retained, totaling 1782 patients (1345 treated with tofacitinib combined with MTX vs 437 received MTX. In the trial of insufficient response to MTX treatment, tofacitinib combined with MTX had significant advantages compared with MTX monotherapy. Numerically higher ACR20, ACR50 and ACR70 response rates were observed in the tofacitinib combined with MTX groups versus MTX monotherapy. ACR20 (odds ratio (OR), 3.62; 95% CI, 2.84-4.61; P < 0.001), ACR50 (OR, 5.17; 95% CI, 3.62-7.38; P < 0.001), and ACR70 (OR, 8.44; 95% CI, 4.34-16.41; P < 0.001), DAS28 (ESR) < 2.6 (OR, 4.71, 95% CI, 2.06-10.77; P < 0.001). The probability of adverse events of tofacitinib combined with MTX was lower than that of MTX monotherapy (OR, 1.42; 95% CI, 1.08-1.88; P = 0.01). The number of cases discontinued due to lack of efficacy or adverse events was similar in both groups (OR, 0.93; 95% CI, 0.52-1.68). The probability of abnormal liver enzymes in the treatment of tofacitinib combined with MTX was significantly lower than that of MTX monotherapy (OR, 1.86; 95% CI, 1.35-2.56). However, there was no significant difference between the two groups in severe adverse reactions, neutropenia, anemia and cardiovascular disease. Conclusions: In terms of ACR20/50/70 and DAS28 (ESR), tofacitinib combined with MTX demonstrated superiority to MTX monotherapy in the treatment of patients with refractory RA. Considering the hepatoprotective and observably therapeutic efficacy, tofacitinib combined with MTX could be effective in treating refractory RA. However, in terms of hepatoprotective, it requires further large-scale and high-quality clinical trials to confirm.

Involvement of Fusobacterium nucleatum in malignancies except for colorectal cancer: A literature review.

Fusobacterium nucleatum (F. nucleatum) is originally an oral opportunistic pathogen and accumulating evidence links the presence of F. nucleatum with the pathogenicity, development, and prognosis of colorectal cancer (CRC). However, only limited preliminary data is available dealing with the role of F. nucleatum in other malignancies except for CRC. The present review aims to update and systematize the latest information about the mechanisms of F. nucleatum-mediating carcinogenesis, together with the detection rates, clinicopathological, and molecular features in F. nucleatum-associated malignancies. Comparing with adjacent non-tumorous tissue, previous studies have shown an overabundance of intratumoural F. nucleatum. Although the prognostic role of F. nucleatum is still controversial, a higher prevalence of F. nucleatum was usually associated with a more advanced tumor stage and a worse overall survival. Preliminary evidence have shown that epithelial-to-mesenchymal transition (EMT) and relevant inflammation and immune response aroused by F. nucleatum may be the probable link between F. nucleatum infection and the initiation of oral/head and neck cancer. Further studies are needed to elucidate the etiologic role of the specific microbiota and the connection between the extent of periodontitis and carcinogenesis in different tumor types. The mechanisms of how the antibiotics exerts the critical role in the carcinogenesis and antitumor effects in malignancies other than CRC need to be further explored.

Beef intake and risk of rheumatoid arthritis: Insights from a cross-sectional study and two-sample Mendelian randomization.

Background: Beef is common in daily diet, but its association with the risk of rheumatoid arthritis (RA) remains uncertain. The objective of this study is to explore the relationship between beef intake and the risk of RA. Materials and methods: We investigated the association between beef intake and risk of RA by multivariate logistic regression, based on the National Health and Nutrition Examination Survey (NHANES) 1999-2016 involving 9,618 participants. The dose-response relationship between beef intake and RA was explored as well. Furthermore, we performed Mendelian randomization (MR) analysis to examine the causal effect of beef intake on RA. Genetic instruments for beef intake were selected from a genome-wide association study (GWAS) including 335,576 individuals from the UK Biobank study, and summary statistics relating to RA were obtained from a GWAS meta-analysis of 14,361 RA patients and 43,923 controls. The inverse-variance weighted (IVW) approach was used to estimate the causal association, and MR-Egger regression and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test were applied to evaluate the pleiotropy and outliers. Results: Compared with the lowest quintile (0 to ≤33.50 g/d), beef intake was found to be significantly associated with the risk of RA [odds ratio (OR): 1.94; 95% confidence interval (CI): 1.20-3.12] in the third quintile (50.26 to ≤76.50 g/d). Moreover, a reversed "U" dose-response relationship between beef and RA (P non-linearity = 0.023) was found. In the MR analysis, beef intake was associated with an increased risk of RA (OR: 3.05; 95% CI: 1.11-8.35; P = 0.030) by the IVW method. The results from MR-Egger regression and MR-PRESSO test showed that there were no pleiotropic variations and outliers. Conclusion: This study indicated that there is suggestive evidence to support the causal effect of beef intake on the risk of RA, while further studies are warranted to elucidate the exact association.

Jieduquyuziyin prescription promotes the efficacy of prednisone via upregulating Nrf2 in MRL/lpr kidneys.

ETHNOPHARMACOLOGICAL RELEVANCE: The Jieduquyuziyin prescription (JP), a traditional Chinese medicine (TCM) formula, has been used as an approved hospital prescription to improve the efficacy of prednisone (Pred) in systemic lupus erythematosus (SLE) and lupus nephritis (LN) treatment. Although the synergistic effect of JP and Pred is prominent, the underlying mechanisms require further investigation. AIM OF THE STUDY: To explore the key therapeutic targets of JP in improving the role of Pred in the treatment of LN. MATERIALS AND METHODS: Lupus-prone female MRL/lpr mice were administered JP, Pred, or JP combined with Pred. The effect of JP on LN was estimated by evaluating renal function and inflammation levels in the kidneys. On this basis, RNA sequencing of kidney tissues was performed, and the differentially expressed genes were analyzed and summarized. The role of JP in the expression of nuclear factor erythroid 2-related factor 2 (NFE2L2 or Nrf2) in the kidneys was further confirmed by real-time PCR, immunohistochemistry, and western blotting. RESULTS: JP combined with Pred exhibited the most remarkable therapeutic effect compared with JP or Pred alone. Transcriptome analysis indicated that Nrf2, a central mediator of the antioxidative response, was significantly upregulated by JP. Based on these results, we speculated that Nrf2 is a critical factor for JP, improving the efficacy of Pred in treating LN by notably suppressing the oxidative stress level in the kidneys. Furthermore, we found that Nrf2 expression decreased with the exacerbation of LN in MRL/lpr mice. In addition, the downregulated Nrf2 was notably restored after JP treatment, accompanied by suppressed oxidative stress levels in the kidneys. It includes inhibited accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA), restored mitochondrial membrane potential (MMP) levels, and increased antioxidant enzyme activity of superoxide dismutase (SOD). CONCLUSIONS: Our findings show that JP increases Pred efficacy by increasing Nrf2 expression, implying that Nrf2 may be a promising therapeutic target for the treatment of LN.

Two-Sample Mendelian Randomization Analysis Investigates Causal Associations Between Gut Microbial Genera and Inflammatory Bowel Disease, and Specificity Causal Associations in Ulcerative Colitis or Crohn's Disease.

Background: Intestinal dysbiosis is associated with inflammatory bowel disease (IBD). Ulcerative colitis (UC) and Crohn's disease (CD), two subtypes of IBD, are characterized by unique microbial signatures, respectively. However, it is unclear whether UC or CD has a specific causal relationship with gut microbiota. Objective: To investigate the potential causal associations between gut microbial genera and IBD, UC, or CD, two-sample Mendelian randomization (MR) analyses were conducted. Materials and Methods: We obtained genome-wide association study (GWAS) summary statistics of gut microbiota and IBD, UC, or CD from published GWASs. Two-sample MR analyses were performed to identify potential causal gut microbial genera for IBD, UC, and CD using the inverse-variance weighted (IVW) method. Sensitivity analyses were also conducted to validate the robustness of the primary results of the MR analyses. Finally, a reverse MR analysis was performed to evaluate the possibility of reverse causation. Results: Combining the results from the primary and sensitivity analyses, six bacterial genera were associated with the risk of IBD, UC, or CD in the IVW method. Briefly, Eubacterium ventriosum group was associated with a lower risk of IBD (P=0.011) and UC (P=1.00×10-4), whereas Coprococcus 2 was associated with a higher risk of IBD (P=0.022) and UC (P=0.007). In addition, we found a positive association between Oxalobacter with IBD (P=0.001) and CD (P=0.002), and Ruminococcaceae UCG014 with IBD (P=0.005) and CD (P=0.007). We also noticed a negative association between Enterorhabdus (P=0.044) and IBD, and between Lachnospiraceae UCG001 (P=0.023) and CD. We did not find causal effects of IBD, UC, or CD on these bacterial genera in the reverse MR analysis. Conclusion: This study expanded gut microbial genera that were causally associated with the risk of IBD, and also revealed specificity-gut microbial genera for UC or CD.

The Causal Relationship Between Blood Lipids and Systemic Lupus Erythematosus Risk: A Bidirectional Two-Sample Mendelian Randomization Study.

Background: Although observational studies have demonstrated that blood lipids were associated with systemic lupus erythematosus (SLE), the causality of this association remains elusive as traditional observational studies were prone to confounding and reverse causality biases. Here, this study attempted to reveal the potential causal link between SLE and the levels of four blood lipids (HDL cholesterol, LDL cholesterol, TG, and TC). Methods: Bidirectional two-sample Mendelian randomization (MR) was employed to explore the unconfounded causal associations between the four blood lipids and SLE. In addition, regression-based Multivariate MR (MVMR) to quantify the possible mediation effects of blood lipids on SLE. After a rigorous evaluation of the quality of studies, the single-nucleotide polymorphisms (SNPs) associated with the four blood lipids were selected from the Global Lipids Genetic Consortium (GLGC) consisted of 188,577 individuals of European ancestry, and the SNPs related to SLE were selected from a large-scale genome-wide association study (GWAS) database named IEU GWAS. Subsequently, MR analyses were conducted with inverse-variance weighted (IVW), weighted median, weighted mode, simple mode, and MR-Egger regression. Sensitivity analyses were performed to verify whether heterogeneity and pleiotropy led to bias in the MR results. Results: Bidirectional two-sample MR results demonstrated that there was no significant causal association between SLE and the four blood lipids (When setting SLE as outcome, HDL cholesterol and SLE, IVW OR: 1.32, 95% CI: 1.05∼1.66, p = 1.78E-02; LDL cholesterol and SLE, IVW OR: 1.26, 95% CI: 1.04∼1.53, p = 2.04E-02; TG and SLE, IVW OR: 1.04, 95% CI: 0.71∼1.51, p = 8.44E-01; TC and SLE, IVW OR: 1.07, 95% CI: 0.89∼1.29, p = 4.42E-01; When setting SLE as exposure, SLE and HDL cholesterol, IVW OR: 1.00, 95% CI: 0.99∼1.01, p = 9.51E-01; SLE and LDL cholesterol, IVW OR: 0.99, 95% CI: 0.98∼1.00, p = 3.14E-01; SLE and TG, IVW OR: 0.99, 95% CI: 0.98∼1.00, p = 1.30E-02; SLE and TC, IVW OR: 0.99, 95% CI: 0.98∼1.00, p = 1.56E-01). Our MVMR analysis also provided little evidence that genetically determined lipid traits were significantly associated with the risk of SLE (HDL cholesterol and SLE, p = 9.63E-02; LDL cholesterol and SLE, p = 9.63E-02; TG and SLE, p = 8.44E-01; TC and SLE, p = 4.42E-01). Conclusion: In conclusion, these data provide evidence that genetic changes in lipid traits are not significantly associated with SLE risk in the European population.

Evaluating the Similarity of Different Collagen-Induced Arthritis Models to the Pre-Clinical Phase of RA in Female Rats.

Since the development of RA is a multistep process, it is critical to take action to prevent RA in the pre-clinical phase. Animal models are currently one of the important methods to study RA, but there are very few animal models for studying the pre-clinical phase of RA (Pre-RA). This study aimed to evaluate the similarity of different collagen-induced arthritis models to Pre-RA in rats. Three types of collagen-induced arthritis (CIA) were as follows: (i) standard collagen-induced group (Std-CIA), injected with 200 µg type II collagen at day 0 and 100 µg type II collagen at day 7; (ii) single collagen-induced group (Mono-CIA), injected with 200 µg type II collagen at day 0; (iii) half-dose collagen-induced group (Half-CIA), injected with 100 µg type II collagen at day 0 and 50 µg type II collagen at day 7. Arthritis score, hind paw swelling, serum antibodies, and inflammatory cytokines were measured every 7 days. Gut microbiota analyses were performed on days 0, 11, 21, 28, and 35. Pain threshold measurement, digital radiography, and joint pathology were also assessed. Both Std-CIA and Mono-CIA could successfully cause RA symptoms, including joint swelling and bone erosion, Half-CIA induced only mild swelling in rats. Serum autoantibodies (anti-CCP and anti-CoII) showed no difference among the three types of CIA models, and so did the pain threshold at day 42. In addition, the pathological changes of joint tissues in the Mono-CIA group were the slightest among the collagen-immunized groups. Gut microbiota analysis demonstrated that Half-CIA could impose similar effects on upregulating genus Prevotella as Std-CIA, but Mono-CIA was weaker than them in rats. According to the characteristics of pre-RA, the Half-CIA model is the best suitable animal model for pre-RA among three types of CIA models in rats and can be a valuable model for pre-RA research.

Alteration of Gut Microbiome and Correlated Amino Acid Metabolism Contribute to Hyperuricemia and Th17-Driven Inflammation in Uox-KO Mice.

Although gut dysbiosis had been demonstrated to be an important factor affecting hyperuricemia (HUA) and gout, little is known for its potential mechanistic connections. In this study, Uox-KO mice model that with spontaneously developed pronounced HUA and urate nephropathy was used to explore the pathophysiologic mechanism of microbiota alterations in HUA and gout with integrated multi-omics analysis. 16S rRNA gene sequencing was performed to characterize the characteristic bacteria, and untargeted LC/MS analysis was applied to reveal the featured metabolites. Our results showed there was a significant shift in gut microbiota composition and function in Uox-KO mice compared to WT mice and apparent metabolomics differences between the two groups. Among them, amino acids metabolism appears to play a critical role. Correlation analysis further revealed that the characteristic metabolites were strongly influenced by the discrepant bacterial genera. Furthermore, impairment of intestinal integrity and profound alterations in the profile of solute carrier family resulted in dysregulation of amino acids transportation, which subsequently impacted serum uric acid level and CD4+ Th17 driven inflammation. Together, these data indicate that gut dysbiosis promotes purine metabolism disorder and inflammation in Uox-KO mice. Remodeling the gut microbiota is a promising strategy to combat HUA and gout.

Genetically Determined Circulating Levels of Cytokines and the Risk of Rheumatoid Arthritis.

Background: Accumulation of inflammatory leukocytes in articular tissues is the hallmark feature of rheumatoid arthritis (RA). Increasing evidence from observational studies has suggested that several cytokines may be involved in the development of RA. However, traditional observational studies are susceptible to bias from confounding and reverse causation; therefore, the potential causal relationships of individual cytokines with the risk of RA remain elusive. Objective: In this study, we evaluated whether genetically determined circulating levels of cytokines were associated with the risk of RA by performing Mendelian randomization (MR). Methods: We identified single nucleotide polymorphisms (SNPs) associated with circulating levels of cytokines and growth factors from a genome-wide association study (GWAS) including 8,293 participants of Finnish ancestry as instrumental variables (IVs). The association estimates of these IVs with the risk of RA were obtained from a GWAS meta-analysis including 14,361 RA cases and 43,923 controls of European ancestry. We conducted a series of MR analyses to assess the relationship between genetically determined circulating cytokines and the risk of RA, including the random-effects inverse variance-weighted, weighted-median, MR-Egger regression, and MR pleiotropy residual sum and outlier tests. For potential cytokine-RA associations supported by MR evidence, sensitivity analyses were further performed using restricted IV sets of SNPs with colocalization evidence and that excluding pleiotropic SNPs. Results: In the primary MR analysis, there was a suggestive inverse association between genetically determined circulating level of macrophage inflammatory protein-1ß (MIP-1b) and the risk of RA [odds ratio (OR): 0.95, 95% confidence interval (CI) = 0.92-0.99, p = 0.016]. The effect estimates were similar in alternative MR analyses. Among SNPs used as IVs for MIP-1b, we found 92 SNPs without documented pleiotropy and three SNPs with evidence of colocalization. The association of MIP-1b with RA from sensitivity analyses using these two sets of restricted IVs remained stable. Conclusion: Our study suggests that genetically determined elevated circulating level of MIP-1b may be associated with a lower risk of RA. Further studies are warranted to determine how MIP-1b and related pathways may contribute to the development of RA.

Gut microbiota mediated the toxicity of high concentration of dietary nitrite in C57BL/6 mice.

Growing evidence indicates that exposure to high levels of nitrite for a prolonged time has adverse health effects. Although gut microbiota is responsible for the transformation of nitrite in the gut, the evidence concerning whether gut microbiota mediates the toxicity of nitrite is still lacking. The present study addressed the long-term effects of dietary nitrite on male C57BL/6 mice and employed fecal microbiota transplantation (FMT) to reveal whether gut microbiota mediated the effects of nitrite. Furthermore, the effect of azoxymethane (AOM) on gut microbiota was detected for mice drinking normal or nitrite-containing water. High nitrite had toxic effects on C57BL/6 mice. Meanwhile, high nitrite induced skin lesions in mice, accompanied with increased serum ALT, colon IL-6, TNF-α, and MDA levels, together with decreased serum Cr, colon sIgA, and T-AOC levels. After fecal microbiota was transplanted into the normal mice, the nitrite-regulated gut microbiota could also induce skin lesions, coupled with reduced serum Cr, and increased colon MDA. The high dose of nitrite caused the upregulations of Alistipes, Prevotella, and Ruminococcus, which could be transplanted into normal mice through FMT. Inversely, gut microbiota from normal mice reduced the effects of nitrite on serum ALT and Cr, together with colon sIgA and MDA. Gut microbiota from normal mice could also upregulate metabolic genes and downregulate stress genes in the nitrite-treated mice. It might due to the upregulation of Akkermansia and Parabacteroides caused by FMT from normal water-treated mice to nitrite-treated mice. In addition, AOM exhibited to be more toxic to the colon in the nitrite-treated mice in comparison with normal water-treated mice, and it might be due to the expression of Hspa1a and Hspa1b in the colon. Interestingly, gut microbiota was more influenced by AOM in the normal water-treated mice than the nitrite-treated mice. Overall, these data demonstrated that gut microbiota mediated the toxicity of a high concentration of dietary nitrite.