Causal relationship between gut microbiota and tuberculosis: a bidirectional two-sample Mendelian randomization analysis.

BACKGROUND: Growing evidence from observational studies and clinical trials suggests that the gut microbiota is associated with tuberculosis (TB). However, it is unclear whether any causal relationship exists between them and whether causality is bidirectional. METHODS: A bidirectional two-sample Mendelian randomization (MR) analysis was performed. The genome-wide association study (GWAS) summary statistics of gut microbiota were obtained from the MiBioGen consortium, while the GWAS summary statistics of TB and its specific phenotypes [respiratory tuberculosis (RTB) and extrapulmonary tuberculosis (EPTB)] were retrieved from the UK Biobank and the FinnGen consortium. And 195 bacterial taxa from phylum to genus were analyzed. Inverse variance weighted (IVW), MR-Egger regression, maximum likelihood (ML), weighted median, and weighted mode methods were applied to the MR analysis. The robustness of causal estimation was tested using the heterogeneity test, horizontal pleiotropy test, and leave-one-out method. RESULTS: In the UK Biobank database, we found that 11 bacterial taxa had potential causal effects on TB. Three bacterial taxa genus.Akkermansia, family.Verrucomicrobiacea, order.Verrucomicrobiales were validated in the FinnGen database. Based on the results in the FinnGen database, the present study found significant differences in the characteristics of gut microbial distribution between RTB and EPTB. Four bacterial taxa genus.LachnospiraceaeUCG010, genus.Parabacteroides, genus.RuminococcaceaeUCG011, and order.Bacillales were common traits in relation to both RTB and TB, among which order.Bacillales showed a protective effect. Additionally, family.Bacteroidacea and genus.Bacteroides were identified as common traits in relation to both EPTB and TB, positively associating with a higher risk of EPTB. In reverse MR analysis, no causal association was identified. No significant heterogeneity of instrumental variables (IVs) or horizontal pleiotropy was found. CONCLUSION: Our study supports a one-way causal relationship between gut microbiota and TB, with gut microbiota having a causal effect on TB. The identification of characteristic gut microbiota provides scientific insights for the potential application of the gut microbiota as a preventive, diagnostic, and therapeutic tool for TB.

The effects of meteorological factors and air pollutants on the incidence of tuberculosis in people living with HIV/AIDS in subtropical Guangxi, China.

BACKGROUND: Previous studies have shown the association between tuberculosis (TB) and meteorological factors/air pollutants. However, little information is available for people living with HIV/AIDS (PLWHA), who are highly susceptible to TB. METHOD: Data regarding TB cases in PLWHA from 2014 to2020 were collected from the HIV antiviral therapy cohort in Guangxi, China. Meteorological and air pollutants data for the same period were obtained from the China Meteorological Science Data Sharing Service Network and Department of Ecology and Environment of Guangxi. A distribution lag non-linear model (DLNM) was used to evaluate the effects of meteorological factors and air pollutant exposure on the risk of TB in PLWHA. RESULTS: A total of 2087 new or re-active TB cases were collected, which had a significant seasonal and periodic distribution. Compared with the median values, the maximum cumulative relative risk (RR) for TB in PLWHA was 0.663 (95% confidence interval [CI]: 0.507-0.866, lag 4 weeks) for a 5-unit increase in temperature, and 1.478 (95% CI: 1.116-1.957, lag 4 weeks) for a 2-unit increase in precipitation. However, neither wind speed nor PM10 had a significant cumulative lag effect. Extreme analysis demonstrated that the hot effect (RR = 0.638, 95%CI: 0.425-0.958, lag 4 weeks), the rainy effect (RR = 0.285, 95%CI: 0.135-0.599, lag 4 weeks), and the rainless effect (RR = 0.552, 95%CI: 0.322-0.947, lag 4 weeks) reduced the risk of TB. Furthermore, in the CD4(+) T cells < 200 cells/µL subgroup, temperature, precipitation, and PM10 had a significant hysteretic effect on TB incidence, while temperature and precipitation had a significant cumulative lag effect. However, these effects were not observed in the CD4(+) T cells ≥ 200 cells/µL subgroup. CONCLUSION: For PLWHA in subtropical Guangxi, temperature and precipitation had a significant cumulative effect on TB incidence among PLWHA, while air pollutants had little effect. Moreover, the influence of meteorological factors on the incidence of TB also depends on the immune status of PLWHA.

Assessing causal association of circulating micronutrients and systemic lupus erythematosus susceptibility: a Mendelian randomization study.

Background: Previous studies showed the conflicting associations between circulating micronutrient levels and systemic lupus erythematosus (SLE). Therefore, we aimed to clarify the causal association between circulating micronutrient levels and the risk of SLE by two-sample Mendelian randomization (MR) analysis. Methods: 56 single nucleotide polymorphisms (SNPs) significantly associated with 14 circulating micronutrients (vitamin A, B6, B9, B12, C, D and E, phosphorus, calcium, magnesium, copper, iron, zinc, and selenium) in published genome-wide association studies (GWAS) were used as instrumental variables (IVs). And summary statistics related to SLE were obtained from the IEU OpenGWAS database. We used the MR Steiger test to estimate the possible causal direction between circulating micronutrients and SLE. In the MR analysis, inverse variance weighting (IVW) method and the Wald ratio was as the main methods., Moreover, the MR-Pleiotropy residuals and outliers method (MR-PRESSO), Cochrane's Q-test, MR-Egger intercept method and leave-one-out analyses were applied as sensitivity analyses. Additionally, we conducted a retrospective analysis involving the 20,045 participants from the Third National Health and Nutritional Examination Survey (NHANES III). Weight variables were provided in the NHANES data files. Univariate and multivariate logistic regression analyses were performed to determine the associations between circulating micronutrients and SLE. Results: The MR estimates obtained from the IVW method revealed potential negative correlations between circulating calcium (OR: 0.06, 95% CI: 0.01-0.49, P = 0.009), iron levels (OR: 0.63, 95% CI: 0.43-0.92, P = 0.016) and the risk of SLE. The results remained robust, even under various pairs of sensitivity analyses. Our retrospective analysis demonstrated that the levels of vitamin D, serum total calcium, and serum iron were significantly lower in SLE patients (N = 40) when compared to the control group (N = 20,005). Multivariate logistic regression analysis further established that increased levels of vitamin D and serum total calcium served as protective factors against SLE. Conclusion: Our results provided genetic evidence supporting the potential protective role of increasing circulating calcium in the risk of SLE. Maintaining adequate levels of calcium may help reduce the risk of SLE.

Activation of the JNK/COX-2/HIF-1α axis promotes M1 macrophage via glycolytic shift in HIV-1 infection.

Chronic inflammation is recognized as a major risk factor for the severity of HIV infection. Whether metabolism reprogramming of macrophages caused by HIV-1 is related to chronic inflammatory activation, especially M1 polarization of macrophages, is inconclusive. Here, we show that HIV-1 infection induces M1 polarization and enhanced glycolysis in macrophages. Blockade of glycolysis inhibits M1 polarization of macrophages, indicating that HIV-1-induced M1 polarization is supported by enhanced glycolysis. Moreover, we find that this immunometabolic adaptation is dependent on hypoxia-inducible factor 1α (HIF-1α), a strong inducer of glycolysis. HIF-1α-target genes, including HK2, PDK1, and LDHA, are also involved in this process. Further research discovers that COX-2 regulates HIF-1α-dependent glycolysis. However, the elevated expression of COX-2, enhanced glycolysis, and M1 polarization of macrophages could be reversed by inactivation of JNK in the context of HIV-1 infection. Our study mechanistically elucidates that the JNK/COX-2/HIF-1α axis is activated to strengthen glycolysis, thereby promoting M1 polarization in macrophages in HIV-1 infection, providing a new idea for resolving chronic inflammation in clinical AIDS patients.

The global burden of cardiovascular diseases and type 2 diabetes attributable to low physical activity, 1990-2019: an analysis from the global burden of disease study.

Background: Cardiovascular diseases (CVD) and type 2 diabetes (T2D) account for the majority of the burden of noncommunicable disease caused by low physical activity (LPA). In order to inform future interventions, this study aims to assess the burden and trends in mortality and disability-adjusted life years (DALYs) of CVD and T2D attributable to LPA by year, location, sex, and age from 1990 to 2019. Methods: Mortality, DALYs, and their age-standardised rates (ASMR, ASDR) for CVD and T2D attributable to LPA were retrieved from Global Burden of Disease (GBD) 2019. The estimated annual percentage changes (EAPCs) were calculated using linear regression model to describe the trend over time. Results: From 1990 to 2019, the number of deaths caused by both CVD and T2D due to LPA increased significantly globally. However, the overall ASMR and ASDR for CVD declined over this same period [EAPC for ASMR (CVD) = -1.44 (95% CI: -1.50-1.38), EAPC for ASDR (CVD) = -1.30 (95% CI: -1.35 to -1.25)]. In terms of disparities, ASMR (CVD) and ASDR (CVD) in North Africa and the Middle East were consistently higher than the global average; also, the sex difference in ASMR was greatest in Central Asia. ASMR among people aged 25-44 in high Socio-Demographic Index (SDI) region has increased significantly over the past three decades. ASMR (T2D) due to LPA showed an increasing trend year by year, with EAPC = 0.26 (95% CI: 0.13-0.39), and this rate increased faster in males than in females. Consistent with cardiovascular diseases, ASMR of type 2 diabetes attributable to LPA increased among people aged 25-44, while decreased in other age groups in high SDI region. Conclusion: Interventions targeting LPA are warranted in controlling the burden of cardiovascular diseases and type 2 diabetes. Countries should adapt strategies to their local contexts, considering the sex and age differences among their populations. The 25-44 age group should be given special attention to prevent the disease burden from worsening among younger people.