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

Abstract

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.

Keywords: Causal relationship; Extrapulmonary tuberculosis; Gut microbiota; Mendelian randomization; Respiratory tuberculosis; Tuberculosis.

Fig. 1

Research design and flow chart of this study. TB, tuberculosis; RTB, respiratory tuberculosis; EPTB, extrapulmonary tuberculosis; SNP, single nucleotide polymorphism; MAF, minor allele frequency; LD, linkage disequilibrium; IVW, inverse variance weighted; MR-PRESSO, Mendelian randomization pleiotropy residual sum and outlier

Fig. 2

Causal effect of the gut microbiota on TB by MR analyses. A In the UK Biobank database; B In the FinnGen ddatabase. From outside to inside, the P values of IVW_p, ML_p, MR Egger_p, WMe_p, and WMo_p were represented, respectively. TB, tuberculosis; IVW, inverse variance weighted; ML, maximum likelihood; WMe, weighted median; WMo, weighted mode

Fig. 3

A forest plot of causal effect of gut microbiota on TB in the UK Biobank database (P-_IVW < 0.05). TB, tuberculosis; OR, odds ratio; CI, confidence interval

Fig. 4

A forest plot of causal effect of gut microbiota on TB in the FinnGen database (P-_IVW < 0.05). TB, tuberculosis; OR, odds ratio; CI, confidence interval

Fig. 5

The common bacterial traits in two databases for TB, RTB, and EPTB. A The common bacterial traits in two databases for TB. B The common bacterial traits in relation to both TB and RTB in two databases. C The common bacterial traits in relation to both TB and EPTB in two databases. TB, tuberculosis; RTB, respiratory tuberculosis; EPTB, extrapulmonary tuberculosis; UKBB, the UK Biobank database; FinnGen, the FinnGen database

Fig. 6

The common bacterial traits in the FinnGen database for RTB and EPTB. A The common bacterial traits in relation to both TB and RTB in the FinnGen database. B The common bacterial traits in relation to both TB and EPTB in the FinnGen database. TB, tuberculosis; RTB, respiratory tuberculosis; EPTB, extrapulmonary tuberculosis; FinnGen, the FinnGen database