Bidirectional Mendelian randomization and potential mechanistic insights into the causal relationship between gut microbiota and malignant mesothelioma

Our plain-English summary of Bidirectional Mendelian randomization and potential mechanistic insights into the causal relationship between gut microbiota and malignant mesothelioma, by Y. Zhou, H. Zhu, L. Zhao, et al (Medicine, 2025).

The study

• Authors: Y. Zhou, H. Zhu, L. Zhao, G. Zhao, J. Sun
• Journal: Medicine
• Published: 2025;104(17):e42245
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a rare but aggressive cancer originating from mesothelial cells, which presents significant challenges to patients' physical and psychological well-being. The gut-lung axis underscores the connection between gut microbiota and respiratory diseases, with emerging evidence suggesting a strong association between gut microbiota and the development of MM. In this study, we conducted a two-sample Mendelian randomization (MR) analysis to investigate the potential causal relationship between gut microbiota and MM, while also exploring the underlying mechanisms through bioinformatics approaches. Gut microbiota summary data were obtained from the MiBioGen consortium, while MM data were sourced from the FinnGen R11 dataset. Causality was examined using the inverse variance weighted method as the primary analysis. Additional methods, including the weighted median, simple mode, MR-Egger, and weighted mode, were also employed. The robustness of the findings was validated through sensitivity analyses, and reverse causality was considered to further strengthen the MR results. Moreover, bioinformatics analyses were conducted on genetic loci associated with both gut microbiota and MM to explore potential underlying mechanisms. Our study suggests that genetically predicted increases in class.Bacilli, family.Rikenellaceae, genus.Clostridium innocuum group, and order.Lactobacillales were suggestively associated with a higher risk of MM, whereas increases in genus.Ruminococcaceae UCG004, genus.Flavonifractor, phylum.Firmicutes, genus.Anaerofilum, genus.Clostridium sensu stricto 1, and genus.Lactobacillus appeared to confer protective effects. Bioinformatics analysis indicated that differentially expressed genes near loci associated with gut microbiota might affect MM by modulating pathways and the tumor microenvironment. The results of this study point to a potential genetic predisposition linking gut microbiota to MM. Further experimental validation is crucial to confirm these candidate microbes, establish causality, and elucidate the underlying mechanisms.

Copyright © 2025 the Author(s). Published by Wolters Kluwer Health, Inc.

In plain English

This study used two-sample Mendelian randomization, which treats inherited genetic variants as stand-ins for gut bacteria levels, to look for possible causal links between gut bacteria and malignant mesothelioma. It used data on gut bacteria from 18,340 people (MiBioGen consortium) and on mesothelioma from Finland's FinnGen R11 database (390 cases, 345,118 controls). It did not estimate asbestos effects, but excluded genetic variants linked to mesothelioma-related traits such as asbestos. Using the main method, genetically predicted higher levels of four bacterial groups, including order Lactobacillales (odds ratio 2.907; 95% CI 1.348 to 6.268), were suggestively linked to higher mesothelioma risk. Higher levels of six groups, including genus Lactobacillus (odds ratio 0.554; 95% CI 0.321 to 0.956), were linked to lower risk. A reverse analysis found no statistically significant associations. Gene-expression analyses identified genes and pathways the authors proposed as possible mechanisms. The authors concluded the results point to a potential genetic predisposition needing experimental confirmation. Their stated limitations were European-only data (though the gut bacteria data were 72.3% European), few cases, no separate pleural and peritoneal analysis, and a relaxed genetic threshold.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Two-sample, bidirectional Mendelian randomization study using publicly available genetic summary data, plus bioinformatics analyses of public gene-expression databases. The article is labeled an observational study.
• Who was studied: Mesothelioma genetic data came from the Finnish FinnGen R11 database: 390 malignant mesothelioma cases and 345,118 controls (excluding all cancers), of European ancestry. Gut microbiota genetic data came from the MiBioGen consortium: 24 population-based cohorts with 18,340 participants from Europe, North America and East Asia, of mixed ancestry (72.3% European). Gene-expression data came from GEO dataset GSE51024: 55 malignant pleural mesothelioma samples and 41 normal lung tissue samples.
• Exposure: Genetically predicted abundance of 196 gut microbiota taxa, represented by 2603 genetic variants (SNPs). The effect of asbestos was not estimated. Variants significantly associated with mesothelioma-related phenotypes such as asbestos were excluded as potential confounders.
• Main results:
  • Main (inverse variance weighted) analysis: genetically predicted increases in four taxa were suggestively associated with higher mesothelioma risk. These were class Bacilli (OR 2.496; 95% CI 1.309 to 4.761; P = .005), family Rikenellaceae (OR 2.175; 95% CI 1.104 to 4.285; P = .025), genus Clostridium innocuum group (OR 1.670; 95% CI 1.046 to 2.664; P = .032) and order Lactobacillales (OR 2.907; 95% CI 1.348 to 6.268; P = .006).
  • Main analysis: genetically predicted increases in these taxa were linked to lower mesothelioma risk: genus Ruminococcaceae UCG004 (OR 0.510; 95% CI 0.26 to 0.998; P = .049), genus Flavonifractor (OR 0.367; 95% CI 0.14 to 0.966; P = .042) and phylum Firmicutes (OR 0.466; 95% CI 0.237 to 0.92; P = .028).
  • Main analysis: genetically predicted increases in these taxa were also linked to lower mesothelioma risk: genus Anaerofilum (OR 0.584; 95% CI 0.362 to 0.943; P = .028), genus Clostridium sensu stricto 1 (OR 0.343; 95% CI 0.152 to 0.772; P = .010) and genus Lactobacillus (OR 0.554; 95% CI 0.321 to 0.956; P = .034).
  • The other methods (MR-Egger, weighted median, weighted mode and simple mode) gave estimates that the authors described as consistent in size and direction with the main method.
  • Sensitivity analyses found no significant heterogeneity or pleiotropy, except for class Bacilli (MR-Egger intercept P = .016).
  • The reverse analysis, testing whether mesothelioma affects these bacterial traits, found no statistically significant associations.
  • In 55 malignant pleural mesothelioma samples compared with 41 normal lung samples, 1651 genes differed in expression. Of the 305 genes located near variants of the mesothelioma-associated gut microbiota, 30 overlapped with these genes.
  • In the GEPIA2 database, higher expression of 5 of these genes (TENM3, CCNB2, SFXN1, KIF14, ANLN) was associated with poorer overall survival and disease-free survival in mesothelioma.
• The authors' conclusion: The authors concluded that the results point to a potential genetic predisposition linking gut microbiota to mesothelioma. They said further experimental validation is needed to confirm the candidate microbes and establish causality.
• Limitations the authors state:
  • The authors stated that the genetic data came exclusively from European populations and need validation in other ethnic groups. Their own Table 1, however, lists the MiBioGen gut microbiota data as mixed ancestry (72.3% European); only the FinnGen mesothelioma data are listed as European.
  • The number of mesothelioma cases was small because the disease is rare, which may introduce bias.
  • Because summary statistics were used, pleural and peritoneal mesothelioma could not be analyzed separately.
  • A relaxed significance threshold was used to select genetic variants, which may include weaker associations.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Mesothelial Cells, Tumor Microenvironment.

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