Causal effect of gut microbiota on the risk of cancer and potential mediation by inflammatory proteins

Our plain-English summary of Causal effect of gut microbiota on the risk of cancer and potential mediation by inflammatory proteins, by Y. Wang, W. Liu, L. Liu, et al (World Journal of Surgical Oncology, 2025).

The study

• Authors: Y. Wang, W. Liu, L. Liu, Y. He, H. Luo, C. Fang
• Journal: World Journal of Surgical Oncology
• Published: 2025;23(1):163
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: While growing evidence highlights the role of gut microbiota and inflammatory proteins in cancer, with cancer-related inflammation now considered the seventh hallmark of cancer, the direct causal relationships between specific microbiota, cancer, and the potential mediating effects of inflammatory proteins have not been fully established.

Methods: We employed Mendelian randomization (MR) to assess the causal relationships between gut microbiota, inflammatory proteins, and eighteen distinct cancers using data from extensive genome-wide association studies (GWAS). The primary statistical method utilized was inverse variance weighting (IVW). We also investigated whether inflammatory proteins could mediate the effects of gut microbiota on cancer development.

Results: Our findings revealed 42 positive and 49 inverse causal impacts of gut microbiota on cancer risk (P < 0.05). Additionally, we identified 32 positive and 28 inverse causal relationships between inflammatory proteins and cancer risk. Moreover, genus Collinsella decreased the risk of lung cancer by decreasing levels of T-cell surface glycoprotein CD5 (mediating effect = 16.667%), while genus Ruminococcaceae UCG005 increased the risk of mesothelioma by increasing levels of CCL4 (mediating effect = 5.134%).

Conclusions: Our study provides evidence for a causal association between gut microbiota, inflammatory proteins, and eighteen different cancer types. Notably, the T-cell surface glycoprotein CD5 and CCL4 were identified as mediators linking the genus Collinsella with lung cancer and the genus Ruminococcaceae UCG005 with mesothelioma, respectively.

© 2025. The Author(s).

In plain English

This Mendelian randomization study used inherited genetic variants, taken from published genetic summary data, as stand-ins for exposures. The authors tested 211 gut microbial taxa (data from 18,340 participants in 24 cohorts) and 91 blood inflammatory proteins (14,824 people of European ancestry) against 18 cancers, including mesothelioma, for which UK Biobank data had 133 samples. The article does not mention asbestos or say whether the mesothelioma was pleural or peritoneal. Across all cancers, the authors reported 42 positive and 49 inverse effects of gut microbiota and 32 positive and 28 inverse effects of inflammatory proteins. For mesothelioma, eight gut microbial groups and three proteins were linked to higher or lower risk. For example, the genus Ruminococcaceae UCG005 had an odds ratio of 3.547 (95% CI 1.179–10.669) and the protein CCL4 1.660 (1.075–2.566). The authors estimated that CCL4 carried 5.134% of the Ruminococcaceae UCG005 effect on mesothelioma, and that CD5 carried 16.667% of the genus Collinsella effect on lung cancer. They concluded that inflammatory proteins seemed to act as mediators. They noted possible pleiotropy, mostly European data and the limited taxonomic resolution of the microbiota data.

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 Mendelian randomization study with mediation analysis, using published genome-wide association (GWAS) summary statistics
• Who was studied: No new participants. Gut microbiota genetic data came from 18,340 participants in 24 cohorts in several countries (MiBioGen). Inflammatory protein data came from 14,824 participants of European ancestry in 11 cohorts. Cancer data for 18 cancer types came from large consortia; mesothelioma data came from the UK Biobank (133 samples). The mesothelioma site is not specified.
• Exposure: Genetically predicted abundance of 211 gut microbiota taxa and genetically predicted levels of 91 circulating inflammatory proteins. No asbestos or other occupational exposure was studied.
• Main results:
  • Across the 18 cancers, the authors reported 42 positive and 49 inverse effects of gut microbiota on cancer, and 32 positive and 28 inverse effects of inflammatory proteins on cancer.
  • Mesothelioma, microbial groups linked to increased risk: family Peptostreptococcaceae (OR = 8.569, 95% CI = 2.342–31.359, P = 0.001), genus Oscillospira (OR = 3.734, 95% CI = 1.041–13.399), genus Ruminococcaceae UCG005 (OR = 3.547, 95% CI = 1.179–10.669, P = 0.049) and genus Streptococcus (OR = 5.181, 95% CI = 1.326–20.241).
  • Mesothelioma, microbial groups linked to decreased risk: class Mollicutes (OR = 0.236, 95% CI = 0.078–0.710), family Clostridiaceae1 (OR = 0.266, 95% CI = 0.071–0.999), genus Anaerofilum (OR = 0.410, 95% CI = 0.184–0.914) and phylum Tenericutes (OR = 0.236, 95% CI = 0.078–0.710).
  • Mesothelioma, inflammatory proteins: higher CCL4 (OR = 1.660, 95% CI = 1.075–2.566, P = 0.034) and TNFLSM14 (OR = 2.110, 95% CI = 1.013–4.396) were linked to increased risk. For cystatin D the OR was 0.559 (95% CI = 0.333–0.937), which the article describes as lower levels being associated with decreased risk.
  • Mediation for mesothelioma: the effect of genus Ruminococcaceae UCG005 on mesothelioma through CCL4 was beta = 0.065 (95% CI 0.001–0.151), with CCL4 mediating 5.134% of the effect.
  • Mediation for lung cancer: genus Collinsella was linked to decreased lung cancer risk (OR = 0.782, 95% CI = 0.629–0.971), and T-cell surface glycoprotein CD5 accounted for approximately 16.667% of this effect.
• The authors' conclusion: The authors concluded that inflammatory proteins seemed to act as a mediating factor in the pathway from gut microbiota to lung cancer and mesothelioma.
• Limitations the authors state:
  • Violations of the Mendelian randomization assumptions, particularly pleiotropy, cannot be entirely ruled out.
  • The genetic data came mainly from European populations, so the findings may not apply to other ethnic groups.
  • Incomplete data prevented further statistical adjustment for confounders.
  • The gut microbiota data used 16S rRNA sequencing, whose lower taxonomic resolution may affect the reliability of the causal inferences.

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Lung Cancer, Glycoprotein, Mesothelioma.

Related studies

• Bidirectional Mendelian randomization and potential mechanistic insights into the causal relationship between gut microbiota and malignant mesothelioma — Y. Zhou, H. Zhu, et al. (2025)
• Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis — H. Ohshima, H. Bartsch (1994)
• A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma — M. Zhang, A. Bzura, et al. (2024)
• CD157: From immunoregulatory protein to potential therapeutic target — E. Ortolan, S. Augeri, et al. (2019)
• Do high glucose levels have differential effect on FDG uptake in inflammatory and malignant disorders? — H.M. Zhuang, A. Cortés-Blanco, et al. (2001)
• Beyond foreign-body-induced carcinogenesis: impact of reactive oxygen species derived from inflammatory cells in tumorigenic conversion and tumor progression — F. Okada (2007)

Browse more research in World Journal of Surgical Oncology, or return to medical research.