According to statistics, lung cancer accounts for 2.2 million new cases and 1.79 million fatalities each year (Thai et al., 2021), making it the second most commonly occurring cancer type globally and the primary cause of cancer-related deaths (Sung et al., 2021; Huang et al., 2022). Several well-known risk factors contribute to the development of lung cancer, including smoking, previous lung diseases, air pollutants, and occupational carcinogens (Samet et al., 2009; Wang et al., 2020). Identifying and discovering potentially modifiable risk factors is crucial to reducing the incidence of lung cancer, which is conducive to early diagnosis and treatment of lung cancer.

Recently, it has been suggested that the gut microbiota (GM) has an impact on the progression of lung cancer. GM refers to the highly complex community of microorganisms that reside within the gastrointestinal tract, including archaea, bacteria, eukaryotes, parasites, and viruses (Ge et al., 2021). Dysbiosis of microbial ecology may lead to changes in metabolism, immunosuppression, and the recruitment of inflammatory factors that can drive lung carcinogenesis. In the study by JinC and LagoudasGK et al., mouse models showed that the local microbiota associated with tumor development promotes inflammatory progression through lung-resident γδ T cells (Jin et al., 2019) and is thought to be associated with lung cancer. The most recent theory holds that even though the gastrointestinal tract and respiratory tract are physically separate, they share an embryonic origin and a high degree of structural similarity (Georgiou et al., 2021). There is a distinct crosstalk between the respiratory tract and the gastrointestinal tract known as the gut–lung axis (Dang and Marsland, 2019; Enaud et al., 2020; Zhang et al., 2020). The gut-lung axis is the pathway through which the GM interacts with the lung (Young et al., 2016; Liu et al., 2021), Microbiota-accessible carbohydrates can alter the GM and improve short-chain fatty acid (SCFA) levels, hence shaping lung immunity (Arrieta et al., 2015; Budden et al., 2017). Through T cell receptor signaling, SCFAs may activate innate lymphoid cells that produce IL-22 type 3, regulatory T cells, and Th2 cells in the lung to reduce inflammation and thus reduce the incidence of lung cancer (Corrêa et al., 2022). SCFAs can also exert effective anti-inflammatory and immunomodulatory effects by activating G protein-coupled cell surface receptors and inhibiting histone deacetylases, as well as exert immunomodulatory effects by activating G protein-coupled cell surface receptors and inhibiting histone deacetylases (Ubachs et al., 2021). Nonetheless, whether there is a clear causal relationship between lung cancer and GM still needs further proof.

In order to investigate the potential causal link between lung cancer and GM, Mendelian randomization (MR) analysis was used. MR analysis is a statistical strategy based on genome-wide association analysis, following the Mendelian rule of “parental alleles randomly assigned to offspring”. It is therefore a natural randomized controlled trial (RCT). MR analysis has been extensively utilized to investigate the connection between GM and diseases such as pre-eclampsia and eclampsia (Li et al., 2022), autoimmune diseases (Xu et al., 2021), and psychiatric disorders (Zhuang et al., 2020). In this research, we employed the two-sample MR analysis method to examine the potential impact of GM in various types of lung cancer. The findings of this research can serve as a foundation for understanding the etiology and diagnosis of lung cancer.

The results of MR estimates for the relationship between the GM and different types of lung cancer are presented in Supplementary Table 1 and Figure 2 . After correction, one microbial taxon was found to be significant at a significance level of 0.05.

In this study, we performed a two-sample MR analysis using the summary statistics of the GM from the MiBioGen consortium’s largest GWAS data and the summary statistics of various subtypes of lung cancer from the TRICL, ILCCO, and FinnGen consortium R7 release data to evaluate the causal association between GM and lung cancer. We found 10 GM to be causally associated with overall lung cancer, 10 with lung adenocarcinoma, 9 with squamous cell carcinoma, and 11 with small cell lung cancer. After FDR correction, we found Peptococcaceae to be causally associated with lung adenocarcinoma.

The GM primarily influences the occurrence of lung cancer via the gut-lung axis, exerting its effects by regulating the lung immune system, influencing lung inflammation response, and producing metabolites (Zhao et al., 2021). Alterations in the GM may lead to disruption of the intestinal mucosal barrier, resulting in the occurrence of inflammation. These inflammatory factors may enter the lungs through the gut-lung axis (Enaud et al., 2020; Zhao et al., 2021), and long-term inflammatory responses can promote the occurrence of lung cancer by activating signal transduction pathways. In addition, intestinal immune cells such as ILC2s, ILC3, and TH17 can migrate directly from the intestine to the respiratory tract via the bloodstream to influence the immune activity of the respiratory system (Ma et al., 2022). The GM can also produce various metabolites, such as SCFAs, carotenoids, and bile acids (Du et al., 2022; Soriano-Lerma et al., 2022). These metabolites may directly or indirectly affect the occurrence of lung cancer by entering the lungs through the gut-lung axis.

The family of Bifidobacteriaceae, as a probiotic, has been reported in a study to have a protective effect against oxidative stress-induced DNA damage in vitro. This study suggests that Bifidobacterium bifidum, a member of the Bifidobacteriaceae family, possesses antioxidant properties that may prevent diseases such as lung cancer by reducing DNA damage (Bhatt et al., 2017). Our research findings are consistent with the notion that Bifidobacteriaceae has a strong causal relationship with lung cancer and serves as a protective factor against it. With regard to cyanobacteria, phycocyanin can be produced, which has a variety of biological functions such as anti-tumor, anti-oxidant, immunomodulatory, and anti-inflammatory activities. Several studies have demonstrated that phycocyanin exerts a dual role in NSCLC cells by not only reducing the activity and proliferation of A549 cells (Hao et al., 2018a), but also inhibiting the proliferation of various NSCLC cell lines (such as H1299, H460, and LTEP-a2) while inducing apoptosis (Hao et al., 2018b). These findings provide a basis for future applications of cyanobacteria in the treatment of NSCLC. It is worth mentioning that our findings align with those of Nam et al., who found that patients with the inflammatory disease “rosacea” had lower levels of Peptococcaceae in the gut (Nam et al., 2018). Furthermore, chronic inflammation is known to be linked to lung cancer. Based on this, we propose that Peptococcaceae may play a role in mitigating lung inflammation damage and could potentially impact the development of lung cancer. However, there is a lack of relevant research evidence to confirm the specific mechanism of the potential causal link between these specific microbial taxa and the incidence of lung cancer.

The study by J et al. suggests that the dysbiosis of lung microbiota in lung cancer patients is associated with upregulation of the PI3K signaling pathway and cancer progression. Specific lung cancer-associated bacteria, such as Prevotella, may impact the tumor microenvironment and initiate a cascade reaction in cancer cells, leading to the upregulation of the PI3K/AKT signaling pathway and cancer development. Overall, this basic research reveals the potential role of Prevotella and other specific lung cancer-associated bacteria in lung cancer development, providing a possible avenue for researching new preventive and therapeutic strategies (He et al., 2022). There is also a study that shows a potential association between Actinomyces and lung cancer development. The relative abundance of Actinomyces is increased in both COPD and NSCLC patients, and its abundance is positively correlated with the risk of developing lung cancer. This study reveals an association between the dysbiosis of lung microbiota and the occurrence of lung cancer. However, further research is necessary to determine the precise impact of Actinomyces on lung cancer development (Peters et al., 2022). It is worth noting that there is currently no research directly determining how the genus Ruminiclostridium 6 and Actinomycetales influence lung cancer. However, a study has shown that patients with a higher relative abundance of Actinomycetales have a lower risk of lung cancer recurrence after surgery (Wei et al., 2023). Further research is needed to determine the exact mechanism of action of Actinomycetales and other bacterial genera in lung cancer development.

It is worth noting that our research shows significant differences in results when compared to two other studies, those by Long et al. and Wei et al (Long et al., 2023; Wei et al., 2023), with the primary difference being that we used a larger and more comprehensive database. This makes our results more reliable, confirming previous research and providing a novel perspective on the potential causal relationship between GM and lung cancer. Additionally, we had stringent requirements for maintaining consistency between beta values and the IVW method in our analysis, which led to the exclusion of certain results due to slight differences. Additionally, unlike studies with limited sample sizes or specific populations, the use of MR studies has the advantage of overcoming confounding factors. MR uses natural genetic variation as instrumental variables to explore causality between the exposure and outcome. This approach can eliminate reverse causality and collinearity and exclude most confounding factors during the estimation process, leading to results that are more likely to reflect the true cause-effect relationship. However, there may still be some confounding factors present in the study, such as smoking, diet, medications, and COPD, which could interfere with the composition of the GM and increase the risk of developing lung cancer. As such, future research should continue to explore and implement advanced methods to reduce the influence of confounding factors.

This research has several advantages. First, we utilized MR analysis to minimize the effects of reverse causation and confounding, thus enhancing the causal inference of lung cancer and the GM. Second, we chose a more comprehensive and larger database, which yielded more results. Additionally, to confirm the robustness of our results, we also employed the MR-Egger regression intercept term test and MR-PRESSO. Nevertheless, this study still has some limitations. One limitation is that the molecular biology of the GM is not yet fully understood, which limits our ability to deduce the molecular mechanisms that link GM and lung cancer. Additionally, the lung cancer cases are primarily from cross-sectional studies, which may introduce a survival bias effect. At the same time, potential influential factors such as smoking, diet, or treatment effects may also affect the results of genome-wide association studies (GWAS). Finally, the majority of data in this study comes from European populations, and while we have included some other ethnic groups, our findings may be somewhat biased.

By conducting an MR analysis on the causal relationship between the GM and various subtypes of lung cancer, we identified potential causal associations between 10 microbial communities and lung cancer, 10 with lung adenocarcinoma, 9 with lung squamous cell carcinoma, and 11 with small cell lung cancer. Following correction, Peptococcaceae still displayed a strong causal relationship with lung adenocarcinoma. However, definitive experimental research is required to further explore the precise mechanism underlying this relationship.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ Supplementary Material .

MZ and YW contributed to the concept and design of this study. YL and KW were responsible for the statistical analysis and writing of the report. YZ and JY reviewed the article and provided critical feedback to improve and structure the report. YL and KW are regarded as co-first authors with the same degree of contribution. All authors contributed to the article and approved the submitted version.