In this study, a two-sample MR analysis was performed to evaluate the causal relationship between gut microbiota and two neoplasms, namely MNBAC and BNBAC. Among the MR methods employed, the random effects IVW method demonstrated more stable and convincing statistical capability, allowing it to be the dominant analytical method used in the present study [16]. The results of the study revealed that there exists a causal relationship between 4 specific taxa of the gut microbiota, including Eubacterium eligens group, Odoribacter, Slackia and Tyzzerella3, and MNBAC. Meanwhile, 3 specific gut microbiota, Eubacterium ruminantium group, Oscillibacter, and Ruminococcustorques group, have also been identified as causally linked to BNBAC. However, there is no reverse causality between two neoplasms, namely MNBAC and BNBAC, and the aforementioned gut microbiota. To the best of our knowledge, the relationship between the gut microbiota and bone neoplasms has only been investigated in a limited number of studies. This is the first MR study, filling the gaps in this area, to investigate the potential causal relationship between the gut microbiota and bone neoplasms.
The gut microbiota, an important regulator of body homeostasis, has been found to be associated with various systemic diseases. In recent years, the gut microbiota-bone axis has been hypothesized, indicating a link between skeletal disorders and disruption of gut microbial ecology [17]. According to Chevalier et al., exposing ovariectomized experimental mice to a warm environment improves gut microbial polyamine generation, which reduces bone loss [18]. The influence of gut microbiota on bone metabolism has been extensively investigated, and transforming microbiome abundance has been proposed as an alternative approach to preserve or improve bone health. In addition, an increasing number of comparative studies have demonstrated that the gut microbiota of those with cancer is distinct from that of healthy persons, which means that changes in the gut flora typically precede or coexist with the development of cancer [19]. The role of the gut microbiota in oncological diseases should also not be underestimated. It has now been demonstrated that the gut microbiota plays an important role in diseases such as colorectal cancer [20], lung cancer [21], liver cancer [22, 23], breast cancer [24], etc. However, the connection between gut microbiota and bone-related tumors has been investigated in a small number of preclinical research to date. Osteosarcoma is known to be one of the most common bone malignancies. According to a study based on 16S rRNA gene sequencing, the abundance of particular gut microbes varied (with a higher relative abundance of the family Lachnospiraceae) between experimental mice with osteosarcoma and control mice without osteosarcoma, which also indicates a potential interaction between the gut microbiota and osteosarcoma [6]. Our research explores the genetically mediated causal connection between gut microbiota and bone neoplasms, and the findings may offer effective prophylactic and therapeutic options for disorders associated with bone cancer.
Based on MR results, we identified 4 gut microbiotas in the current study that act as potentially protective factors against the development of MNBAC. It has been demonstrated that Eubacterium eligens is capable of flavonoid biotransformation to generate bioactive metabolites, including 2,4,6-trihydroxybenzoic acid (2,4,6-THBA), 3,4-dihydroxybenzoic acid (3,4-DHBA), and 3,4-dihydroxyphenylacetic acid (3,4-DOPAC), which inhibit the proliferation of tumor cells [25]. The immune system exerts a variety of complicated impacts that are crucial to the pathophysiology of tumors. As a potential protective factor against MNBAC, Odoribacter, whose altered abundance mediates the deletion of the adaptive immune signaling molecule TAK1, stimulates protective immunity to confer resistance to colitis and colorectal cancer in wild-type mice [26]. A human intestinal bacterium, Slackia, which generates estragole, has been noticed to have a substantial correlation with prostate [27], colorectal [28], and stomach cancers [29]. In addition, there have been several studies that have established the association of this flora with various forms of infectious disorders [30]. Compared to the 3 gut microbiotas mentioned above, relatively few studies have been conducted on Tyzzerella3. Only a few MR studies have shown its genetic causality with COVID-19 [31] and erectile dysfunction [32]. In our opinion, these types of bacteria might be used to create probiotics that would enhance gut health in humans and serve as a potential means of avoiding and addressing MNBAC.
Furthermore, two types of gut flora (Oscillibacter and Ruminococcus torques group) believed to be protective against BNBAC were found in this study, along with a gut microbiota (Eubacterium ruminantium group) that might increase the risk of BNBAC. According to the latest research by Yu et al., fecal microbiota transplantation may inhibit the growth of colorectal cancer by reversing the pattern of gut microbiota abundance (including Oscillibacter) and allowing a large influx of immune cells (including CD8 T and CD49b NK), which can directly kill cancer cells [33]. In addition, another protective factor for BNBAC, the Ruminococcus torques group, was first reported in 1985 as a dominant population colonizing the colon that consistently produces blood group antigen-specific α-glycosidases to degrade mucin oligosaccharides [34]. In recent years, several studies have also explored the relevance of the Ruminococcus torques group to urological and colorectal cancers [35, 36]. Similarly to the Ruminococcus torques group, the study by Wang et al. found a substantial correlation between the Eubacterium ruminantium group and urological tumors [36]. In addition, a MR study also revealed that the abundance of the Eubacterium ruminantium group was significantly correlated with bone mineral density (BMD) and that bone tumors typically include localized changes in BMD [37]. The above facts may be helpful in understanding the causal relationship between the aforementioned gut microbiota and BNBAC.
Nevertheless, there are several limitations regarding our study that should be acknowledged. First, the aggregated GWAS data included in this paper are only from European populations, limiting the generalizability of the results to larger demographic groups. Second, the bacterial taxa have only been analyzed at the level of the genera and not at the more specialized levels such as the species or the strain. Finally, the data of gut microbiota from a meta-analysis of mostly adult patients was employed in our study, while the majority of patients with certain tumors (osteosarcoma, osteochondroma, etc.) are children or adolescents.