Recent studies have shown an increasing interest in the complex relationship between gut bacteria and immune-related diseases. The intricate interaction between the microbiome and immune system significantly impacts health and disease, with imbalances potentially leading to immune disorders.
Growing evidence suggests that gut microbiota dysbiosis is closely related to the occurrence and development of cancer[17]. Our Mendelian randomization (MR) analysis identified 22 gut microbiotas associated with RCC, with 15 negatively correlated and 7 positively correlated. The results indicated no significant heterogeneity based on Cochrane’s Q test and excluded pleiotropy and outliers using the MR-Egger intercept and MR-PRESSO tests. This suggests that specific gut bacteria might influence RCC onset and progression through various pathways.
Further analysis of 731 immune cell traits revealed numerous immune markers significantly linked to RCC. Resting regulatory T cells (Treg) with CD28, IgD-, CD38dim B cells with CD24, and IgD + CD24 + B cells percentage were linked to a decreased RCC risk. These findings indicate that specific immune cell characteristics might protect against RCC occurrence.
To explore how gut microbiota influences RCC through immune cell characteristics, we conducted mediation analysis. Borreliaceae, Borreliales, CAG-345 sp000433315, and Enterococcus impacted RCC through SSC-A on monocytes. Thioalkalivibrionaceae notably controlled RCC by influencing factors like the proportion of CD39 + Treg cells within CD4 Tregs, CD80 expression on granulocytes, and HLA DR levels on CD33dim HLA DR + CD11b- myeloid cells. Certain intestinal bacteria had conflicting effects on RCC by influencing various immune cell features, such as Demequinaceae, which suppressed RCC by interacting with CD45 on HLA DR + NK cells but promoted RCC by interacting with CD14- CD16- AC Monocyte cells. These findings highlight the intricate interactions between gut microbiota exposure and RCC.
Recent research highlights the significance of the microbiome, particularly polymorphic microbes, as a novel characteristic of cancer[18, 19]. The composition of the intestinal microbiome may indicate direct cancer-causing effects or influence the body’s immune reaction to cancerous cells, potentially shielding against cancer onset and advancement, and controlling treatment response.[20]. Several studies have elucidated the inherent connection between the microbiota and malignancies[21]. The gut microbiome may impact the host’s energy and lipid metabolism by regulating the synthesis of short-chain fatty acids (SCFAs), thereby altering conditions favorable for tumor cell growth[21–24]. SCFAs such as butyrate, propionate, and acetate are essential metabolites produced by the gut microbiota. They modulate immune cell activity by interacting with G protein-coupled receptors like GPR41 and GPR43, leading to the development of T cells and the growth of regulatory T cells, which help maintain balance in intestinal immune responses[25]. Additionally, bile acids generated by the gut microbiota can regulate tumor-related signaling pathways by activating specific receptors, such as the farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5. This activation can ultimately influence tumor development and metastasis[26]. 2) The gut microbiota also influences the balance between Treg and Th17 cells by stimulating dendritic cells (DCs) in the intestinal mucosa with their metabolites and antigens. Treg cells inhibit inflammation by releasing anti-inflammatory cytokines such as IL-10, whereas Th17 cells enhance inflammation by secreting pro-inflammatory cytokines like IL-17[27–30]. A well-functioning gut microbiome is crucial for protecting the intestinal barrier and preventing harmful pathogens and toxins from entering the bloodstream. Disruption of microbial homeostasis can result in certain bacteria or their components failing to elicit effective inflammatory responses in the host. Conversely, some microbes may cause impaired immune cell activation, leading to immune deficiency, thereby evading recognition by the host’s immune system and shielding tumors from immune cell attacks[31–33]. Metabolites or secretions produced by harmful microorganisms can alter the host’s tissue environment, compromising typical biological defenses in host cells. Additionally, these microbial products can travel through the host’s circulatory system, influencing tumor development even at sites distant from the microbial growth[34–36].
The impact of gut microbiota on immunotherapy is gaining increasing recognition. Studies have shown that modifying the structure and function of the gut microbiome can enhance the efficacy of immune checkpoint inhibitors (ICIs). For instance, specific gut microbiota can improve the effectiveness of ICIs in killing tumor cells by modulating the host immune system. This synergistic effect suggests that regulating the gut microbiota could become a new strategy to enhance the effectiveness of immunotherapy.
Renal cell carcinoma (RCC) is a type of cancer that originates in the kidney tissue and is notorious for its resistance to chemotherapy. In recent years, ICIs have shown promising advancements in treating RCC. These inhibitors stimulate CD8 + T cells by blocking the interaction between cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed death protein 1 (PD-1) and its ligand PD-L1, resulting in the destruction of cancer cells[37]. The combination treatment of Nivolumab and Ipilimumab has demonstrated improved overall survival and reduced symptoms in patients with advanced RCC, along with a higher health-related quality of life compared to traditional tyrosine kinase inhibitors like Sunitinib[38, 39]. Nevertheless, despite the improved survival time and response rate from ICIs or combination treatments, many patients still experience initial resistance or lack of response, leading to tumor progression[40].
New studies suggest that the diversity of gut bacteria can significantly impact the effectiveness of immune checkpoint inhibitor (ICI) treatments. Salgia et al. found that individuals who responded well to ICI therapy had a more diverse range of gut bacteria[41]. Further investigation revealed that among individuals with cancer undergoing immunotherapy, the administration of antibiotics was linked to a decrease in objective response rate, progression-free survival, and overall survival[42]. However, this impact was not observed in individuals receiving mTOR inhibitors or VEGF-T treatment [43]. Derosa et al. noted that the administration of antibiotics significantly reduced the objective response rate in patients with advanced renal cell carcinoma (RCC) undergoing Nivolumab monotherapy[44]. Furthermore, an imbalance in gut bacteria was associated with a reduced response to immunotherapy in patients with RCC. Multiple studies have shown that RCC patients with different treatment responses exhibit distinct gut microbiota distributions and abundances. The use of antibiotics may lead to gut dysbiosis in RCC patients receiving ICIs treatment, resulting in poor treatment outcomes. Moreover, studies have indicated that the gut microbiome can impact how different types of cancer respond to treatment by influencing the body’s immune system. In instances of colorectal cancer, higher amounts of Fusobacterium nucleatum may enhance the efficacy of PD-L1 inhibition[45]. Research has shown that the presence of Bifidobacterium symbiosis can improve the efficacy of anti-PD-L1 therapy for melanoma [46]. Therefore, it is speculated that the gut microbiota plays a crucial role in regulating how RCC patients respond to ICIs. Research indicates that the composition of intestinal bacteria significantly influences the effectiveness of ICIs in treating RCC. Modifying the gut microbiota could be a potential approach to enhance the outcomes of RCC patients receiving ICI therapy.
This study has some limitations. First, the results are only applicable to European populations, not accounting for significant differences in gut microbiota composition among various populations. Additionally, the 16S rRNA gene sequencing technique is limited to distinguishing between genera and cannot provide further classification. Third, the lack of information on fundamental traits such as cultural background, gender, and occupation makes it challenging to conduct stratified MR analysis, thereby limiting the interpretation of the impact on specific populations. Finally, the gut microbiome can be influenced by dietary patterns and various external factors, yet the connection between genetic tools and these influencing factors cannot be determined due to insufficient data.