Based on current literature, our study is the first to investigate the causal effects of the gut microbiome on multiple myeloma using Mendelian Randomization. Our results indicate a causal relationship between specific gut microbial taxa and multiple myeloma.
There is already existing literature on the role of the gut microbiome in multiple myeloma, with numerous studies indicating a correlation between the two. For instance, Brevi et al [29]found a close link between the gut microbiome and immunodynamics in adults undergoing immune reconstitution post-hematopoietic stem cell transplantation (HSCT). The interaction between the microbiome and the host immune system is not just local but systemic, impacting distant sites. Liu et al [11]used an antibiotic mixture to deplete specific gut microbial communities in mice and observed significant changes in the gut microbiome through 16S rRNA sequencing. Micro-CT scans of the mice revealed reduced bone damage caused by multiple myeloma, as well as increases in mineral density, bone volume fraction, trabecular thickness, and number. These studies suggest that the reduction or absence of certain gut microbial taxa can either increase or decrease the risk of multiple myeloma. They provide new research directions for the potential role of the gut microbiome in the development of multiple myeloma, but further clarification of the underlying mechanisms is needed to provide effective potential targets for the prevention and treatment of multiple myeloma.
Multiple myeloma, a malignant hematologic tumor characterized by the clonal proliferation of plasma cells in the bone marrow, is the second most common hematological malignancy. It is characterized by destructive bone lesions, renal damage, anemia, and hypercalcemia[30]. Treatment targeting these characteristic lesions is crucial for managing multiple myeloma. Yang et al[9]found that multiple myeloma can cause excessive accumulation of urea (an amino acid metabolite) in the blood, leading to renal damage - a characteristic lesion of multiple myeloma. This, in turn, alters the gut microbiome, which actively contributes to the malignant progression of multiple myeloma. The interaction between the gut microbiome and the host's amino acid metabolism is significant, and exploring this relationship from the perspective of adjusting the gut microbiome and host amino acid metabolism is of great importance [31].
The genus Slackia, part of the Actinobacteria phylum, has been found to participate in human amino acid metabolism[32]. Proteins ingested into the human gut are hydrolyzed into amino acids, which are then converted into ammonia by the gut microbiome and other substances. Ammonia is reused by some nitrogen bacteria in the gut to produce glutamine, which multiple myeloma cells utilize for proliferation, leading to rapid cancer cell growth and exacerbation of the condition [33] [34]. Slackia inhibits the conversion of amino acids into ammonia, thereby reducing glutamine levels and slowing the proliferation rate of multiple myeloma cells [35].
On the other hand, the genus Ruminiclostridium5, known for its cellulolytic activity as a strict anaerobe, participates in the degradation of dietary fiber in the gut [36]. Short-chain fatty acids (SCFAs) [37], the main products of dietary fiber fermentation, are absorbed and metabolized by colon cells, providing energy and substrates. Studies have found that SCFAs produced in the gut are absorbed and distributed in the bone marrow, significantly reducing the proliferation rate of multiple myeloma cells [9]. Figure 5(A) shows the possible mechanism of action between Genus Slackia and multiple myeloma. Figure 5(B) shows the possible mechanism of action between Genus Ruminiclostridium 5 and multiple myeloma.
In the current literature, research on the association between multiple myeloma and the Anaerotruncus is still in its preliminary stages [38]. While existing studies have provided clues about the link between Anaerotruncus and the metabolites of multiple myeloma, the in-depth relationship between this specific microorganism and multiple myeloma requires further exploration. Additionally, this study is the first to reveal associations between microbes like Bilophila, Victivallis, and Butyrivibrio with the risk of multiple myeloma, thereby paving new pathways for future research.
In investigating the relationship between multiple myeloma and the gut microbiome, this study expands upon the familial-level correlation analysis to explore the potential causal effects of specific gut microbial taxa on multiple myeloma at a more granular taxonomic level, identifying key microbial groups that may influence the development of multiple myeloma. Simultaneously, compared to previous randomized controlled studies, our research, based on extensive genome-wide association studies (GWAS), adopted the Mendelian Randomization (MR) approach, providing a larger scale of sample analysis. Furthermore, we conducted reverse Mendelian Randomization to explore potential reverse causal relationships, but found no significant evidence [39].
However, our study has certain limitations in its design. Although it meets the requirements of the Mendelian Randomization hypothesis, the possibility of instrumental variable bias cannot be entirely ruled out [40] ,This leads to a slight deviation in the results.