AUTHOR=Feng Zuxi , Liao Minjing , Bai Jun , Li Yanhong , Chen Yue , Zhang Li , Guo Xuege , Li Lijuan , Zhang Liansheng 

TITLE=Exploring the causal relationship between gut microbiota and multiple myeloma risk based on Mendelian randomization and biological annotation

JOURNAL=Frontiers in Microbiology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1310444

DOI=10.3389/fmicb.2024.1310444

ISSN=1664-302X

ABSTRACT=<sec><title>Introduction</title><p>The microbial genome-wide association studies (mbGWAS) have highlighted significant host-microbiome interactions based on microbiome heritability. However, establishing causal relationships between particular microbiota and multiple myeloma (MM) remains challenging due to limited sample sizes.</p></sec><sec><title>Methods</title><p>Gut microbiota data from a GWAS with 18,340 participants and MM summary statistics from 456,348 individuals. The inverse variance-weighted (IVW) method was used as the main bidirectional Mendelian randomization (MR) analysis. To assess the robustness of our results, we further performed supplementary analyses, including MR pleiotropy residual sum and outlier (MR-PRESSO) test, MR-Egger, Weighted median, Simple mode, and Weighted mode. Moreover, a backward MR analysis was conducted to investigate the potential for reverse causation. Finally, gene and gene-set-based analyses were then conducted to explore the common biological factors connecting gut microbiota and MM.</p></sec><sec><title>Results</title><p>We discovered that 10 gut microbial taxa were causally related to MM risk. Among them, family <italic>Acidaminococcaceae</italic>, <italic>Bacteroidales</italic> family S24-7, family <italic>Porphyromonadaceae</italic>, genus <italic>Eubacterium ruminantium group</italic>, genus <italic>Parabacteroides</italic>, and genus <italic>Turicibacter</italic> were positively correlated with MM. Conversely, class <italic>Verrucomicrobia</italic>, family <italic>Verrucomicrobiaceae</italic>, genus <italic>Akkermansia</italic>, and order <italic>Verrucomicrobiales</italic> were negatively correlated with MM. The heterogeneity test revealed no Heterogeneity. MR-Egger and MR-PRESSO tests showed no significant horizontal pleiotropy. Importantly, leave-one-out analysis confirmed the robustness of MR results. In the backward MR analysis, no statistically significant associations were discovered between MM and 10 gut microbiota taxa. Lastly, we identified novel host-microbiome shared genes (AUTS2, CDK2, ERBB3, IKZF4, PMEL, SUOX, and RAB5B) that are associated with immunoregulation and prognosis in MM through biological annotation.</p></sec><sec><title>Discussion</title><p>Overall, this study provides evidence supporting a potential causal relationship between gut microbiota and MM risk, while also revealing novel host-microbiome shared genes relevant to MM immunoregulation and clinical prognosis.</p></sec>