Association between gut microbiota and lymphomas: A bidirectional multivariable Mendelian randomization study

To the Editor: Lymphomas, classified as hematological malignancies (HMs),[1,2] continue to pose significant challenges to public health. Although gut microbiota is widely connected with lymphoma via several plausible mechanisms,[1–4] the causality and directionality of this relationship are not fully understood. Therefore, a bidirectional multivariable Mendelian randomization (MR) study design was adopted to establish a robust causal relationship between gut microbiota and the development of lymphomas. Genetic variants from a genome-wide association study (GWAS) dataset obtained from the international consortium MiBioGen were used as instrumental variables (IVs) to address limitations associated with confounding factors and reverse causality often encountered in observational studies.[5] This consortium conducted a large-scale GWAS that involved 18,340 participants from 24 cohorts across multiple countries, including the USA, Canada, Israel, South Korea, Germany, Denmark, the Netherlands, Belgium, Sweden, Finland, and the UK. The GWAS dataset included both 16S ribosomal RNA gene sequencing profiles and genotyping data. A comprehensive set of 211 taxa, consisting of 131 genera, 35 families, 20 orders, 16 classes, and 9 phyla, was considered in the analysis. All data are available from the Integrative Epidemiology Unit (IEU) OpenGWAS project (https://gwas.mrcieu.ac.uk/). Single-nucleotide polymorphisms (SNPs) significantly associated with the gut microbiome were selected as IVs using two distinct thresholds. Using a stringent genome-wide significance threshold (5 × 10−8),[6] we identified primary IVs with strong association evidence to minimize false-positive instruments. To ensure comprehensive causal inference, we established a secondary threshold at the locus-wide significance level (1 × 10−5), enabling the inclusion of additional SNPs as supplementary IVs for detecting putative causal relationships.[7] IV strength was assessed via the F statistic [Figure 1].Figure 1: Flow chart of IVs selection for studying association between gut microbiota and lymphomas (two-way causality). LD: Linkage disequilibrium; IVs: Instrumental variables; SNP: Single-nucleotide polymorphisms.A meticulous series of steps was undertaken to maintain the rigor and reliability of the IVs included in the MR analysis. The variants of interest underwent rigorous scrutiny by way of a minor allele frequency (MAF) threshold of 0.01.[8] A linkage disequilibrium (LD) threshold of r2 <0.01 and a clumping distance set at 10,000 kb were applied[9] to ensure the inclusion of nonredundant and independent IVs in the subsequent MR analysis. Five widely recognized MR methods, including the inverse variance weighted (IVW) test,[10] MR-Egger regression,[11] weighted median estimation (WME),[12] MR-PRESSO (Pleiotropy RESidual Sum and Outlier),[13] and simple mode estimation,[14] were used to elucidate the potential causal associations between gut microbiome characteristics and the risk of developing lymphomas. Cochran’s Q statistics and the two-sample MR package were used to examine heterogeneity and identify potentially invalid instruments. Q statistics with a significance level less than 0.05 indicate the potential existence of heterogeneity.[15] MR-Egger, weighted median, and MR-PRESSO were conducted as sensitivity analyses. The MR Steiger directionality test was used to evaluate the directionality of the causal relationship between gut microbiota and lymphomas. The key findings illustrated are summarized as follows: For lymphomas overall, several taxa, including class Deltaproteobacteria, class Lentisphaeria, family Desulfovibrionaceae, family Victivallaceae, genus Eubacterium hallii group, genus Lachnospiraceae UCG001, genus Ruminiclostridium 5, genus Ruminococcaceae UCG011, and order Desulfovibrionales, exhibited a protective effect against lymphomas development (odds ratio [OR] <1, P <0.05). Conversely, genus Ruminococcus gauvreauii group, phylum Lentisphaerae, and phylum Proteobacteria emerged as potential risk factors (OR >1, P <0.05). For Hodgkin’s and non-Hodgkin’s lymphomas, taxa, including phylum Lentisphaerae, class Methanobacteria, and class Negativicutes showed protective effects, while genus Bifidobacterium, and genus Eubacterium brachy group increased risk. For follicular and non-follicular lymphomas, class Methanobacteria and family Methanobacteriaceae demonstrated protective effects, while class Clostridia and genus Adlercreutzia were associated with increased risk. Previous studies have suggested that gut microbiota is widely connected with lymphoma via several plausible mechanisms. Our results showed that the class Lentisphaeria consistently acted as a protective factor against lymphomas. The class Lentisphaeria comprises a group of bacteria that have been found to play a role in maintaining gut homeostasis and promoting immune regulation.[16] One possible reason for the protective effect of the class Lentisphaeria against lymphomas could be its ability to interact with immune cells, such as T cells and B cells, and promote an anti-inflammatory immune response.[17] By modulating immune cell activity, these bacteria may help suppress abnormal or malignant cell growth within lymphoid tissues, reducing the risk of lymphoma development. Additionally, the classes Methanobacteria and the family Methanobacteriaceae had a protective influence on the development of FL. The presence of the class Methanobacteria and the family Methanobacteriaceae might contribute to a favorable gut environment that promotes SCFA production and subsequently influences immune function, potentially protecting against the development of FL. In contrast, our study revealed that the presence of the genus Ruminococcus 1 was associated with an increased risk of developing lymphoma. The genus Ruminococcus 1 is a diverse group of bacteria in the gut microbiota.[18] Certain strains or metabolites produced by this genus may promote an inflammatory environment or disrupt immune regulation, thereby increasing the risk of lymphoma.[19] Importantly, there are insufficient research data to support the specific relationship between Ruminococcus 1 and lymphoma development. These explanations are speculative, and further studies are needed to validate and understand the specific mechanisms by which these bacteria affect lymphoma risk. This study, however, also has several limitations. First, the causal relationships identified through MR analysis require further validation using experimental and longitudinal studies. Second, the analysis focused on a limited set of lymphoma subtypes, and the results may not be generalizable to other subtypes. Additionally, the study did not consider the potential influence of confounding factors, such as diet, lifestyle, or medication use, which could impact the gut microbiota composition. In conclusion, this study provides potential targets for future interventions or therapeutic strategies. Moreover, these findings highlight the complex and dynamic interplay between the gut microbiome and lymphomas, emphasizing the importance of considering the microbiota in lymphoma research and clinical management. Funding This work was supported by grants from the National Natural Science Foundation of China (No. 82020108004), Chongqing Young and Middle-aged Medical High-end Talent Project (No. YXGD202467), and Natural Science Foundation of Chongqing (No. CSTB2022NSCQ-MSX084). Acknowledgements The authors thank Jun Rao, Chi Zhu, Xiaoqi Wang, and Ruihao Huang for their assistance with the statistical analysis. Conflicts of interest None.

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