Gut Microbiota Found to Influence MDS Risk Through Immune Cells

A recent study published in Discover Oncology identifies a causal link between gut microbiota and myelodysplastic syndrome (MDS) risk, mediated by key immune cell phenotypes. The research identified 8 gut microbiota traits that may significantly influence MDS risk and pinpointed 5 key immune cell phenotypes through which these microbiota exert their effects.¹

The study used a bidirectional 2-sample, 2-step Mendelian randomization (MR) approach using summary statistics from genome-wide association studies (GWAS) involving a substantial number of participants, including 456,348 for MDS, 18,340 for gut microbiota, and 3757 for immune cell signatures. The researchers aimed to elucidate the bidirectional correlation between gut microbiota and MDS and investigate immune cells' mediating role in this relationship. Through biological annotation of host-microbiome shared genes, the researchers also found that immune regulation may mediate the impact of gut microbiota on MDS.

This research highlights the importance of considering both microbiota composition and immune response in understanding and managing MDS. | Image Credit: © sdecoret - stock.adobe.com

The study identified 8 gut microbiota traits significantly associated with MDS risk. These microbiota traits include genus Blautia, genus Intestinibacter, and genus RuminococcaceaeUCG003, which were found to increase the risk of MDS. Conversely, traits such as class Clostridia, family Veillonellaceae, genus Coprococcus1, genus LachnospiraceaeNK4A136group, and order Clostridiales were associated with a reduced risk of MDS. These findings suggest a one-way causal relationship where gut microbiota influences the risk of developing MDS, but not vice versa.

Twenty-three immunophenotypes showed significant associations with MDS risk, and 5 of these were causally influenced by gut microbiota. The 5 specific immunophenotypes identified as potential causal mediators are CD4+ T cell % leukocyte, CD127 on CD45RA- CD4 non-regulatory T cell, CD45 on CD33+ HLA-DR+ WHR, CD33 on basophil, and Monocyte AC. Previous study findings had shown that some CD4+ and CD8+ T-cell subsets are dysregulated in MDS, which can impact response to immunosuppressive therapy.² "The interplay between gut microbiota and the immune system may significantly impact the genesis, progression, and treatment outcomes of hematological malignancies," the authors of the current study noted.¹

The forward MR analyses revealed positive relationships between 3 microbiota features and MDS risk. These include the genus Blautia, which showed an OR of 2.8096 with a 95% CI of 1.0516 to 7.5060 (P = .0394), indicating a significant increase in MDS risk. Similarly, genus Intestinibacter had an OR of 2.3335 (95% CI, 1.0996-4.9519; P = .0273) and genus RuminococcaceaeUCG003 had an OR of 2.2414 (95% CI, 1.1497-4.3698; P = .0178).

On the other hand, traits that were associated with a reduced risk of MDS include class Clostridia (OR, 0.3595; 95% CI, 0.1481-0.8726; P = .0238), family Veillonellaceae (OR, 0.5062; 95% CI, 0.2751-0.9313; P = .0286), genus Coprococcus1 (OR, 0.3178; 95% CI, 0.1387-0.7284; P = .0067), genus LachnospiraceaeNK4A136group (OR, 0.4256; 95% CI, 0.2222-0.8151; P = .0100), and order Clostridiales (OR, 0.3592; 95% CI, 0.1479-0.8727; P = .0238). These findings were corroborated through sensitivity analyses, including MR-Egger intercept, heterogeneity tests, and MR-PRESSO global tests.

Through biological annotation of host-microbiome shared genes, the researchers found that immune regulation could be a potential mechanism through which gut microbiota influences MDS. "Therefore, we speculate that immune cells serve as mediators between the microbiota and MDS."

This research highlights the importance of considering both microbiota composition and immune response in understanding and managing MDS. "In essence, these findings collectively affirm the strength and dependability of our primary conclusions that the genetic predisposition to gut microbiota is intricately associated with heightened susceptibility to MDS. Moreover, our research highlights the potential involvement of five distinct immune cell traits in facilitating the causal relationship between gut microbiota and MDS," the authors conclude.

References

1. Feng Z, Liao M, Guo X, Li L, Zhang L. Effects of immune cells in mediating the relationship between gut microbiota and myelodysplastic syndrome: a bidirectional two-sample, two-step Mendelian randomization study. Discov Oncol. 2024;15(1):199. doi:10.1007/s12672-024-01061-6doi:10.1007/s12672-024-01061-6

2. Zou JX, Rollison DE, Boulware D, et al. Altered naive and memory CD4+ T-cell homeostasis and immunosenescence characterize younger patients with myelodysplastic syndrome. Leukemia. 2009;23(7):1288-1296. doi:10.1038/leu.2009.14.