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Updated: Jul 8, 2026
Induction of Intestinal Graft-versus-host Disease and Its Mini-endoscopic Assessment in Live Mice
Published on: February 11, 2019
Large-scale mediator Mendelian randomization analysis identifies multiple immune cells mediating the causal link
Yiyin Chen1, Xinghao Yu1, Yiming Cai1
1National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
Abstract:
Disorders of gut microbiota and immune cells have been observed to be involved in the occurrence of chronic graft-versus-host disease (cGVHD), but their causal connections have yet to be fully understood. This study utilized Mendelian randomization (MR), integrating genome-wide association study (GWAS) meta-analyses from the MiBioGen consortium (microbial taxa), the SardiNIA project (immune traits), and disease data from the Fred Hutchinson Cancer Research Center (FHCRC) cohort to investigate their relationships. The aim was to explore the causal effects of microbiota and immune traits on the incidence of cGVHD, using mediation analysis to identify which immune traits might mediate the effects of microbiota on this condition. The main analysis observed significant causal associations of 3 specific microbial taxa with cGVHD: Lactococcus.id.1851 (odds ratio [OR] = 1.989, 95% confidence interval [CI] = 1.311-3.019, p = 0.001), Ruminiclostridium9.id.11357 (OR = 3.273, 95% CI = 1.604-6.679, p = 0.001), and Intestinimonas.id.2062 (OR = 0.400, 95% CI = 0.230-0.697, p = 0.001). Sensitivity analysis and multivariable MR analysis ruled out possible horizontal pleiotropy and bias. Additionally, 10 immune traits, predominantly covering regulatory T cells (Tregs) and B cells, were identified as influencing cGVHD risk. The two-step mediation MR analysis presented the effect of identified microbial taxa on Tregs and B cells and detailed the pathways through which Intestinimonas impacts cGVHD via CD27 on memory B cells (proportion mediated = 4.2%). Similarly, the role of interactions between Ruminiclostridium9 and effector memory double-negative T cells in mediating cGVHD was quantified, accounting for 9.5% of the total effect.
Insights
This study reveals causal links between gut microbes and chronic graft-versus-host disease (cGVHD). Specific bacteria like Lactococcus and Ruminiclostridium influence cGVHD risk, partly mediated by immune cell changes.
Area of Science:
- Immunology
- Microbiology
- Genetics
Background:
- Chronic graft-versus-host disease (cGVHD) is a significant complication of hematopoietic stem cell transplantation.
- The roles of gut microbiota and immune cells in cGVHD pathogenesis are implicated but not fully elucidated.
- Understanding causal relationships is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the causal effects of gut microbial taxa on cGVHD incidence.
- To explore the causal effects of immune traits on cGVHD risk.
- To identify immune mediators in the causal pathway from microbiota to cGVHD using mediation analysis.
Main Methods:
- Mendelian randomization (MR) analysis integrating GWAS data from microbial taxa (MiBioGen), immune traits (SardiNIA), and cGVHD cases (FHCRC).
- Two-step mediation MR analysis to assess indirect effects of microbial taxa on cGVHD via immune traits.
- Sensitivity analyses and multivariable MR to ensure robustness and rule out pleiotropy.
Main Results:
- Significant causal associations were found for three microbial taxa: Lactococcus.id.1851 (OR=1.989), Ruminiclostridium9.id.11357 (OR=3.273), and Intestinimonas.id.2062 (OR=0.400) with cGVHD.
- Ten immune traits, including regulatory T cells (Tregs) and B cells, were associated with cGVHD risk.
- Mediation analysis identified pathways: Intestinimonas impacted cGVHD via CD27+ memory B cells (4.2% mediated), and Ruminiclostridium9 via effector memory double-negative T cells (9.5% mediated).
Conclusions:
- Gut microbiota composition causally influences cGVHD risk.
- Specific immune cell populations mediate the effects of gut microbes on cGVHD.
- These findings highlight potential microbial and immune targets for cGVHD prevention and treatment.
