Inflammatory Cytokines May Mediate the Causal Relationship between Metabolites and Primary Sclerosing Cholangitis: A Bidirectional Mediation Mendelian Randomization Study
Hui Liu, Zhiwei Zhong, Shoubin NingIntroduction:
The causal links between metabolites, inflammatory cytokines, and Primary Sclerosing Cholangitis (PSC) remain elusive. This study used Mendelian Randomization (MR) to elucidate these mechanistic pathways.
Methods:
Genome-Wide Association Study (GWAS) summary statistics for 1,400 metabolites (n = 8,299), 91 inflammatory plasma proteins (n = 14,824), and PSC (2,871 cases and 12,019 controls) were leveraged. Bidirectional MR evaluated potential causal directionality, and mediation analysis examined the intermediary roles of cytokines. Sensitivity analyses ensured the robustness of the findings.
Results:
The findings revealed that 52 metabolites are associated with PSC, with 18 identified as risk factors and 34 as protective factors. Four inflammatory proteins were implicated, with IL-10RB acting as a protective mediator, while NKR2B4, CXCL9, and TNFSF12 served as risk factors. Mediation analysis revealed that these cytokines partially mediated the associations between eight metabolites and disease susceptibility, indicating a complex regulatory network involving metabolic and immune pathways.
Discussion:
This study provides suggestive evidence for links among metabolites, inflammatory cytokines, and PSC. Mediation MR analysis revealed that four inflammatory cytokines, IL-10RB, CXCL9, TNFSF12, and NKR2B4, partially mediate the effects of specific metabolites on PSC risk. This finding suggests that metabolites may indirectly influence disease progression by modulating distinct inflammatory pathways.
conclusion:
This study enhances the understanding of the complex interactions among metabolites, cytokines, and PSC, offering valuable insights into the pathophysiological mechanisms underlying PSC. The protective metabolites identified may guide the nutritional management of PSC patients and suggest new avenues for clinical drug development.
Conclusion:
This study delineates a preliminary metabolic-immune interactome in PSC from a genetic standpoint, offering novel insights into the disease's complex pathogenesis. The prioritized cohorts of metabolites and cytokines identified herein represent prime candidates for the future development of novel biomarkers and the design of targeted therapeutic interventions.