In this study, we performed a comprehensive bidirectional two-sample Mendelian randomization analysis to evaluate causal relationships between 1,091 circulating metabolites, 309 metabolite ratios, 731 immune cell phenotypes, and colorectal cancer risk. Our robust statistical approach integrating large-scale GWAS datasets provides unique insights into metabolic and immunologic factors potentially driving colorectal carcinogenesis. The findings nominate promising candidates for prognostic biomarkers and therapeutic targets, as well as illuminate novel strategies for early detection and prevention. More broadly, this work demonstrates the power of genetic instrumental variable techniques to elucidate causal mechanisms underlying complex multifactorial diseases like colorectal cancer.
Notably, we identified 58 blood metabolites that demonstrated significant causal associations with altered colorectal cancer risk. The implicated metabolites span diverse biochemical classes including amino acids, lipids, nucleotides, cofactors, and xenobiotics [21]. Molecular networking approaches have revealed that many of these metabolite categories participate in pathways relevant to hallmarks of cancer like proliferation, survival, and metastasis [22]. Our results provide orthogonal human genetic evidence linking specific metabolic perturbations to colorectal tumorigenesis. For example, elevated levels of tryptophan betaine, an amino acid derivative, were positively correlated with colorectal cancer risk. Tryptophan betaine possesses antioxidant properties but can also inhibit apoptosis and promote angiogenesis – effects that may enable tumor growth [23]. Its causal role revealed here warrants further functional investigation.
Conversely, metabolites like erythronate and citrulline exhibited protective effects against colorectal cancer in our analysis. Erythronate is involved in carnitine synthesis, which is essential for beta-oxidation and energy production [24]. Its reduction may reflect metabolic insufficiencies in the tumor microenvironment [25]. Citrulline helps maintain intestinal barrier function, and its preservation may mitigate tumorigenic signals from gut microbes [26]. Overall, our study nominates metabolic pathways involved in energy metabolism, redox homeostasis, and epithelial integrity as potential modulators of colorectal cancer risk.
The metabolite ratio findings provide additional insights into metabolic crosstalk in colorectal cancer. For instance, the histidine/asparagine ratio demonstrated a negative correlation with colorectal cancer risk, suggesting imbalances between these amino acids may influence pathogenesis. Histidine possesses antioxidant effects as noted above, while asparagine is required for protein and nucleotide synthesis during rapid tumor growth [27]. Their relative deficiencies could critically alter colorectal cancer cell metabolism. Modulating metabolite co-dependencies and networks through combination therapies represents an emerging frontier in cancer metabolism.
Beyond metabolites, we found 38 immune cell phenotypes that exhibited significant causal links with colorectal cancer. Colorectal tumorigenesis is enabled in part by evasion of immune surveillance. Our findings reveal specific immune cell populations that may mediate protective or deleterious effects. For example, the HLA-DR + NK cell subset showed a positive correlation with colorectal cancer risk, indicating aberrant activation of this group may promote cancer development. HLA-DR + NK cells have enhanced effector functions but require tight regulation to prevent excessive inflammation [28]. Conversely, the HLA-DR + CD4 + T helper cell population exhibited a protective effect, aligning with its critical immunoregulatory roles [29]. Overall, these results identify lead immunological candidates for subsequent functional investigation.
A key advantage of our study was the use of bidirectional Mendelian randomization to explore reciprocal relationships between circulating factors and colorectal cancer. We found that colorectal cancer risk was itself causally associated with altered levels of two lipids, suggesting a potential feedback loop. Tumor cells can co-opt metabolic pathways to support malignancy, exemplified by the finding here that colorectal cancer enhances fluxes through lipid synthesis and remodeling routes. Additionally, colorectal cancer showed a positive causal effect on CD86 + plasmacytoid dendritic cells, possibly reflecting systemic immune activation by tumor-associated signals. These results provide unique insights into the interplay between metabolic and immune traits with colorectal cancer.
Several findings from our study could hold clinical utility once validated. First, the identified circulating metabolites and immune cell phenotypes represent candidate prognostic biomarkers that warrant evaluation for colorectal cancer detection, staging, and monitoring. These minimally invasive factors could complement imaging and tissue-based techniques. For example, combinations of causal blood metabolites may enable liquid biopsy tests to predict occult colorectal cancer or early recurrence with high accuracy [30]. Second, metabolites showing causative effects highlight potential preventive targets. For instance, dietary or pharmacologic interventions modulating tryptophan betaine levels could mitigate colorectal cancer risk [31]. Third, implicated immune cell types like HLA-DR + NK cells could be selectively modulated to enhance anti-tumor immunity [32]. Our multilevel analysis linking immune dysregulation, metabolic dysfunction, and colorectal cancer risk synergistically informs multi-pronged therapeutic strategies.
However, some limitations should be acknowledged. The predominantly European ancestry subjects may constrain generalizability of findings [33]. The finite set of assessed metabolites and immune traits provides an incomplete picture lacking additional layers of omics data. Experimental validation in model systems is imperative to confirm functional effects of prioritized candidates on colorectal cancer phenotypes. Nonetheless, our approach integrating large GWAS datasets overcomes biases in observational studies to reveal causal factors contributing to colorectal cancer.
In summary, this two-sample Mendelian randomization study elucidates metabolic and immunologic pathways causally linked to colorectal cancer risk. Our findings nominate novel biomarkers for risk stratification and highlight potential therapeutic targets. This work exemplifies the power of emerging genetic techniques to unravel causal mechanisms relevant to cancer. Continued mapping of complex molecular networks through integrative strategies promises to inform development of next-generation diagnostics, preventives, and precision therapies to improve colorectal cancer outcomes.