Abstract
Introduction: Neuroendocrine tumors (NETs) are a heterogeneous group of epithelial tumors originating from different anatomical sites, and identifying the gut microbiota and metabolic mechanisms involved in the onset of NETs may help to develop appropriate disease prevention and monitoring strategies. Methods: We employed a mediated two-sample Mendelian randomization (MR) approach, analyzing gut microbiota from German studies and NET datasets from the 10th round of the FinnGen project. Mediation analyses were conducted using the metabolites dataset from the Canadian Longitudinal Study of Aging (CLSA) and the TwinsUK study. Instrumental variables were chosen according to established MR criteria and analyzed using the Wald ratio, inverse-variance weighted (IVW), MR-Egger, and weighted median methods. To ensure robustness, sensitivity analyses were performed using Cochrane’s Q, Egger’s intercept, MR-PRESSO, and leave-one-out methods. Results: Causal relationships were identified between the genetic determinants of 6, 5, 2, 1, 2, 3 gut microbiotas and the risk of colorectal, lung, pancreatic, rectum, small intestine, and stomach NETs. Similarly, the genetic determinants of 4, 6, 1, 5, 10, and 7 metabolites were found to be causally related to the risk of colorectal, lung, pancreatic, rectum, small intestine, and stomach NETs, respectively. Through Wald ratio and IVW methods, we preliminarily identified 957 microbiota-metabolite pairs with significant causal associations and formed 13 mediated relationships between the impact of gut microbiotas on NETs. Conclusion: Our study suggests that gut microbiotas and its derived metabolites may contribute to the onset of NET, offering a novel insight into the disease’s pathogenesis.
Plain Language Summary
Neuroendocrine tumors (NETs) are a rare type of cancer that can develop in different parts of the body, including the intestines, lungs, and pancreas. These tumors are often hard to detect early because they may not cause noticeable symptoms until they have spread to other parts of the body. This study aimed to better understand how certain bacteria in the gut, known as the gut microbiota, and the substances they produce, called metabolites, might influence the development of NETs. To investigate this, we used a method called Mendelian randomization, which helps to identify cause-and-effect relationships by analyzing genetic data. We looked at genetic information from large groups of people to see if there is a link between specific gut bacteria and the risk of developing NETs. We also explored whether certain metabolites produced by these bacteria might play a role in this process. Our findings suggest that some types of gut bacteria and their metabolites may either increase or decrease the risk of NETs, depending on the specific bacteria and metabolites involved. For example, some bacteria were found to protect against certain types of NETs, while others were linked to a higher risk. This research provides new insights into how gut bacteria and their products might contribute to the development of NETs and highlights potential areas for future studies aimed at preventing or treating these tumors.
