Yaoxian Xiang, Chan Zhang, Jing Wang, Yurong Cheng, Kangjie Wang, Li Wang, Yingying Tong, Dong Yan
{"title":"血液代谢物在调解肠道微生物组对突变-RAS/BRAF 转移性结直肠癌特异性生存的影响中的作用","authors":"Yaoxian Xiang, Chan Zhang, Jing Wang, Yurong Cheng, Kangjie Wang, Li Wang, Yingying Tong, Dong Yan","doi":"10.1007/s00384-024-04686-9","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Recent studies have linked alterations in the gut microbiome and metabolic disruptions to the invasive behavior and metastasis of colorectal cancer (CRC), thus affecting patient prognosis. However, the specific relationship among gut microbiome, metabolite profiles, and mutated-RAS/BRAF metastatic colorectal cancer (M-mCRC) remains unclear. Furthermore, the potential mechanisms and prognostic implications of metabolic changes induced by gut microbiome alterations in patients with M-mCRC still need to be better understood.</p><p><strong>Methods: </strong>We conducted Mendelian randomization (MR) to evaluate the causal relationship of genetically predicted 196 gut microbiome features and 1400 plasma metabolites/metabolite ratios on M-mCRC-specific survival. Additionally, we identified significant gut microbiome-metabolites/metabolite ratio associations based on M-mCRC. Metabolite information was annotated, and functional annotation and pathway enrichment analyses were performed on shared proteins corresponding to significant metabolite ratios, aiming to reveal potential mechanisms by which gut microbiome influences M-mCRC prognosis via modulation of human metabolism.</p><p><strong>Results: </strong>We identified 11 gut microbiome features and 49 known metabolites/metabolite ratios correlated with M-mCRC-specific survival. Furthermore, we identified 17 gut microbiome-metabolite/metabolite ratio associations specific to M-mCRC, involving eight lipid metabolites and three bilirubin degradation products. The shared proteins corresponding to significant metabolite ratios were predominantly localized within the integral component of the membrane and exhibited enzymatic activities such as glucuronosyltransferase and UDP-glucuronosyltransferase, crucial in processes such as glucuronidation, bile secretion, and lipid metabolism. Moreover, these proteins were significantly enriched in pathways related to ascorbate and aldarate metabolism, pentose and glucuronate interconversions, steroid hormone biosynthesis, and bile secretion.</p><p><strong>Conclusion: </strong>Our study offers novel insights into the potential mechanisms underlying the impact of the gut microbiome on the prognosis of M-mCRC. These findings serve as a meaningful reference for exploring potential therapeutic targets and strategies in the future.</p>","PeriodicalId":13789,"journal":{"name":"International Journal of Colorectal Disease","volume":"39 1","pages":"116"},"PeriodicalIF":2.5000,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11269474/pdf/","citationCount":"0","resultStr":"{\"title\":\"Role of blood metabolites in mediating the effect of gut microbiome on the mutated-RAS/BRAF metastatic colorectal cancer-specific survival.\",\"authors\":\"Yaoxian Xiang, Chan Zhang, Jing Wang, Yurong Cheng, Kangjie Wang, Li Wang, Yingying Tong, Dong Yan\",\"doi\":\"10.1007/s00384-024-04686-9\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Recent studies have linked alterations in the gut microbiome and metabolic disruptions to the invasive behavior and metastasis of colorectal cancer (CRC), thus affecting patient prognosis. However, the specific relationship among gut microbiome, metabolite profiles, and mutated-RAS/BRAF metastatic colorectal cancer (M-mCRC) remains unclear. Furthermore, the potential mechanisms and prognostic implications of metabolic changes induced by gut microbiome alterations in patients with M-mCRC still need to be better understood.</p><p><strong>Methods: </strong>We conducted Mendelian randomization (MR) to evaluate the causal relationship of genetically predicted 196 gut microbiome features and 1400 plasma metabolites/metabolite ratios on M-mCRC-specific survival. Additionally, we identified significant gut microbiome-metabolites/metabolite ratio associations based on M-mCRC. Metabolite information was annotated, and functional annotation and pathway enrichment analyses were performed on shared proteins corresponding to significant metabolite ratios, aiming to reveal potential mechanisms by which gut microbiome influences M-mCRC prognosis via modulation of human metabolism.</p><p><strong>Results: </strong>We identified 11 gut microbiome features and 49 known metabolites/metabolite ratios correlated with M-mCRC-specific survival. Furthermore, we identified 17 gut microbiome-metabolite/metabolite ratio associations specific to M-mCRC, involving eight lipid metabolites and three bilirubin degradation products. The shared proteins corresponding to significant metabolite ratios were predominantly localized within the integral component of the membrane and exhibited enzymatic activities such as glucuronosyltransferase and UDP-glucuronosyltransferase, crucial in processes such as glucuronidation, bile secretion, and lipid metabolism. Moreover, these proteins were significantly enriched in pathways related to ascorbate and aldarate metabolism, pentose and glucuronate interconversions, steroid hormone biosynthesis, and bile secretion.</p><p><strong>Conclusion: </strong>Our study offers novel insights into the potential mechanisms underlying the impact of the gut microbiome on the prognosis of M-mCRC. These findings serve as a meaningful reference for exploring potential therapeutic targets and strategies in the future.</p>\",\"PeriodicalId\":13789,\"journal\":{\"name\":\"International Journal of Colorectal Disease\",\"volume\":\"39 1\",\"pages\":\"116\"},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2024-07-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11269474/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International Journal of Colorectal Disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00384-024-04686-9\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Colorectal Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00384-024-04686-9","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
Role of blood metabolites in mediating the effect of gut microbiome on the mutated-RAS/BRAF metastatic colorectal cancer-specific survival.
Background: Recent studies have linked alterations in the gut microbiome and metabolic disruptions to the invasive behavior and metastasis of colorectal cancer (CRC), thus affecting patient prognosis. However, the specific relationship among gut microbiome, metabolite profiles, and mutated-RAS/BRAF metastatic colorectal cancer (M-mCRC) remains unclear. Furthermore, the potential mechanisms and prognostic implications of metabolic changes induced by gut microbiome alterations in patients with M-mCRC still need to be better understood.
Methods: We conducted Mendelian randomization (MR) to evaluate the causal relationship of genetically predicted 196 gut microbiome features and 1400 plasma metabolites/metabolite ratios on M-mCRC-specific survival. Additionally, we identified significant gut microbiome-metabolites/metabolite ratio associations based on M-mCRC. Metabolite information was annotated, and functional annotation and pathway enrichment analyses were performed on shared proteins corresponding to significant metabolite ratios, aiming to reveal potential mechanisms by which gut microbiome influences M-mCRC prognosis via modulation of human metabolism.
Results: We identified 11 gut microbiome features and 49 known metabolites/metabolite ratios correlated with M-mCRC-specific survival. Furthermore, we identified 17 gut microbiome-metabolite/metabolite ratio associations specific to M-mCRC, involving eight lipid metabolites and three bilirubin degradation products. The shared proteins corresponding to significant metabolite ratios were predominantly localized within the integral component of the membrane and exhibited enzymatic activities such as glucuronosyltransferase and UDP-glucuronosyltransferase, crucial in processes such as glucuronidation, bile secretion, and lipid metabolism. Moreover, these proteins were significantly enriched in pathways related to ascorbate and aldarate metabolism, pentose and glucuronate interconversions, steroid hormone biosynthesis, and bile secretion.
Conclusion: Our study offers novel insights into the potential mechanisms underlying the impact of the gut microbiome on the prognosis of M-mCRC. These findings serve as a meaningful reference for exploring potential therapeutic targets and strategies in the future.
期刊介绍:
The International Journal of Colorectal Disease, Clinical and Molecular Gastroenterology and Surgery aims to publish novel and state-of-the-art papers which deal with the physiology and pathophysiology of diseases involving the entire gastrointestinal tract. In addition to original research articles, the following categories will be included: reviews (usually commissioned but may also be submitted), case reports, letters to the editor, and protocols on clinical studies.
The journal offers its readers an interdisciplinary forum for clinical science and molecular research related to gastrointestinal disease.