Circulating Gut Microbe-Derived Metabolites Are Associated with Hepatocellular Carcinoma
Rakhee Banerjee,
Chase J. Wehrle,
Zeneng Wang,
Jennifer D. Wilcox,
Vinayak Uppin,
Venkateshwari Varadharajan,
Marko Mrdjen,
Courtney Hershberger,
Ofer Reizes,
Jennifer S. Yu,
Justin D. Lathia,
Daniel M. Rotroff,
Stanley L. Hazen,
W. H. Wilson Tang,
Federico Aucejo,
J. Mark Brown
Affiliations
Rakhee Banerjee
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Chase J. Wehrle
Department of Hepato-Pancreato-Biliary and Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Zeneng Wang
Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
Jennifer D. Wilcox
Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Vinayak Uppin
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Venkateshwari Varadharajan
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Marko Mrdjen
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Courtney Hershberger
Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Ofer Reizes
Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
Jennifer S. Yu
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Justin D. Lathia
Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
Daniel M. Rotroff
Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Stanley L. Hazen
Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
W. H. Wilson Tang
Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
Federico Aucejo
Department of Hepato-Pancreato-Biliary and Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, OH 44195, USA
J. Mark Brown
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. The gut microbiome has been implicated in outcomes for HCC, and gut microbe-derived products may serve as potential non-invasive indices for early HCC detection. This study evaluated differences in plasma concentrations of gut microbiota-derived metabolites. Methods: Forty-one patients with HCC and 96 healthy controls were enrolled from surgical clinics at the Cleveland Clinic from 2016 to 2020. Gut microbiota-derived circulating metabolites detectable in plasma were compared between patients with HCC and healthy controls. Hierarchical clustering was performed for generating heatmaps based on circulating metabolite concentrations using ClustVis, with Euclidean and Ward settings and significant differences between metabolite concentrations were tested using a binary logistic regression model. Results: In patients with HCC, 25 (61%) had histologically confirmed cirrhosis. Trimethylamine (TMA)-related metabolites were found at higher concentrations in those with HCC, including choline (p p p = 0.007), TMA (p p p p = 0.038), 5-hydroxyindoleacetic acid (p p p p = 0.42). Conclusions: Gut microbiota-derived metabolites were differentially abundant in patients with HCC versus healthy controls. The observed perturbations of the TMAO pathway in HCC seem particularly promising as a target of future research and may have both diagnostic and therapeutic implications.
