Role of gut microbiota-derived metabolites in liver carcinogenesis: a correspondence

Dear Editor, I read with great interest the comprehensive review by Yan et al. entitled “The landscape of gut microbiota in hepatocarcinogenesis: a comprehensive review of pathogenesis and therapeutic interventions”[1]. The authors provide a valuable synthesis of the rapidly evolving field of gut–liver axis research in hepatocellular carcinoma (HCC), highlighting mechanisms such as metabolic reprogramming, immune microenvironment remodeling, and the potential of microbiota-targeted therapies (e.g. probiotics, fecal microbiota transplantation). However, while the review thoroughly discusses broader metabolite-mediated effects, I believe that incorporating recent findings on specific gut microbiota-derived metabolites would significantly enhance its impact. For instance, the review could be strengthened by including large-scale epidemiological evidence linking specific bile acid (BA) species to HCC risk. Watling et al[2] conducted a nested case-control analysis of 12 prospective cohorts, demonstrating that pre-diagnostic concentrations of primary conjugated BAs (e.g. glycocholic acid) are significantly and specifically associated with an increased risk of HCC, but not with intrahepatic cholangiocarcinoma. This robust evidence underscores that gut microbiota-derived metabolites like BAs are not mere bystanders but active players in hepatocarcinogenesis, providing concrete biomarkers for risk stratification. Additionally, the review could delve deeper into trimethylamine N-oxide (TMAO), a key microbiota-derived metabolite. Zhou et al[3] demonstrated that TMAO promotes HCC cells proliferation and migration through MAPK pathway activation in vitro and in vivo, offering mechanistic insights into metabolite-driven oncogenesis. Banerjee et al[4] further reported elevated circulating TMAO levels in HCC patients compared to healthy controls, highlighting its potential as a non-invasive diagnostic biomarker. A parallel review by Saha et al[5] links TMAO to cancer risk via inflammation and oxidative stress, aligning with the broader themes discussed in Yan et al[1]. Integrating this evidence would further solidify the review’s central thesis on metabolite-driven pathways. Looking ahead, exploring TMAO-lowering strategies, such as dietary modifications or targeted inhibitors, could present a promising adjunct to microbiota-focused therapies. In conclusion, Yan et al[1] provided an invaluable resource that significantly advances our understanding of the gut–liver axis in HCC. By incorporating these recent advances on specific pathogenic metabolites like certain BAs and TMAO, a future update could offer an even more comprehensive and powerful perspective on the molecular mechanisms linking the gut microbiome to HCC, ultimately providing promising avenues for HCC prevention and treatment.