Editor’s note: The gut microbiota is one of the most complex microbial communities in the human body and plays a crucial role in both health and disease development. Recently, at the 10th Beijing Liver Disease Annual Meeting in 2024, Dr. Yinying Lu from the Fifth Medical Center of the Chinese PLA General Hospital delivered an insightful report titled "Gut Microecology and Hepatobiliary Tumors," highlighting the close link between gut microecology and hepatobiliary tumors. She analyzed the potential of gut microbiota in the early diagnosis of hepatobiliary tumors and its mechanisms influencing the effectiveness of immunotherapy.1. The Close Relationship Between Gut Microecology and Tumor Occurrence
The gut microbiota is closely related to human health and the occurrence of diseases. A balanced gut microecology helps maintain the body’s metabolism and nutritional state, while gut dysbiosis is associated with various diseases. When the gut microbial community changes, with protective bacteria decreasing or pathogenic bacteria becoming dominant, gut microbial imbalance can occur, leading to various diseases. Current research has confirmed that common gut microbes (such as Helicobacter pylori, Escherichia coli, Fusobacterium nucleatum, and Bacteroides fragilis) promote tumor occurrence by altering the gut immune environment, increasing DNA damage and chromosomal instability, and triggering oxidative stress and inflammation through bacterial antigens, toxin release, and metabolite production.
2. The Role of Gut Microecology in Hepatobiliary Tumor Development
Mechanism of Gut Microecology in Liver Cancer Development
In liver cancer, the mechanism of gut microecology involves gut dysbiosis and the phenomenon of “leaky gut.” Dysbiotic gut microbes release metabolites like bile acids, inhibiting antitumor immune responses and activating anti-apoptotic signals, thus promoting tumor development. Damage to the intestinal barrier increases the liver’s exposure to microbial-associated molecular patterns (MAMPs), which can activate hepatic macrophages and trigger inflammation that promotes tumor progression, directly or indirectly affecting hepatic stellate cells and leading to fibrosis, which may further drive liver cancer development.
Gut Microbiota Reshapes Liver Inflammatory Microenvironment, Promoting Liver Cancer Development
One study found that in NEMOΔhepa-induced fatty liver disease mice, NLRP6-dependent gut dysbiosis, characterized by gut barrier disruption and the absence of specific bacteria, was associated with inflammation progression and increased tumor burden. This promoted the progression of fatty liver disease to hepatocellular carcinoma (HCC) by inducing an immunosuppressive phenotype in the liver and altering the hepatic inflammatory microenvironment.
Additionally, research from Dr. Yinying Lu’s team revealed that abnormal colonization of Candida albicans in the gut not only altered plasma metabolic profiles and signaling pathways but also promoted HCC progression through NLRP6 upregulation and metabolic reprogramming. Excessive growth of intestinal fungi exacerbated liver inflammation via metabolic pathways, further emphasizing the complex role of gut microbial communities—both bacterial and fungal—in liver disease development.
3. The Application of Gut Microbiota in Diagnosing Hepatobiliary Tumors
Most HCC patients are still diagnosed at an advanced stage, and non-invasive early diagnosis remains a challenge. Studies have reported distinct gut microbiota profiles in HCC patients, identifying 30 optimal microbial markers that were used to build a diagnostic model, validated across regional cohorts. The results demonstrated that gut microbiota-targeted biomarkers could serve as potential non-invasive tools for early HCC diagnosis.
Similarly, in another study led by Dr. Lu’s team, researchers explored the relationship between gut microbiota, bile acid metabolism, and cytokines in an intrahepatic cholangiocarcinoma (ICC) cohort using microbiomics and metabolomics. They confirmed the diagnostic value of specific gut bacteria combined with secondary bile acids for ICC, along with the predictive power of plasma inflammatory factors for vascular invasion. This study highlighted the immense potential of gut microbiota in the early diagnosis of hepatobiliary tumors.
4. The Role of Gut Microecology in Treating Hepatobiliary Tumors
Gut Microbiota’s Influence on Tumor Immunotherapy
Among advanced HCC patients receiving immunotherapy, only 10% to 30% achieve complete remission (CR) or partial remission (PR). As previously mentioned, the gut microbiota can regulate the tumor immune microenvironment. Microbes and their metabolites enter the bloodstream through a damaged gut barrier, activating immune responses as pathogen-associated molecular patterns (PAMPs). They also release immunomodulatory metabolites such as inosine, bile acids, and short-chain fatty acids. Additionally, cross-reactivity between microbial epitope-specific T cells and tumor antigen-specific T cells promotes tumor-specific immune responses. In summary, gut microbes and their metabolites can modulate immune responses in liver cancer, influencing the efficacy of immunotherapy.
Recent research suggests that the gut microbiota can also predict the efficacy of PD-1 antibody therapy in advanced hepatobiliary tumors. Researchers analyzed fecal samples from patients with hepatobiliary malignancies treated with anti-PD-1 monoclonal antibodies, revealing a relationship between microbial diversity and abundance with clinical response and adverse reactions. This confirmed the feasibility of using gut microbiota as a biomarker for liver cancer immunotherapy and provided new targets for modulating therapy responses and side effects.
Similar findings were observed in a biliary tract cancer (BTC) immunotherapy cohort. Specific gut bacteria and metabolites in the group with long-term clinical benefit (DCB) were closely associated with the survival rate of BTC patients undergoing immunotherapy. A combined prediction model comprising three bacteria and two metabolites effectively distinguished DCB patients, emphasizing the potential of gut microbes and metabolites as prognostic and predictive markers for PD-1/PD-L1 immunotherapy outcomes in BTC.
In studies on how gut microbes influence liver cancer immunotherapy mechanisms, Dr. Lu’s team analyzed an advanced liver cancer immunotherapy cohort, dividing participants into responders and non-responders based on their response to PD-1 therapy. Multi-omics analysis revealed significant differences in the gut microbiome and metabolome between the two groups, with Bacteroides identified as a significant differentiating bacterium associated with therapy response through bile acid metabolism pathways.
Additionally, a study published in Cell this year proposed using 12-month survival to assess immunotherapy efficacy, creating a scoring model based on gut microbiota topology to predict treatment outcomes for lung and renal cancers. Dr. Lu’s team validated this model in a cohort of 200 liver cancer patients, demonstrating significant predictive value (P=0.02). However, the model’s complexity, due to its inclusion of numerous feature vectors, may lead to overfitting in pan-cancer immunotherapy cohorts, and the inclusion of too many factors increases computational cost and model complexity. The team further streamlined the model by identifying key feature vectors, reducing dimensionality, and improving its interpretability and applicability, with enhanced predictive performance in the HCC cohort (P<0.001).
5. Summary and Outlook
The close connection between the gut and liver provides numerous opportunities for microbiome-based diagnosis, treatment, or prevention in hepatobiliary tumor patients. However, several challenges remain, such as most studies on hepatobiliary tumors and gut microecology being limited to animal models, small clinical sample sizes, and a lack of high-quality clinical cohort validation. Future research should expand clinical studies through large-scale, longitudinal cohort studies with paired multi-dimensional biobanks, leveraging innovative algorithms and technologies to enable deeper clinical insight from multi-omics data. Ultimately, this will enable the development of novel microbiome-based biomarkers to improve early diagnosis and prognosis assessment of hepatobiliary tumors.
