From June 5-8, 2024, the European Association for the Study of the Liver (EASL) Annual Meeting was held in Milan, Italy. This event brought together over 7,000 liver disease specialists from around the world. On the third day of the conference, "Hepatology Digest" invited Dr. Wenyi Gu, a protégé of Professors Jonel Trebicka from University Hospital Münster and Hai Li from Renji Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, to share her insights on two exciting studies presented at this year's Milan EASL conference and her takeaways from the event.Interview with Dr. Wenyi Gu
Hepatology Digest: This year’s EASL conference has been very exciting. Could you share the research findings you reported at the conference?
Dr. Wenyi Gu: We presented two studies at this year’s EASL conference. Let me introduce them one by one.
Study 1: Temporal Dynamics of the Human Microbiome in Different Body Sites and Stages of Decompensated Cirrhosis
This study delved into the distribution changes of the human microbiome across various body sites, with a particular focus on their dynamic evolution in patients with decompensated cirrhosis, including stable decompensated cirrhosis (SDC), unstable decompensated cirrhosis (UDC), pre-acute-on-chronic liver failure (pre-ACLF), and acute-on-chronic liver failure (ACLF).
Decompensated cirrhosis is the end stage of liver disease, mainly induced by chronic heavy drinking and viral infections. Patients may experience relatively stable conditions or progress to acute decompensation, leading to the most severe state, ACLF, where survival rates plummet. Often, these rapid changes are triggered by bacterial infections or severe alcoholic hepatitis. Surprisingly, more than half of the cases lack clear precipitating factors, which is why we focused on the role of the microbiome and “bacterial translocation”—where bacteria migrate to places they shouldn’t be, often due to “gut leakage.”
We aimed to understand how the microbiome changes in different body parts and its correlation with clinical complications in decompensated cirrhosis. By analyzing samples from various body sites over time, we hoped to uncover new insights that could pave the way for novel treatment or prevention strategies.
From the MUCOSA-PREDICT cohort, we selected 93 patients with valid mucosal samples from the larger PREDICT cohort, which includes about 1,300 patients studying cirrhosis and ACLF progression. We collected multiple samples, including blood, saliva, and feces, dynamically from each patient. Through endoscopy, we obtained mucosal samples from the upper and lower gastrointestinal tracts, totaling 11 different sampling points per patient, categorized into groups based on disease progression (SDC, UDC, pre-ACLF, and ACLF at admission). Using 16S rRNA sequencing, we examined the microbial composition and its relationship with clinical events.
Our findings revealed several key points:
- Microbial load and alpha diversity in the blood increased with cirrhosis severity.
- Alpha and beta diversity of the microbiome were significantly affected by the sampling site, highlighting the impact of different body environments on disease progression.
- Specific microbial taxa in smaller intestines (e.g., duodenum) and blood were directly associated with clinical events.
- Dynamic analysis indicated greater variability in microbiome composition in patients progressing to ACLF, potentially linked to bacterial translocation.
These insights highlight the complex interplay between microbiome diversity and liver disease severity, suggesting that microbial translocation plays a crucial role in the progression from cirrhosis to ACLF.
Study 2: Differential Impact of Proton Pump Inhibitors, Statins, and Non-Selective Beta-Blockers on Survival in Patients with Chronic Liver Disease at Various Stages
Under the Microb-Predict framework, we analyzed data from 16 clinical cohorts worldwide, encompassing non-cirrhotic, varying severity of decompensated cirrhosis, and ACLF patients. This study aimed to understand how different treatments affect short-term and long-term health outcomes in chronic liver disease.
We focused on three commonly used medications in chronic liver disease treatment: statins, proton pump inhibitors (PPI), and non-selective beta-blockers (NSBB). Our study included 3,358 patients from 17 countries in Europe and the United States, with treatment records and categorized by disease stage. Alcohol-related liver disease was the main etiology.
Using multivariate regression and competing risk models, we discovered:
- PPI use was associated with increased long-term mortality in early-stage liver disease, particularly in stable decompensated cirrhosis and non-cirrhotic stages.
- Statin use increased mortality in SDC patients.
- NSBB use significantly reduced short-term mortality in severe liver disease stages (pre-ACLF and ACLF), improving survival.
These findings underscore the importance of considering the disease stage when selecting treatment strategies for chronic liver disease patients.
Hepatology Digest: What are the latest trends in your field that caught your attention at this year’s EASL conference?
Dr. Wenyi Gu: My mentors in Europe lead the PREDICT and MICROB-PREDICT projects, focusing on ACLF progression and disease course, including the gut-liver axis and gut microbiome translocation’s role in ACLF. The gut is increasingly recognized as a crucial factor in ACLF’s multi-organ failure, often referred to as “gut failure.”
- EMBL Peer Bork Marisa: The human gut microbiome is vital for health, classified into several enterotypes associated with various health and disease states. Dysbiosis’ definition, causes, and consequences are not fully understood, but it typically manifests as increased beta diversity among patients, including those with liver disease. By integrating 16,772 fecal metagenomes from 129 studies, we revisited the enterotype concept and introduced an enterotype disturbance score (EDS). This score quantifies a sample’s classification strength and assesses dysbiosis levels. Liver cirrhosis patients had higher EDS than healthy individuals, with ACLF and 90-day mortality patients showing significant disturbance. EDS correlated with MELD scores and combined use improved survival prediction accuracy. We developed an online “Enterotyper” tool for predicting enterotypes and EDS in external cohorts, potentially aiding early detection of pre-ACLF.
- Lindsey Edwards KCL: Fecal microbiota transplantation (FMT) reduces antibiotic resistance and pathogen carriage while enhancing gut barrier function in cirrhosis patients. In a prospective, randomized, single-blind, placebo-controlled trial with 32 advanced stable cirrhosis patients, FMT significantly reduced gut barrier damage and altered mucosal and systemic inflammation at days 7, 30, and 90 post-intervention. FMT almost eliminated carriage of enterococci, pathogenic E. coli, and related antibiotic resistance genes. Phage networks were remodeled, with beneficial phages like Bacteroides species increasing, while those associated with pathogenic E. coli and Klebsiella decreased. Fecal proteomics showed changes in over 300 proteins related to host and microbial immune metabolism. These results support further evaluation of FMT as a potential strategy to reduce antibiotic resistance in cirrhosis.
In Europe, research is shifting from ACLF to pre-ACLF, emphasizing early identification and intervention to break the vicious cycle of ACLF progression and systemic inflammatory response. At this EASL conference, I focused on pre-ACLF-related studies, including multi-omics biomarkers and treatment impacts on patient survival, guiding future research directions.
Hepatology Digest: What are your thoughts and takeaways from attending this year’s EASL conference?
Dr. Wenyi Gu: It was an honor to present my research and learn from global peers at the EASL conference. This event provided a platform to showcase my work and absorb cutting-edge scientific developments. My oral presentation on “Temporal Dynamics of the Human Microbiome in Different Body Sites and Stages of Decompensated Cirrhosis” and poster on “Differential Impact of Proton Pump Inhibitors, Statins, and Non-Selective Beta-Blockers on Survival in Patients with Chronic Liver Disease at Various Stages” received valuable feedback and sparked engaging discussions.
Overall, the conference was an incredible opportunity to learn, be inspired, and collaborate. I am grateful to all organizers and participants, and I look forward to applying these insights to future research, hoping to hear more from domestic studies in this field.
