Insights and future directions in studying intestinal microbiota post-transjugular intrahepatic portosystemic shunt for hepatitis B virus-related portal hypertension

Abstract

The gut microbiota (GM) plays a major role in the progression and treatment response of liver diseases, with diverse compositions based on different etiologies. In China, hepatitis B virus (HBV) infection is the leading cause of cirrhosis and affects the GM composition in patients with cirrhosis-related portal hypertension (PH). However, a few studies have been conducted on GM alterations after transjugular intrahepatic portosystemic shunt (TIPS) in patients with HBV-related PH. A recent study investigated the changes in the GM in these patients after TIPS. This study found an increase in potentially pathogenic bacteria and a decrease in beneficial bacteria post-TIPS, particularly in patients with hepatic encephalopathy (HE), indicating the potential role of the GM in HE prediction and management post-TIPS. Nevertheless, the study had several limitations, including a small sample size, limited follow-up, a single time point for sample collection, and inadequate analysis of the correlation between intestinal flora, HBV infection status, and clinical parameters. Future research should address these limitations by expanding the sample size, prolonging the follow-up duration, collecting samples at multiple time points, and conducting comprehensive analyses to confirm the findings and evaluate the effectiveness of individualized microbiome-based therapies.

Key Words: Gut microbiota; Hepatitis B virus; Portal hypertension; Transjugular intrahepatic portosystemic shunt; Hepatic encephalopathy

Core Tip: Hepatitis B virus (HBV) infection promotes cirrhosis in China, causing changes in the gut microbiota (GM) in patients with portal hypertension (PH) GM linked to hepatic encephalopathy (HE). Although a transjugular intrahepatic portosystemic shunt (TIPS) is used to treat PH complications, postoperative HE persists. A recent study explored GM dynamics in patients with HBV-PH post-TIPS and found higher GM synergism in patients without HE than that in those with HE, suggesting it may predict post-TIPS HE risk. However, limitations, such as small sample size, short follow-up, single fecal sampling, and lack of comprehensive analysis of the flora-HBV clinical interplay exist. Future research should prioritize addressing these issues to validate our findings and assess personalized microbiome therapies for post-TIPS HE.

TO THE EDITOR

Hepatitis B virus (HBV) infection is the most widespread chronic viral disease worldwide and poses a formidable challenge to public health in numerous nations[1]. Nearly 30% of the world's population has serological markers indicative of current or past HBV exposure[2]. Chronic hepatitis B affects an estimated 275-316 million individuals worldwide annually, culminating in 820000 fatalities and 1.5 million fresh infections[3]. As a hepatotropic DNA virus, HBV can cause lingering infections, resulting in a myriad of liver-related complications, ranging from dysfunction to fibrosis, cirrhosis, liver failure, and even hepatocellular carcinoma[3]. The prevalence of HBV infection, marked by the presence of the hepatitis B surface antigen, exhibits notable regional variation[4]. While infant immunization programs, childhood vaccination initiatives, and antiviral interventions have contributed to a decline in incidence rates and mortality, HBV continues to persist owing to the lack of a definitive virological cures[5].

The gut microbiota (GM) plays a pivotal role in the progression and therapeutic responsiveness of liver diseases, and its composition is diverse and intricately linked to various liver disease etiologies[6]. To date, studies examining GM alterations in patients with HBV-related portal hypertension (PH) following transjugular intrahepatic portosystemic shunt (TIPS) remains scarce. Recently, Zhao et al[7] published a groundbreaking study titled " Alterations in the gut microbiome after transjugular intrahepatic portosystemic shunt in patients with hepatitis B virus-related portal hypertension" in the prestigious "World Journal of Gastroenterology". This study investigated the dynamics of GM changes in patients with HBV-related PH post-TIPS. Nevertheless, the multifaceted and multi-targeted nature of GM presents unique challenges. This article critically reviews this study from several perspective.

Study overview and discussion

HBV-related PH, which is intricately intertwined with cirrhosis, frequently results in intestinal mucosal edema, augmented intestinal permeability, microbial translocation, and alterations in the structure and function of the intestinal microecology. The GM, a pivotal player in liver disease progression and treatment outcomes, has diverse compositions that correlate with various liver disease etiologies. In the context of HBV-related PH, modifications in GM may underlie the emergence and progression of hepatic encephalopathy (HE).

This study focused on TIPS, an efficacious treatment for PH-associated complications, which is sometimes followed by HE. By comparing the GM profiles of patients with HBV-related PH before and after TIPS, the research revealed post-TIPS increases in potentially pathogenic bacteria (such as Haemophilus and Eggerthella), decreases in beneficial bacteria (such as Anaerostipes and Dialister), and the emergence of the pathogenic genus Morganella exclusively in the HE group. Conversely, in the non-HE group, the abundance of potentially pathogenic bacteria (such as Eggerthella and Streptococcus) also increased, which was accompanied by a decrease in beneficial bacteria (such as Roseburia and Ruminococcus). These findings underscore the link between GM alterations and occurrence of HE after TIPS.

Strengths and limitations

This study, grounded in the outlined research content, has several notable strengths. First, it embraces a forward-looking and observational clinical research framework, ensuring patient follow-up, and fostering high data credibility. Central to its focus is the pivotal clinical question concerning alterations in the GM in patients with HBV-related PH subsequent to TIPS. By leveraging 16S rRNA amplicon sequencing and a comprehensive array of analytical tools, including alpha diversity indices (ACE, Chao1, Shannon, and Simpson), beta diversity analysis (ANOSIM), and the Linear Discriminant Analysis effect size algorithm, this study delved into multi-faceted analyses of the GM, reinforcing the robustness of its findings. The results of this investigation revealed a compelling link between variations in GM synergy and HE risk. Specifically, patients after TIPS and without HE exhibited heightened GM synergy, suggesting its potential as a predictive biomarker for HE risk.

Nevertheless, this study has some limitations. The sample size was only 30 patients, which was relatively small and may have affected the universality and reliability of the results. Changes in the GM may be influenced by various factors, including patient age, sex, underlying diseases, and medication status. Although this study considered HBV infection as the major factor, to eliminate or reduce the influence of these factors, a larger sample size is needed to reduce the impact of related factors on GM. The follow-up time was only 11.5 ± 2.05 months, which may be insufficient to evaluate the occurrence of long-term complications and the long-term changes in the GM. Fecal samples were only collected one month after TIPS, which cannot completely assess the dynamic changes in the GM over time. This study was descriptive, without analyzing the correlation between the GM and HBV infection status, exploring the relationship between the GM and clinical parameters, or discussing the specific mechanisms behind the association. These limitations indicate that future research needs to increase the sample size, extend the follow-up time, analyze the correlation between the microbiota and HBV infection status and clinical parameters, and further explore the mechanism by which changes in the GM lead to the occurrence and development of HE by influencing the gut-liver-brain axis. For example, it provides new targets for the prevention and treatment of HE, thereby deepening our understanding of the biological importance of microbial changes in HE.

Future research directions

In light of the current study investigating GM alterations in patients with HBV-related PH after TIPS placement, several avenues for future research have emerged as promising directions to further our understanding of the intricate interplay between the gut microbiome and liver health. First, a compelling need remains to delve deeper into the mechanisms underlying the relationship between GM and the HBV immune response. Previous studies have highlighted the capacity of the GM and its metabolites to modulate the host immune response to HBV, subsequently influencing viral replication levels[8,9]. However, the specific pathways and mechanisms through which this occurs remain largely unexplored. Future investigations should aim to unravel these intricate interactions, potentially opening novel avenues for HBV treatment strategies that target the gut microbiome. Second, establishing a clear link between GM dynamics and progression of liver cirrhosis is another crucial research direction. The present study and other studies have highlighted the dominant role played by gut microbial alterations in the development of HE. Nevertheless, the broader implications of changes in the GM in cirrhosis progression remain largely unelucidated. By investigating the impact of the GM on cirrhosis progression, researchers can pave the way for novel therapeutic and management strategies aimed at mitigating liver damage and improving clinical outcomes. Precision medicine, particularly in the context of GM regulation, has immense potential for future research. As our understanding of individual microbial profiles deepens, it is becoming increasingly feasible to tailor GM modulation strategies according to specific patient needs. This may involve personalized approaches, such as fecal microbiota transplantation, tailored diets, or the use of targeted probiotics and prebiotics. Such precision-guided interventions have the potential to maximize therapeutic efficacy while minimizing adverse effects and ultimately enhancing patient care. Simultaneously, alternative medicines, such as traditional Chinese medicine, may also have an effect on improving intestinal microecology, and there is potential for application in this aspect to explore the combination of multiple medical treatments to improve the treatment effect and quality of life of patients. Finally, a comprehensive examination of the relationship between the GM composition and clinical parameters is essential for advancing personalized medicine. By identifying specific microbial signatures that correlate with disease severity, prognosis, and treatment response, researchers can refine patient stratification and develop targeted interventions. This knowledge will be instrumental in providing individualized treatment plans tailored to the unique microbial profile and clinical presentation of each patient.

Future research should focus on elucidating the mechanisms underlying the influence of the GM on the HBV immune response and liver cirrhosis progression, leveraging precision medicine principles to guide GM modulation strategies, and elucidating the intricate relationships between gut microbial composition and clinical outcomes. By addressing these key research directions, we can pave the way for more effective and personalized treatments for patients with HBV-related liver diseases.

CONCLUSION

Modulation of the GM significantly affects the progression of HBV-related PH, emphasizing the importance of thorough research. A study by Zhao et al[7] revealed that its synergy may predict post-TIPS HE risk, suggesting prophylactic microbiome therapies for prevention and treatment. Future research should verify these findings, explore their mechanisms, and utilize modern techniques, such as 16S rRNA sequencing and QIIME2 analysis to comprehend GM changes and clinical correlations, fostering novel treatments. In conclusion, in-depth GM studies have enriched theories and advanced therapies for HBV-related PH.