Gut microbiota shifts in hepatitis B-related portal hypertension after transjugular intrahepatic portosystemic shunt: Mechanistic and clinical implications

Abstract

In this article, we provide commentary on the recent article by Zhao et al. We focus on the shifts in the gut microbiota of patients with hepatitis B virus (HBV)-associated cirrhosis/portal hypertension (PH) following transjugular intrahepatic portosystemic shunt (TIPS) and the implications for understanding the mechanisms, diagnosis, and treatment. By comparing the gut microbiota composition and dynamic changes before and after TIPS in patients with and without hepatic encephalopathy, the authors found an increase in non-probiotic bacteria in those who developed hepatic encephalopathy post-TIPS, with Morganella species present only in the hepatic encephalopathy group. The gut microbiota changes post-TIPS among patients without the occurrence of hepatic encephalopathy suggest potential therapeutic benefits through prophylactic microbiome therapies. Furthermore, the specific gut microbiota alterations may hold promise to predict the risk of hepatic encephalopathy in individuals undergoing TIPS for HBV-related PH. Despite these promising findings, future studies are needed to address limitations, including a small sample size, a relatively short evaluation period for gut microbiota alterations, the absence of data on dynamic alterations in gut microbiota post-TIPS and their correlation with blood ammonia levels, and the lack of validation in animal models. In conclusion, Zhao et al's study has shed new light on the link of gut microbiota with post-TIPS hepatic encephalopathy, potentially through the intricate gut-liver axis, and has important clinical implications for improving the management of patients with HBV-related PH.

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

Core Tip: Shifts in gut microbiome composition are closely related to hepatic encephalopathy, yet there is limited research on changes before and after transjugular intrahepatic portosystemic shunt (TIPS) in hepatitis B virus-related portal hypertension patients. The findings by Zhao et al highlight the potential involvement of the bacterial genus Morganella in post-TIPS hepatic encephalopathy. Meanwhile, they also emphasize the importance of the elevation of probiotics in post-TIPS patients without hepatic encephalopathy. Future studies with a larger sample size and a longer evaluation period are needed to address dynamic gut microbiota changes post-TIPS, their correlation with blood ammonia levels, and clinical outcomes.

TO THE EDITOR

Chronic hepatitis B virus (HBV) infection presents a significant global health challenge, affecting over 250 million individuals worldwide[1,2]. Patients with chronic HBV are at a persistently high risk of developing severe liver conditions, including cirrhosis and hepatocellular carcinoma[1]. As the major consequence of cirrhosis[3], portal hypertension (PH) is associated with increased mortality rates in patients with cirrhosis. Additionally, variceal hemorrhage is often a sequela of PH[4]. The transjugular intrahepatic portosystemic shunt (TIPS) procedure is currently recognized as the most effective treatment for PH and is recommended in the treatment guidelines for liver disease[5]. Nevertheless, hepatic encephalopathy may occur as a serious complication in patients with HBV-related PH receiving TIPS placement. Indeed, the onset or worsening of hepatic encephalopathy is documented in 30% to 50% of patients with cirrhosis undergoing TIPS[6]. TIPS placement diverts blood flow, bypassing the natural detoxification process of the liver and increasing the likelihood of elevated ammonia levels in patients treated with TIPS. Although the subsequent rise in blood ammonia levels may induce neurotoxic effects and neural dysfunction, which is considered a key factor contributing to hepatic encephalopathy, the mechanisms underlying the pathogenesis of hepatic encephalopathy in this context remain incompletely understood.

Compositional and functional alterations in gut microbiota, known as gut dysbiosis, have been associated with a wide spectrum of human diseases[7,8]. This dysbiosis can lead to changes in gut microbiota-related molecules (i.e., ammonia) and enhance gut permeability, facilitating translocation of products into the liver and exacerbating hepatic damage[7,8]. The presence of gut dysbiosis has been well-established in patients with cirrhosis, particularly those in advanced stages of the disease[9-11]. The gut microbiota composition varies depending on the underlying etiology of cirrhosis[12]. Recent studies have demonstrated the role of the gut microbiome in influencing the outcomes of chronic HBV infection[13,14]. Patients with chronic hepatitis B and HBV-related cirrhosis exhibit a reduced ratio of Bifidobacteriaceae to Enterobacteriaceae (B/E)[15]. Post-TIPS decompression of PH alleviates intestinal mucosal edema. Currently, little research has been conducted on gut microbiome alterations in patients with HBV-related PH following TIPS placement.

Gut microbiota shifts post-TIPS in patients with HBV-related PH and mechanistic and clinical implications

In the latest issue of the World Journal of Gastroenterology, Zhao et al[16] published the interesting article: Alterations in the gut microbiome after transjugular intrahepatic portosystemic shunt in patients with hepatitis B virus-related portal hypertension. In this prospective observational study, the authors examined the alterations in gut microbiota composition following the placement of TIPS in a cohort of 30 patients with HBV-related PH. The study further stratified the patients into two groups based on the occurrence of hepatic encephalopathy, with 8 patients developing hepatic encephalopathy and 22 patients not experiencing this condition one month after treatment with TIPS. The authors identified significant alterations in the gut microbiome post-TIPS. Notably, there was an increase in the abundance of beneficial bacteria such as Dialister, Coprococcus, and Ruminococcaceae, which are associated with improved gut health. Conversely, harmful bacteria like Granulicatella showed a significant reduction. In the hepatic encephalopathy group, the abundance of Haemophilus and Eggerthella increased, while Anaerostipes, Dialister, Butyricicoccus, and Oscillospira showed a decrease one month after the placement of TIPS. Furthermore, members of the pathogenic genus Morganella were present in the hepatic encephalopathy group but not in the non-hepatic encephalopathy group after TIPS placement.

While this study is still in its infancy and future studies are necessary due to the following apparent limitations, including but not limited to a small sample size, a relatively short evaluation period for gut microbiota alterations, the absence of data on the dynamic alterations in gut microbiota following TIPS and their correlation with blood ammonia levels, the lack of validation of the identified gut microbiota in animal models, and the need for further research to establish causal relationships between microbiota alterations and clinical outcomes.

Despite the limitations, the findings have important potential implications for understanding mechanisms and management of patients with HBV-related cirrhosis and PH undergoing TIPS procedure. Firstly, the accumulation of blood ammonia is considered a crucial factor in the onset of hepatic encephalopathy, with ammonia being a byproduct of urease-producing bacteria in the gut converting urea to ammonia. In this study, the authors demonstrated that the bacterial genus Morganella, known for its high urease production[17], was detected in patients who developed hepatic encephalopathy one month after treatment with TIPS, but not in patients without this condition. This novel finding suggests a potential link of the bacterial genus Morganella with an increased risk of developing hepatic encephalopathy in patients treated with TIPS. Further studies are required to establish its involvement in the mechanism underlying the development of hepatic encephalopathy in patients with HBV-related cirrhosis and PH undergoing TIPS procedure through conducting studies in animal models. Secondly, the changes in gut microbiota post-TIPS in the non-hepatic encephalopathy group suggest a potential therapeutic benefit of TIPS in modulating gut microbiota and improving liver health. Prophylactic microbiome therapies, such as the utilization of probiotics, prebiotics, synbiotics, antibiotics, fecal microbiota transplantation, or dietary modifications[18], could aid in mitigating the risk of hepatic encephalopathy by modulating the identified changes in the composition of the gut microbiota as identified in this study. Thirdly, it has been demonstrated that the use of rifaximin prior to TIPS placement diminishes the incidence of hepatic encephalopathy, suggesting that regardless of the etiology of cirrhosis, a general practice prophylaxis with rifaximin before TIPS placement should be implemented[19]. It is worthwhile to investigate if rifaximin, in combination with modulating the gut microbiota using prophylactic microbiome therapies, could provide additional benefits in reducing the risk of and preventing hepatic encephalopathy. Fourthly, the specific alterations in the gut microbiota may hold promise to predict the risk of hepatic encephalopathy in individuals undergoing TIPS for HBV-related PH.

CONCLUSION

In conclusion, this study by Zhao et al[16] has shed light on the link of gut microbiota shifts with post-TIPS hepatic encephalopathy in patients with HBV-related PH and on the interplay between the gut microbiota and liver diseases through the intricate gut-liver axis, particularly in the context of chronic HBV infection. Understanding the mechanistic underpinnings of these shifts is crucial for a better understanding of the pathophysiology of hepatic encephalopathy, identifying new therapeutic approaches, and pinpointing specific microbial changes with predictive value, ultimately improving patient outcomes.