Editorial: direct anti-viral agents, hepatitis C virus eradication, and gut-liver axis—another mechanistic piece to the puzzle

Patients with cirrhosis, regardless of the aetiology, develop significant changes in the composition of gut microbiome (dysbiosis), with an abundance of harmful bacteria of the Enterobacteriaceae family with a decrease in beneficial bacteria of the Clostridiales XIV and Ruminococcaceae families.1, 2 Gut microbial dysbiosis is not only associated with progression of liver damage in early stage liver disease but has also been linked to the complications of cirrhosis.3

Progress in hepatitis C virus (HCV) treatment has led to the emergence of interferon-free combinations of oral direct-acting anti-virals (DAA). These have revolutionised the treatment of HCV infection, with excellent safety and high cure rates. Studies have also demonstrated that DAA treatment is associated with a decrease in liver fibrosis and stiffness.4, 5 However, effect of DAAs on gut microbial dysbiosis and systemic inflammation remains unclear.

The recent study by Ponziani et al addresses the impact of treatment of HCV infection with DAA on the gut microbiome, changes in inflammatory markers, and their correlation to parameters of liver fibrosis.6 To our knowledge, this is the first study demonstrating significant improvement in gut microbial dysbiosis after successful eradication of HCV infection among patients with cirrhosis. This beneficial effect was not associated with improvement in the intestinal inflammation and permeability. A prior study suggested that gut microbial dysbiosis with associated inflammation and endotoxaemia persists in patients with HCV despite achieving sustained virologic response with interferon and ribavirin.7

Some interesting issues can be highlighted from the present study. Based on the strict exclusion criteria, patients with most common comorbid conditions, past or present history of excessive alcohol consumption, and those taking microbiota-altering medicines including probiotics, antibiotics, and proton pump inhibitors were excluded.8 Hence, it might be difficult to generalise the results to real world and routine practice. Additionally, patients included in the current study had well-compensated cirrhosis, raising an important question as to whether there will be any similar change in the gut microbiome in patients with decompensated cirrhosis. It also remains to be seen whether this effect of DAA on the gut microbiome is an indirect effect of improved inflammation and fibrosis or a direct effect of the DAA on the gut microbiome. It will also be interesting to see whether these changes in gut microbiome are in any way associated with the perceived increased risk of hepatocellular carcinoma after exposure to DAA among patients with HCV-related cirrhosis.9 A prior study showed improved gut microbial dysbiosis and a decrease in inflammatory markers with Lactobacillus GG in patients with compensated cirrhosis from any aetiology.10 It could be interesting to see that a combined approach with probiotic-based therapy and DAAs could potentially be synergistic to exert further beneficial effect on the microbiome.

Although limited by small sample size, lack of metabolomics profile, and short follow-up, the results of this study are encouraging and compelling to design further studies for in depth understanding of this association of DAAs with the gut-liver axis and to examine the durability of such beneficial effects. Additionally, possible implications for the use of probiotics with DAAs might be the future to change the natural history of cirrhosis progression.

FUNDING INFORMATION

None.