Gut microbiota alteration and modulation in hepatitis B virus-related fibrosis and complications: Molecular mechanisms and therapeutic inventions

Table 3 Gut microbiota-related treatment toward hepatitis B virus-related fibrosis and complications (studies in human)

Ref.	Study populations (n)	Treatment and grouping (n)	Conclusions
Antiviral therapy
Lu et al[97]	Healthy volunteers (n = 30); CHB (n = 30)	8 wk of daily ETV treatment. ETV (n = 30)	After ETV treatment, gut microbiota abundance increased markedly, blood biochemical, immunological and virological responses improved significantly
Lu et al[98]	Healthy volunteers (n = 30); CHB patients (n = 60)	8 wk of daily ETV treatment, or with additional CB. ETV (n = 30); ETV + CB (n = 30)	Additional CB fail to improve blood biochemical, immunological and virological responses, but affects the gut microbiota in the CHB patients treated with ETV
Rifaximin
Bajaj et al[104]	Decompensated LC patients with MHE (n = 20):CHB (NM)	8 wk of rifaximin 550-mg BD. Rifaximin (n = 20)	Rifaximin affected little on gut microbiota, there was just a modest decrease in Veillonellaceae and increase in Eubacteriaceae. Rifaximin significantly improved cognition and endotoxemia, it increased increase in serum saturated and unsaturated fatty acids post-rifaximin
Lutz et al[144]	Decompensated LC patients with ascites (n = 152): Viral hepatitis (n = 35)	Prophylactic antibiotic treatment before the time of paracentesis. Rifaximin (n = 27); Other systemic antibiotics (n = 17)	Prophylactic rifaximin did not reduce SBP occurrence. Prophylactic rifaximin was associated with the dominant bacteria in ascites: Escherichia coli and enterococci were dominant of patients without prophylaxis, klebsiella species were mostly recovered from the rifaximin group
Kimer et al[102]	Decompensated LC patients (n = 54): CHB (NM)	4 wk of rifaximin 550-mg BD or placebo BD. Rifaximin (n = 36); Placebo (n = 18)	Rifaximin had minor effects on bacteria translocation and gut microbiota. Rifaximin showed little impact on the inflammatory state (reflected as the level of TNF-α, IL-6, IL-10, IL-18, SDF-1α, TGF-1β, CRP)
Kaji et al[103]	Decompensated LC patients (n = 30): CHB (n = 4)	4 wk of rifaximin 1200 mg/d. Rifaximin (n = 30)	Rifaximin alleviated HE and endotoxemia with improved intestinal hyperpermeability, and it is involved in a gut microbial change. Rifaximin didn’t affect serum proinflammatory cytokine levels (TNF-α, IL-6, IFN-γ, IL-10)
Probiotics
Agrawal et al[117]	LC patients with recovered HE (n = 235): CHB (n = 49)	3 mo of lactulose 30–60 mL/d, or 3 capsules of probiotics per day, which contained 4 strains of Lactobacillus. Lactulose (n = 80); Probiotics (n = 77)	Lactulose and probiotics were effective for secondary prophylaxis of HE in cirrhotic patients
Ziada et al[115]	Decompensated LC patients with MHE (n = 90): CHB (NM)	4 wk of lactulose 30–60 mL/d, or 3 capsules of probiotics per day, which contained Lactobacillus acidophilus. Lactulose (n = 30); Probiotics (n = 30)	Probiotic was better tolerated than lactulose. Both of them can improve blood ammonia and psychometric tests and reduce the risk of developing overt HE. Magnetic resonance spectroscopy showed more improvement in the levels of brain neurometabolites in the probiotic group
Xia et al[116]	Decompensated HBV-LC patients with MHE (n = 67)	3 mo of probiotics 1500-mg TD, which contained Clostridium butyricum combined with Bifidobacterium infantis. Probiotics (n = 30)	After probiotics treatment, the therapeutic bacteria were significantly enriched, while Enterococcus and Enterobacteriaceae were decreased. Probiotics contributed to the improved cognition and the decreased ammonia levels
FMT
Ren et al[132]	CHB with positive HBeAg, received over 3 yr of antiviral treatment (n = 18)	FMT was performed by gastroscope every 4 wk until HBeAg clearance. FMT (n = 5)	FMT was effective on HBeAg-positive CHB, especially in patients who could not cease the oral antiviral treatment even after long-term treatment
Bajaj et al[135]	Decompensated LC patients with recurrent HE (n = 20). CHB (NM)	After 5 d of antibiotics, FMT was performed by enema, or standard of care (SOC, rifaximin/lactulose) was applied. FMT (n = 10); SOC (n = 10)	FMT increased diversity and beneficial taxa of gut microbiota, improved cognition and showed good tolerance, other than SOC
Bajaj et al[136]	Decompensated LC patients with recurrent HE (n = 20). CHB (NM)	FMT was performed by enema, or standard of care (SOC, rifaximin/lactulose) was applied. FMT (n = 10); SOC (n = 10)	Oral FMT capsules are safe and well tolerated. Post-FMT, duodenal mucosal diversity increased with higher Ruminococcaceae and Bifidobacteriaceae and lower Streptococcaceae and Veillonellaceae. Reduction in Veillonellaceae were noted post-FMT in sigmoid and stool
Chauhan et al[133]	CHB with positive HBeAg, received over 1 years of antiviral treatment (n = 18)	6 FMTs were performed by gastroscope every 4 wk FMT (n = 12)	FMT appeared to be safe and effective on HBeAg-positive CHB in viral suppression and HBeAg clearance

CHB: Chronic hepatitis B; CB: Clostridium butyricum; CRP: C-reactive protein; EcN: Escherichia coli Nissle 1917; ETV: Entecavir; HBeAg: Hepatitis B e antigen; HE: Hepatic encephalopathy; IFN: Interferon; IL: Interleukin; LC: Liver cirrhosis; MHE: Minimal hepatic encephalopathy; NM: Not mentioned; SBP: Spontaneous bacterial peritonitis; SDF-1α: Stromal cell-derived factor 1-α; TDF: Tenofovir disoproxil fumarate; TGF-1β: Transforming growth factor β-1; TNF: Tumor necrosis factor; FMT: Faecal microbiota transplantation.