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

Table 2 Gut microbiota-related treatment toward hepatitis B virus-related fibrosis and complications (studies in animal models)

Ref.	Study populations (n)	Treatment and grouping (n)	Conclusions
Antiviral therapy
Li et al[96]	AAV-mediated persistent HBV infection (AAV-HBV) mice (n = 10)	35 d after HBV infection, 4 wk of daily ETV treatment. ETV (n = 5)	Gut microbiota dysbiosis of the AAV-HBV mice was reversed by ETV treatment with restored α diversity and changed proportion of Akkermansia, Lacnospiracea and Marvinbryantia
Rifaximin
Kang et al[105]	Germ-free mice (n = 16)	15 d of rifaximin 100 mg/(kg·d), or humanized with stools from a HCV-induced cirrhotic patient with MHE. Rifaximin (n = 4); Humanized (n = 4); Rifaximin + humanized (n = 4)	Rifaximin beneficially altered intestinal ammonia generation by regulating intestinal glutaminase expression independent of gut microbiota. MHE-associated fecal colonization resulted in intestinal and systemic inflammation. It was ameliorated with rifaximin
Engineered probiotics
Nicaise et al[120]	Ornithine transcarbamoylase-deficient Sparse-fur mice; Carbon tetrachloride rats; Thioacetamide-induced acute liver failure mice	NCIMB8826 (wild-type strain Lactobacillus plantarum), or EV101 (engineered Lactobacillus plantarum, LDH-/AlaD+) oral and intrarectal administration	EV101 administration was effective in controlling hyperammonemia in constitutive animal models with a significant effect on survival, which might be involved with direct ammonia consumption in the gut
Kurtz et al[121]	Ornithine transcarbamylase-deficient spfash mice; Thioacetamide-induced acute liver failure mice; Healthy volunteers (n = 52)	Non-modified Escherichia coli Nissle 1917 (EcN), SYNB1020 (engineered EcN, ΔargR, ΔthyA, malEK:PfnrS-argAfbr) administration	SYNB1020 converted NH3 to l-arginine in vitro, and reduced systemic hyperammonemia, improved survival in mouse models. SYNB1020 was well tolerated in healthy volunteers
Ochoa-Sanchez et al[122]	Bile-duct ligated rats	Non-modified EcN, S-ARG, or S-ARG + BUT administration	S-ARG converted ammonia to arginine, it was further modified to additionally synthesize butyrate, which had the potential to prevent HE
FMT
Liu et al[134]	Germ-free mice	Sterile supernatant or entire stool from pre-FMT and post-FMT cirrhotic patients with HE was transplanted to Germ-free mice	Transferred microbiota mediated neuroinflammation. Cirrhosis-associated dysregulation of gut microbiota was related with frontal cortical inflammation

AAV: Adeno-associated virus; HBV: Hepatitis B virus; ETV: Entecavir; HCV: Hepatitis C virus; MHE: Minimal hepatic encephalopathy; HE: Hepatic encephalopathy; FMT: Fecal microbiota transplantation.