Gut microbiome in non-alcoholic fatty liver disease associated hepatocellular carcinoma: Current knowledge and potential for therapeutics

Table 1 Microbiota profiles in liver disease

Study	Bacterial species increased	Bacterial species decreased	Putative impact of microbial change in group	Comparison group
Advanced fibrosis/cirrhosis
Loomba et al[49], 2017, Cell Metab	Proteobacteria Include E. coli	Firmicutes	Higher incidence of enzymes for butyrate, and lower for lactate and acetate	NAFLD advanced fibrosis/cirrhosis compared to NAFLD mild/moderate fibrosis
Ponziani et al[18], 2019, Hepatology	Phylum: Proteobacteria, Bacteroidetes, Cyanobacteria; Family: Lactobacillaceae, Enterobacteriaceae, Prevotellaceae, Bacteroidaceae, Streptococcaceae, Enterococcaceae, Veillonellaceae	Phylum: Verrucomicrobia; Family: Verrucomicrobiaceae; Methanobacteriaceae	Intestinal inflammation, Increase in Intestinal permeability, increased systemic inflammation	NAFLD cirrhosis compared to healthy controls
HCC
Ren et al[52], 2019, Gut	Phylum: Acinetobacter; Genus: Gemmiger, Parabacteroides, Paraprevotella, others	Phylum: Verrucomicrobia	Increased LPS producer with liver inflammation and oxidative damage; Decreased butyrate production resulting in intestinal mucosal disruption	Early HCC compared to cirrhosis
Ren et al[52], 2019, Gut	Genus: Klebsiella, Haemophilus	Verrucomicrobia (Akkermansia); Genus: Alistipes, Phascolarctobacterium, Ruminococus	Increased LPS producer with liver inflammation and oxidative damage; Decreased butyrate production resulting in intestinal mucosal disruption	Early HCC compared to healthy controls
Ponziani et al[16], 2019, Hepatology	Phylum: Bacteroidetes; Family: Bacteroidaceae, Streptococcaceae, Enterococcaceae	Family: Verrucomicrobiaceae, Bifidobacteriaceae	Intestinal inflammation, Increase in Intestinal permeability, increased systemic inflammation	HCC in NAFLD Compared to NAFLD cirrhosis without HCC
Grat M et al[15], 2016, Transplant Proc	E. coli		LPS and inflammation within liver	HCC cirrhosis Compared to non-HCC cirrhosis

Selected studies (human) showing different microbiota profiles in cirrhosis and hepatocellular carcinoma (HCC) with emphasis on non-alcoholic fatty liver disease associated HCC. HCC: Hepatocellular carcinoma; NAFLD: Non-alcoholic fatty liver disease; LPS: Lipopolysaccharide.

Table 2 Therapeutics, gut microbiome, role in liver cancer

Study	Agents	Population	Outcomes
Animal models
Borges Haubert et al[64], 2015, Nutr Metab Insights	Prebiotics fructoligosaccharides	NAFLD rat model	Decreased liver fat via decreased lipogenesis
Liu et al[65], 2020, J Nutr Biochem	Probiotic Lactobacillus rhamnosus	Mouse model of liver disease (HFD)	Reduced NASH frequency, reduced steatosis inflammation and apoptosis in liver
Zhou et al[56], 2017, Sci Rep	FMT	Mouse model of liver disease (HFD)	Decreased hepatic lipid and proinflammatory cytokines, increased lactobacillus, improved gut barrier function, reduced endotoxemia, increase butyrate
Yoshimoto et al[33], 2013, Nature	Vancomycin	Mouse model of liver disease (HFD)	Reduced liver cancer
Janssen et al[58], 2017, Lipid Res	Antibiotics (ampicillin, neomycin, vancomycin and metronidazole)	Mouse model of NAFLD	Decreased secondary bile acids, decreased liver inflammation and fibrosis
Friedman et al[63], 2018, Gastroenterology	FXR agonist obeticholic acid	Mouse model of NAFLD	Decreased endogenous bile acid; Increased bacterial profile with Gram + including Firmicutes
Humans studies
Yang et al[5], 2020, Br J Nutrition	Diet and incident cancer risk- summary of studies	Worldwide epidemiologic studies of diet and liver cancer risk	Higher risk for liver cancer: Red Meat, Added Sugar, Processed food; Lowered risk for liver cancer: Vegetables, Fruits, Omega 3 oil, Coffee
Monem et al[55], 2017, Euroasian J hepatogastro	Probiotics Lactobacillus	NAFLD patients	Decreased AST and ALT
Bomhof et al[54], 2019, Eur J Nutrition	Prebiotic Oligofructose	NASH patients	Decreased hepatic inflammatory markers, deceased weight, improved glucose tolerance, decreased steatosis, decreased clostridium cluster XA and I and enhanced Bifidobacterium
Vrieze et al[57], 2012, Gastroenterology	FMT trial	FMT from lean donor to individuals with metabolic syndrome	Improved insulin sensitivity, Increase in butyrate producing bacteria

Selected studies (animal and human) of microbiome modulating therapies tested in non alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) with emphasis on NASH HCC. NASH: Non alcoholic steatohepatitis; NAFLD: Non alcoholic fatty liver disease; HCC: Hepatocellular carcinoma; FMT: Fecal microbiota transplant; PD-1: Programmed death-1; FXR: Farnesoid X receptor.