Gut-liver axis signaling in portal hypertension

Table 1 Farnesoid X receptor-targeting therapies in liver disease: Experimental vs clinical evidence

Location	Target	Experimental evidence	Clinical evidence
Liver	Metabolism and inflammation	OCA/NASH/mouse: Decreased hepatocyte apoptosis and less fibrosis; similar steatosis[194] OCA/NASH/hamster: Higher LDL and lower HDL[195] OCA/NAFLD/rabbit: Decreased steatosis, inflammation, insulin resistance and improved lipid profile[196]	OCA/NASH/NCT01265498: Improved histological features; 20% pruritus, impaired lipid profile[183] OCA/PBC/NCT01473524: Improved biochemical laboratory values; frequent pruritus[184,185] OCA/PSC/NCT02177136: Completed; statistical results pending; PEP: Change of ALP levels as compared to BL
	Fibrosis and portal hypertension	PX20606/CCl4/rat: Reduced fibrosis, PP, and sinusoidal remodeling[192] OCA/TAA/rat: Reduced fibrosis, PP, hepatic inflammation[182]	OCA/NASH/NCT02548351: Recruiting; PEP: 1 stage of liver fibrosis improvement; NASH resolution OCA/PBC/NCT02308111: Recruiting; PEP: Death, OLT; MELD ≥ 15; decompensation NGM282/PSC/NCT02704364: reduced fibrosis biomarkers[193] OCA/ALD/PESTO: PEP: Lower HVPG after 7 d of treatment by 15% or more, or HVPG < 12 mmHg[188]
Gut	Microbiome	OCA/Healthy/mouse: Lower endogenous BA levels; elevated Firmicutes in small intestine[197] Fexaramine/NAFLD/mouse: Microbiome changes induce different BA profile; GLP-1 signaling improves insulin sensitivity[198]	OCA/Healthy/NCT01933503: Reversible changes in gram-positive bacterial strains[197]
	Intestinal barrier	OCA/BDL/rat: Upregulation of TJ proteins, decrease of intestinal inflammation and BT[90] OCA/CCl4/rat: Upregulation of antimicrobial peptides, TJ proteins; reduced BT and liver fibrosis[91] GW4064/BDL/mouse: Upregulation of enteroprotective genes and improvement of barrier function[127] Fexaramine/ALD/mouse: Improvement of intestinal barrier, lipid metabolism and alcohol-induced liver injury[190] OCA + Fexaramine/PPVL + BDL + CCl4/mouse: reduction of BT; OCA: Improvement of muco-epithelial and gut-vascular barrier; Fexaramine: Improvement of muco-epithelial but no effect on gut-vascular barrier[151]	No human data available
	Metabolism/inflammation	Fexaramine/NAFLD/mouse: Amelioration of metabolic syndrome, induction of FGF15, decreased insulin resistance[189] OCA/IBD/mouse: Decreased intestinal inflammation and permeability[191]	No human data available

OCA: Obeticholic acid; NASH: Non-alcoholic steatohepatitis; LDL: Low density lipoprotein; HDL: High density lipoprotein; NAFLD: Non-alcoholic fatty liver disease; NCT: National clinical trial identifier; PEP: Primary efficacy endpoint; ALP: Alkaline phosphatase; BL: Baseline; CCl4: Carbon tetrachloride; PP: Portal pressure; TAA: Thioacetamide; OLT: Orthotopic liver transplantation; MELD: Model for end-stage liver disease; ALD: Alcoholic liver disease; HVPG: Hepatic venous pressure gradient; BA: Bile acid; GLP-1: Glucagon like peptide 1; TJ: Tight junction; BT: Bacterial translocation; BDL: Bile duct ligation; FGF15: Fibroblast growth factor 15; IBD: Inflammatory bowel disease.