Table 1.

Selected studies targeting the gut-liver axis

Type	Study subjects	Intervention details	Key outcomes	Safety	Reference
FMT	n=20 cirrhotic patients (mainly due to chronic hepatitis C virus and/or alcohol use disorder) with MELD <17 and recurrent HE	Single FMT enema following antibiotic treatment vs. SOC	FMT well tolerated, significantly less patients receiving FMT developed HE. FMT increased microbial diversity and increased beneficial bacterial taxa	Less SAEs in the FMT group compared with SOC, no complications related to FMT	(Bajaj et al., 2019)
	n=8 severe AH patients, n=18 historical controls with severe AH, both groups steroid-ineligible	Daily FMT via naso-jejunal tube for 7 days	87.5% of patients who received FMT survived for 1 year, compared with 33.5% of matched controls	Excessive flatulence was a complaint of 50% of patients with FMT	(Philips et al., 2017)
	n=51 patients with severe AH	n=8 corticosteroids, n=17 nutritional support only, n=10 pentoxifylline, n=16 FMT (daily via naso-jejunal tube for 7 days)	Proportions of patients surviving at the end of 3 months in the steroids, nutrition, pentoxifylline, and FMT group were 38%, 29%, 30%, and 75%, respectively	Not reported	(Philips et al., 2018)
	n=38 patients with metabolic syndrome	Single allogenic FMT via naso-jejunal tube from lean donor vs. autologous FMT	No metabolic changes at 18 weeks after FMT, insulin sensitivity at 6 weeks after allogenic FMT was significantly improved	No SAEs in both groups	(Kootte et al., 2017)
	n=18 patients with metabolic syndrome	Single allogenic FMT via naso-jejunal tube from lean donor vs. autologous FMT	Significantly improved peripheral insulin sensitivity 6 weeks after FMT	No SAEs in both groups	(Vrieze et al., 2012)
	n=22 obese subjects without diabetes, NASH or metabolic syndrome	Randomized, double-blind study, FMT by capsules from a lean donor or placebo capsules	No significant changes in BMI at 12-week follow-up	No adverse events in both groups	(Allegretti et al., 2020)
	n=24 obese subjects with mild to moderate insulin resistance	Randomized, double-blind study, weekly FMT by capsules vs. placebo capsules for 6 weeks	No significant differences between groups for insulin sensitivity, body mass index and fat mass	No significant differences in adverse events, no FMT related SAEs	(Yu et al., 2020)
Next-generation engineered bacteria	Mouse models of hyperammonemia	Oral gavage of engineered Escherichia coli Nissle strains (SYNB1020)	Significant lowering of blood ammonia levels		(Kurtz et al., 2019)
	n=23 patients with cirrhosis	Escherichia coli Nissle strains (SYNB1020) for 6 days vs. placebo	No evidence of blood ammonia lowering or changes in other exploratory endpoints relative to placebo	No adverse events reported	(Synlogic, 2019)
	Experimental alcoholic liver disease (mice)	Oral gavage of engineered Lactobacillus reuteri-producing IL-22 vs. non-engineered Lactobacillus reuteri	Reduced bacterial translocation to the liver by increasing the expression of REG3G in the intestine, reduced ethanol-induced liver damage		(Hendrikx et al., 2019)
Bacteriophages	Humanized mouse models of ethanol-induced liver damage	Oral gavage of bacteriophages targeting cytolysin-positive E. faecalis vs. control phages	Bacteriophage administration reduced the severity of ethanol-induced liver disease		(Duan et al., 2019)
Targeting the bile acid pathway	Mouse models of ethanol-induced liver damage	Non-tumorigenic variant of FGF19 vs. vehicle	Improved gut barrier function and reduced liver damage		(Hartmann et al., 2018)
	n=19 AH patients	Obeticholic acid (OCA) vs. placebo	Decrease in MELD score from baseline to Day 42 of −3.4 in the OCA arm, and −2.2 in the placebo arm (P-Value of 0.62)	No AEs related to study drug but discontinued due to safety concerns in patients with advanced liver disease	Clinicaltrials.gov identifier: NCT02039219
	n=82 biopsy-proven NASH	Randomized, double-blind, placebo-controlled, phase 2 study, NGM282 (engineered FGF19 analogue) vs. placebo	Significant reduction in histological features, such as the NAFLD activity score and liver fibrosis after 12 weeks of treatment	AEs included diarrhea, nausea, frequent bowel movements, and abdominal pain. No SAE related to study drug	(Harrison et al., 2018; Harrison et al., 2019)
	n= 931 biopsy-proven NASH	Interim analysis of a randomized, double-blind, placebo-controlled study, OCA vs. Placebo	OCA 25 mg significantly improved fibrosis and key components of NASH disease activity after 18 months of treatment	Most common adverse event were pruritus and increases in LDL cholesterol related to OCA	(Younossi et al., 2019)
SCFAs	Mouse models of ethanol-induced liver damage	Administration of tributyrin (ester composed of butyrate and glycerol)	Gut barrier stabilization, reduced liver injury,however, no effect on liver injury from long-term ethanol administration		(Cresci et al., 2014).
	n=60 overweight subjects	Randomized, controlled study, inulin-propionate ester vs. inulin-control administration over 24 weeks	Significantly reduced weight gain, intra-abdominal adipose tissue distribution, hepatic lipid content in the Inulin-propionate ester group	No increased AEs in the inulin-propionate ester group	(Chambers et al., 2015)
	n=10 patients with metabolic syndrome, n=9 healthy	Oral administration of sodium butyrate daily for 4 weeks	No effect on plasma and fecal butyrate levels after treatment. Significantly improved insulin sensitivity only in healthy lean subjects	Not reported	(Bouter et al., 2018)

Bold font in the second column highlights the studied organism or disease. AEs, adverse events, AH, alcoholic hepatitis; BMI, body mass index; FMT, fecal microbiota transfer; HE, hepatic encephalopathy; OCA, obeticholic acid; REG3G, antimicrobial molecule regenerating islet derived 3 gamma; SAEs, severe adverse events; SCFAs, short-chain fatty acids; SOC, standard of care