Fecal microbiota transplantation: A promising treatment strategy for chronic liver disease

Table 1 Clinical trials and animal studies on fecal microbiota transplantation for chronic liver disease treatment

Disease	Ref.	Year	Type	Comparison	Frequency	Key findings
MASLD/NAFLD	Zhou et al[20]	2017	Mice	Control vs HFD vs HFD + FMT	8 consecutive weeks	FMT mitigated HFD-induced steatohepatitis through its beneficial effects on intestinal microbiota
	García-Lezana et al[21]	2018	Rat	Autologous FMT vs allogenic FMT	Once	Allogeneic FMT led to a significant decrease in portal vein pressure
	Witjes et al[22]	2020	Human	Autologous FMT vs lean vegan donor FMT	3 times within eight weeks	After allogeneic FMT, the expression of hepatic genes related to lipid metabolism and inflammation was significantly reduced. The observed changes in intestinal microbiota composition were found to be connected to changes in plasma metabolites and markers
	Craven et al[23]	2020	Human	Autologous FMT vs allogenic FMT	Once	Patients who received allogeneic FMT showed a significant reduction in intestinal permeability after 6 weeks
	Xue et al[24]	2022	Human	Oral probiotics vs FMT + three enemas	Once	FMT effectively improved the therapeutic outcomes in NAFLD patients. It demonstrated greater efficacy in lean NAFLD patients than those with obesity
ALD	Llopis et al[11]	2016	Mice	SAH FMT vs alcoholism FMT	Once	Transplanting intestinal microbiota from mice with alcoholism, but without AH, alleviated alcohol-induced liver injury
	Ferrere et al[28]	2017	Mice	Pectin vs FMT	One per week	Manipulating the intestinal microbiota can prevent alcohol-induced liver injury, positioning it as a new therapeutic target for ALD
	Wolstenholme et al[29]	2022	Mice	Placebo vs FMT	Once	Mice in the FMT group reduced ethanol acceptance, intake, and preference
	Philips et al[30]	2017	Human	Case report	7 consecutive days	After FMT, clinical indicators, biochemical markers, and severity scores improved in SAH patients, with significant changes in intestinal microbiota observed
	Philips et al[31]	2017	Human	Control vs FMT	7 consecutive days	After FMT, there was a improvement in liver disease severity, an increase in survival rates, and notable changes in the composition of the intestinal microbiota
	Philips et al[32]	2018	Human	Corticosteroids vs nutrition vs pentoxifylline vs FMT	7 consecutive days	FMT showed a higher survival rate compared to other treatments for SAH, potentially serving as a cost-effective bridge to liver transplantation or improving survival without it
	Philips et al[33]	2022	Human	Pentoxifylline vs FMT	7 consecutive days	FMT improves 6-month survival and reduces liver-related complications, related to beneficial modulation of the gut microbiota
	Philips et al[34]	2022	Human	SOC vs FMT	7 consecutive days	FMT significantly reduces ascites, infections, encephalopathy, and alcohol relapse, with a trend toward higher survival, associated with beneficial modulation of the gut microbiota
	Sharma et al[35]	2022	Human	SOC vs FMT	Once	FMT is safe and could improve short- and medium-term survival rates, and clinical severity scores in patients with SAH-ACLF
	Pande et al[36]	2023	Human	Prednisolone vs FMT	28 consecutive days	FMT is safe, improves 90-day survival, and reduces infections by positively modulating microbial communities
CHB	Ren et al[39]	2017	Human	Antiviral therapy vs antiviral therapy + FMT	Once every 4 weeks, until HBeAg clearance was achieved	In patients with sustained positive HBeAg after long-term antiviral therapy, FMT can reduce or even eliminate HBeAg levels
	Chauhan et al[40]	2021	Human	Antiviral therapy vs antiviral therapy + FMT	Once every 4 weeks for a total of six times	FMT is safe and effective in HBeAg clearance in HBeAg-positive CHB patients
PSC	Philips et al[43]	2018	Human	Case report	Once a week for a total of four times	After FMT, significant changes were observed in the liver biochemistry, bile acids, and the composition of the intestinal microbiota in PSC patients
	Allegretti et al[46]	2019	Human	Control vs FMT	Once	The improvement in ALP levels may be linked to an increase in the diversity of the intestinal microbiota, as well as the frequency of FMT
AIH	Liang et al[47]	2021	Mice	Control vs FMT	28 consecutive days	FMT can alleviate liver injury and bacterial translocation, partially reverse the elevation of serum ALT and AST, restore the balance between follicular regulatory T and helper T cells in the spleen, and effectively correct the intestinal microbiota dysbiosis
Cirrhosis/HE	Wang et al[51]	2017	Rat	Control vs probiotics vs low-dose FMT vs moderate-dose FMT vs high-dose FMT	3 consecutive weeks	FMT prevents liver necrosis, improves behavioral performance, HE scores, and spatial learning ability in rats, enhances the expression of intestinal tight junction proteins, and repairs intestinal mucosal barrier damage. It also reduces the expression of TLR4 and TLR9 in the liver, along with a decrease in circulating pro-inflammatory factors (IL-1β, IL-6, TNF)
	Kao et al[52]	2016	Human	Case report	Once a week for 5 times	FMT can reverse intestinal microbiota dysbiosis and lead to the obvious improvement of cognitive function in dominant HE
	Bajaj et al[53]	2017	Human	SOC vs FMT + SOC	Once	FMT can reduce the hospitalization rate, improve cognitive function, and restore intestinal microbiota dysbiosis
	Bajaj et al[54]	2019	Human	SOC vs FMT + SOC	Once	Follow-up for more than one year demonstrated that the positive effects of FMT may be long-lasting
	Bajaj et al[55]	2019	Human	Placebo capsules vs FMT capsules	15 capsules	Oral FMT capsules are safe and well-tolerated. FMT is associated with improvements in duodenal mucosal diversity, intestinal microbiota dysbiosis, and AMP expression, along with a decrease in LBP levels and better performance in the brain App test
	Bajaj et al[56]	2019	Human	Placebo capsules vs FMT capsules	15 capsules	FMT has a beneficial effect on the intestinal microbiome function in patients with cirrhosis, leading to improvements in inflammation and cognitive performance. However, recipients with lower levels of secondary bile acids may experience poorer outcomes
	Bloom et al[57]	2022	Human	Case report	5 doses of 15 capsules within 3 weeks	FMT capsules improved cognitive performance in patients with HE, with the effect varying based on both donor and recipient factors
	Mehta et al[59]	2018	Human	Case report	Once	FMT can significantly reduce arterial ammonia concentrations, alleviate neurological symptoms, and lower CTP and MELD scores in patients with HE
	Li et al[60]	2022	Human	Case report	3 times	FMT can improve liver function, relieve clinical symptoms, and significantly reduce the number of HE episodes in patients
	Huang et al[61]	2021	Rat	Sham operation vs BDL vs BDL + FMT vs BDL + GMT	5 consecutive days	FMT increased the abundance of Bifidobacterium and significantly reduced portal vein pressure
	Bajaj et al[62]	2018	Human	SOC vs SOC + antibiotic + FMT	Once	FMT has also been shown to restore the diversity and function of the intestinal microbiota altered by antibiotics in patients with advanced cirrhosis who are treated with lactulose and rifaximin

ACLF: Acute on chronic liver failure; AH: Alcoholic hepatitis; AIH: Autoimmune hepatitis; ALD: Alcohol liver disease; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AMPs: Antimicrobial peptides; AST: Aspartate aminotransferase; BDL: Bile duct ligation; CHB: Chronic hepatitis B; CTP: Child-Turcotte-Pugh; FMT: Fecal microbiota transplantation; GMT: Transplantation of gut content from the terminal ileum; HBeAg: Hepatitis B e antigen; HE: Hepatic encephalopathy; HFD: High-fat diet; LBP: Lipopolysaccharide-binding protein; MASLD: Metabolic dysfunction-associate steatotic liver disease; MELD: Model for end-stage liver disease; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; PSC: Primary sclerosing cholangitis; SAH: Severe alcoholic hepatitis; SOC: Standard of care; TLRs: Toll-like receptors; TNF: Tumor necrosis factor.

Table 2 Ongoing clinical trials of fecal microbiota transplantation in chronic liver diseases from Clinicaltrial.gov

Disease or condition	Study title	Study arms	Intervention	Primary outcomes measures	Clinical trials ID, country
NAFLD, NASH	Fecal microbiota transplantation for the treatment of non-alcoholic steatohepatitis	Lean healthy donor frozen FMT		Efficacy (histological resolution of NASH defined as ballooning disappearance with or without persistence of minimal lobulillar inflammation and no progression of fibrosis stage) (time frame: 72 weeks)	NCT03803540, Spain
NAFLD	Effects of fecal microbiota transplantation on weight in obese patients with non-alcoholic fatty liver disease	Diet + exercise + FMT vs diet + exercise	3 times IMT with 15-day intervals	Proportion of patients achieving ≤ 5% of the weight loss in kg from baseline (time frame: 3 months)	NCT04594954, India
NAFLD	Dietary counseling coupled with FMT in the treatment of obesity and NAFLD-the DIFTOB study	Healthy diet counseling + FMT vs healthy diet counseling + placebo		A change in HOMA-IR (time frame: At week 12 and at week 52)	NCT05607745, Finland
NAFLD with history of diabetes melitus	A prospective, randomized, placebo-controlled pilot study to characterize the intestinal microbiome and to evaluate the safety and fecal microbiome changes following administration of lyophilized PRIM-DJ2727 or placebo given orally for 12 weeks in subjects with NAFLD	Oral PRIM-DJ2727 vs oral placebo	twice weekly for 12 weeks	Microbiome diversity in fecal samples as indicated by the Shannon diversity index (time frame: 10 months)	NCT04371653
NASH	Evaluate the efficacy, safety and tolerability of fecal microbiota transfer for the treatment of patients with nonalcoholic steatohepatitis	Capsules of FMT vs capsules of placebo	An initial dose of 24 oral capsules and a maintenance dose of 12 oral capsules every 3 months for 12 months	Proportion of patients with improvement of fat fraction by proton density by MRI and no worsening of activity or fibrosis (time frame: 72 weeks)	NCT05622526
NASH	Fecal microbiota therapy versus standard therapy in NASH related cirrhosis	FMT vs standard treatment care	Once a month for 5 months	Reduction in hepatic venous pressure gradient in the two groups from baseline (time frame: 1 year)	NCT02721264, India
Alcohol-related liver disease, alcohol use disorder, cirrhosis	Intestinal microbiota transplant in alcohol-associated chronic liver disease and cirrhosis	IMT capsules vs placebo capsules	Twice during the trial	Change in alcohol consumption (time frame: Baseline to 3 months after treatment)	NCT05548452, United States
Liver disease, alcohol dependence, HE and etc.	Safety and efficacy of fecal microbiota transplantation	FMT		The efficacy of FMT in treating dysbiosis-associated disorder will be assessed by number of patients who have improvement in clinical symptoms (depends on each disease as stated in outcome) (time frame: 1 year)	NCT04014413, HongKong, China
SAH	A comparison of fecal microbiota transplantation and steroid therapy in patients with severe alcoholic hepatitis	FMT vs steroids	7 days	Proportion of participants with overall survival at 3 months (time frame: 3 months)	NCT03091010, India
SAH	Fecal microbiota transplantation in severe alcoholic hepatitis- assessment of impact on prognosis and short-term outcome	FMT vs standard of care treatment	1 time	Survival (time frame: 3 months)	NCT03827772, India
AH	Fecal microbiota therapy in steroid ineligible alcoholic hepatitis	FMT vs standard medical treatment	7 times	Mortality at 3 months (time frame: 3 months), liver transplant free survival (time frame: 3 months)	NCT05285592, India
AH	Safety evaluation of fecal microbiota transplantation in severe alcoholic hepatitis	Standard of care + oral PRIM-DJ2727 vs oral placebo	Every day for a week followed by once weekly for 3 weeks	To assess survival in patients with severe alcoholic hepatitis receiving PRIM-DJ2727 capsules in comparison to standard of care (time frame: Day 1 to 12 months)	NCT05006430, United States
CHB	Study on effect of intestinal microbiota transplantation in chronic hepatitis B	IMT + antiviral therapy vs antiviral therapy	6 times IMT with 2-week intervals	Change of serum HBeAg level (Time Frame: 1 month, 3 months, 6 months)	NCT03429439, China
HBV induced cirrhosis	Study on effect of intestinal microbiota transplantation in hepatitis B virus induced cirrhosis	Intestinal microbiota transplantation	4 times IMT with 2-week intervals	Change of liver Fibroscan score (time frame: 3 months, 6 months, 12 months)	NCT03437876, China
Acute-on-chronic liver failure, hepatitis B	Efficacy of addition of FMT and plasma exchange to tenofovir in comparison to monotherapy with tenofovir in ACLF-HBV	Plasma exchange + tenofovir + FMT vs tenofovir	7 days	Overall survival in both groups (time frame: Day 28)	NCT04431375, India
Decompensated cirrhosis	Fecal microbiota transplantation for decompensated cirrhosis	FMT + traditional treatment vs traditional treatment		Number of adverse events complication rate in all patients in both groups (time frame: 3 months)	NCT03014505, Chian
Cirrhosis, liver	Fecal microbiota transplantation in cirrhosis	FMT vs control		Blood ammonia, ALT, AST, gut microbiome, albumin, blood glucose, serum creatinine, direct bilirubin, indirect bilirubin, prothrombin time activity percentage and liver stiffness (time frame: Change from baseline, at 12 months)	NCT04591522
Cirrhosis of the liver	Trial of faecal microbiota transplantation in cirrhosis	FMT vs placebo		Assessment of the feasibility of FMT (time frame: 18 months)	NCT02862249, United Kingdom
Liver cirrhosis	Faecal microbiota transplantation for liver cirrhosis	FMT vs placebo	3 times	Time to death or readmission due to episode of acute decompensation in FMT treated vs placebo treated patients (Time Frame: 1 year)	NCT04932577, Denmark
Cirrhosis, HE	FMT in cirrhosis and hepatic encephalopathy	Dual oral and rectal FMT vs oral FMT and rectal placebo vs oral placebo and rectal FMT vs oral and rectal placebo		Adverse events related to FMT (time frame: 6 months), change in microbial diversity in stool (time frame: 6 months)	NCT03796598, United States
HE	Fecal microbiota transplant as treatment of hepatic encephalopathy	FMT oral capsules vs placebo oral capsule	days 1, 2, 7, 14, and 21	PHES [time frame: Before the first administration of FMT (day 0) and one week after the last administration of FMT (day 28)]	NCT03420482, United States
HE	Efficacy and safety of fecal microbiota transplant for secondary prophylaxis of hepatic encephalopathy	FMT + standard medical therapy vs standard medical therapy	3 times	Proportion of patients developing an episode of hepatic encephalopathy within 6 months (time frame: 6 months)	NCT05229289, India

ACLF: Acute on chronic liver failure; AH: Alcoholic hepatitis; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CHB: Chronic hepatitis B; FMT: Fecal microbiota transplantation; HBeAg: Hepatitis B e antigen; HBV: Hepatitis B virus; HE: Hepatic encephalopathy; HOMA-IR: Homeostasis model assessment of Insulin Resistance; MRI: Magnetic resonance imaging; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; PHES: Psychometric Hepatic Encephalopathy Score; SAH: Severe alcoholic hepatitis.