Fecal Microbiota Transplantation for the Treatment of Refractory Hepatic Encephalopathy After TIPS Surgery

A Prospective Exploratory Study on Fecal Microbiota Transplantation for the Treatment of Refractory Hepatic Encephalopathy After TIPS Surgery

This is a single-center, prospective, open-label, parallel-group exploratory clinical study designed to evaluate the safety and preliminary efficacy of fecal microbiota transplantation combined with standard medical therapy in patients with refractory overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunt. The study also aims to explore whether adjunctive prebiotic supplementation may improve clinical outcomes and support gut microbiota reconstruction after fecal microbiota transplantation.

A total of 26 participants with recurrent overt hepatic encephalopathy after TIPS despite standard therapy with rifaximin and lactulose will be enrolled. All participants will continue to receive standard medical therapy, including rifaximin and lactulose. During an episode of overt hepatic encephalopathy, all participants will receive fecal microbiota transplantation via a nasojejunal tube at a dose of 100 mL per administration, twice daily, for 3 consecutive days. Participants will be assigned in a 1:1 ratio to either the fecal microbiota transplantation group or the fecal microbiota transplantation plus prebiotic group. Participants in the combination group will receive dietary fiber prebiotic supplementation at 24 g/day for 4 weeks in addition to the same fecal microbiota transplantation and standard medical therapy.

Participants will be followed for up to 6 months. The primary efficacy assessment will focus on recurrence of hepatic encephalopathy, including recurrence rate, time to first recurrence, episode grade, and duration. Secondary assessments will include time to reversal of hepatic encephalopathy, West Haven grade, blood ammonia, liver and kidney function, inflammatory markers, liver function scores, neurocognitive function, and changes in gut microbiota composition. Safety assessments will include adverse events, fecal microbiota transplantation-related adverse events, infection, worsening hepatic encephalopathy, hospitalization, and serious adverse events. This study is expected to provide preliminary clinical evidence for a microbiota-based therapeutic strategy in patients with refractory overt hepatic encephalopathy after TIPS.

Study Overview

• Status: Recruiting
• Conditions: Hepatic Encephalopathy; Fecal Microbiota Transplantation; TIPS; Refractory Hepatic Encephalopathy
• Intervention / Treatment: Biological: Fecal Microbiota Transplantation; Drug: Rifaximin、Lactulose; Dietary supplement: Dietary Fiber Prebiotic

Detailed Description

Hepatic encephalopathy is one of the most common and clinically significant complications after transjugular intrahepatic portosystemic shunt. After TIPS, portosystemic shunting may increase the systemic exposure to gut-derived neurotoxins and inflammatory mediators, thereby increasing the risk of overt hepatic encephalopathy. Although lactulose and rifaximin are widely used as standard medical therapy, some patients continue to experience recurrent overt hepatic encephalopathy despite adequate treatment. For patients with refractory overt hepatic encephalopathy after TIPS, current therapeutic options remain limited, particularly in terms of rapid recovery of consciousness, prevention of recurrence, and restoration of gut microbial homeostasis.

Fecal microbiota transplantation may provide a microbiota-based therapeutic approach by reshaping the intestinal microbial ecosystem, modulating gut-derived toxin production, improving intestinal barrier and metabolic function, and regulating the gut-liver-brain axis. Previous studies have suggested that fecal microbiota transplantation may be safe and potentially effective in patients with cirrhosis-related hepatic encephalopathy. However, clinical evidence remains limited in patients with refractory overt hepatic encephalopathy specifically occurring after TIPS. In addition, prebiotics may support the growth and engraftment of beneficial bacterial taxa after fecal microbiota transplantation by providing fermentable dietary substrates. Therefore, this study is designed to evaluate the safety and preliminary efficacy of fecal microbiota transplantation combined with standard therapy in patients with refractory overt hepatic encephalopathy after TIPS, and to compare the clinical and microbiome-related effects of fecal microbiota transplantation with or without adjunctive prebiotic supplementation.

This is a single-center, prospective, open-label, parallel-group exploratory clinical study. A total of 26 eligible participants with refractory overt hepatic encephalopathy after TIPS will be enrolled. Eligible participants will be adults aged 18 to 75 years who have successfully undergone covered-stent TIPS and have experienced at least two episodes of overt hepatic encephalopathy with West Haven grade 2 or higher within 6 months despite treatment with rifaximin and lactulose. Participants must also be suitable for fecal microbiota transplantation via a nasojejunal tube and able to tolerate tube placement and subsequent infusion procedures. Key exclusion criteria include active major gastrointestinal bleeding or perforation, severely impaired intestinal barrier function, congenital or acquired immunodeficiency, recent high-risk immunosuppressive or cytotoxic therapy, hepatic or gastrointestinal malignancy, spontaneous bacterial peritonitis, Budd-Chiari syndrome, severe cardiac, renal, or pulmonary dysfunction, unstable vital signs, recent gastrointestinal surgery, planned liver transplantation within 6 months, recent fecal microbiota transplantation, alcohol dependence, use of medications that may affect neuropsychiatric status, other neuropsychiatric disorders, pregnancy or lactation, and poor compliance as judged by the investigator.

All enrolled participants will continue to receive standard medical therapy. Standard therapy consists of rifaximin 0.4 g three times daily, with a total daily dose of 1200 mg, and lactulose 25 mL twice daily, adjusted as clinically needed. During an episode of overt hepatic encephalopathy, all participants will receive fecal microbiota transplantation via a nasojejunal tube. The fecal microbiota suspension will be administered at 100 mL per infusion, twice daily, for 3 consecutive days. The fecal microbiota product will be prepared from rigorously screened healthy donors under standardized conditions, with controlled storage and traceability. Participants will be assigned in a 1:1 ratio to the fecal microbiota transplantation group or the fecal microbiota transplantation plus prebiotic group, with 13 participants in each group. Participants in the combination group will receive additional dietary fiber prebiotic supplementation at a total dose of 24 g/day, administered as 12 g twice daily, starting on the day of fecal microbiota transplantation and continuing for 4 weeks.

Efficacy and safety will be systematically assessed during treatment and follow-up. Clinical assessments will include vital signs, mental status, West Haven grade, time to reversal of hepatic encephalopathy, recurrence of hepatic encephalopathy, hospitalization, and adverse events. Laboratory assessments will include complete blood count, liver function, renal function, coagulation function, plasma ammonia, hepatitis B virus DNA when applicable, alpha-fetoprotein, endotoxin, C-reactive protein, and interleukin-6. Liver disease severity will be assessed using Child-Pugh and MELD scores. Minimal hepatic encephalopathy testing and neurocognitive assessments will be performed when clinically feasible.

The primary efficacy endpoint is recurrence of hepatic encephalopathy, including recurrence rate, time to first recurrence, episode grade, episode duration, and the time from fecal microbiota transplantation to the first recurrence of hepatic encephalopathy. Secondary efficacy endpoints include changes in blood ammonia, liver function, renal function, inflammatory markers, liver function scores, psychological or neurocognitive test results, and gut microbiota diversity and taxonomic composition before and after fecal microbiota transplantation. Safety endpoints include overall adverse events, fecal microbiota transplantation-related adverse events, and serious adverse events, with particular attention to gastrointestinal symptoms, infection, worsening hepatic encephalopathy, hospitalization, septic shock, and death.

Participants will be followed at baseline before fecal microbiota transplantation, day 0 after completion of transplantation, day 15, month 1, month 3, and month 6. Additional assessments will be performed when hepatic encephalopathy occurs. At each scheduled time point, 5 mL of peripheral venous blood and 5 g of stool will be collected for laboratory testing and gut microbiota analysis. These data will be used to explore associations between microbial changes, clinical improvement, recurrence of hepatic encephalopathy, and safety outcomes.

Statistical analyses will be performed using the intention-to-treat principle. Clinical variables will be summarized using appropriate descriptive statistics and compared between groups when applicable. Time-dependent outcomes, including time to first recurrence and recurrence-free survival, will be analyzed using the Kaplan-Meier method and the Log-rank test. Competing risk models may be used to account for death or liver transplantation as competing events. Cox proportional hazards regression models will be used to explore factors associated with clinical outcomes. Microbiome data will be analyzed using diversity analysis, donor-recipient similarity assessment, changes in dominant bacterial taxa, and correlation or multivariable models to explore the relationship between gut microbiota dynamics and clinical outcomes.

• Study Type: Interventional
• Enrollment (Estimated): 26
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Guohong HAN, Professor; Phone Number: 13991969930; Email: 13991969930@126.com

Study Locations

• China
  • Xi'an, China
    • Recruiting
    • Xi'an International Medical Center Hospital
    • Contact: Guohong HAN, Professor; Phone Number: 13991969930; Email: 13991969930@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age: 18 - 75 years old, both genders are eligible
• Successful implementation of covered stent TIPS
• Those who experienced recurrence of hepatic encephalopathy after TIPS surgery and still used lactulose and rifaximin (within 6 months after intervention with rifaximin and lactulose, West Haven grade ≥ 2 hepatic encephalopathy occurred at least 2 times)
• Meet the conditions for receiving fecal microbiota transplantation through nasogastric tube (no severe anatomical abnormalities in the upper digestive tract; basic intestinal motility is normal; can tolerate the insertion of nasogastric tube and the subsequent infusion process)
• Obtain the patient's written informed consent

Exclusion Criteria:

• Patients with active gastrointestinal bleeding or perforation accompanied by severe damage to the intestinal barrier due to various reasons
• Patients with congenital or acquired immunodeficiency diseases, those who have received high-risk immunosuppressive or cytotoxic drug treatment within the recent 3 months, and those with severe immunosuppression (neutrophil count < 1.5×10⁶ cells/L; CD4+ T cell count < 2.0×10⁵ cells/L)
• Patients with malignant tumors of the liver or gastrointestinal tract, patients with spontaneous bacterial peritonitis, and patients with Budd-Chiari syndrome
• Patients with severe heart, kidney, or lung dysfunction (NYHA III-IV grade or unstable heart failure; eGFR < 30 ml/min/1.73m² or requiring dialysis; respiratory failure or requiring long-term oxygen therapy)
• Unstable vital signs (body temperature, heart rate, blood pressure, breathing)
• History of gastrointestinal surgery within the past 3 months, such as colon resection
• Patients planning to undergo liver transplantation within 6 months
• Patients who have undergone FMT within the past 3 months
• Alcohol dependence or use of psychotropic drugs (benzodiazepines, opioids, etc.)
• Other neurological and psychiatric disorders, including dementia, Parkinson's disease, and post-stroke sequelae
• Pregnant or lactating subjects
• Subjects considered to have poor compliance by the investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fecal Microbiota Transplantation; The fecal microbiota was transplanted via nasojejunal tube infusion. The infusion protocol was 100 mL per time, twice a day, for three consecutive days. The donor was strictly screened for infectious diseases and fecal pathogenic microorganisms, and was free of pathogenic bacteria and rich in beneficial bacteria such as Lachnospiraceae, Ruminococcaceae and Bifidobacteriaceae. The fecal microbiota preparation was prepared under sterile conditions and stored in a standardized manner.	Biological: Fecal Microbiota Transplantation; Fecal microbiota transplantation is used to reconstruct gut microbiota structure, regulate intestinal microecological homeostasis, improve intestinal barrier function, reduce systemic endotoxin load and inflammatory level, for the prevention and treatment of refractory hepatic encephalopathy after TIPS. The preparation is made from stool of qualified screened donors, processed under sterile conditions.; Other Names: FMT; Drug: Rifaximin、Lactulose; Rifaximin is a non-absorbable oral rifamycin antibiotic, used as standard medical therapy for hepatic encephalopathy, to reduce intestinal urease-producing bacteria and intestinal ammonia production.Lactulose is a synthetic disaccharide laxative, used as first-line standard medical therapy for hepatic encephalopathy, to acidify the intestinal lumen, reduce ammonia production and promote ammonia excretion.
Experimental: Fecal Microbiota Transplantation plus Prebiotic Group; Participants in this arm received the same fecal microbiota transplantation protocol as the fecal microbiota transplantation group. The fecal microbiota was transplanted via nasojejunal tube infusion at a dose of 100 mL per administration, twice daily, for three consecutive days. The donor was strictly screened for infectious diseases and fecal pathogenic microorganisms, and the fecal microbiota preparation was prepared under sterile conditions and stored in a standardized manner. In addition to fecal microbiota transplantation, participants received dietary fiber prebiotic supplementation at a total dose of 24 g per day, administered as 12 g twice daily, starting on the day of fecal microbiota transplantation and continuing for four weeks. All participants continued standard medical therapy with rifaximin and lactulose during the study period.	Biological: Fecal Microbiota Transplantation; Fecal microbiota transplantation is used to reconstruct gut microbiota structure, regulate intestinal microecological homeostasis, improve intestinal barrier function, reduce systemic endotoxin load and inflammatory level, for the prevention and treatment of refractory hepatic encephalopathy after TIPS. The preparation is made from stool of qualified screened donors, processed under sterile conditions.; Other Names: FMT; Drug: Rifaximin、Lactulose; Rifaximin is a non-absorbable oral rifamycin antibiotic, used as standard medical therapy for hepatic encephalopathy, to reduce intestinal urease-producing bacteria and intestinal ammonia production.Lactulose is a synthetic disaccharide laxative, used as first-line standard medical therapy for hepatic encephalopathy, to acidify the intestinal lumen, reduce ammonia production and promote ammonia excretion.; Dietary supplement: Dietary Fiber Prebiotic; Participants assigned to the FMT plus prebiotic group will receive dietary fiber prebiotic supplementation in addition to fecal microbiota transplantation and standard medical therapy. The prebiotic will be administered at a total dose of 24 g per day, given as 12 g twice daily, starting on the day of fecal microbiota transplantation and continuing for four weeks. Standard medical therapy with rifaximin and lactulose will be continued during the study period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of treatment-related adverse events (AEs) and serious adverse events (SAEs)	Record the number, incidence, severity (graded by NCI-CTC v3.0 criteria), correlation with trial intervention, and outcome of all AEs, FMT-related AEs and SAEs in subjects from randomization to the end of follow-up. Key monitoring includes gastrointestinal reactions, infection, exacerbation of hepatic encephalopathy and other intervention-related adverse events.	From the date of randomization to the end of 6-month follow-up after intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The colonization status of the intestinal microbiota	The survival rate (%) of the donor microbiota in the patient's intestinal tract	Baseline, 15 days after intervention, 1 month after intervention, 3 months after intervention, 6 months after intervention
Changes in the α diversity of the intestinal microbiota	Using metagenomic sequencing technology, the α diversity of the intestinal microbiota (Shannon index, Simpson index) was evaluated.	Baseline, 15 days after intervention, 1 month after intervention, 3 months after intervention, 6 months after intervention
Reversal time of hepatic encephalopathy	The reversal time of hepatic encephalopathy is defined as the time required from the start of fecal microbiota transplantation treatment until the patient's clinical consciousness state recovers to the remission state of hepatic encephalopathy. Hepatic encephalopathy remission is defined as a significant improvement in the West Haven classification compared to the baseline and a return to grade 0-1, with significant relief of related neurological and mental symptoms. The reversal time is recorded in hours or days and is used to assess the speed of improvement in hepatic encephalopathy after treatment.	Throughout the entire period from the end of the intervention to 6 months after the intervention
Recurrent rate of hepatic encephalopathy	The recurrent rate of hepatic encephalopathy is defined as the proportion of subjects who experienced overt hepatic encephalopathy again during the follow-up period after receiving fecal microbiota transplantation treatment. Overt hepatic encephalopathy is evaluated according to the West Haven classification, and is defined as a hepatic encephalopathy event with a West Haven grade of ≥2. During the study period, the time of the first recurrence, the number of recurrences, and the severity of recurrence of the subjects were recorded, and the recurrence rates at each follow-up time point and throughout the entire follow-up period were calculated.	Throughout the entire period from the end of the intervention to 6 months after the intervention

Collaborators and Investigators

• Sponsor: Air Force Military Medical University, China
• Investigators: Study Chair: Guohong HAN, Professor, Xi'an International Medical Center Hospital; Principal Investigator: Guohong HAN, Professor, Xi'an International Medical Center Hospital; Study Director: Mingtao ZHAO, Xi'an Jiaotong University; Study Director: Heng ZENG, Xi'an International Medical Center Hospital; Study Director: Na ZHANG, Xi'an International Medical Center Hospital; Study Director: Zhengyu WANG, Xi'an International Medical Center Hospital; Study Director: Bohan LUO, Xi'an International Medical Center Hospital; Study Director: Yiwei SHANG, Xi'an International Medical Center Hospital; Study Director: Jing LI, Xi'an International Medical Center Hospital

Publications and helpful links

General Publications

• Bajaj JS, Kassam Z, Fagan A, Gavis EA, Liu E, Cox IJ, Kheradman R, Heuman D, Wang J, Gurry T, Williams R, Sikaroodi M, Fuchs M, Alm E, John B, Thacker LR, Riva A, Smith M, Taylor-Robinson SD, Gillevet PM. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial. Hepatology. 2017 Dec;66(6):1727-1738. doi: 10.1002/hep.29306. Epub 2017 Oct 30.
• Bajaj JS, Fagan A, Gavis EA, Sterling RK, Gallagher ML, Lee H, Matherly SC, Siddiqui MS, Bartels A, Mousel T, Davis BC, Puri P, Fuchs M, Moutsoglou DM, Thacker LR, Sikaroodi M, Gillevet PM, Khoruts A. Microbiota transplant for hepatic encephalopathy in cirrhosis: The THEMATIC trial. J Hepatol. 2025 Jul;83(1):81-91. doi: 10.1016/j.jhep.2024.12.047. Epub 2025 Jan 10.
• Bajaj JS, Salzman NH, Acharya C, Sterling RK, White MB, Gavis EA, Fagan A, Hayward M, Holtz ML, Matherly S, Lee H, Osman M, Siddiqui MS, Fuchs M, Puri P, Sikaroodi M, Gillevet PM. Fecal Microbial Transplant Capsules Are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo-Controlled Trial. Hepatology. 2019 Nov;70(5):1690-1703. doi: 10.1002/hep.30690. Epub 2019 Jun 18.
• Bloom PP, Donlan J, Torres Soto M, Daidone M, Hohmann E, Chung RT. Fecal microbiota transplant improves cognition in hepatic encephalopathy and its effect varies by donor and recipient. Hepatol Commun. 2022 Aug;6(8):2079-2089. doi: 10.1002/hep4.1950. Epub 2022 Apr 5.
• Quan X, Li Y, Wu H. Reply to "Probiotics for Hepatic Encephalopathy Prevention After TIPS: Still an Open Question". Liver Int. 2025 Nov;45(11):e70383. doi: 10.1111/liv.70383. No abstract available.
• Li M, Li K, Tang S, Lv Y, Wang Q, Wang Z, Luo B, Niu J, Zhu Y, Guo W, Bai W, Wang E, Xia D, Wang Z, Li X, Yuan J, Yin Z, Trebicka J, Han G. Restoration of the gut microbiota is associated with a decreased risk of hepatic encephalopathy after TIPS. JHEP Rep. 2022 Feb 15;4(5):100448. doi: 10.1016/j.jhepr.2022.100448. eCollection 2022 May.
• Porcari S, Ciccarese C, Heidrich V, Rondinella D, Quaranta G, Severino A, Arduini D, Buti S, Fornarini G, Primi F, Stumbo L, Giannarelli D, Giudice GC, Damassi A, Giron Berrios JR, Puncochar M, Barbazuk TB, Piccinno G, Pinto F, Armanini F, Asnicar F, Schinzari G, Derosa L, Kroemer G, Sanguinetti M, Masucci L, Gasbarrini A, Tortora G, Cammarota G, Zitvogel L, Segata N, Iacovelli R, Ianiro G. Fecal microbiota transplantation plus pembrolizumab and axitinib in metastatic renal cell carcinoma: the randomized phase 2 TACITO trial. Nat Med. 2026 Apr;32(4):1316-1324. doi: 10.1038/s41591-025-04189-2. Epub 2026 Jan 28.
• Duttagupta S, Messaoudene M, Hunter S, Desilets A, Jamal R, Mihalcioiu C, Belkaid W, Marcoux N, Fidelle M, Suissa D, Ponce M, Geiger M, Malo J, Piccinno G, Puncochar M, Filin A, Heidrich V, Rusu D, Mbaye B, Durand S, Ben Aissa I, Puller V, de Lahondes R, Blais N, Tehfe M, Owen S, Belanger K, Parvathy SN, Shieh B, Raphael J, Lenehan J, Breadner D, Rothenstein J, Rozza N, Maillou J, Nili S, Prifti DK, Pinto F, Armanini F, Kim-Schulze S, Marron TU, Kroemer G, Derosa L, Zitvogel L, Silverman M, Segata N, Maleki Vareki S, Routy B, Elkrief A. Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial. Nat Med. 2026 Apr;32(4):1337-1350. doi: 10.1038/s41591-025-04186-5. Epub 2026 Jan 28.
• Fernandes R, Jabbarizadeh B, Rajeh A, Hong MMY, Baines KJ, Ernst S, Winquist E, Ali AS, Penny S, Figueredo R, Parvathy SN, Lenehan JG, Pinto DM, Silverman MS, Maleki Vareki S. Fecal microbiota transplantation plus immunotherapy in metastatic renal cell carcinoma: the phase 1 PERFORM trial. Nat Med. 2026 Apr;32(4):1325-1336. doi: 10.1038/s41591-025-04183-8. Epub 2026 Jan 28.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2026
• Primary Completion (Estimated): January 31, 2027
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: June 29, 2026
• First Submitted That Met QC Criteria: June 29, 2026
• First Posted (Actual): July 6, 2026

Study Record Updates

• Last Update Posted (Actual): July 6, 2026
• Last Update Submitted That Met QC Criteria: June 29, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Fecal Microbiota Transplantation; TIPS; Hepatic Encephalopathy; Refractory Hepatic Encephalopathy
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolic Diseases; Digestive System Diseases; Liver Diseases; Brain Diseases, Metabolic; Liver Failure; Hepatic Insufficiency; Nutritional and Metabolic Diseases; Hepatic Encephalopathy; Therapeutics; Biological Therapy; Fecal Microbiota Transplantation
• Other Study ID Numbers: TIPS-HE-FMT002

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No