Fecal Microbiota Transplant as Treatment of Hepatic Encephalopathy
Fecal Microbiota Transplant as Treatment of Hepatic Encephalopathy
A common complication of advanced liver disease is a condition called hepatic encephalopathy,
 which leads to confusion. The current treatment options cause side effects, are costly, and
 do not always work. An abnormal population of bacteria in the intestines may be causing this
 condition, and transplanting bacteria from the colon of a healthy person may treat it. In
 this research study, the investigators will first find two healthy stool donors whose stool
 donation improves the gut bacteria of patients with advanced liver disease and helps them
 think more clearly. Then, in a randomized controlled trial, the investigators will compare
 the ability of stool donation from these two best donors versus a placebo to improve the
 neurological function of patients with advanced liver disease. If the investigators find the
 expected results, there will be a new effective therapy for patients with advanced liver
 disease and the very troublesome complication of hepatic encephalopathy.
Decades of investigation demonstrate that hepatic encephalopathy (HE), a common complication
 of cirrhosis characterized by impaired cognition, develops as a consequence of intestinal
 microbial products reaching the brain. Recent investigation has found that cirrhotic
 patients, especially those who have developed HE, have intestinal dysbiosis compared to
 normal controls. Several plausible mechanisms explain how intestinal dysbiosis could lead to
 HE. There is limited prior literature on the efficacy of FMT in cirrhosis. The largest
 documented study of 10 cirrhotic patients receiving a single FMT enema found no significant
 change in microbiome diversity as assessed by 16S rRNA sequencing. The investigators
 hypothesize that aggressive manipulation of the microbial composition with fecal microbiota
 transplant (FMT) will improve neurological function in patients with a history of cirrhosis
 and HE. The investigators additionally hypothesize that five oral FMT capsule administrations
 from a previously efficacious stool donor will significantly change the intestinal microbiome
 composition of a cirrhotic patient. The study will consist of a 10-patient open-label pilot
 study to identify efficacious stool donors, defined as donors who precipitate the largest
 improvement in recipient neurological function and microbiome composition. The two most
 efficacious pilot study stool donors will be selected to donate stool for the randomized
 controlled trial (RCT). The 20-patient RCT will investigate the effect of FMT on neurological
 outcomes in patients with cirrhosis and a history of HE. Subjects will be randomized to
 receive 5 doses of oral FMT capsules or placebo capsules over 21 days. Cognitive testing and
 stool collections will occur at 4 time points, to assess for changes in neurological function
 and microbiome composition. The primary outcome is change in neurological function after FMT.
 The main secondary outcome is change in microbiome composition after FMT. This study could
 provide valuable information about the ability of FMT to improve intestinal dysbiosis in
 cirrhosis and treat HE.
Inclusion Criteria:

 -  Diagnosis of cirrhosis: Based on liver biopsy or clinical assessment of a hepatologist
 based on history, exam, laboratory and radiographic evidence

 -  History of at least one episode of overt HE, defined by West Haven Criteria Grades II
 to IV; episodes of HE that were precipitated by gastrointestinal hemorrhage requiring
 transfusion of at least 2 units of blood, by medication use, by renal failure
 requiring dialysis, or by injury to the central nervous system will not be counted as
 previous HE episodes

 -  Compliant with lactulose and rifaximin treatment (lactulose: at least one dose at
 least 5 days per week; rifaximin: at least one dose at least 5 days per week)

 Exclusion Criteria:

 -  Current episode of overt HE as defined by West Haven Criteria Grades II to IV

 -  Expectation of liver transplantation within two months of the screening visit

 -  Current infection

 -  Variceal bleeding in the last 4 weeks

 -  Gut-absorbable or intravenous antibiotic therapy (including ciprofloxacin for SBP
 prophylaxis) in the last 3 months

 -  Alcohol or illicit drug intake within 3 months, by history and available serum
 testing; alcohol use will be characterized as >1 alcoholic drink / month

 -  PSC as etiology of liver disease, as prior literature has suggested these individuals
 have a unique microbiome

 -  History of Roux-en-Y Gastric bypass

 -  On immunosuppressive medications

 -  Positive C. difficile test

 -  Scoring above a threshold cut-off on the Psychometric Hepatic Encephalopathy Score
 (PHES)

 -  MELD > 17

 -  History of spontaneous bacterial peritonitis

 -  History of low ascites protein ( ≤ 1g/dL) in the last year

 -  Hemodialysis in the last 30 days

 -  Other significant laboratory abnormalities: serum creatinine > 2.0 mg/dL, hemoglobin <
 8 g/dL, serum sodium < 125 mmol/L, serum calcium > 11.0 mg/dL, serum potassium < 2.5
 mmol/L

 -  Placement of a portosystemic shunt or transjugular intrahepatic portosystemic shunt

 -  Unstable doses of opiates, benzodiazepines or other sedating medication

 -  Unable to provide consent; a. If MMSE is < 18 or the patient is deemed to not have
 capacity by an investigator, a legally authorized representative (surrogate) will be
 allowed to provide consent