Microbiota augmentation to restore healthy gut bacteria in hospitalized liver patients

The Microbiota Augmentation to Reestablish Commensal Organisms (MARCO) Trial

This trial will test whether giving defined groups of healthy gut bacteria is safe and can restore key gut metabolites in hospitalized adults with liver disease who have low fecal butyrate and deoxycholic acid.

Quick facts

• Phase: PHASE1
• Study type: Interventional
• Enrollment: 24 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of Chicago (other)
• Drugs / interventions: rituximab, prednisone
• Locations: 1 site (Chicago, Illinois)
• Trial ID: NCT06871111 on ClinicalTrials.gov

What this trial studies

The MARCO trial is a single-center, adaptive phase 1b study at the University of Chicago enrolling hospitalized adults with liver disease and low fecal butyrate and deoxycholic acid. Participants receive one of several live commensal consortia, each made of eight bacterial strains from healthy donors, with an initial cohort of eight patients given the same combination for seven doses. Safety and tolerability are the primary endpoints, while fecal samples will be analyzed for engraftment of administered strains and for changes in bacterial metabolite production as exploratory outcomes. The adaptive design allows sequential testing of additional consortia based on safety and early biological signals.

Who should consider this trial

Good fit: Hospitalized adults (age ≥18) with liver disease or cirrhosis admitted for hepatic decompensation, MELD ≤30, and documented low fecal butyrate (≤700 µM) and deoxycholic acid (≤10 µM) are the intended participants.

Not a fit: Patients with very advanced or unstable liver disease (e.g., MELD >30), those who do not meet the low fecal metabolite thresholds, or people not hospitalized for decompensation are unlikely to benefit from this study.

Why it matters

Potential benefit: If successful, the approach could safely rebuild beneficial gut bacteria and increase protective metabolites, potentially lowering infection risk and repeat liver decompensation.

How similar studies have performed: Prior work with fecal microbiota transplantation and defined bacterial consortia has shown biological effects on microbiome composition and metabolites in other conditions, but rigorous safety and efficacy data in decompensated liver disease are limited.

Eligibility criteria

Inclusion Criteria:

* Age 18 years or older
* Diagnosis of liver disease, liver failure, and/or cirrhosis
* All patients will be hospitalized and have a hepatology consult in place.
* They will be identified as having liver disease, liver failure, and/or cirrhosis based on a combination of at least one of the following:

  * Labs demonstrating elevated liver chemistries (AST and ALT), elevated serum bilirubin levels, prolonged INR, or radiologic evidence of cirrhosis (e.g. nodular liver contour);
  * Liver biopsy results; and/or
  * Clinical or radiologic evidence of portal hypertension (e.g. splenomegaly, known varices, ascites, or hepatic venous pressure gradient ≥ 10mmHg).
  * All diagnoses will be confirmed by the attending hepatologist's interpretation and consult note attestation.
* Admitted to the hospital for hepatic decompensation
* MELD score ≤ 30 at time of enrollment
* Subject has ≤ 700µM butyrate and ≤ 10µM deoxycholate in fecal sample

Exclusion Criteria:

* MELD score \>30 at time of enrollment
* Patients receiving any antibiotics for treatment of an infection.
* Chronic or prophylactic antibiotic administration other than rifaximin, ciprofloxacin, or trimethoprim-sulfamethoxazole.

  -Rifaximin will be either temporarily held or switched to another non-antibiotic therapy (e.g. lactulose or sodium benzoate) during the treatment phase of the trial. Potential subjects in whom the treating hepatologist deem it unsafe to pause or switch from Rifaximin therapy during the 7-10 day treatment phase will be excluded from the study.
* Patients who are currently admitted to the intensive care unit for vasoactive support or mechanical ventilation.
* Patients meeting the North American Consortia for Study of End Stage Liver Disease (NACSELD) criteria for acute-on-chronic liver failure (ACLF) with ≥ 2 organ failures by NACSELD-ACLF criteria at time of enrollment.
* Patients with known intestinal barrier dysfunction, including active GI bleeding, enteropathy (including celiac disease), clinically active inflammatory bowel disease (Crohn's or Ulcerative Colitis), ischemic colitis, microscopic colitis, graft versus host disease (GVHD), or gastrointestinal malignancy.

  o Active inflammatory bowel disease (IBD) will be defined based on a combination of:
  * Symptoms (diarrhea and/or abdominal pain without another explanation)
  * Laboratory evidence of inflammation (e.g. elevated CRP or fecal calprotectin without another explanation); and
  * Either radiologic, endoscopic, and/or histologic evidence of active IBD.
  * If IBD is suspected, this will be investigated with the general GI consult service prior to approaching for enrollment.
  * If patients carry a diagnosis of IBD but do not meet the above criteria, they will be eligible for enrollment unless their IBD is managed with a systemic immunosuppression medication (e.g. anti-TNF-alpha therapy).
  * If any form of the above intestinal disorders is suspected, they will be investigated with the general GI consult service prior to approaching for enrollment.
* Profoundly immunocompromised patients, including patients with primary immunodeficiency, solid organ transplant recipients, any history of hematopoietic stem cell transplant (HSCT), ongoing cancer treatment, neutropenia \< 500 cells/mm3, HIV untreated or with CD4 \< 200 cells/mm3, immunosuppressive medications, including rituximab, anti-cytokine therapy, anti-rejection medications, chronic corticosteroids (a dose ≥ 20mg of prednisone daily for ≥ 1 month), biologic therapy for autoimmune condition.
* Patients with delayed gastrointestinal motility as evidenced by ≤ 2 bowel movements per week at the time of enrollment.
* Patients who are allergic to both ampicillin/sulbactam and meropenem.

  * These are the two empiric antibiotic therapies that every strain is susceptible to.
  * If a patient is allergic to only one of these medications, they may still be approached for enrollment.
* A history of allergy to any of the investigational products/components.
* Patients with liver disease from Hepatitis C.
* Patients with existing inflammatory arthritis.
* History of total colectomy.
* Patients who do not intend to continue their care on a routine basis at the University of Chicago beyond 6 months from the time of enrollment.
* Patients with untreated psychiatric conditions, including illicit substance use disorders, that may interfere with reliable follow-up.
* Unable to participate based on medical judgement of the care team.
* Special populations:

  * Women of childbearing age will have a:

    * Negative serum pregnancy test at screening
    * Use a medically acceptable and highly effective method of birth control for at least 6 weeks following completion of treatment.
  * Another investigational drug or LBP:

    * Prior use will be permitted;
    * Concurrent use will preclude enrollment;
    * Use will be restricted for the duration of the study (12 months after commensal consortia completion)
  * Patients who are prescribed ACE-inhibitors and receive a consortium containing C. comes will receive more frequent blood pressure monitoring.
  * Patients who are prescribed metformin will require either:

    * Switch to another medication for diabetes control; or
    * More frequent Vitamin B12 monitoring at 1, 3, 6, and 12 months of enrollment.
* If a Vitamin B12 deficiency is discovered, it will be repleted as clinically indicated.

Where this trial is running

Chicago, Illinois

• The University of Chicago Medical Center — Chicago, Illinois, United States (RECRUITING)

Study contacts

• Study coordinator: Matthew A Odenwald, MD, PhD

Conditions: Liver Diseases, Liver Failure, Cirrhosis, Liver