Gut Microbiota Changes After Fecal Microbiota Transplantation

The exact mechanism by which FMT is effective is presently unknown. A recent study of 14
patients with recurrent CDI treated with FMT35 showed decreased diversity pre-FMT with gut
microbiota becoming more diverse and similar to donors post-FMT. This group showed
significant changes in 3 taxonomic orders but no single organism or species was universally
associated with success. Weingarden et al. showed that FMT restored normal bile acid
composition in patients with recurrent CDI36, suggesting that correction of bile acid
metabolism is likely a major mechanism by which FMT results in a cure and prevents
recurrence of CDI. Understanding mechanisms of FMT more completely may enable development of
synthetic microbiota-based therapeutics which would be a safe and effective alternative to
traditional FMT. We hypothesize that early changes in distal gut microbiota post-FMT may
help identify key species associated with efficacy. Furthermore, we believe there are
measurable metabolic and immunologic effects which may also be beneficial after FMT. This
study aims to document early changes in the distal gut microbiota (both fecal and
mucosa-associated) post FMT. Furthermore, whole blood and urine samples will facilitate
collaborative immunologic and metabolomic analyses.

This will be an open label clinical trial of FMT to prevent further recurrence in patients
who have suffered at least a third episode of Clostridium difficile infection (CDI) and who
have previously been treated with oral vancomycin. Subjects will consist of 6 adult
outpatients referred after 3 (or more) episodes of CDI. Subjects, who will have been treated
with at least a 10 day course of anti-CDI therapy (metronidazole, vancomycin or fidaxomicin)
for the most recent acute infection, will then receive FMT with donor stool administered at
the time of sigmoidoscopy. After the procedure, subjects will be followed for 8 weeks for C.
difficile recurrence. Subjects who relapse during that period will be offered a repeat FMT
using donor stool. We plan to collect baseline and post-FMT stool samples for microbiome
analyses as well samples of urine and blood for metabolomic and immunologic studies.
Subjects will be contacted at 24 weeks to assess long term safety outcomes

Inclusion Criteria:

- Adult outpatients (age ≥18 and ≤90) referred to Dr. Kelly after suffering a third (or
further) documented episode CDI and 2) who have failed to maintain CDI cure after
standard therapy.

- Previous treatment with at least one course of tapered/pulse dose vancomycin as
per SHEA-IDSA C difficile treatment guidelines or

- Inability to taper or stop anti-CDI therapy without developing diarrhea
requiring anti-infective therapy

Exclusion Criteria:

- • Patients who are pregnant

- Patients who are nursing

- Patients who are incarcerated

- Patients with cognitive impairment or severe neuropsychiatric co morbidities who
are incapable of giving their own informed consent

- Patients who are immunocompromised specifically:

- HIV infection (any CD4 count)

- AIDS-defining diagnosis or CD4<200/mm3

- Inherited/primary immune disorders

- Immunodeficient or Immunosuppressed due to medical condition/medication:

- Current or recent (<3 most) treatment with anti-neoplastic agent

- Current or recent (<3 mos) treatment with any immunosuppressant medications
(including but not limited to monoclonal antibodies to B and T cells,
anti-TNF agents, glucocorticoids, antimetabolites (azathioprine,
6-mercaptopurine), calcineurin inhibitors (tacrolimus, cyclosporine),
mycophenolate mofetil). Subjects who are otherwise immunocompetent and have
discontinued any immunosuppressant medications 3 or more months prior to
enrollment may be eligible to enroll.

- Patients with a history of severe (anaphylactic) food allergy

- Patients who have previously undergone FMT

- Patients who are unwilling or unable to undergo sigmoidoscopy

- Patients with untreated, in-situ colorectal cancer

- Patients with a history of inflammatory bowel disease (ulcerative colitis,
Crohn's disease or microscopic colitis) or diarrhea-predominant irritable bowel
syndrome

- Unable to comply with protocol requirements

- Patients who are American Society of Anesthesiologists (ASA) Physical Status
classification IV and V

- Patients with acute illness or fever on the day of planned FMT will be excluded
(not undergo randomization or treatment with FMT) with the option of including
that subject at a future date.