To better understand the role of the microbiota un PSC using fecal transplantation we will proceed in the following way.
- Performing 3-5 fecal transplantations in 3-5 days from a single donor to Davide Patti using fresh enema infusions, measuring the impact on following outcome measures: Repeat step 1 using different donors until a donor is found that yields fulfillment of outcome measures.
- Symptoms: Right upper quadrant pain, itching, dry eyes, energy levels
- Liver biochemistry markers, stool consistency
- Sequential trials for efficacy, noting outcome measure results:
- FMT using enema of frozen FMT sample
- Ingestion of frozen pills
- Find single PSC patient in stage 1 to try best solution found in step 2. using posology described in study “pattibiomed_psc1”.
- If results of 3 are encouraging start study “pattibiomed_psc1” using best dosage form found.
Study “pattibiomed_psc1”, Version 13.03.2018:
Choosing to participate in a study is an important personal decision. If you need help to decide if you want to participate you can talk with your doctor and family members or friends and you can get in touch with me; the author if you have any question (firstname.lastname@example.org).
Title: Using Fecal Microbiota Transplantation (FMT) to investigate the role of intestinal dysbiosis in cases of Primary Sclerosing Cholangitis.
Study Codename: pattibiomed_psc1
Status: Study design review with “epatocententro Ticino”, Switzerland”.
Study Sponsor: TBD
Information provided by (Responsible Party & Contact Person): Davide Patti, pattibiomed Ltd, email@example.com.
Purpose: The primary purpose of this open trial is to investigate the intestinal microbial abnormalities in patients with primary sclerosing cholangitis intervening with a fecal microbiota transplantation therapy.
Study Type: Interventional.
Study Design: Single Group Assignment. Masking: None (Open Label). Primary Purpose: Investigation. Secondary Purpose: Intent to treat.
Estimated Enrollment: Up to 6 patients for the FMT therapy & up to 12 patients for single sample microbiome sequencing.
Bias: The author is a PSC patient. The circumstances warrant that scientific rigor and depth of investigation will be sacrificed for speed and clinical relevance. The author has personally tried different dietary approaches, oral Vancomycin as well as FMT with the latter showing better results in symptoms and liver biochemistry. This is an independent research effort by Davide Patti (pattibiomed Ltd), anonymised results will be made available to the general public.
Study Rationale: The microbiota is suspected to play a central role in primary sclerosing cholangitis (PSC). Same as in other autoimmune diseases a considerable portion of recent research has been investigating the role of the microbiome. In this context, studies employing Vancomycin as a therapeutic approach to PSC have shown positive results, with improvement of symptoms, liver biochemistry as well as associated IBD activity. Furthermore PSC patients in personal contact with the author report halting or slowing down the progression of the disease with dietary approaches (low FODMAP or ketogenic or plant based diet).
Antibiotics and dietary interventions both directly modulate the intestinal microbiota. Another approach to directly influence the microbiota is the use of probiotics, with fecal matter being the strongest probiotic at our disposal today, by number of strains and number of microbes per strain.
In literature FMT has shown to be especially effective in ulcerative colitis and C.Diff. infections while the application on PSC in literature so far is limited to one successful case study, with an additional ongoing clinical trial with interim results here and reporting the therapy’s safety here. Although FMT can be an inconvenient treatment it is the author’s favourable approach considering the hypothesis described in the next paragraph.
The degree of results using oral Vancomycin vary from individual to individual with almost everyone experiencing a positive result. FMT on the other hand seems to either affect the patient positively or not at all, this considering the author’s experience, anecdotal experience of other patients as well as recently reported by the authors of the ongoing study mentioned previously, where 3 out of 6 patients responded to the therapy.
The Hypothesis: Due to the variable results in literature using antibiotics as well as anecdotal experience using antibiotics and/or dietary interventions to modulate the microbiota and improve disease activity, we can say that PSC is a multifactorial disease and/or a disease with multiple phenotypes . My theory is that at least one phenotype of PSC patients lack one or multiple essential microbes in their large intestine. This theory is advanced based on the three following observations:
- The microbiota is a complex microcosm and can be compared to the human society where we observe that a certain heterogeneity is required for a stable and healthy system.
- Fecal transplants (adding microbes from a healthy donor) can temporarily improve liver biochemistry.
- Vancomycin (reducing a selection of microbes) can temporarily improve liver biochemistry.
A disturbed equilibrium can be adjusted either by addition of what was removed or by removal of the antagonist.
Based on this hypothesis the author assumes that FMT sometimes does not work because the donor’s intestinal microbiota lacks microbes missing in the recipient’s intestinal microbiota / the recipient lacks some of the intestinal microbes to improve the pathogenic activity.
- Preparation: Moviprep the day of the start and prior to the first fecal transplant. The goal of the preparation is to empty out the large bowel which allows the first FMTs to better distribute on the intestinal wall of the colon.
- Treatment round of 5 fecal transplants in 5 weeks. Each fecal transplant consists of ingesting 30 capsules.
Primary Outcome Measures:
- Investigating the development of the patients’ microbiome pre, 2 weeks post, and 3 months post in relation to health markers (liver biochemistry, subjective symptoms).
- Investigating the microbiome of the PSC patient population, comparing with the ubiome database as well as with the donor’s microbiome.
- Investigating and comparing the microbiome of PSC patients who are directly modulating their microbiota (FMT or antibiotic or diet) with positive or negative clinical results.
Donor Selection: Donor requirements are listed on https://pattibiomed.com/fmt/fmt-donor-screening/. They are based on the most recent donor requirement recommendations from the 2017 EU Consensus Conference as well as the www.openbiome.org standards. The added requirements are a product of the author’s literature research. The donor was previously tested on a single PSC patient, with positive results.
- Inclusion criteria:
- Of age 16 and older.
- PSC diagnosis, stage 1 or 2 with elevated ALT and/or AST and/or ALP and/or bilirubin (total) or symptomatic (pruritus and/or right upper quadrant pain).
- Resident in the USA, CA, ZA and European territory.
- Exclusion criteria:
- Use of concomitant immunomodulators including methotrexate, mycophenolate mofetil, tacrolimus, cyclosporine, thalidomide, Interleukin-10, or Interleukin-11 within 4 weeks prior to starting with FMT.
- Patients who have a confirmed malignancy or cancer.
- Treatment within last 8 weeks with infliximab, adalimumab, certolizumab, natalizumab, vedolizumab or thalidomide.
- Current antibiotic.
- Participation in a clinical trial in the preceding 30 days or simultaneously during this trial.
- Congenital or acquired immunodeficiencies.
- Chronic kidney disease as defined by a GFR <60 mL/min/1.73m2 44.
- Steroid dose >20 mg/day.
The 12 patients for single sample microbiome must meet criteria 1a), 1b), 1c). The patient must meet one of the following criteria:
- Successfully using Vancomycin only.
- Unsuccessfully tried Vancomycin, no current medication.
- Successful with a dietary intervention only.
- With fast progressing PSC without antibiotic use.
- With slow progressing PSC without antibiotic use.
Outcome Measure Details (objective and subjective markers):
- Measured the week before intervention, 2 week after and 3 months after:
- Liver biochemistry: ALT, AST, ALP, GGT, direct and indirect Bilirubin
- Inflammatory markers: Ferritin, hsCRP
- Complete Blood Count
- Ubiome explorer microbiome sequencing. Phylum, Class, Order, Family, Genus, Species levels.
- Bristol Stool Scale
- Subjective symptoms: Right upper quadrant pain, pruritus, fatigue, digestive complaints, sleep
- Measured before and 3 months after:
Main Risks and Benefits:
- For the researchers:
- The eventual identification of relevant bacterial marker(s) is strong support of the advanced hypothesis.
- A 100% positive response rate to the therapy is strong support for the advanced hypothesis and would grant the effort to work on a treatment using the donor’s microbiota.
- For the patients:
- FMT is technically considered a low risk invasive procedure. The fecal solutions are prepared from a thoroughly screened, clinically tested donor and successfully used in a FMT on a PSC patient, this does not exclude there are risks associated with the therapy and using human stool. Reported side effects of FMT are generally mild and gastrointestinal in nature.
- There is evidence in literature suggesting FMT can improve IBD, especially UC, in particular within the first year after onset of the disease.
- In the author’s own experience and his experience helping others with the practice of FMT the positive effects in autoimmune diseases are generally temporary and patients can consider periodic top ups (1 weekly / 1 biweekly / 1 monthly). The author is willing to further supply the study participants with solutions from the same donor at a no profit cost (~35$ per sample) after completion of the experimental phase.
- There is one scientist executing the study. If circumstances should hinder the scientists from working on the study it could compromise the study’s outcome.
Study Phases (expected Duration):
- Gathering study funds and preparation (4 months)
- Implementation (10 months)
- Analyses and publishing (2+ months)
Remarks about FMT from the Author:
- In the author’s opinion the term “fecal microbiota transplant” is incorrect. Fecal microbial infusion or fecal probiotic infusion are the more correct terms.
- It is highly probable that the study won’t identify the mechanism(s) of how successful FMT might interrupt or slow down the pathogenic process of the disease. There are many pharmaceutical drugs whose mechanism of action we do not understand, mechanism that remains a hypothesis and/or whose therapeutic effect was discovered by chance or mistake. The author primarily wishes a safe and effective treatment, before understanding the mechanism of action.