Randomized Controlled Trial of Fecal Microbiota Transplantation in Severe Obesity (RCTFMTOb)

Norwegian University of Science and Technology, Lovisenberg Diakonale Hospital, Nordlandssykehuset HF, Helse Nord, University of Tromso, Norwegian University of Life Sciences, University of Oslo

This is a randomized, double-blinded and placebo controlled prospective trial with sixty patients to investigate the effect of fecal microbiota transplantation (FMT) on body weight in patients with severe obesity. We will also collect data that possibly could give a better understanding of mechanisms of this correlation.

Obesity is a main threat to public health in western countries. This condition increases the risk of developing type 2 diabetes, cardiovascular diseases, physical stress disorders, dispose for cancer and contributes to increased overall morbidity and mortality. However sustained weight loss lead to the reduction of risk factors and improvement of several obesity related co-morbidities. Currently there are mainly two established treatments for severe obesity: a conservative approach through lifestyle intervention and a surgical approach with bariatric surgery. The gut microbiota is recognized as an environmental modulator of nutritional uptake and body weight. This has led to the hypothesis that the gut microbiota could be a therapeutic target fighting obesity. Fecal microbiota transplantation (FMT) has been applied for more than 50 years, and is a established treatment for refractory recurrent infection with Clostridium Difficile (CDI). Recent scientific studies have also applied FMT as treatment for other diseases like inflammatory bowel disease, irritable bowel disease and even metabolic syndrome and the results are promising. The sample size is determined based on data from the outpatient clinic at UNN Harstad medical department. Patients here have an average weight loss of 2,5 % with conservative treatment. This will therefore be the expected result in the control group (receiving placebo). A weight reduction of 5-10% leads to significant improvement of health and quality of life, and a weight change of this magnitude is therefore the hypothesis. The difference between the two groups is estimated to 7,5 %. With these historical results, the sample size is estimated to be 19 patients in each group. Extreme values will be eliminated; more than 3 SD out of the average in the group. In this patient group, we must also be prepared to high degree loss of follow-up near one third, which is also the experience from the clinic. We will include totally 60 patients, 30 in each group. The investigators are planning a randomized, double-blinded and placebo controlled prospective trial with sixty patients to investigate the effect of fecal microbiota transplantation (FMT) on body weight in patients with severe obesity. In the trial there will also be collected data that possibly could give a better understanding of mechanisms of this correlation; with insulin resistance, blood pressure, complete body scan, inflammation and biochemical parameters of hepatic steatosis, changes in the patients microbiota and the development in quality of life as secondary outcome measures.

Active Comparator. Transplant from Donor A or Donor B, or Donor C or Donore D, one transplant consist of 50-80g of feacal matter.

The intervention treatment is fecal microbiota transplantation made of frozen donor feces. The FMT is transferred as rectal enema where we use a rectal probe with a balloon to prevent leakage and keep the solution long enough in the colon. The patient will stay on the bench in different positions for 20 minutes. We will encourage the participant to keep the solution in the colon as long as possible and give them four pills of loperamide before the procedure in order to reduce bowel motility.

The placebo group get fecal microbiota transplantation made of their own feces. The FMT is transferred as rectal enema where we use a rectal probe with a balloon to prevent leakage and keep the solution long enough in the colon. The patient will stay on the bench in different positions for 20 minutes. We will encourage the participant to keep the solution in the colon as long as possible and give them four pills of loperamide before the procedure in order to reduce bowel motility.

Partisipants will be measured at the outpatient clinic, medical department UNN Harstad, and weight in kilograms (kg) will be recorded. The data will be represented both as average weight change and as bar charts with >10%, with comparison between the intervention and control group. Chi Square or Fischer exact test will be used to present responders and non-responders in the active and controll group. We will use odds ratio to present responders in the active group.

Partisipants will be measured at the outpatient clinic, medical department UNN Harstad, and weight in kilograms (kg) will be recorded. The data will be represented both as average weight change and as bar charts with >5%, >15% and >20% weight loss, with comparison between the intervention and control group at each controll point. Chi Square or Fischer exact test will be used to present responders and non-responders in the active and controll group. We will use odds ratio to present responders in the active group.

Participants will be measured at the outpatient clinic, medical department UNN Harstad, and waist circumference (cm) will be recorded.

Together with C-peptide, fasting glucose and insuline it will be used to research insuline resistance.

Together with HbA1c, C-peptide, and insuline it will be used to research insuline resistance and calculate HOMA-IR and HOMA-B

Together with HbA1c, C-peptide, and fasting glucose it will be used to research insuline resistance and calculate HOMA-IR and HOMA-B

Participants blood pressure (mmHg) will be measured at the outpatient clinic, medical department UNN Harstad. Blood pressure is collected as the average of the last two out of three measurements, at the end of 5 min resting period in supine position.

We will measure sedimentation rate, and together with hs-CRP and cytokine panel we will investigate inflamation between the group recieving placebo and the group recieving active transplant.

We will measure hs-CRP, and together with sedimentation rate and cytokine panel we will investigate inflamation between the group recieving placebo and the group recieving active transplant.

We will run a multiplex cytokinepanel consiting of 27 different cytokines to see if the consentration of blood cytokines changes in participants after active treatment/placebo. The cytokine panel consists of TNF-a, IFN-g, IL-1b, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12(p70), IL-13, IL-15, IL-17A, MCP-1(MCAF), IP-10, Eotaxin, MIP-1a, MIP-1b, RANTES, G-CSF, GM-CSF, Basic FGF, PDGF-BB, VEGF.

Photometric analysis. We will measue AST, ALT, ALP, ɣGT and amylase to look at changes in biochemical parameters of hepatic steatosis between the group recieving placebo and the group recieving active transplant

Photometric analysis. Changes in cholesterol and HDL/LDL be used to look at changes in lipid profile between the group recieving placebo and the group recieving active transplant

RAND-36- Item Short Form Health Survey. The SF-36 consists of eight scaled scores (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning and mental health), which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. By an independent sample T-test (or, if necessary, non-parametric Mann-Whitney) we will compare change in global score. We will apply last value forward for missing values

HSCL-25. Consists of 25 questions. Each answer to a question has a value of 1-4. A total score over 1,75 points to psychological issues or impaired mental health

FFQ Change in dietary intakes measured using Food Frequency Questionnaire at baseline and at 3, 6 and 12 months after FMT will be examined. Energy measured as kcal, nutrition (gram) and different food groups reported as gram/day

IPAQ Categorical Score Three levels (categories) of physical activity are proposed: Category 1: Low This is the lowest level of physical activity. Those individuals who not meet criteria for categories 2 or 3 are considered low/inactive. Category 2: Moderate Any one of the following 3 criteria: 3 or more days of vigorous activity of at least 20 minutes per day OR 5 or more days of moderate-intensity activity or walking of at least 30 minutes per day OR 5 or more days of any combination of walking, moderate-intensity or vigorous intensity activities achieving a minimum of at least 600 MET-min/week. Category 3: High Any one of the following 2 criteria: Vigorous-intensity activity on at least 3 days and accumulating at least 1500 MET-minutes/ week OR 7 or more days of any combination of walking, moderate-intensity or vigorous intensity activities achieving a minimum of at least 3000 MET-minutes/week

A dysbiotic gut microbiota that signals with the vagal nerve can cause an exaggerated stress response in obesity characterised by decrease in heart rate variability.

Comparison between baseline profile, post FMT and donor profile will show if engraftment of donor microbiota parallels clinical response to active FMT.

Participants which had undergone intervention and were in the follow up period, had all their appointments at the obesity clinic at UNN Harstad canceled, due to the covid-19 outbreak in the period march-20 to juli-20. This might have impacted their weight loss motivation and life style changes. We therefore asked them five questions, which we hope will shed light on the challenges they might encountered during the period of restrictions implemented by the Norwegian government.

Inclusion Criteria: BMI > 40 or BMI > 35 kg/m2 combined with comorbidity related to obesity. Exclusion Criteria: Symptomatic cardiovascular disease, lung disease, cirrhosis or significant renal failure. Patients who are pregnant or breastfeeding Patients who have a confirmed malignancy or cancer Patients who are immunocompromised Previous gastric or small intestinal surgery that alters gut anatomy such as fundoplication, gastric resection, gastric bypass, small bowel resection, and ileoectomy Established drug- or alcohol abuse or particularly unstable psychosocial circumstances. History of cholecystektomy (gut microbiota composition could be affected by bile acid composition) New drugs the last three months or during the follow-up period that can impact on metabolism or body weight Antibiotic treatment the last three months