Clinical trial NCT02970877: Stool Transplantation for Treatment of Insulin Resistance in Morbidly Obese Patients
Official title: Fecal Microbiota Transplant From Healthy Lean Donors to Morbidly Obese Individuals: Effect on Insulin Resistance and Other Obesity-related Parameters. A Randomized Controlled Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Obesity, Morbid
Insulin Resistance
Keywords: Fecal microbiota transplant
Intestinal microbiome
Mucosa associated microbiome
Appetite
Metabolome
Depression
Anxiety
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: MOUNT SINAI HOSPITAL
name: University of Toronto
First posted: 2016-11-22
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: More and more people in Canada and around the world are severely (morbidly) obese, and this is associated with a high risk for poor blood sugar control (insulin resistance, IR) and diabetes. Weight loss is often very hard to achieve for morbidly obese patients. Bariatric surgery is a very effective treatment, but it has some risks and is not available to all patients. Therefore, alternative treatments are needed.

The gut bacteria (intestinal microbiome) might play a role for the development of obesity and IR. Several studies in animals have shown that transferring stool from lean mice or humans into obese animals could lead to weight loss and improve IR. One human study has confirmed this. The investigators are therefore examining, whether transfer of stool from healthy lean people into morbidly obese patients with IR will improve blood sugar control, weight, and other obesity related parameters. This will be done in a randomized controlled trial. Effects on mental health and the bacterial in the mouth related to gum disease will also be assessed.

If successful, fecal transfer could be a new alternative treatment approach for morbidly obese patients or those with IR who do not have access to or do not want to undergo bariatric surgery.

Detailed description: The coupled disorders of morbid obesity and type 2 diabetes (T2D) are a major and growing public health problem in Canada. The Public Health Agency of Canada 2011 report, Obesity in Canada, showed that 5.1% and 2.7% of Canadians had obesity class II (body mass index (BMI) 35.0-39.9) and III (BMI \>40 kg/m2), respectively. Morbid obesity is associated with not only T2D (up to 42% of morbidly obese patients), but also cardiovascular complications, non-alcoholic fatty liver disease and sleep apnea, and the prevalence of psychiatric disorders, particularly depression and anxiety, is high in this population. As morbid obesity is very difficult to treat, drastic measures are required, and bariatric surgery is often the only viable treatment option. Bariatric surgery is nowadays a frequently performed procedure (about 400 surgeries/year at the University Health Network (UHN)), and there are different techniques, including gastric banding, sleeve gastrectomy, and Roux-en-Y gastric bypass. Of these procedures, the Roux-en-Y gastric bypass surgery has become the gold standard, and it is highly effective in inducing long-term weight loss and improving or even resolving all of the obesity associated comorbidities. However, bariatric surgery is invasive, costly, has a risk of complications, and requires life-long commitment to a restricted diet. Therefore, a significant proportion of patients with morbid obesity is not willing to undergo the procedure, and a small proportion is excluded from the procedure due to other physical or mental health problems.In addition, depending on the health care system, bariatric surgery might not be available to a large proportion of patients. Regarding the growing rates of obesity and morbid obesity world-wide, less expensive and less invasive alternatives to bariatric surgery are urgently needed.

Even though obesity largely results from an imbalance between energy intake and energy expenditure, it has been shown that several factors, including the genetic background can render individuals susceptible to obesity. Most recently, the role of the intestinal microbiome has been under investigation. It has been shown that obese people have an intestinal microbiome and metagenome that is significantly different from lean controls, and this is even true in identical twins discordant for obesity. In addition, patients with T2D have a different intestinal microbiome than controls. Work done in rodents showed that fecal microbiota transplant (FMT) from lean to obese animals (and vice versa) can affect fat mass and parameters of the metabolic syndrome. It is thus possible that FMT may benefit human obesity with related metabolic abnormalities. FMT is becoming standard therapy for patients with refractory Clostridium difficile colitis and may become a treatment option in other gastrointestinal disorders. Only one human study (n=9) investigated FMT from lean subjects to obese patients (\~BMI 35 kg/m2) with metabolic syndrome and showed improvement in insulin sensitivity. Taken altogether, these very exciting results led us to hypothesize that that FMT from healthy lean donors could effectively induce metabolic improvement (i.e. insulin resistance (IR)) and weight loss) by distinct microbe-specific mediated mechanisms. The investigators will examine this in a single-center, double-blind, randomized controlled parallel-group trial (RCT).

Furthermore, emerging evidence shows that the intestinal microbiome, through the gut-brain axis, can influence mood disorders. First animal studies suggest that FMT can transfer depression and anxiety and therefore, FMT from healthy individuals may provide some benefits. Therefore, the investigators will also assess, whether FMT influences depression and anxiety, which are highly prevalent in obese patients. Finally, our Canadian Institutes for Health Research (CIHR) Team Grant, which supports this RCT, is also studying the potential relationship between obesity, T2D and the oral microbiome (OM). Considering that microbes present in the saliva are swallowed in significant numbers-about 10\^12 oral bacteria per day-and that this may influence the composition of the intestinal microbiome, the investigators are also exploring the potential relationship between oral and intestinal microbiome and their associations with obesity and T2D. Having a FMT protocol gives us the unique opportunity to further assess this potential relationship and determine if FMT may change OM by improving obesity and metabolic parameters. This has not been previously studied in animals or humans.

The aims of this RCT are to assess whether FMT from healthy lean individuals into morbidly obese patients with IR who decline bariatric surgery, leads to 1) improvement in metabolic parameters: IR, BMI, and other obesity related parameters; 2) improvement in mood disorders: depression and anxiety scores; 3) changes in the intestinal microbiome and metabolome. 4) In addition, by assessing the OM through the FMT protocol and by combining these results with the results of our other protocols in a similar patient population going through bariatric surgery, the investigators will explore the relationship between oral/intestinal microbiome and obesity/metabolic parameters. 5) Furthermore, as planned in our CIHR Team Grant, the investigators will use the FMT from the lean donors and transfer into obese mice to assess the effect of FMT on mechanisms related to glucose metabolism. These additional experiments are not part of this protocol but are mentioned briefly, as stool samples and data from the patients and donors participating in the FMT trial will be used for the other studies in our CIHR Team Grant.

Significance. The number of obese patients is growing world-wide. The investigators are examining here a'medical bypass' solutions to treat the 40-50% of obese patients that meet the criteria set by the National Institutes for Health (NIH) for bariatric surgery (12, 36) but decline (13), or the much larger population of obese patients (BMI 30-40 kg/m2) who may not be considered for surgical treatment.

Eligibility criteria: Inclusion Criteria:

* Men and women
* age 18 years or older
* morbidly obese (BMI \>40 kg/m² or BMI \>35-40 kg/m² with other severe weight loss responsive comorbidities)
* referred to the Bariatric Clinic at the Toronto Western Hospital for weight loss surgery, but declining or deferring the surgery
* insulin resistance (HOMA-IR value \>2.73)

Exclusion Criteria:

* In the 3 months prior to study entry, regular intake of:

  * non-steroidal anti-inflammatory drugs;
  * iron supplements;
  * prebiotics or probiotics from other than food sources;
  * antibiotics; or
  * any experimental drug
* Type 1 or type 2 diabetes
* chronic gastrointestinal diseases
* previous gastrointestinal surgery modifying the anatomy
* smoking
* pregnancy or breastfeeding

Primary outcomes:
measure: Change in Insulin Resistance Compared to Baseline
timeFrame: 1 month, 3 month
Secondary outcomes:
measure: Weight
timeFrame: Baseline, 1 mo, 3 mo
measure: Body Mass Index
timeFrame: Baseline, 1 mo, 3 mo
measure: Appetite Score
timeFrame: Baseline, 1 mo, 3 mo
measure: Quality of Life Questionnaire
timeFrame: Baseline, 3 mo
measure: Depression Score
timeFrame: Baseline, 3 mo
measure: Anxiety Score
timeFrame: Baseline, 3 mo
Other outcomes:
measure: Hemoglobin A1c
timeFrame: Baseline, 1 mo, 3 mo
measure: Change in Intestinal Microbiome in Stool, Composition
timeFrame: Baseline, 1 mo, 3 mo
measure: Blood Lipid Profile
timeFrame: Baseline, 1 mo, 3 mo
measure: Change in Food Intake
timeFrame: Baseline, 1 mo, 3 mo
measure: Change in Food Intake
timeFrame: Baseline, 1 mo, 3 mo
measure: Change in Food Intake
timeFrame: Baseline, 1 mo, 3 mo
measure: Change in Food Intake
timeFrame: Baseline, 1 mo, 3 mo
measure: Change in Food Intake
timeFrame: Baseline, 1 mo, 3 mo
measure: Physical Activity
timeFrame: Baseline, 1 mo, 3 mo
measure: Stool Metabolomics
timeFrame: Baseline, 1 mo, 3 mo
measure: Serum Metabolomics
timeFrame: Baseline, 1 mo, 3 mo
Locations:
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
Study officials:
affiliation: University Health Network, University of Toronto
name: Johane P Allard, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vrieze A, Van Nood E, Holleman F, Salojarvi J, Kootte RS, Bartelsman JF, Dallinga-Thie GM, Ackermans MT, Serlie MJ, Oozeer R, Derrien M, Druesne A, Van Hylckama Vlieg JE, Bloks VW, Groen AK, Heilig HG, Zoetendal EG, Stroes ES, de Vos WM, Hoekstra JB, Nieuwdorp M. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology. 2012 Oct;143(4):913-6.e7. doi: 10.1053/j.gastro.2012.06.031. Epub 2012 Jun 20.
citation: Kelly CR, Kahn S, Kashyap P, Laine L, Rubin D, Atreja A, Moore T, Wu G. Update on Fecal Microbiota Transplantation 2015: Indications, Methodologies, Mechanisms, and Outlook. Gastroenterology. 2015 Jul;149(1):223-37. doi: 10.1053/j.gastro.2015.05.008. Epub 2015 May 15.
citation: Hamilton MJ, Weingarden AR, Unno T, Khoruts A, Sadowsky MJ. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria. Gut Microbes. 2013 Mar-Apr;4(2):125-35. doi: 10.4161/gmic.23571. Epub 2013 Jan 18.