Stool Transplantation for Treatment of Insulin Resistance in Morbidly Obese Patients

Insulin Resistance Clinical Trial

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.

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02970877
• Other study ID #: 16-5475
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: March 1, 2017
• Est. completion date: November 30, 2022

Study information

• Verified date: November 2022
• Source: University Health Network, Toronto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 48
• Est. completion date: November 30, 2022
• Est. primary completion date: June 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Insulin Resistance
• Obesity
• Obesity, Morbid

Intervention

Biological:
• Fecal filtrate from 150 g stool from healthy lean donors
150 g stool from healthy lean donors will be diluted in 0.9% normal saline to a total volume of 450 mL. Preparation from frozen stool.
• Fecal filtrate from 150 g of the recipient's own stool
150 g stool from the recipient will be diluted in 0.9% normal saline to a total volume of 450 mL. Preparation from frozen stool.

Locations

Country	Name	City	State
Canada	University Health Network	Toronto	Ontario

Sponsors (4)

Lead Sponsor	Collaborator
Johane Allard	Canadian Institutes of Health Research (CIHR), MOUNT SINAI HOSPITAL, University of Toronto

Country where clinical trial is conducted

Canada, 

References & Publications (3)

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. — View 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. Review. — View Citation

Vrieze A, Van Nood E, Holleman F, Salojärvi 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. Erratum in: Gastroenterology. 2013 Jan;144(1):250. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Hemoglobin A1c	Blood measurement	Baseline, 1 mo, 3 mo
Other	C-reactive protein	Blood measurement	Baseline, 1 mo, 3 mo
Other	HOMA-B%	HOMA steady state beta cell function (%B)	Baseline, 1 mo, 3 mo
Other	Intestinal microbiome in stool, composition	Measured by 16S sequencing	Baseline, 1 mo, 3 mo
Other	Intestinal microbiome in stool, function	Metagenome sequencing	Baseline, 1 mo, 3 mo
Other	Intestinal microbiome in stool, quantitative	Quantitative real-time polymerase chain reaction (qPCR)	Baseline, 1 mo, 3 mo
Other	Blood lipid profile	Blood measurement	Baseline, 1 mo, 3 mo
Other	Physical examination performed by the physician	All major signs will be checked to see if apparatus are normal or if abnormal findings are present (Head, Ears, Eyes, Nose, Throat, Neck, Lungs, Heart, Abdomen, Skin, Neurological, Anal, Gynecological).	Baseline, 3 mo
Other	Change in food intake	Total daily energy intake from 3-day food record	Baseline, 1 mo, 3 mo
Other	Change in food intake	Daily fat intake (amount g/d, energy and % of energy) from 3-day food record	Baseline, 1 mo, 3 mo
Other	Change in food intake	Daily carbohydrates intake (amount g/d, energy and % of energy) from 3-day food record	Baseline, 1 mo, 3 mo
Other	Change in food intake	Daily protein intake (amount g/d, energy and % of energy) from 3-day food record	Baseline, 1 mo, 3 mo
Other	Change in food intake	Daily fiber intake (amount g/d, energy and % of energy) from 3-day food record	Baseline, 1 mo, 3 mo
Other	Physical activity	Activity log, self-completed	Baseline, 1 mo, 3 mo
Other	Environmental questionnaire	Questionnaire assessing environmental factors that may influence the intestinal microbiome	Baseline, 1 mo, 3 mo
Other	Stool metabolomics	Nuclear magnetic resonance spectroscopy	Baseline, 1 mo, 3 mo
Other	Serum metabolomics	Nuclear magnetic resonance spectroscopy	Baseline, 1 mo, 3 mo
Other	Oral microbiome	16S sequencing, metagenome, quantification by qPCR	Baseline, 3 mo
Other	Dental questionnaire	Questionnaire assessing oral health and hygiene	Baseline, 3 mo
Other	Mucosa-associated microbiome	Mucosa from intestinal pinch biopsies, taken during colonoscopy 16S sequencing, metagenome, qPCR	Baseline
Primary	Change in Insulin Resistance compared to baseline	Homeostasis model of assessment for insulin resistance (HOMA-IR)	1 month, 3 month
Secondary	Weight	Body weight (kg)	Baseline, 1 mo, 3 mo
Secondary	Body mass index	Weight (kg) / height (m)²	Baseline, 1 mo, 3 mo
Secondary	Percentage weight change compared to baseline	% weight change compared to baseline	1 mo, 3 mo
Secondary	Appetite score	Appetite score according to rating scale	Baseline, 1 mo, 3 mo
Secondary	Quality of Life Questionnaire	RAND 36-Item Health Survey 1.0 (SF-36)	Baseline, 3 mo
Secondary	Depression score	Montgomery-Åsberg Depression Rating Scale (MADRS)	Baseline, 3 mo
Secondary	Anxiety score	Hamilton Anxiety Rating Scale (Ham-A)	Baseline, 3 mo