FECAL TRANSPANT FOR OBESITY?

Could fecal microbiota transplantation (FMT), whereby medical-processed stool material from a healthy donor is introduced into the intestine of a patient with obesity, be one of the answers to tackling this disease?

That is the belief of several groups of researchers who are currently studying the potential of this novel approach.

Fecal transplants have initially proven successful in tackling life-threatening Clostridium difficile infection, and it is also being investigated as a possible treatment for ulcerative colitis, irritable bowel syndrome, and recurrent urinary tract infections.

The theory is that a "healthy" microbiome in the stool will have beneficial effects, and so fecal transplantation is also being tested as a strategy in a number of animal and human studies for the treatment of obesity and metabolic disease. A review published in 2016 (J Biol Med. 2016;89:383-388) concluded that it is "an exciting therapy with abundant potential" but for which "there has been a lack of controlled, randomized trials."

Amir Zarrinpar, MD, PhD, assistant professor, Division of Gastroenterology, University of California San Diego, La Jolla, who coauthored the 2016 review, told Medscape Medical News that there have been several more studies published in the interim, but with less than convincing results.

"That's not to say that this has put the nail in the coffin," he added, pointing out that there are currently around 20 studies registered on ClinicalTrials.gov examining the potential of fecal microbiota transplants for the treatment of obesity, metabolic syndrome, or type 2 diabetes.

Results of Double-Blind Trial Expected in May

Some of the most keenly awaited results are those from a randomized, double-blind, placebo-controlled clinical trial, which started in June 2016, by Elaine W. Yu, MD, and colleagues from Harvard Medical School, Boston, Massachusetts.

For the study, 24 individuals aged 25-60 years with a body mass index (BMI) ≥ 30 kg/m² were randomized to fecal microbiota transplant (frozen stool) capsules from lean, metabolically healthy donors or placebo capsules for 24 weeks.

Changes in weight, insulin sensitivity, and body composition were assessed from baseline to 12 weeks, and the impact of the intervention on the intestinal microbiome of the recipient is being determined using fecal samples.

Yu told Medscape Medical News that the trial is now complete and they are analyzing the results, with the hope they will be able to present them at Digestive Disease Week this May.

Yu agreed with Zarrinpar that "there has been really a paucity of data" on this approach in humans, and noted that "there continues to be a lot of activity in animal research that connects the microbiome with obesity and the metabolic syndrome."

And she pointed out that the two randomized clinical trials with fecal microbiota transplants published so far were from the same group, led by Max Nieuwdorp, MD, PhD, professor of internal medicine, University of Amsterdam, the Netherlands.

Although they found that endoscopic delivery of fecal microbiota transplant achieved small changes in insulin sensitivity, Yu described them as "proof of principle," adding, "this clearly needs to be verified with other groups and with other styles of administration of fecal microbiota transplant."

Indeed, another clinical trial has just begun in Wales, where clinicians are delivering fecal transplants endoscopically from healthy donors to obese individuals with type 2 diabetes, following on from Nieuwdorp's work.

The study will involve people aged 18-70 years diagnosed with type 2 diabetes in the last 2 years with a BMI between 30 and 40 kg/m².

Dean Harris, a colorectal surgeon at Singleton Hospital in Swansea, is one of the trial leaders.

"We know in patients with diabetes and obesity that their gut organisms are over-efficient in extracting energy from their food, so you have a greater number of calories absorbed from a given meal than somebody who doesn't have those conditions," he told Wales Online.  

"If we can change the bacteria and organisms in the gut...we're hoping weight loss can be seen and also tighter control of diabetes."

Fecal Transplant Capsules a Better Mode of Delivery?

An issue that still needs to be addressed when trying to alter the microbiome through fecal transplant is to figure out how often it needs to be done, as it is known that the intestinal microbiome reverts to its former composition after a few weeks.

Zarrinpar made the point that "we have our microbiome for a reason," saying that it is "specific to our genetics, what our parents have passed on to us, what we eat, where we live, who we live with."

To change the microbiome without completely changing one's diet, he believes it is probably necessary to maintain a constant "pressure" on the microbiome to change using fecal transplant.

Being able to do this, Yu pointed out, "depends on how you administer the fecal transplants, and that can vary from study to study, and from group to group."

She said: "The most prevalent way of administering fecal transplants is...endoscopic delivery, which just by its more invasive nature is something that is not done frequently."

As fecal microbiota transplant capsules are an oral treatment, "it's something that can be administered potentially more frequently, more than just once or twice," she noted.

"By bringing other techniques to delivery of fecal transplants we may have the ability to modulate the microbiome on a more consistent basis and for longer periods of time."

If fecal transplants are indeed shown to be effective in tackling obesity and metabolic disease, Zarrinpar believes that it will be easier to obtain approval for a capsule version of fecal transplants because the very nature of the process would get rid of a lot of the "variability" seen with endoscopically delivered transplants.

Will Physicians and Patients Be Keen to Use Fetal Microbiota Transplants? 

However, Zarrinpar doubts whether fecal microbiota transplant capsules would end up being used much, even if they do become an approved treatment.

"We would all like to think that something like this would be beneficial. On the one hand, we all know people who will do anything to lose weight, even go on crazy diets that are unsustainable...but at the same time we...already have a whole bunch of anti-obesity drugs that physicians tend not to use," he said.

He added: "There are a group of people, a certain population, that will do it but there's a lot of miseducation about obesity both in the medical field and [among] the public."

"People think that the treatment they take should revert them back to a normal BMI, whereas, besides bariatric surgery, there's nothing we have that can really do that on a regular basis on a population level."

Yu, on the other hand, had a different experience when she ran the randomized controlled trial, finding that people were very keen to take part.

"Clearly we have a lot of self-selection in those people who contact us about wanting to participate in this study, who have already gotten over the 'yuck factor' of swallowing capsules of essentially frozen stool," she said.

"But I've been doing clinical research for quite some time and I have to say that...it’s a bit like pulling teeth trying to get people to enroll.

"This is the one project where I've actually had people knocking on my door asking me to participate because there's so much interest on the lay public side about this potential question," she said.

Adding a note of caution, however, she continued: "I want to say that the excitement and enthusiasm from the lay public have, at this point, outstripped our hard data and science on this topic."

"We don't know yet whether or not this will be effective, and there are some potential harms that can come with fecal microbiota transplant."

"What I get most nervous about as a clinician is when I hear of these people who are doing these do-it-yourself fecal transplants...Outside of a monitored clinical setting, that can have potential risks that are very much unanticipated."

Some See Fecal Transplant as a More " Natural" Approach

Yu believes patients are so enthusiastic to try fecal transplants because obesity is "a notoriously difficult disease to manage and to treat."

"Anytime there is buzz about a new potential avenue to try, people are very excited [which] speaks to a level of desperation, unfortunately, amongst many patients who are looking for anything that can provide some potential help."

In addition, she thinks another reason patients are keen to try fecal transplants is that "there is already a lot of acceptance in many communities of the use of probiotics and specialized yoghurts and...going to something like fecal transplants seems less foreign to many people, and potentially more 'natural'."

Zarrinpar, in the meantime, wonders whether fecal transplants, as a microbiome-mediated treatment, will work on a population-clinical level and believes other approaches may supersede it.

"One thing that...I think could potentially have promise...is using engineered bacteria, either to express a satiety hormone or express genes that would help someone increase their metabolism."

"Those kinds of things are now being investigated in labs and could potentially have a future."