Fecal Transplants May Hold Promise in Treating Obesity

This transcript has been edited for clarity.

Alok S. Patel, MD: This is Dr Alok Patel with Medscape. I'm here at Digestive Disease Week 2019 with Dr Jessica Allegretti, the director of the fecal microbiota transplantation (FMT) program at Brigham and Women's Hospital in Boston, Massachusetts. We're going to talk about her study of FMT in the treatment of obesity, the results of which were presented here.^[1]

Dr Allegretti, I'm fascinated to speak with you about your research, because I feel like everyone is talking about the gut microbiome. Could you tell us a little bit about why you decided to look at FMT as a possible obesity treatment?

Jessica R. Allegretti, MD, MPH: Absolutely. To begin with a little bit of background context, FMT is something I do in my clinical practice all the time for recurrent or refractory Clostridium difficile infections, and we've learned a lot from the data we've collected in that area. Now with the expansion of the microbiome space, we're starting to understand that there are many diseases associated with an altered gut microbiome, and that we can really use FMT to try to understand the microbial pathogenesis to some of these diseases.

Obesity seemed like an obvious target. It affects over a third of Americans and has many comorbid conditions associated with it. We wanted to understand if we could come up with some better therapeutic options for these patients.

Patel: I'm not as familiar with the space as you are, but I have seen some previous headlines about how the gut microbiome may affect hormones related to obesity or feelings of satiety. Were there any specific earlier findings that led you to your own study of FMT and obesity?

Allegretti: The impetus for this trial really comes from a few things. As you know, usually before things end up in humans, they're tested out in mice. It was shown that this obesity phenotype can be essentially transplanted in mice. If you take stool from a lean mouse and place it into an obese mouse, and vice versa, you can actually see weight gain and weight loss. That really got people thinking that maybe this is something that is transmittable via the gut microbiome.

A group in the Netherlands took it a step further and actually used FMT in humans with metabolic syndrome.^[2] They were able to show an improvement in insulin sensitivity at 6 weeks after treatment, but it really wasn't sustained further than that.

We thought these were interesting and promising data, but we really wanted to look at what we call the obese metabolically uncomplicated patient. There are so many patients who are healthy overall but just cannot lose weight. We wanted to try to understand if we could help them. That's really where our study enters the picture.

Patel: What was the design of your study?

Allegretti: We designed this as a single-center pilot study because, of course, whenever you're testing a new therapeutic in a new patient population, safety has to be the first thing you confirm. That was really the primary goal, but we also wanted to begin gathering data about the utility of this therapy in this patient population.

We enrolled patients who were obese, which we defined as having a body mass index of 35 or higher, and had no other obesity-related conditions such as type 2 diabetes, metabolic syndrome, or nonalcoholic fatty liver disease. We then randomized patients on a 1-to-1 basis, meaning they equally got into the group to receive either FMT capsules or identical placebo capsules. We decided to dose patients three different times: a single induction dose of 30 capsules and then two maintenance doses of 12 capsules at week 4 and week 8.

We then measured hormones, specifically glucagon-like peptide 1 (GLP-1), at various time points: before they got the treatment, at week 6, and at week 12. The reason why we chose GLP-1, which is a hormone released from your gut, is because we know it is stimulated by short-chain fatty acids, which are a byproduct of the gut bacteria. We know that in weight loss surgery you see a rise in GLP-1.

Patel: And that should result in a decrease of appetite?

Allegretti: Yes. You can think about GLP-1 like this: When you eat fiber, it gets into your intestines, then your gut bacteria eat it up and release short-chain fatty acids. The short-chain fatty acids then interact with a receptor in your small bowel that releases GLP-1, which sends a signal to your brain that basically says, "I'm full; stop eating." Your stomach actually slows, and there's a lot of physiologic effect with that. So we thought, wouldn't it be great if by just augmenting the gut microbiome we could mimic what we see in weight loss surgery without doing surgery?

Patel: So, what did you find?

Allegretti: We found that it was very safe and very well tolerated, which was, of course, the first thing we wanted to confirm to move forward. We unfortunately did not see any changes in GLP-1 between the two groups. What we did see, however, was successful engraftment of that lean donor microbiota. When we looked post-FMT, we saw that the stool of the patients looked much similar to that of the lean donor, which was actually sustained through week 12. And we also checked several other metabolites and bile acids, which is another really interesting compound that's metabolized by your gut microbiome, and also saw really significant changes.

When we put it all together, we found that although we went in with a GLP-1 hypothesis, maybe that wasn't the right pathway. Perhaps a bile acid pathway might actually be driving some of the factors we're seeing in this study. Certainly, when we do the next round of this we will be focusing on bile acids.

Also, I think the biggest question I took away from this study was whether we used the right dose. I just don't know. We went with our best hypothesis, but perhaps we needed more capsules or more frequent dosing to really start to see some of those clinical outcomes.

Patel: Well, we know that it's safe, that there's stool engraftment, and as you just mentioned, there are a lot of directions moving forward. So the future looks promising for FMT.

Allegretti: I agree.

Patel: Dr Allegretti, thank you so much for talking to us. We're excited to learn more.

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