The Ethics of Fecal Microbiota Transplant (FMT) Therapy for Obesity
Clare Goggins
Advisor: Professor Rosenwald, Biology Department
30 March 2015
After a semester-long investigation into the effects of the human gut microbiota on the risk of obesity, I concluded that the connection between the gut microbiota and obesity is undeniable. In particular, the gut microbiota of obese individuals have lower genetic richness and a greater proportion of the phylum Firmicutes compared to the gut microbiota of lean individuals (Feehley and Nagler, 2014). With this information, I began to postulate novel treatments for obesity, which led to the creation of a grant proposal for a phase I clinical trial (intended as a thought exercise and not for actual use, at least not currently). The goal of this clinical trial will be to determine whether the transfer of gut microbiota from lean to obese individuals via fecal microbiota transplant (FMT) is a feasible and effective method for reducing obesity. The aim of this paper is to serve as a bioethical defense of the clinical trial that I have proposed, in addition to serving as a platform for raising questions about the potential bioethical issues that may arise as a result of FMT therapy for obesity becoming commonplace in the future. I will argue that the benefits that could be gained from this clinical trial far outweigh the risks and that, despite not knowing all of the risks of FMT, subjects who participate in this trial will still be able to give a fully informed consent. In addition, I will examine potential bioethical issues with FMT therapy for obesity that may arise in the future, particularly whether lean individuals should be allowed to sell their fecal matter for use in FMT therapy for obese patients.
In order to make an educated bioethical judgment on the proposed clinical trial, it is essential to have a general understanding of the FMT procedure. A fecal microbiota transplant involves obtaining a stool sample from one individual and transferring it to another individual usually via colonoscopy. However, transfer can also occur via a nasogastric tube, a nasojejunal tube, a duodenal tube, an upper tract endoscopy, or a retention enema (Smits et al., 2013). Studies have shown that infusion of donor fecal matter via a duodenal tube is safe and effective for the treatment of metabolic diseases (Vrieze et al., 2012). Because obesity classifies as a metabolic disease, I chose to propose using a duodenal tube for the FMT procedure, which is inserted through the mouth or nose and ends in the duodenum, the initial section of the small bowel (“Nutrition; Feeding”). After FMT, the obese subjects will be divided into two groups – one group will follow a healthy, primarily vegetarian diet, consisting of many grains, legumes, fruits, and vegetables, while the other group will follow their typical diet before the procedure (David et al., 2014). The obese subject will have a checkup 6 weeks, 12 weeks, and 24 weeks after the procedure. At each of these checkups, the subject will provide a stool sample so that metagenomic analysis, “the genomic analysis of microbial DNA that is extracted directly from communities in environmental samples,” can occur (“Focus on Metagenomics”). Essentially, metagenomics enables a survey of the different microorganisms present in a specific environment, such as the human body, to be conducted. This analysis, which will occur before the procedure and three times post procedure, will show how the gut microbiota of the individual changes after FMT. In addition, at each checkup, measurements of obesity will be taken in the form of body mass index (BMI), waist circumference (WC), and waist-hip ratio (WHR). These measurements will show whether the FMT procedure leads to a decrease in obesity.
The development of a clinical trial requires the consideration of many aspects, including how to protect subjects participating in the trial. The National Institutes of Health (NIH) proposes seven key principles that should be considered in order to protect individuals involved in clinical trials. These principles include social value, scientific validity, fair subject selection, favorable risk-benefit ratio, independent review, informed consent, and respect for enrolled subject (“National Institutes of Health”). Of these seven principles, two are especially relevant for this paper – favorable risk-benefit ratio and informed consent. These two principles are arguably the most important and most problematic in reference to the clinical trial under consideration.
A favorable risk-benefit ratio entails that the risks of a study are outweighed by the benefits to subjects and/or the benefits to society from gaining new scientific knowledge. In addition, any research burdens must be minimized. According to the NIH, a research burden “can be the time it takes people to participate or the inconvenience or discomfort it causes them” (“National Institutes of Health”). In order to have a favorable risk-benefit ratio, researchers have to show that the research question they are addressing cannot be answered in a less risky or less burdensome way.
There are many potential benefits of conducting the proposed trial, including the acquirement of more information on the effects of the gut microbiota on the risk of obesity and possibly the discovery of a novel treatment for obesity. The potential for discovery of a new method for treating obesity is very compelling. Obesity-related health issues are responsible for many disability-adjusted life years (DALYs) in addition to being very costly. In 2008 alone, the estimated annual medical cost of obesity in the United States totaled $147 billion (“What causes overweight”). Finding a new and effective treatment for obesity would not only improve the lives of obese individuals but would also significantly reduce the costs of the United States’ health care system. However, it is important to note that none of these benefits are guaranteed and that FMT may provide little or no benefit to obese subjects. In light of this realization, are the risks of this clinical trial justified even though it is possible that no benefit may come of the trial? In order to answer this question, it is important to examine the nature of these risks.
One potential risk that FMT presents is disruption of the gut microbial balance, otherwise known as dysbiosis. Although this risk is very small, it is possible that in some cases FMT could make matters worse rather than better. For example, a donor’s fecal sample may contain a previously unidentified pathogen, which would then be passed on to the subject via FMT. In order to address this minor risk, in this clinical trial the obese subjects will provide a stool sample two days before the procedure and this sample will be frozen in case it is needed to restore a subject’s original gut microbiota.
In addition to the risk of dysbiosis, there can be other negative side effects of FMT. On the day of infusion, most patients experience diarrhea and a small percentage of patients experience belching and/or abdominal cramping or constipation; however, these side effects are relatively minor and do not present any serious risks to health (Smits et al., 2013). More serious side effects are very uncommon – in a systematic review of FMT for Clostridium difficile infection, researchers found that out of 317 patients treated across 27 case series and reports, only three patients reported adverse events, such as upper gastrointestinal tract bleeding, peritonitis, or enteritis (Gough, Shajkh, and Manges, 2011).
Based on these statistics, it is clear that FMT does not typically pose serious risks to health; however, it does cause a burden to the subjects by leading to some discomfort and inconvenience. In order to reduce discomfort and inconvenience, I have proposed to conduct FMT via a duodenal tube rather than a colonoscopy, the more common route of infusion. A colonoscopy requires that the patient receive sedatives, anesthesia, or pain medicine in order to relax during the procedure. This presents more risk to the patient and is also an inconvenience since the patient must wait for the sedatives and anesthesia to wear off, preventing them from driving for 24 hours after the procedure (“Colonoscopy”). Duodenal transfusion, on the other hand, does not require any sedative, anesthesia, or pain medicine and only requires two hours of monitoring post-procedure (van Nood et al., 2013).
In general, long-term follow-up studies have shown that FMT is relatively free of adverse effects (Brandt et al., 2012). Even if there are no benefits from this clinical trial, the risks are minor enough to justify pursuing this trial. However, although FMT appears to be safe, it is still considered an experimental treatment and more long-term follow-up data is needed. In particular, the potential association between FMT and infection, inflammation, or gastrointestinal malignancies should be further studied (Smits et al., 2013). Additionally, although FMT treatment for Clostridium difficile infection seems to be safe, the proposed trial is the first instance where FMT will be used to treat obesity, which may have unique risks.
This leads to the question of whether a subject can provide informed consent for FMT therapy for obesity when all of the risks of this therapy are not fully understood. There are two main purposes of informed consent – 1) to ensure that the subject truly understands the treatment and/or procedure, including the potential risks, and 2) to respect the autonomy of the subject. In the case of FMT therapy for obesity, it will not be problematic for the subject to truly understand how the procedure works. What will be problematic, however, is ensuring that the subject fully understands all of the risks associated with FMT therapy for obesity, since some of these risks are not known due to the fact that this therapy has not been attempted before. Some bioethicists argue that a truly informed consent cannot be obtained if the subject does not have complete understanding of all of the risks; therefore, bioethicists who take this stance may disapprove of the clinical trial under consideration (Hansson et al., 2006). However, this argument fails to recognize that almost any medical procedure can have unforeseen risks. Any time a patient undergoes a medical procedure, no matter how minor that procedure may be, there is a small chance that an unexpected, adverse event will occur. Even though all of the risks of FMT therapy for obesity cannot be described in a consent form, the use of FMT for Clostridium difficile infection thus far has not resulted in many serious harmful effects (Brandt et al., 2012). Therefore, it is unlikely that unforeseen adverse effects will occur when FMT is used to treat obesity, although this cannot be stated with absolute certainty.
The second goal of informed consent, to respect the autonomy of the subject, is arguably the most important, and the fact that all of the risks of FMT therapy for obesity are not fully understood does not interfere with obtaining this goal. For an autonomous action to be made, the action has to be intentional, the actor must adequately understand the action, and the actor must be free of controls exerted either externally or internally (Beauchamp and Childress 104). As long as the subject makes an autonomous decision to provide consent, despite knowing that there are unknown risks of FMT, his autonomy is not being disrespected. In the clinical trial under consideration, the consent form will notify the subjects that FMT is still considered an experimental treatment and that there is a possibility that unknown and unscreened pathogens could be transmitted via FMT (Ray, Smith, and Breaux, 2014). With this forewarning, patients can weigh the risk of unforeseen consequences against the potential benefits and make an autonomous decision about whether to participate.
It is also important to consider the potential bioethical issues that may arise if FMT therapy for obesity becomes commonplace in the future. The most significant issue that I foresee is whether lean individuals should be able to sell their fecal matter for use in FMT therapy for obesity. This issue is similar to the controversy surrounding whether people should be able to sell their organs for profit. There is currently a scarcity of organs available for transplantation and, because of this, many people die prematurely while waiting for an organ transplant. Some have proposed that a market for human organs should be formed in order to increase the amount of organs available for transplantation (Erin and Harris, 2003). However, there are many risks involved with the creation of a market for organs, including undue inducement and exploitation of vulnerable populations.
The risks and inconvenience of live organ donation is what prevents most people from donating, unless a close friend or family member is in desperate need. If there were a monetary payment for donating an organ, people would be far more likely to donate. However, this may constitute undue inducement, which “involves a gratuitously large, and therefore distorting, offer of benefit” (Ballantyne). Undue inducement prevents subjects’ from rationally weighing the risks and benefits of participating in a clinical trial because the reward that has been offered to them is too great. In addition to undue inducement, the creation of a market for organs may also lead to the exploitation of vulnerable populations. For example, it would benefit the rich, while putting pressure on low-income populations to jeopardize their health for monetary gain (Andre and Velasquez).
Similar to organ failure, many people around the world die prematurely due to obesity-related health concerns (“Adult Obesity Facts”). If FMT therapy for obesity were shown to be effective, would it be just to allow lean individuals to sell their fecal matter to be used for FMT? This seems more ethical than creating a market for organs since there are far fewer health risks involved in selling one’s fecal matter compared to selling one’s organs. In fact, selling one’s fecal matter would not have any negative consequence on one’s physical health. The only undesirable effect on the seller is the inconvenience of collecting one’s stool sample. Unlike the creation of an organ market, there would not be issues with undue inducement or exploitation of vulnerable populations with the creation of a market for fecal samples. This is because the physical risk of providing fecal samples is almost negligible. In order for undue inducement to take place, there has to be serious risk present. If there are no risks involved, then there are no risks to weigh against the benefits of participating and undue inducement would not take place. In addition, in order for exploitation to occur, some harm or risk of harm has to be present. Again, there is no harm or risk in providing fecal samples; therefore, exploitation of vulnerable populations would not occur.