Fecal Microbiota Transplantation: The Future of Feces

BY MCKENNA TENNANT

With almost a third of the world’s population either obese or overweight, and no end to the epidemic in sight, the need for pharmacological aids to stem global weight gain has only increased over the past decade. This issue most deeply affects the United States, since we have the highest proportion of obese people in the world.¹ The emergence of a potential new therapy for this rising health hazard might come as a surprise to many… human feces.

Fecal microbiota transplantation (FMT), previously known as “fecal bacteriotherapy,”² transfers human stool from a healthy donor into a patient’s stomach, colon, or small intestine.³ The procedure attempts to restore the balance of bacteria in the digestive tract by replenishing the population of “good” bacteria that had either been killed or suppressed by the over-population of “bad” bacteria.⁸ Processed FMT capsules contain microbiota preparations that have been thoroughly screened and processed, and these pills can be administered orally, through the lower gastrointestinal tract via colonoscope or enema, or into the upper gastrointestinal tract via the nasogastric or nasoduodenal tube.⁴ During an enema, a solution is injected into the lower bowel through the rectum,⁵ whereas a colonoscopy consists of the insertion of a tube into the colon through the same pathway.⁶ In 2011, approximately 75% of the estimated 325 cases of FMT that had been reported worldwide were treated by colonoscopy or retention enema, and the other 25% by nasogastric or nasoduodenal tube.³ FMT ultimately introduces a community of stable gut microorganisms to stabilize the imbalanced microbiome.²

The human microbiome, defined as “the collection of all the microorganisms living in association with the human body,” plays a crucial role in human health.⁹ The gut microbiome has the greatest bacterial density of all microbial communities that populate human body surfaces, and many consider gut microbiota a “distinct human organ,” responsible for many functions of energy metabolism and immunity.² The evolution of the two branches of our immune system occurred alongside the acquisition of diverse microbiota in our bodies, suggesting that the immune system evolved to maintain the symbiotic relationship between humans’ complex microbiota so that microbiota could adjust and promote aspects of the immune system in return. Many believe that the microbiome regulates immune responses, because events in high-income countries, such as the overuse of antibiotics and diet changes, have been linked to the selection of microbiota lacking the diversity and resilience needed to establish balanced immune responses.¹⁰ Data suggest that gut microbiota play a role in various aspects of the development and function of the innate and adaptive immune system in the intestines,¹¹ such as regulating immune homeostasis as well as aiding the development of helper T cells and the maintenance and function of intestinal cytotoxic T cell populations.¹²

Strong evidence supports the benefits of FMT for the gut microbiome,¹³ and research in FMT has increased largely due to growing interest in the relationship between the human microbiome, health, and disease. Many studies have suggested that changes in microbiome composition are correlated with disease, so the microbiome offers potential targets for therapy.¹⁴ The desire to understand our microbiome led the NIH to launch the Human Microbiome Project in 2008, which examines the role of these microbial communities in health and catalyzes research to characterize and further analyze the human microbiome.⁹ The nonprofit organization OpenBiome, which became the United States’ first stool bank in 2012, works to improve access to FMT and increase the amount of research done on the human microbiome.¹⁵

The success of FMT in the battle against Clostridium difficile demonstrates the potential efficacy of therapeutic microbiota alterations for certain diseases. Infection with C. difficile (CDI) causes inflammation of the colon and commonly occurs as a complication of antibiotic therapy. It typically spreads via fecal-oral transmission, and has become the most common cause of healthcare-associated infections in U.S. hospitals.¹⁶ CDI can cause severe disease and death, and in 2011, it was associated with approximately 29,000 deaths in the U.S..¹⁷ Upon the discontinuation of standard CDI antibiotic treatment, recurrent infection may occur.2 Extremely high rates of mortality and colectomy, or colon removal, associated with this form of CDI often result from the death of most “good” bacteria, which often die during the course of such intense antibiotic treatment.² The CDC, on its CDI webpage, claims that “fecal transplants” currently represent the most effective treatment of CDI, resulting in the total eradication of infection with a success rate of approximately ninety percent.¹⁶ Reports have also shown that FMT treats recurrent CDI more effectively than antibiotics, and few incidences of adverse effects or complications as a result of FMT have yet occurred.¹⁸

In the United States, FMT currently has FDA approval only for the treatment of recurrent CDI not responsive to standard therapy, with the added requirements of signed patient consent and donor stool testing. The FDA classified fecal matter as an Investigational New Drug (IND) in the spring of 2013, so that only physicians who possessed an approved IND application could perform FMT for clinical practice or research. This decision effectively reduced the number of physicians qualified to work with fecal transplants to less than twenty.⁸ Later that year, however, the FDA announced its intent “to exercise enforcement discretion regarding the IND requirements for the use of FMT.”¹⁹ This declaration meant that physicians without an IND application could perform FMT as treatment for recurrent CDI outside of a clinical trial. IND applications, however, must be filed in order to use FMT as a treatment for other diseases.²⁰

Given the success of FMT with CDI, we must now look toward other health issues that could benefit from the use of FMT. Recent findings have shown that an imbalanced intestinal microbiome not only predisposes the human body to CDI but also to inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). As a result, FMT has been used to treat IBD, IBS, ulcerative colitis, and even non-gastrointestinal disorders. Four publications have described FMT use for refractory ulcerative colitis in a total of nine patients, all of who experienced complete resolution of all symptoms. Multiple infusions, however, seem necessary to maintain remission, and controlled trials need to establish the role of FMT or even determine if one truly exists for ulcerative colitis. A case series study of patients with IBS and IBD treated with FMT reported a cure in 36% of the patients, decreased symptoms in 16%, and no response to FMT in 47% of the patients. While FMT does not appear to be incredibly effective against IBS and IBD, in another study of 45 patients who underwent FMT treatment for chronic constipation, 89% of patients experienced relief immediately after the procedure, demonstrating the potential benefits of FMT treatment to those whom it does help.²¹

Observations of improvement have occurred even for extra-intestinal conditions not thought to be related to microbiota, so new possibilities for FMT materialize every day. FMT treatment has been linked with the normalization of severe multiple sclerosis symptoms, as well as an improvement of chronic fatigue syndrome.² Fourteen of the 34 patients who underwent FMT for a long-term follow-up study on the improvement of chronic fatigue syndrome obtained continuous relief, and 7 reported mild or gradual improvements.² Three patients with multiple sclerosis underwent FMT for chronic constipation, but they also experienced improvements in motor symptoms and urinary function, allowing them to remove their catheters and regain the ability to walk. Additionally, neurological improvement was reported in one patient with Parkinson’s disease who underwent FMT for chronic constipation. In addition, intestinal microbiota metabolize ingested nutrients for the host and commensal bacteria, and can modify their metabolism depending on nutrient availability.²¹ Because gut microbiota alter energy metabolism, the microbiome influences body size. One woman successfully treated with FMT for CDI recurrence developed obesity after receiving stool from her overweight but otherwise healthy daughter. The woman was unable to lose weight, even on a medically supervised diet and exercise program, even though she had never been obese before FMT.²² Given that FMT can affect obesity, it might also enable weight loss.

The potential of FMT to treat a variety of health disorders, including obesity, has sparked research that is currently underway to study the relationship between altered gut microbiota and disease development. A study on the impact of gut bacteria taken from a pair of twins, one obese and one lean, in separate groups of recipient mice showed that microbiota influence the body weight phenotype of host mice. Adiposity, defined by the Merriam-Webster medical dictionary as the quality or state of being fat,²³ was transmitted from the obese twin to the recipient mice through the transplantation of human fecal microbiota, and the mice experienced increases in body weight and mass.²⁴ Furthermore, humans have utilized gut bacteria modification to promote weight gain in farm animals for more than 50 years.²⁶

Several publications have hypothesized that individuals with or lacking certain gut microbiota may face greater risk for obesity.²⁵ The microbiome may affect fat storage, and, by means of increasing or decreasing the amount of energy harvested from ingested food, it provides or limits calories. Mixes of certain gut microbiota, therefore, possibly offer protection from excessive weight gain.²⁶ Restoring the microbiome to a healthy state might improve obesity-associated conditions and help maintain healthy weight.²⁷ Currently, preparations have begun for a March 2016 clinical trial that will study the impact of FMT capsules on weight. The study, which will enroll 21 obese subjects, is expected to run for 12 weeks, and will transfer stool from a metabolically healthy, lean subject to an obese subject.²⁸

Ultimately, more research needs to be done to determine the role of the microbiome in human metabolism and weight. The main cause of obesity often lies in an imbalance between energy intake and expenditure; however, many researchers agree that a clear link exists between gut microbiota and metabolic diseases like obesity.²⁵ Before FMT can be applied widely, however, we must overcome various challenges and barriers, such as the obvious “yuck factor” that surrounds the topic of human feces.² If queasiness over feces threatens to overwhelm the conversation on FMT, it must be considered that FMT is not necessarily a novel treatment. The first documentation of fecal transplant comes from 4th century China, where it was known as “yellow soup,” dating the practice of FMT to around 1,700 years ago. In some parts of the world, it is also customary to give a newborn a sample of its mother’s feces because of the belief that it immediately provides a population of good bacteria for the baby’s colon, thus stimulating the newborn’s immune system.⁸ Other barriers also limit future applications of FMT. Because of the legal ambiguity created by the FDA’s enforcement discretion on its IND classification, some researchers may hesitate to prepare fecal microbiota for sale, making access to the procedure a challenge and creating a potential risk for the rise of fecal sales on the black market.²⁹ The risk of the potential transmission of infectious agents, another source of concern, warrants very strict regulation and screening processes for fecal donors.³

Because FMT remains in the early stages of therapeutic application, with the number of total FMT treatments in the U.S. estimated below five hundred,⁸ the future of FMT remains obscure. We need more knowledge about the role of gut microbiota in health maintenance, calling for an increase in the number and range of FMT trials. The undoubted link, however, between gut microbiota and weight demands a greater exploration into the possibilities of FMT, especially for its potential influence on obesity.

McKenna Tennant is a junior in Davenport College from Los Angeles, California pursuing a major in History of Science, Medicine and Public Health. She is particularly interested in the study of infectious diseases. She can be contacted at mckenna.tennant@yale.edu.

__________

References:

1. Murray, C. & Ng, M. (n.d.). Nearly one-third of the world’s population is obese or overweight, new data show. Institute for Health Metrics and Evaluation. Retrieved from http://www.healthdata.org/news-release/nearly-one-third-world’s-population-obese-or-overweight-new-data-show.
2. Borody, T. & Khoruts, A. (2012). Fecal microbiota transplantation and emerging applications. Nature Reviews Gastroenterology and Hepatology(9), 88-96. http://www.nature.com/nrgastro/journal/v9/n2/full/nrgastro.2011.244.html.
3. Surawicz, C.M., Brandt, L.J., Binion, D.G., Ananthakrishnan, A.N., et al. (2013). Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile Infections. American College of Gastroenterology. Retrieved from http://gi.org/guideline/diagnosis-and-management-of-c-difficile-associated-diarrhea-and-colitis/.
4. Treatment Formats. (n.d.). OPENBIOME. Retrieved from http://www.openbiome.org/safety/.
5. Enemas. (n.d.) Gale Encyclopedia of Medicine. Retrieved from http://medical-dictionary.thefreedictionary.com/Enemas.
6. Marks, J.W. (2014). Colonoscopy. MedicineNet.com. Retrieved from http://www.medicinenet.com/colonoscopy/article.htm.
7. Types of Feeding Tubes and Terms to Know by the Feeding Tube Awareness Foundation. (n.d.). RAREDaily. Retrieved from https://globalgenes.org/raredaily/types-of-feeding-tubes-and-terms-to-know-by-the-feeding-tube-awareness-foundation/.
8. What is FMT. (n.d.). The Fecal Transplant Foundation. Retrieved from http://thefecaltransplantfoundation.org/what-is-fecal-transplant/.
9. About the HMP. (n.d.). NIH Human Microbiome Project. Retrieved from http://hmpdacc.org/overview/about.php.
10. Belkaid, Y. & Hand, T.W. (2014). Role of the Microbiota in Immunity and Inflammation. Cell, Volume 157(1), 121-141. http://www.sciencedirect.com/science/article/pii/S0092867414003456.
11. Purchiaroni, F., Tortora, A., Gabrielli, M., Bertucci, F., et al. (2013). The role of intestinal microbiota and the immune system. European Review for Medical and Pharmacological Sciences, Volume 17(3), 323-333. http://www.ncbi.nlm.nih.gov/pubmed/23426535.
12. Wu, H. & Wu, E. (2012). The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes, Volume 3(1), 4-14. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337124/.
13. Nield, D. (2016). Human trials will test freeze-dried poop pills as a weight-loss treatment. ScienceAlert. Retrieved from http://www.sciencealert.com/human-trials-will-test-freeze-dried-poop-pills-as-a-weight-loss-treatment.
14. van Nood, E., Speelman, P., Nieuwdorp, M., & Keller, J. (2014). Fecal microbiota transplantation: facts and controversies. Current Opinion in Gastroenterology, Volume 30(1), 34-49. http://www.ncbi.nlm.nih.gov/pubmed/24241245.
15. About. (n.d.). OPENBIOME. Retrieved from http://www.openbiome.org/about.
16. Clostridium difficile Infection Information for Patients. (2015) Centers for Disease Control and Prevention. Retrieved from http://www.cdc.gov/hai/organisms/cdiff/Cdiff-patient.html.
17. Lessa, F.C., Mu, Y., Bamberg, W.M., Beldavs, Z.G., et al. (2015). Burden of Clostridium difficile Infection in the United States. The New England Journal of Medicine(372), 825-834.
18. Kinross, J.M., von Roon, A.C., Holmes, E., Darzi, A., et al. (2008). The Human Gut Microbiome: Implications for Future Health Care. Current Gastroenterology Reports, Volume 10(4), 396-403. http://www.ncbi.nlm.nih.gov/pubmed/18627653.
19. Guidance for Industry: Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies. (2013). US. Food and Drug Administration. Retrieved from http://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/vaccines/ucm361379.htm.
20. FMT and the FDA. (n.d.) OPENBIOME. Retrieved from http://www.openbiome.org/the-basics/.
21. Aroniadis, O.C., Brandt, L.J. (2013). Fecal microbiota transplantation: past, present, and future. Current Opinion in Gastroenterology, Volume 29(1), 79-84. http://www.ncbi.nlm.nih.gov/pubmed/23041678.
22. Alang, N. & Kelly, C.R. (2015). Weight Gain After Fecal Microbiota Transplantation. Open Forum Infectious Diseases, Volume 2(1). http://ofid.oxfordjournals.org/content/2/1/ofv004.full.
23. Adiposity. (n.d.). Merriam- Webster. Retrieved from http://www.merriam-webster.com/medical/adiposity.
24. Ridaura, V.K., Faith, J.J., Rey, F.E., Cheng, J., et al. (2013). Gut Microbiota from Twins Discordant for Obesity Modulate Metabolism in Mice. Science, Volume 341(6150). http://science.sciencemag.org/content/341/6150/1241214.full-text.pdf+html.
25. Valiquette, L., Sirard, S., & Laupland, K. (2014). A microbiological explanation for the obesity pandemic? The Canadian Journal of Infectious Diseases & Medical Microbiology, Volume 25(6), 294-295. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277155/.
26. Tsai, F., Coyle, W.J. (2009). The Microbiome and Obesity: Is Obesity Linked to Our Gut Flora? Current Gastroenterology Reports, Volume 11(4), 307-313. http://www.ncbi.nlm.nih.gov/pubmed/19615307.
27. Ley, R.E. (2010). Obesity and the Human Microbiome. Medscape. Retrieved from http://www.medscape.com/viewarticle/714569.
28. Yu, E.W. (2016). Fecal Microbiota Transplant for Obesity and Metabolism. ClinicalTrials.gov. Retrieved from https://clinicaltrials.gov/ct2/show/study/NCT02530385.
29. Smith, P.A. (2014). A New Kind of Transplant Bank. The New York Times. Retrieved from http://www.nytimes.com/2014/02/18/health/a-new-kind-of-transplant-bank.html.