Fighting Infections with Feces: The Promise of Fecal Microbiota Transplantation

by Brendan Pease

The phrase “cutting-edge medical treatment” often conjures up images of complex technologies derived from neural mapping or stem cell research.  However, one of the newest medical treatments may not originate from neurons or progenitor cells, but from fecal matter.

Every year, the bacterium Clostridium difficile kills 14,000 Americans and infects many more, causing severe diarrhea and inflammation of the colon. Statistics point to a growing problem: incidence has increased dramatically in recent years, with over 500,000 cases in 2012 (2). Though most infections have communal or zoonotic origins, roughly 20% of infections are spread through hospital settings (3). The bacterium is particularly dangerous for patients with weakened immune systems, such as the elderly and those with autoimmune disorders, as well as those with Inflammatory Bowel Disease. While standard antibiotics such as vancomycin and metronidazole are often used to treat C. difficile infection, they are ineffective for up to 26% of patients due to drug resistance by the bacterium.  A significant portion of patients will also have recurrent infections, for which there are no effective antibiotics (1).  Yet, recent reports point to a solution. Though unsavory to a squeamish some, the experimental medical procedure known as a Fecal Microbiota Transplant (FMT) holds enormous therapeutic promise for both C. difficile and a variety of other diseases.

While there is no standard procedure for a FMT, most follow a common framework.  Prior to the actual procedure, a healthy donor usually related to the recipient is identified and a sample of their stool is collected (4).  Once a sample is obtained, the contents of the recipient’s colon – including all C. difficile bacteria – are flushed out. The stool sample is then transferred to the recipient’s duodenum, the primary location of the gut microbiota, via an enema, a colonoscopy, or a nasogastric tube.  This restores a healthy bacterial flora in the patient’s gut because the bacteria contained in the donor’s stool now inhabit the recipient’s intestines (5).

Although there are rumors of similar procedures being performed for decades, the first well documented FMT transplant was performed in 2006 by Max Nieuwdorp, a young Amsterdam-based researcher and physician.  Frustrated by the lack of effective treatments for recurrent C. difficile, Nieuwdorp developed the idea for a transplant that would flush out a patient’s gut microbiota and replace it with a healthy donor’s microbiota. The treatment proved exceptionally successful. Yet, the procedure’s novelty, indecorous basis, and youthful inventor caused it to be doubted and even ridiculed by some of Nieuwdorp’s colleagues (5).

However, there is much less skepticism about FMT today than there was six years ago.  In January 2013, the first randomized controlled clinical trial was published in the New England Journal of Medicine.  The study focused on patients who had recurrent C. difficile, despite successful treatment of the initial infection with antibiotics..  Of the 16 patients given FMT, 13 were cured after one transplant, while two of the remaining three were cured by a second; thus, FMT cured 94% of subjects overall. By comparison, only 31% of those given the antibiotic vancomycin were cured (1).  Similar rates were observed in another study performed in the same year, with patients returning to normal bowel patterns within one week of the procedure (6).

The merits of FMT, however, extend beyond its efficacy in combatting recurrent infections. The procedure is extremely cost efficient, requiring nothing more than basic nasogastric tubes or enemas (4).  Patients are also attracted to the procedure, despite its nature, once they weigh the results of FMT.  In a recent survey on patient perceptions of FMT, 85% of respondents would choose to have the procedure.  Though respondents generally rated the aesthetics of FMT “somewhat unappealing,” they were ultimately won over by its end results (7).   Further, FMT may be able to halt initial as well recurrent C. difficile infection. Initial infections are treated with broad-spectrum antibiotics that eliminate not only C. difficile, but also many beneficial members of the gut microbiome. As a result, patients are more susceptible to subsequent infections, leading to a high recurrence rate. Using FMT to replace, rather than diminish, individuals’ microbial communities could break this cycle of infection (4).

Despite growing evidence for its benefits, FMT also has a few drawbacks. Though patients are willing to receive the procedure, the unpleasant aesthetics of FMT results in it being used as a “last resort” treatment, reserved for extreme cases (7).  In addition, the procedure carries the risk of spreading infectious diseases, including HIV, hepatitis B and C, cytomegalovirus, Epstein-Barr virus, and Campylobacter jejuni. Because donors are usually relatives of recipients, donors can be hard to find for patients whose families are affected by an infectious disease that could be spread by the procedure or does not have healthy gut microbiota (5).

The greatest danger of FMT, however, occurs when it is taken from hospital to home. Since there is no standardized procedure for FMT, demand for transplants vastly outstrips supply., leading some desperate patients, jaded by waves of ineffective antibiotics, to look to the internet, where they can find dubious instruction for “do-it-yourself” home transplant procedures. In one such video on YouTube, the instructor informs his viewers to store the stool sample in Tupperware kept in the refrigerator and to use a kitchen blender to change the consistency of the sample.  The only methods of sanitation are rubbing alcohol wipes and basic hand soap (8).  Besides jeopardizing FMT’s legitimacy as a medical procedure, these videos can result in their performers suffering complications as harsh as norovirus gastroenteritis (5).

These “do-it-yourself” videos reflect the obstacles to the development of FMT as a common medical procedure. Though a growing body of literature testifies to its success, the transplant procedure remains unstandardized; thus, further clinical trials examining a standardized method are needed to establish a general protocol and verify its efficacy. These measures would promote its adoption among the medical community, improving health outcomes for C. difficile patients.

As FMT itself is continuing to be developed, researchers at the University of Calgary have begun preliminary work on an alternative to the procedure.  Instead of using an enema, a nasogastric tube, or another conventional method of transferring the stool sample, researchers created pills containing donor bacteria.  These pills were equally effective, curing 30 out of 31 patients with C. difficile infections; however, as a therapy still in development, their higher cost hinders mainstream adoption. Thus, these pills may instead be used to treat “niche” cases, including patients who cannot tolerate enemas or nasogastric tubes (9).

Though most FMT-related research focuses on C. difficile, FMT has the potential to treat other diseases as well.  The most apparent of these additional applications are other bacterial infections in the gut microbiota.  In addition, some researchers are beginning to look into whether FMT could be used on patients with autoimmune diseases such as Inflammatory Bowel Disease, in which the body’s immune system attacks elements of its own digestive system (5).  Researchers at Harvard Medical School (HMS) believe that because modern humans live in overly hygienic environments and eat processed foods, their gut microbiota composition is different than that of their ancestors.  This change, according to Dr. Dennis Kasper, William Ellery Channing Professor of Medicine and an HMS professor of Microbiology and Immunobiology, may explain rising incidence of autoimmune disease, as modern humans now lack the microorganisms that have been properly balancing our immune systems for millennia (10).

Recent research has also indicated that the microorganisms in the gut microbiota are metabolically significant. Intestinal microbes have the ability to generate short-chain fatty acids, SCFAs, which can stimulate the secretion of peptide YY, a hormone that reduces appetite and is thought to play a key role in obesity; thus, an individual’s body weight results from the metabolism of their microbes as well as their own.  While fecal transplants are hardly a conventional anti-obesity therapy, a growing body of scientific evidence supports its efficacy for treating disorders of energy balance (11).  The influential metabolic role of gut microbiota has also led some physicians to propose the procedure as a treatment for diseases such as diabetes (11). While further investigation is required, FMT may prove to have broad clinical relevance.

While its efficacy in treating C. difficile infections is increasingly well-documented, FMT is arguably in the infancy of its therapeutic development. Though procedural standardization and more clinical validation are required for widespread adoption, transplants are becoming better accepted among both the medical community and general public.  With the potential to treat pathologies ranging from known bacterial infections to the politically significant obesity epidemic, FMT possesses far too many benefits to be ignored – despite its unsightly nature.

References

  1. Van Nood, E. et al.  Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile.  The New England Journal of Medicine 368, 407-415.  (Jan, 2013).
  2. “Fecal microbiota transplants effective treatment for C. difficile, inflammatory bowel disease, research finds.”  American College of Gastroenterology. (Dec, 2011).
  3. Gallagher, J.  “Most C. diff infections are ‘not hospital spread.’”  BBC.  (Sep, 2013).
  4. McKenna, M.  Swapping Germs: Should Fecal Transplants Become Routine for Debilitating Diarrhea? Scientific American (2011).
  5. De Vrieze, J. The Promise of Poop.  Science 341, 954-957. (Aug, 2013).
  6. Petrof, E. et al.  “Stool Substitute Transplant Therapy for the Eradication of Clostridium difficile Infection: ‘RePOOPulating’ the Gut.” Microbiome 1, 3. (Jan, 2013).
  7. Zipursky, J. et al. Patient Attitudes Toward the Use of Fecal Microbiota Transplantation in the Treatment of Recurrent Clostridium difficile Infection.  Clinical Infectious Diseases 55, 1652-1658.  (Dec, 2012).
  8. Hurst, M.  “Fecal Transplants: How to Do it Yourself Video.”  (June, 2013; http://fecaltransplant.org/fecal-transplants-how-to-do-it-yourself-video/).
  9. Zhang, S. Feces-Filled Pill Stops Gut Infection.  Nature (Oct, 2013).
  10. Karcz, S.  “Cottage Industry.” (Oct, 2013; http://hms.harvard.edu/news/harvard-medicine/harvard-medicine/how-bugs-are-built/cottage-industry?utm_source=Silverpop Mailing&utm_medium=email&utm_campaign=10.03.daily%20(1)).
  11. Nieuwdorp, M.  Metabolic Function of Microbiota and their Produced Short Chain Fatty Acids: Animal and Human Data.  International Scientific Association for Probiotics and Prebiotics.  (2013).

Categories: Fall 2013

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