Poop Transfer – Past, Present, And (No) Future

The topic is delicate (although this already is a misnomer), as most people shiver if they are not disgusted hearing for the first time what is called “fecal microbiota transfer” (FMT) or “stool transplantation” – but for quite a number of patients, it is a life-saving procedure. 

If – for whatever reason – a single toxic bacterial species – Clostridium difficile (C-diff) – has taken over your entire gut ecosystem, has banished many of the commensal gut bacteria needed for a healthy life, and does not respond any longer to the most aggressive therapy available, antibiotics, while you are losing weight, suffering from diarrhea and abdominal pain, and are at risk for dissolution of the gut wall, allowing bacteria to enter the body’s cavity and induce infections in other organs (and you may die of sepsis), then you may be desperate enough for even the wildest ideas for therapy that doctors may come up with. This is where FMT entered the armamentarium of medicine.

C-diff infections (CDI) are on the rise both in terms of numbers and associated costs (1), due to excessive use of antibiotics and development of resistance towards many of them and their spread, especially in hospitals and medical settings. So part of the problem is home-made: because we have been exposed to antibiotics excessively in the past (even with minor infections, or when they cannot help at all, e.g. with viral infections), the bacteria have learned to cope and adapt, requiring more and other antibiotics to fight them in case of severe infections. Patients with chronic intestinal diseases (e.g. inflammatory bowel diseases) are especially prone to develop CDI.

When the first report of successful long-term outcomes of clinical trials treating patients with CDI by FMT reached the scientific community in 2011/2012 (2), this set off an enthusiastic wave of research along with the questions of what would be the best delivery strategy for stool “transplants,” who would be the best donor for stool, what would be the best clinical condition to treat, the best patients to respond, and whether and to what degree the same strategy — transferring a healthy microbiota into a diseased gut — would work for other intestinal disorders, e.g. for inflammatory bowel diseases.

Why this wave happened at all, and why now and not years before, when occasional reports of FMT had been presented (see below): it certainly coincided with a growing interest into the gut microbiome in general, after deciphering the human genome in 2003 had left many genetic experts jobless or near-to, when the gut microbiota with its thousands of commensal bacterial strains and a 100-fold number of regulating genes as compared to the human genome offered new research opportunities, and all the technology developed during the Human Genome Project was already in place. Both the NIH-funded Human Microbiome Project as well as the EU-funded MetaHit Project started in 2008 and have paved the way for this clinical application – and FMT in CDI has remained the most (and thus far only) convincing paradigmatic disease of all the clinical conditions that came under suspicion to be triggered by the gut microbiome ever since.

There had been precursors of FMT, occasional reports of “fecal enema” or “fecal bacteriotherapy” in patients with pseudomembranous enterocolitis (3) and CDI (4), but these were case reports or small series of patients only (5), that left questions open and concerns aside. “Toying with human motion” (6) is probably what many thought at that time, given the much older tradition of FMT in medical history.

The oldest information of FMT is from China: “During the Dong-jin dynasty in the 4th century in China, Ge Hong, a well-known traditional Chinese medicine doctor, described the use of human fecal suspension by mouth for patients who had food poisoning or severe diarrhea … Later, in the Ming dynasty of the 16th century, Li Shizhen described a series of prescriptions using fermented fecal solution, fresh fecal suspension, dry feces, or infant feces for elective treatment of abdominal diseases with severe diarrhea, fever, pain, vomiting, and constipation in the most-known book of traditional Chinese medicine, “Ben Cao Gang Mu” (Compendium of Materia Medica). For aesthetic considerations, the herb doctors did not label the fecal suspension by its original name, but called it yellow soup …” (7). There may be more ancient traditions (8).

A medieval European source can also be cited for FMT practice: An extensive description of the use of feces  and urine in medical healing was published in 1696 by Christian Franz Paullini (1643 –1712), a German physician whose “therapeutic filth pharmacy” (heylsame Drecks Apotheke) assembled recipes from folk medicine and oral medical traditions, and proposed, as the subtitle says, “… how feces and urine cures nearly all, even the severest and most poisoning diseases …” — details can be studied in the available original reprint (available at Google books) (in German) (9).

And a third tradition can be identified for the use of FMT, originating from veterinary medicine since around 1900, that was and still is called “rumen transfaunation”: treating sick ruminating animals (cows, sheep) by transferring rumen content from a healthy animal to a diseased animal of the same species, to colonize its gastrointestinal tract with normal bacteria (10); also this tradition profits from the rise in interest in microbiome research (11).

Nonetheless, it is surprising that — despite the clear efficacy of FMT in therapy-refractory life-threatening CDI — a “medieval” if not “ancient” treatment approach with such an obscure history has made its way into the medicine of the 21st century. Nowadays, FMT is tested as therapy option in inflammatory bowel diseases (Crohn’s Disease, ulcerative colitis), and in functional bowel disorders such as in irritable bowel syndrome (12) and chronic constipation (13). And with increasing evidence that the gut microbiota may be involved in non-intestinal chronic disorders as well, FMT is proposed (and likely already tested) for diabetes, metabolic syndrome, obesity, cancer, liver cirrhosis, and other diseases (14). And at the end of this development, central nervous system disorders are seen as potential FMT test grounds as well, as if FMT would bring cure to diseases such as autism spectrum disorders, neurodegenerative diseases (Parkinson’s, Alzheimer), attention-deficit-hyperactivity disorder (ADHD), depression, anxiety and panic disorders, eating disorders, and the more (15), that have a hundred years of research tradition, solid diagnostics and many therapeutic options that are at risk to be extinguished for a pure hope for a new magic bullet.

Needless to say, there are risks involved in FMT, not only the risk for uncontrolled usage of FMT outside hospitals, as promoted via the internet (16). Also within medical settings, the need for regulations is apparent and has been taken over by drug authorities (17). Unwanted and serious adverse events have been seen with FMT (18), and while there are good and bad stool donors (19), their characteristics are identified more empirically (by trial and error) than by screening techniques and solid scientific criteria. There is much room and need for improvement.

There are alternatives, however, and there is light at the end of the tunnel: The ultimate goal would be to create an “artificial stool,” a consortium of commensal bacteria fermented and harvested in vitro, tested individually for their efficacy and compatibility under human gut conditions, composed to exert synergy when mixed together, and applied in an acceptable form, encapsulated but living (20).  Meanwhile and for the time being, FMT in CDI may remain a reminiscent therapy that has its empirical justification, until it may be replaced by something equally or more effective. And another reminiscence may remain: storage of one’s own stool (in an acceptable form) as a safety measure in case of a future health problem (e.g. a serious infection) that may require restoration of one’s own gut ecosystem. But dealing with one’s own motions is far less aversive, anyway.

References:

1. Desai K, Gupta SB, Dubberke ER, Prabhu VS, Browne C, Mast TC. Epidemiological and economic burden of Clostridium difficile in the United States: estimates from a modeling approach. BMC infectious diseases. 2016;16:303.
2. Brandt LJ, Borody TJ, Campbell J. Endoscopic fecal microbiota transplantation: “first-line” treatment for severe clostridium difficile infection? Journal of clinical gastroenterology. 2011;45(8):655-7.
3. Eiseman B, Silen W, Bascom GS, Kauvar AJ. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958;44(5):854-9.
4. Schwan A, Sjolin S, Trottestam U, Aronsson B. Relapsing Clostridium difficile enterocolitis cured by rectal infusion of normal faeces. Scandinavian journal of infectious diseases. 1984;16(2):211-5.
5. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. Lancet. 1989;1(8648):1156-60.
6. Borody TJ, Warren EF, Leis SM, Surace R, Ashman O, Siarakas S. Bacteriotherapy using fecal flora: toying with human motions. Journal of clinical gastroenterology. 2004;38(6):475-83.
7. Zhang F, Luo W, Shi Y, Fan Z, Ji G. Should we standardize the 1,700-year-old fecal microbiota transplantation? The American journal of gastroenterology. 2012;107(11):1755.
8. Du H, Xu T, Li HJ, Li Q, GangHuan CL, Fan G, et al. [Fecal Tibetan medicines]. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica. 2018;43(5):1054-61.
9. Lehrer S. Duodenal infusion of feces for recurrent Clostridium difficile. The New England journal of medicine. 2013;368(22):2144.
10. DePeters EJ, George LW. Rumen transfaunation. Immunol lett. 2014;162:69-76.
11. Zhou M, Peng YJ, Chen Y, Klinger CM, Oba M, Liu JX, et al. Assessment of microbiome changes after rumen transfaunation: implications on improving feed efficiency in beef cattle. Microbiome. 2018;6(1):62.
12. Johnsen PH, Hilpusch F, Cavanagh JP, Leikanger IS, Kolstad C, Valle PC, et al. Faecal microbiota transplantation versus placebo for moderate-to-severe irritable bowel syndrome: a double-blind, randomised, placebo-controlled, parallel-group, single-centre trial. Lancet gastroenterology & hepatology. 2018;3(1):17-24.
13. Ding C, Fan W, Gu L, Tian H, Ge X, Gong J, et al. Outcomes and prognostic factors of fecal microbiota transplantation in patients with slow transit constipation: results from a prospective study with long-term follow-up. Gastroenterol Rep (Oxf). 2018;6(2):101-7.
14. Khanna S. Microbiota Replacement Therapies: Innovation in Gastrointestinal Care. Clinical pharmacology and therapeutics. 2018;103(1):102-11.
15. Evrensel A, Ceylan ME. Fecal Microbiota Transplantation and Its Usage in Neuropsychiatric Disorders. Clin psychopharmacol neurosci. 2016;14(3):231-7.
16. Segal JP, Abbasi F, Kanagasundaram C, Hart A. Does the Internet promote the unregulated use of fecal microbiota transplantation: a potential public health issue? Clinical and experimental gastroenterology. 2018;11:179-83.
17. Hoffmann D, Palumbo F, Ravel J, Roghmann MC, Rowthorn V, von Rosenvinge E. Improving regulation of microbiota transplants. Science. 2017;358(6369):1390-1.
18. Wang S, Xu M, Wang W, Cao X, Piao M, Khan S, et al. Systematic Review: Adverse Events of Fecal Microbiota Transplantation. PloS one. 2016;11(8):e0161174.
19. Kump P, Wurm P, Gröchenig HP, Wenzl H, Petritsch W, Halwachs B, et al. The taxonomic composition of the donor intestinal microbiota is a major factor influencing the efficacy of faecal microbiota transplantation in therapy refractory ulcerative colitis. Alimentary pharmacology & therapeutics. 2018;47(1):67-77.
20. Petrof EO, Khoruts A. From stool transplants to next-generation microbiota therapeutics. Gastroenterology. 2014;146(6):1573-82.