By Mark Davis, ND. Fecal microbiota transplantation (FMT), most commonly known as fecal transplant, is the process of applying microbes from the stool of a healthy person to the GI tract of a sick person in order to restore the patient’s microbial community, and thus the patient, to good health. The US Food and Drug Administration presently regulates FMT as a drug and a biological agent to treat patients with Clostridium difficile infection not responding to standard therapies. In addition to clinician use of FMT, sick people all over the world are preparing FMT retention enemas themselves at home. This article examines the evidence for the safety and efficacy of FMT for various conditions.
Fecal microbiota transplantation (FMT), commonly known as fecal transplant, consists of transplanting microbes from the stool of a healthy person to the gastrointestinal tract of a patient. This article examines the evidence for the safety and efficacy of FMT for various conditions. FMT appears to be the most effective intervention available for refractory Clostridium difficile infection (rCDI), and it may be our most effective intervention as a first-line therapy for CDI. It appears to be safe and variably effective for inflammatory bowel disease. There is growing evidence that FMT may benefit patients with metabolic syndrome, irritable bowel syndrome, and chronic fatigue. Animal studies and human case reports suggest possible benefit for other conditions.
Fecal microbiota transplantation (FMT) has been referenced in historical medical literature as far back as the 4th century1 and was first reported in the modern literature in the United States in 1958.2 There has been an explosion of interest in this therapy in the past 5 years.3 Since April 2013, the US Food and Drug Administration (FDA) has regulated FMT as a drug and a biological agent.4 Since July of 2013, the FDA has officially not enforced that policy when clinicians use FMT to treat patients with Clostridium difficile infection (CDI) not responding to standard therapies.5 With or without clinician knowledge or supervision, patients are preparing FMT retention enemas themselves at home.
Refractory Clostridium difficile Infection
CDI can be difficult to define, because roughly 6% of healthy, asymptomatic individuals test positive for toxigenic C difficile.6 That being said, refractory CDI (rCDI) is a significant burden on the US population, leading to half a million infections and approximately 29,000 deaths per year.7 Two small randomized controlled trials (RCTs) have evaluated the safety and efficacy of FMT for rCDI. The first found a 94% cure rate with 2 administrations of nasoduodenal FMT following a standard 4-day course of vancomycin.8 The second found a 90% cure rate with 1 or more administrations of colonoscopic FMT following a 4-day course of vancomycin.9 Both trials were stopped early upon interim analysis because their cure rates were so much higher than the treatment-as-usual (vancomycin alone) groups.
Several meta-analyses or systematic reviews of case series have indicated that FMT administered via lower gastrointestinal (GI) tract via colonoscopy or enema has a cure rate of over 90%,10,11 and FMT administered via upper GI via nasoenteric tube or gastroduodenoscopy has a cure rate greater than 80%.12,13 Despite a trend towards more benefit from lower-GI FMT, no authors have reported a significant difference in efficacy between the 2 routes.14 FMT appears to be significantly more effective than the antibiotics commonly used for CDI,15 which have a durable success rate for severe CDI of about 65%16; fewer than 30% of the patients with rCDI in the vancomycin groups in the RCTs mentioned above were cured. Two small uncontrolled trials support the use of fresh and frozen encapsulated FMT for rCDI, with cure rates between 90% and 100%.17,18 FMT from screened donors prepared and administered by patients at home can be safely and effectively curative for rCDI.19 FMT appears to be more cost-effective for rCDI than the current standard therapy of tapered vancomycin.20
Early Use of Fecal Microbiota Therapy for Clostridium Difficile Infection
A retrospective case series examined the use of early FMT for a virulent subset of CDI called CD027. Some patients received FMT in the first week of hospitalization rather than waiting until standard therapies failed. That group had an 81% cure rate, while the group treated only antibiotics or a later course of FMT had a 36% cure rate.21
FMT appears to be safe and inexpensive for patients with rCDI,22 including pediatric23 and immune-compromised24 populations. There have been adverse events reported following FMT for rCDI, but aside from minor transient events like fever and abdominal discomfort, those adverse events are generally not attributed to FMT.10,25,26 Following are some adverse events reported after FMT:
- Two cases of norovirus diarrhea occurred after and may have been caused by FMT, despite asymptomatic donors27;
- a 78-year-old patient with a history of recurrent diverticulitis experienced an episode of diverticulitis following FMT that was used to successfully cure her rCDI28;
- a 78-year-old patient with previously quiescent ulcerative colitis (UC) experienced a flare of UC following FMT that was used to successfully cure his rCDI29;
- a 61-year-old patient with a history of frequent Escherichia coli bacteremia experienced an episode of E coli bacteremia following FMT that was used to successfully cure his rCDI30; and
- a 68-year-old with a history of septic shock experienced fatal sepsis following FMT that was used unsuccessfully in an attempt to cure his severe rCDI.31 In this case, the fecal slurry may have inadvertently been delivered to the peritoneum.32
Inflammatory Bowel Disease
About 0.2% of adults in the United States have UC or Crohn’s disease (CD), the 2 major forms of inflammatory bowel disease (IBD).33 A systematic review of FMT for IBD reported a 76% response rate and 63% remission rate following FMT.34 A more recent and thorough systematic review and meta-analysis of FMT for IBD reported that 45% of IBD patients achieved clinical remission following FMT. A subgroup analysis of cohort studies demonstrated clinical remission in 22% of patients with UC and in 60% of patients with CD. Low incidence of adverse events but very wide confidence intervals in both subgroups led the authors to report that FMT is a safe but variably efficacious treatment for IBD.35 Since the publication of those meta-analyses, there have been several more RCTs.
In the first RCT of FMT for IBD, 5 people with moderate to severe UC received FMT via nasojejunal (NJ) tube and enema. All participants experienced fevers and increased inflammation, and only 1 experienced measurable benefit. The lack of efficacy in this study may have been related to the small number of infusions (3); small amount of donor stool used (36 g via NJ tube and 24 g via enema); small volume of enema (100 mL); the addition of a proton pump inhibitor, antibiotics, and a bowel-slowing agent; and the fact that the researchers had participants stop immunosuppressive treatments 2 to 8 weeks before FMT.36
A colleague recently remarked that 'We used to live in a world where people got sick from exposure to feces and lives were saved with antibiotics. Now we live in a world where people are dying from antibiotics and their lives are being saved by feces.'
In a more recent, larger RCT by the same research team, 75 people with active UC were randomized to receive an enema of 50 mL of FMT (prepared using 50 g stool and 300 mL of water) or an enema of water (as a control group) once per week for 6 weeks. At 7 weeks, 24% of those in the FMT group were in remission and only 5% of those in the placebo group were, a statistically significant difference. Stool donated by 1 particular donor led to remission in 39% of recipients, while stool from other donors led to remission in only 10% of the participants, suggesting statistical evidence for donor dependence. Participants who had had UC for less than 1 year were also significantly more likely to respond. There was no difference in adverse events between the verum and control groups.37
In the other published RCT of FMT for UC, 50 people with mild to moderately active UC were randomized to receive 500 mL of fecal slurry via nasoduodenal tube prepared using stool from a healthy screened donor or from their own (autologous) stool. The latter group acted as the control group. Both groups received a second identical treatment 3 weeks after the first. There was no difference in remission rates between the 2 groups, but microbiome analysis that participants in the verum group who responded had a significant shift towards the microbiome of their donor, which nonresponders did not experience. The authors suggested (and I agree) that the lack of significant difference between the 2 groups may have been due to the upper GI method of administration, the small number of infusions, and the relatively small number of participants in the trial (compared to numbers used to find significance in newer IBD drugs).38
Pediatric Inflammatory Bowel Disease
A single nasoduodenal FMT was deemed safe but not beneficial for 4 children with UC39 and safe and beneficial for 9 children with CD.40 A series of FMT retention enemas has been deemed safe and beneficial for 10 children and young adults with UC.41
Significant Adverse Events in Inflammatory Bowel Disease
There is a report of an anaphylactoid reaction to FMT in a 1-year-old girl with colonic IBD.42 She experienced sweating, tachycardia, high fever, and listlessness, all of which resolved within 24 hours. Her colonic IBD also resolved and remained resolved for the subsequent 6 months she was followed by the authors.
An RCT studied the effects of administering nasoduodenal FMT to men with metabolic syndrome using stool from lean donors or autologous stool as a control group. Insulin sensitivity significantly improved in the men who received FMT from lean donors.43
Irritable Bowel Syndrome
There are many people with irritable bowel syndrome (IBS) trying home FMT, and there have been clinical reports of successful use of FMT for patients with IBS as early as 1989.44 There has been 1 clinical study of FMT for IBS, a single-center retrospective of 13 patients with IBS nonresponsive to standard treatments. Following esophagogastroduodenoscopic administration of FMT, 70% reported resolution or improvement of symptoms and 46% reported overall improvement of overall well-being.45
Chronic Fatigue Syndrome
A chart review from a single center examined 60 patients with chronic fatigue syndrome (CFS), 52 of whom also had IBS. The patients were treated with a colonoscopic dose (and up to 2 additional enema-delivered doses) of 13 bacteria sourced from human stool. CFS symptoms resolved in 70% of the participants following the procedure, and of the 29% of responders who were available for follow-up 15 to 20 years later, 58% reported that they remained CFS-free.46
FMT resolved 87% of polymicrobial sepsis in mice vs only 17% resolution in the control group that received autoclaved FMT.47 A case of polymicrobial sepsis and diarrhea following vagotomy in a human was successfully cured with FMT.48
There are reports of other possible benefits of FMT: a published report of 3 patients with severe multiple sclerosis (MS) whose symptoms completely reversed after FMT49; 2 patients with MS in my practice who have not had new MS symptoms or new lesions since FMT; a case of idiopathic thrombocytopenic purpura (ITP) reversing after FMT50; and cases of myoclonus dystonia and Parkinson’s disease that may have responded to FMT.51
A colleague recently remarked that “We used to live in a world where people got sick from exposure to feces and lives were saved with antibiotics. Now we live in a world where people are dying from antibiotics and their lives are being saved by feces.” Certainly, the landscape of health and disease has changed massively over the past 100 years, as infectious disease incidence and severity has decreased and autoimmune and allergic diseases have increased in inverse correlation.52 FMT may have the power to benefit patients who are ill with both infectious and autoimmune etiologies. With clinicaltrials.gov listing 66 trials of FMT for various conditions as of this publication, we are likely to know much more in the ensuing decade.
In the language of the US Department of Health and Human Services National Guidelines Clearinghouse,53 we can give our patients grade A recommendation to use FMT for C difficile infections, IBD, and metabolic syndrome; grade B recommendation to use FMT for IBS and CFS; and grade C or D recommendations to use FMT for sepsis, MS, ITP, myoclonus dystonia, and Parkinson’s disease.
Mark Davis, ND, is the sole owner of Bright Medicine Clinic, Portland, Oregon, and has a financial interest in Microbiomes, LLC, Portland. These entities provide encapsulated fecal microbiota therapy for patients with refractory Clostridium difficile infection.