In The Shawshank Redemption, Andy Dufresne (Tim Robbins) manages to escape prison by crawling through 500 yards of a filthy sewage pipe. It seems like a similar effort will be needed to find out how to benefit from fecal transplantation when given for problems like irritable bowel syndrome and metabolic disease/obesity. Some recent studies and associated editorials are noted below.
This editorial stresses that trials of FMT in IBS have had inconsistent results and risks are unclear. “How many clinicians inform patients receiving FMT that the donor microbiota might include components that increase (or decrease) one’s risk of colorectal cancer?” Part of the problem is “due, in part, because a normal microbiome has not been defined.”
In this randomized controlled trial with 90 participants, autologous FMT (aFMT) significantly attenuated weight regain in the green-Mediterranean group (aFMT, 17.1%, vs placebo, 50%; P = .02) and improved insulin resistance: insulin rebound (aFMT, –1.46 ± 3.6 μIU/mL vs placebo, 1.64 ± 4.7 μIU/mL; P = .04) (Graphical abstract below)
In mice, Mankai-modulated aFMT in the weight-loss phase compared with control diet aFMT, significantly prevented weight regain and resulted in better glucose tolerance during a high-fat diet–induced regain phase (all, P < .05).
“These findings add support to the current body of evidence that the gut microbiota have a role in weight gain and metabolism. However, many questions remain. Indeed, although studies have shown varying degrees of effectiveness of FMT in the improvement of metabolic parameters in human participants, there has been no evidence yet that FMT can induce weight loss in obese patients.”
“The finding that maintenance of weight loss was only seen in the one dietary group consuming the Mediterranean diet plus green tea and Mankai supplement who received autologous FMT, would suggest that specific microbial profiles may be involved and that weight loss per se may not result in the required microbial profiles.”
My take: Both of these studies show that modulation of the fecal microbiome may be helpful under the right set of circumstances to help with both irritable bowel syndrome and metabolic syndrome. However, ‘hundreds of yards’ of more research is needed to determine if this is really feasible and to assure that the benefits outweigh the potential risks.
Methods: Single course of oral encapsulated fecal microbiome from 4 healthy lean donors or saline placebo.
In this randomized, double-masked, placebo-controlled trial of 87 adolescents with obesity, FMT alone did not lead to weight loss at 6 weeks.
There were no observed effects on insulin sensitivity, liver function, lipid profile, inflammatory markers, blood pressure, total body fat percentage, gut health, and health-related quality of life
In post-hoc exploratory analyses among participants with metabolic syndrome at baseline, FMT led to greater resolution of this condition (18 to 4) compared with placebo (13 to 10) by 26 weeks (adjusted odds ratio, 0.06; 95% CI, 0.01-0.45; P = .007)
Background: “The FMT National Registry was designed to assess FMT methods and both safety and effectiveness outcomes from North American FMT providers.” n=259 with 222 who completed short-term follow-up.
All FMTs were done for CDI and 249 (96%) used an unknown donor (eg, stool bank).
90% (n=200) were considered cured at one month. Of these, 197 (98%) received only 1 FMT.
Among 112 patients with initial cure who were followed to 6 months, 4 (4%) had CDI recurrence.
Safety: Severe symptoms reported within 1-month of FMT included diarrhea (n = 5 [2%]) and abdominal pain (n = 4 [2%]); 3 patients (1%) had hospitalizations possibly related to FMT. At 6 months, new diagnoses of irritable bowel syndrome were made in 2 patients (1%) and inflammatory bowel disease in 2 patients (1%). Milder adverse events were noted in 45% with symptoms including diarrhea, abdominal pain, bloating or constipation.
My take: Overall, the findings from this prospective registry confirm that FMT works fairly well for CDI. Long-term follow-up will provide more answers on the safety of FMT.
A recent pilot (n=22) double-blind study (JR Allegrett et al. Clin Gastroenterol Hepatol 2020; 18: 855-63) pours cold water on the idea that repopulating one’s microbiome would be helpful in treating obesity.
In this study, the authors examined obese patients without diabetes, nonalcoholic steatohepatitis, or metabolic syndrome. In the treatment group, patients received FMT by capsules: 30 capsules at week 4 and then a maintenance dose of 12 capsules at week 8. All FMT was derived from a single lean donor.
There were no significant changes in mean BMI at week 12 in either group.
Patients in the FMT group had sustained shifts in microbiomes associated with obesity toward those of the donor (P<.001). In addition, bile acid profiles became more similar to the donor.
My take: Though this was a small study, it suggests that changing the microbiome by itself is likely insufficient to result in significant weight loss.
We report temporal patterns of viral shedding in 94 patients with laboratory-confirmed COVID-19 and modeled COVID-19 infectiousness profiles from a separate sample of 77 infector–infectee transmission pairs. We observed the highest viral load in throat swabs at the time of symptom onset, and inferred that infectiousness peaked on or before symptom onset. We estimated that 44% (95% confidence interval, 25–69%) of secondary cases were infected during the index cases’ presymptomatic stage, in settings with substantial household clustering, active case finding and quarantine outside the home. Disease control measures should be adjusted to account for probable substantial presymptomatic transmission.
A recent retrospective multi-center study (MR Nicholson et al. Clin Gastroenterol Hepatol 2020; 18: 612-9) provides data on fecal microbiota transplantation (FMT) for Clostridium difficile infection (CDI). Congratulations to one of my partners, Jeffery Lewis, who is one of the coauthors. This paper’s abstract is noted in a separate blog: Large Study Show FMT Efficacy/Safety in Children.
Though this is a pediatric study, the authors included patients up to 23 years. 335 of the patients had followup for at least 2 months following FMT.
81% of patients had a successful outcome after a single FMT and 86.6% after single or repeated FMT
Higher success rates were associated with fresh donor stool (OR 2.66), FMT via colonoscopy (OR 2.41), and with not having a feeding tube (OR 2.08)
Though not reaching statistical significance, patients with inflammatory bowel disease had a high failure rate of 23% (26/111). Short bowel syndrome patients had a 50% failure rate (5/10), solid organ transplant recipients had a 56% failure rate (5/9), and patients with feeding tubes had a 32% failure rate (21/65).
Seventeen patients (4.7%) had a severe adverse event during the 3-month follow-up period, including 10 hospitalizations; however, the majority were unrelated to FMT. Specific adverse reactions that were related or may have been included aspiration pneumonia on day of procedure (n=1), IBD flare/colectomy (n=5), and vomiting/dehydration (n=1)
Common adverse reactions included diarrhea, abdominal pain, and bloating. (These symptoms have been reported in up to 70% of adults following FMT.)
The authors note that a prior systematic review had indicated that delivery of FMT via colonoscopy was more successful in adults (95% vs 88%), though there are some additional risks with colonoscopy.
It is worth considering that the failure rate in some patients could be due to misdiagnosis, particularly in certain populations like patients with IBD and or organ transplant recipients. In these populations, PCR assays may result in false-positive diagnosis and should be confirmed with an ELISA assay. While eradication of CDI with FMT improves clinical symptoms and reduces the use of antibiotics the true benefit and risks will not be known for a long time. Does FMT increase or reduce the risk of downstream infections, autoimmune disease, and metabolic syndrome?
My take: Many of the concerns with FMT can only be adequately addressed with prospective studies (with strict definitions of CDI) and longer followup.
In June 2019, the FDA delivered a warning about the potential danger of transmitting drug-resistant E coli with fecal microbiota tranplantaion (FMT). (FDA Warning for FMT)
A report on this issue has now been published: Z DeFilipp et al. NEJM 381: 2043-50, editorial M Blaser pgs 264-6.
The authors describe two patients, a 69 year-old with cirrhosis and a 73 year-old sp stem cell transplantation, who developed bacteremia due to transmission of a drug-resistant (extended-spectrum beta-lactamase [ESBL]) E coli following FMT which was delivered by oral capsules. The latter patient died from sepsis. The two patients had a genomicly-identical strain isolated that was also found in the donated aliquot.
In the commentary, a couple of important points:
“Up to now, the complications have been infrequent [from FMT], and for recurrent C difficile infection, the benefits of FMT clearly outweigh the risks; however, as the use of FMT is broadened and more compromised patients are treated, complications may be more frequently observed.”
“In the short term, improved and uniform screening of FMT material is needed to reduce the risks.”
My take: Both of these patients who became developed bacteremia were at risk for more severe infections. However, we need to remain aware that severe complications can and do occur with FMT. In context, though, there are risks of severe complications from routine use of antibiotics as well.
A recent letter (Z Kassam et al. NEJM 2019; 381: 2070-2) describes the arduous process involved in being selected as a stool donor for fecal microbiota transplantation (FMT).
In a previous blog (2015), it appeared that 17% of donors were accepted for FMT: Rejected! Most Stool is Not Good Enough for FMT This current review of the donor program from a stool bank (OpenBiome) prospectively evaluated 15,317 donor candidates from 2014-2018.
Only 3% (n=386) made it through all the steps to become donors
Reasons for exclusion:
Stage 1: common reasons for exclusion:
geographical -living too far away to donate regularly
not in age range
Stage 2: “failing” the 200-item clinical assessment –common reasons for exclusion:
lost to followup
mental health concerns
infectious disease history
social history/sexual history/other reasons
Stage 3: “failing” the stool and nasal screening which included (in 2016) carbapenem-resistant Enterobacteriacea (CRE), extended-spectrum beta-lactamase-producing organisms (ESBL) and MRSA. –common reasons for exclusion:
lost to followup
infectious disorders (including C diff in 7 patients)
Briefly noted: GR D’Haens, C Jobin. Gastroenterol 2019; 157: 624-36. This review sums up the emerging evidence for use of fecal microbial transplantation for conditions besides recurrent Clostridium difficile infection.
Table 2 succinctly provides list of disease, types of study/evidence, and potential effect.
Among gastrointestinal diseases, the authors note that there is an “overall positive” effect for ulcerative colitis, “suggestive” benefits for IBS, GVHD, post-antibiotic diarrhea, constipation, and hepatic encephalopathy. No effect has been evident with Crohn’s disease or pouchitis.
Among nongastrointestinal diseases, the authors note a “suggestive” benefit in autism and metabolic syndrome and “unknown” effect with psoriasis and multiple sclerosis.
My take: The review indicates a need for more studies and the need to define which factors in fecal material mediate the therapeutic effects.
A recent letter to the editor (A Khoruts, LJ Brandt, Am J Gastroenterol 114: 1176) suggests that the terms “Fecal Transplant” or “Fecal Microbiota Transplantation” (FMT) should be abandoned in favor of “intestinal microbiota transplant.”
First of all, the authors argue that the word “fecal” is no longer accurate as some transplants occur by swallowing capsules of purified microbiota and the days of “blending raw stool near the bedside are largely over.”
Secondly, the term “fecal” is highly problematic. “We are hard-wired to perceive feces to be disgusting.”
Third, the media sensation from the terms FMT or fecal transplant “has not translated into substantial positive consequences, such as funding research…[or] philanthropic fundraising.”
Thus, the authors advocate “Intestinal Microbiota Transplant” or IMT.
My take: (borrowed from authors) It is time to “abandon the scatologic humor that is arguably threatening further development of this promising therapeutic approach.”
This article highlights a concern that pharmaceutical companies may persuade the FDA to regulate fecal transplants similar to medications. This will exponentially increase the cost and limit the access to beneficial human excrement. Thanks to one of my sons for pointing out this commentary to me.
As pharmaceutical companies seek to profit from the curative wonders of human feces, doctors worry about new regulations, higher prices and patients attempting DIY cures…
At the heart of the controversy is a question of classification: Are the fecal microbiota that cure C. diff a drug, or are they more akin to organs, tissues and blood products that are transferred from the healthy to treat the sick? The answer will determine how the Food and Drug Administration regulates the procedure, how much it costs and who gets to profit…
Human feces, it turns out, are a potential gold mine, for both medical researchers and drug makers…
For now, most of the material used in fecal transplants comes from OpenBiome, the public stool bank in Cambridge …The material comes from donors who earn $40 a pop and must pass intensive screenings and regular medical checkups. “It’s harder to become a stool donor than it is to get into M.I.T.,” said Carolyn Edelstein, who runs the organization…The F.D.A. has ramped up oversight of OpenBiome’s production, leading to more rigorous testing and higher prices, which will double to $1,600 this month.