This good update provides a lot of useful information regarding fecal microbiota transplantation (FMT) and a word of caution regarding its future availability.
Key pointsregarding FMT:
Long-term safety remains unknown. FMT may lead to susceptibility to chronic inflammatory, allergic, and autoimmune diseases. “FMT has been associated with durable transmission of pro-carcinogenic bacteria from adult donors to pediatric recipients…although the long-term consequences…are unknown.”
Due to transfer of extended spectrum beta-lactamase (ESBL) E coli to 2 immunocompromised adult recipients, further screening of FMT was implemented.
Though there is no published evidence of SARS-CoV-2 fecal transmission, the FDA “advised additional precautions and testing in March 2020; “however, there are no molecular tests with stool…which have received emergency use authorization.” Hence, most FMT programs were on hold as of January 2021.
After 2021, OpenBiome, whose product was recently available again, is expected to stop distribution of FMT donor product due to increased costs of screening and the “promising biotherapeutics” that are in phase III trials.
Biotherapeutic is “loosely defined as drug therapy products where the active substance is extracted from a biological specimen.” The new products are likely to have “increased standardization, safety and practicality.”
The problem in pediatrics: none of these biotherapeutic products have started trials in children. This will lead to treatment problems. Even if one wanted to set up donor-directed FMT, it will be difficult to complete all of the screening recommended by the FDA. It could lead to self-administration by families with uncertain risks.
My take: My first reaction to this article: ‘Oh crap!’ It is sad and ironic that I will miss having available commercial stool for FMT.
In this prospective study (2012-2018) with 609 patients (median age 56 years), the authors studied long-term outcomes. Key findings:
At 1 year, 9.5% reported additional CDI episodes. Diarrhea occured in more than half of all patients, although it lasted for than a week in most patients.
Among 477 with long-term data, 188 patients post-FMT developed new medical conditions/symptoms.
Weight gain was reported by 46 patients (10.3%) post-FMT. In these patients, the median weight gained was 30 pounds (range, 10–70). Of these patients, 11 (23%) had preexisting obesity.
Approximately 3% of patients each reported new-onset diabetes mellitus and dyslipidemia, whereas 2.3% reported thyroid disease.
Gastrointestinal symptoms were the second most frequently reported (13.4%). New-onset IBS was reported by 4%, IBD by 0.3%, chronic diarrhea by 5.0%, and chronic constipation by 1.6% of patients.
Serious infections were reported by 11.8% of patients: CDI in 5.7%, Pneumonia in 4.5%, UTI in 1.8% and Sepsis in 1.2%. Median time to the infections was 29 months (range, 0–73) following FMT; only 1 patient reported an infection (CDI) within the first month after FMT.
No deaths were considered related to FMT
Limitation: no control group
My take (borrowed from authors): “FMT appears safe and effective, both in the short-term and long-term. Several new medical conditions were reported post-FMT, in particular, weight gain and IBS.”
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)
Surgical options include Ileal pouch–anal anastomosis (IPAA), rectal-sparing colectomy with end ileostomy (RCEI), and ileorectal anastomosis (IRA). Conclusions based on “a patient-level state transition microsimulation in TreeAge Pro:”… “Despite an increased risk of infertility, our model results suggest that IPAA may be the optimal surgical strategy for female UC patients aged 20–30 years who desire children. For patients aged 35 years, RCEI should additionally be considered, as QALYs for RCEI and IPAA were similar.” In older age group, RCEI’s increase rate of childbirth (28%), decrease time to childbirth (14 months) and 77% reduction in IVF are important factors.
In this retrospective study with 145 patients, the overall cure rate of CDI after FMT was 80.0%, without CDI recurrence at median follow-up of 9.3 (range, 0.1–51) months. The authors concluded that “fecal microbiota transplantation effectively treats recurrent CDI in IBD patients but has no apparent beneficial effect on the IBD course.”
In this clinical review (N Chande et al Inflamm Bowel Dis 2020; 26: 843-51) assess evidence from Cochrane reviews of four popular nontraditional treatments for inflammatory bowel disease (IBD):
Fecal Microbiota Transplantation (FMT)
Nutritional Therapies including Enteral Nutrition (EN)
Naltrexone for Crohn’s Disease (CD)
Cannabis for IBD
So what does the literature have to say about these treatments:
FMT: FMT for mild to moderate ulcerative colitis (UC) increased the proportion of patients achieving clinical remission. “However, the number of included studies was small and the quality of evidence was low.” Other problems included uncertainty regarding serious adverse events and short duration of followup.
“As a result, no solid conclusions [the authors did not indicate this as a pun] can be drawn at this time.”
Nutritional Therapies: For remission in CD, “EN may be more effective than corticosteroids in children, although the opposite was true in adults.”
“Exclusion diets did not promote clinical remission or reduce clinical relapse in UC”
“The overall certainty of evidence in these studies were generally very low, largely due to sparse data.”
Naltrexone for Crohn’s Disease (CD): “The paucity of data makes it impossible to draw any firm conclusions about the effectiveness and safety” of low dose naltrexone.
Cannabis for IBD: “The risk of adverse events was significantly higher in cannabis-treated patients”…though these events were generally mild (eg. sleepiness, confusion, nausea).
“The results of these studies suggest that cannabis is not effective for the treatment of IBD” This conclusion is limited by the small number of patients in prior studies. Cannabis may be helpful as an adjunct for some symptoms though this “warrants further study.”
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.
To lessen obesity, three health risk behaviors have been targeted:
Sedentary behavior -goal is to limit to 2 hours of screen time in 24 hours
Physical activity -goal is 1 hour (or more) of moderate to vigorous activity
Sleep duration -goal is 9-12 hours (ages 6-12 years) and 8-10 hours (13-18 years)
A recent study (X Zhu et al. J Pediatr 2020; 218: 204-9) shows that <10% of U.S. kids meet these goals. The authors examined data (2016-17) from the National Survey of Children’s Health (NSCH) dataset (n=71,811)
80.9% did NOT meet physical activity goal
76.2% did meet screen time goal
581% did meet sleep goal
However, only 9.4% met all 3 goals
Not meeting these ‘movement’ guidelines was associated with obesity, particularly in females (aOR 4.97 compared to aOR 3.99 for males)
My take: We are all made to be different shapes and sizes. Nevertheless, we should strive for healthy behaviors and healthy eating which could improve outcomes.
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.