Fecal Microbiota Transplantation

Abstract

Fecal microbiota transplantation (FMT) is the process of transplanting stool from a healthy donor into the gut of a patient for therapeutic purposes. Current guidelines recommend FMT for the prevention of multiply recurrent Clostridioides difficile infection (CDI) after two recurrences, with cure rates approaching 90%. Emerging evidence also supports the use of FMT in the management of severe and fulminant CDI, resulting in decreased mortality and colectomy rates compared with standard of care approach. FMT shows promise as salvage therapy for critically-ill, refractory CDI patients who are poor surgical candidates. FMT should be considered early in the clinical course of severe CDI, preferably within 48 hours of failing to respond to antibiotic therapy and volume resuscitation. Besides CDI, ulcerative colitis was more recently identified as a potential treatment target for FMT. Several live biotherapeutics for microbiome restoration are on the horizon.

Fecal microbiota transplantation (FMT) is the process of administering minimally processed stool from a healthy donor into the gut of a diseased recipient with a therapeutic intent. The origins of FMT date back to the fourth century in China, when human fecal suspension was prescribed for the cure of gastrointestinal ailments such as food poisoning and severe diarrhea, yielding positive results. ¹ In the modern era of medicine, the Chief Surgeon of Denver General Hospital, Ben Eiseman reported on four patients with pseudomembranous colitis who were cured after rectal instillation of donor feces. ² Notably, he performed FMT in 1958, nearly 20 years before the identification of Clostridioides difficile as causative agents of antibiotic-induced pseudomembranous colitis. In his publication, Dr. Eiseman described the results as a “miraculous cure” aiming to “re-establish the balance of nature” within the intestinal flora to correct the disruption caused by antibiotic treatment. He observed “immediate and dramatic” responses and suggested “this simple yet rational therapeutic method should be given more extensive clinical evaluation.” Interest in FMT resurfaced around 2008 triggered by the emergence of a C. difficile infection (CDI) epidemic. Since then, the success of FMT in the treatment of CDI bolstered tremendous interest in the science of gut microbiome, and cosmic efforts were undertaken to understand the complex interactions between host and microbiome. FMT is now a widely accepted and guideline-recommended therapeutic modality for CDI. There is significant interest in FMT's role in treating other diseases associated with alterations in gut microbiota on the horizon as well, such as ulcerative colitis (UC), metabolic syndrome, hepatic encephalopathy, and irritable bowel syndrome, just to name a few.

Mechanisms of Fecal Microbiota Transplantation

C. difficile (previously called Clostridium difficile ) is one of the most common supergerms of our time. ³ Its outbreak has reached epidemic proportions due to widespread use of antibiotics and resultant disruption of the innate gut flora, ⁴ making the host susceptible to invasion, colonization, and ultimately infection by C. difficile . The mainstream therapy of CDI is antibiotics that are effective at clearing infection, but paradoxically worsen the dysbiosis at the same time. Although the currently available anti-CDI antibiotics such as vancomycin and fidaxomicin are highly effective against the vegetative form of C. difficile , they do not possess antisporicidal activity. ⁵ Retainment and germination of C. difficile spores in the gut is thought to be the driving force in the development of recurrent infection. ⁶ It is to no surprise that the likelihood of CDI recurrence is amplified after each successive CDI despite successful treatment, ⁷ a phenomenon attributable to progressively decreasing microbial diversity proportional to the number of previous antibiotic treatments. ⁸ FMT quickly restores microbial diversity and the dominance of protective organisms, suppressing C. difficile activity via multiple mechanisms of action. First, healthy microbiota competes for niche and nutritional resources. ⁹ Second, the microbiota actively produce bacteriostatic or bacteriocidal peptides, the so-called bacteriocins. ⁴ Third, the metabolism of the primary bile acids (cholic acid) into secondary bile acids (chenodeoxycholic acid) with ratios inhibitory to C. difficile's spore germination and vegetative growth is restored by transplanted microbes. ¹⁰ Finally, indigenous microbial organisms in the gut achieve homeostasis with the host, which optimizes gut barrier function and promotes a tolerance of the mucosal immune system to the commensal flora. ¹¹ Putting it all together, the transplanted microbes assist in stamping out C. difficile and resisting colonization.

Current U.S. Regulations of FMT

The U.S. Federal Food and Drug Administration (FDA) permits clinicians to administer FMT for the treatment of CDI unresponsive to standard of care antibiotic therapy. For this indication only, the FDA does not require submission of an Investigational New Drug (IND) application provided that the clinician obtains an informed consent detailing potential FMT-related risks and its investigational nature. At the beginning of the CoVID-19 epidemic, the FDA announced that only material produced before December 1, 2019 was eligible for use. Since then, biobanks have implemented SARS-CoV-2 screening in stool donors via nasopharyngeal swabs and stool substrate testing. Transmission of SARS-CoV-2 via FMT has not been reported to date. The FMT material is most often sourced from OpenBiome and it is often administered in clinical trials.

Current Guideline Recommendations for FMT

In 2021, three medical societies (the American College of Gastroenterology [ACG], ¹² the Infectious Diseases Society of America [IDSA], ¹³ and the European Society of Clinical Microbiology and Infectious Diseases [ESCMID]) ¹⁴ issued guidelines regarding CDI management. While their recommendations slightly differ concerning antibiotic treatment regimens, they uniformly agree that FMT should be considered after the second CDI recurrence or the third episode to prevent further recurrences. These recommendations are based on a large number of cohort studies and multiple randomized controlled trials on FMT for recurrent CDI with success rates approaching 90%. ¹⁵ Furthermore, rates of CDI recurrence are lower after FMT (5–15%) ^{16 17} compared with antibiotics vancomycin (35–65%) ¹⁸ and fidaxomicin (25%). ¹⁹ If the patient experiences CDI recurrence within 8 weeks of the initial FMT, guidelines suggest repeat FMT. ¹² Beyond multiply recurrent CDI, the ACG guidelines ¹² recommend FMT for severe and fulminant infection refractory to antimicrobial therapy, even as first-line therapy, particularly, when patients are deemed poor surgical candidates. While the latter recommendation was issued as strong, it is based on low quality of evidence given the lack of randomized controlled trials. ¹²

FMT for Severe and Fulminant CDI

About 8 to 10% of patients hospitalized with severe CDI are classified as severe and historically, 30% of them require surgery due to failure of medical therapy, toxic megacolon, peritonitis, or colonic perforation. ^{20 21} Unfortunately, rates of success after surgery are also far from ideal. The 30-day postoperative mortality of transabdominal colectomy reported between 32.7% in a large National Surgical Quality Improvement Program (NSQIP) database study ²² and 41.3% in a meta-analysis. ²⁰ Diverting loop ileostomy followed by anterograde vancomycin lavage was adopted across the United States with annual proportion of patients undergoing only diversion increasing from 11.16% in 2011 to 25.30% in 2015. ²³ While more loop ileostomies were performed promptly within 24 hours of admission compared with transabdominal subtotal colectomies (23.31 vs. 12.21%; p  < 0.01), the in-hospital mortality rates were similar between the two groups (25.98 vs. 31.18%; p  = 0.28). ²³ Loop ileostomy may be a viable surgical alternative to total abdominal colectomy (TAC), but no clear survival benefit was demonstrated to date, ²⁴ and with preservation of the colon recurrence of difficult-to-treat CDI is a concern. ²⁵

Despite improved surgical techniques and predictive models, postsurgical mortality remains high. ^{23 26} The emergent nature of surgery or delay in surgical intervention after medical failure may contribute to this. It is challenging to determine the optimal window for surgery and avoid the “too early” and “too late” case scenarios. To avoid futile surgery in patients with medically refractory CDI being considered for TAC, a risk of death model was constructed but has not been externally validated. ²² The risk of death score ranged from 8.0 to 96.1% and included age greater than 80 years (odds ratio [OR]: 5.5; p  = 0.003), need for preoperative mechanical ventilation (OR: 3.1; p  < 0.001), chronic steroid use (OR: 2.9; p  < 0.001), underlying cardiopulmonary disease (OR: 2.0; p  = 0.001), acute renal failure (OR: 1.7; p  = 0.03), liver disease, active cancer, and diabetes mellitus diagnosis. ²²

Over the last decade, convincing evidence emerged to suggest that FMT should be considered for the treatment of severe and fulminant CDI. While a single FMT resulted in cure in 66 to 91% patients in case series, ^{27 28} for many others with severe and fulminant presentation a single treatment only provided temporary symptom improvement and multiple FMTs in short succession was needed for sustained cure. ^{17 29} These observations have led to the development of sequential FMT protocols. Fischer et al proposed a pseudomembrane-driven protocol with selective use of oral vancomycin that had high rates of success in both severe and fulminant CDI refractory to standard therapy. ³⁰ In this protocol, patients with severe or fulminant infection who fail to respond to standard of care therapy consisting of volume resuscitation and 5 days of vancomycin ± intravenous metronidazole therapy undergo FMT via colonoscopy. If pseudomembranes are present at the index colonoscopy, oral vancomycin is restarted within 24 to 48 hours following the colonoscopic FMT, and subsequent FMT(s) are delivered at 3- to 5-day intervals until complete resolution of pseudomembranes is accomplished. In a retrospective analysis of 57 patients treated with this protocol, 100% of severe CDI and 87% of fulminant patients were cured during the same hospital admission. ³¹ In an open-label randomized trial by Ianiro et al, a similar, pseudomembrane-driven FMT protocol in combination with a 14-day vancomycin treatment was compared with a single colonoscopic FMT infusion followed by a 14-day vancomycin course. ³² The overall success was 75% for a single FMT-vancomycin group and 100% for multiple FMT-vancomycin group ( p  = 0.01). Notably, 57% of cases in the multiple FMT-vancomycin group were classified as fulminant. Importantly, no serious adverse events were noted with the use of either protocol.

FMT can be safely administered via careful colonoscopy even in patients with toxic megacolon with gentle CO ₂ insufflation and careful advancement of the scope beyond the splenic flexure. The availability of screened and frozen donor stool–derived microbiota from stool banks has facilitated prompt treatment of such patients. Clinical response after FMT can be gauged by stool consistency and frequency, as well as decreasing white blood cell count and C-reactive protein levels. While FMT and colectomy should both be considered when the patient fails to respond to maximum standard therapy, there is currently no standard set of criteria to determine when colectomy should be performed. Therefore, patients should be monitored closely as their clinical course rapidly evolves.

Early surgical consultation is recommended in patients with underlying IBD, vasopressor requirements, and impending sepsis or multi-organ failure. ²¹ While early colectomy has been associated with improved rates of survival in fulminant and refractory CDI, ³³ the substantial morbidity and mortality associated with colectomy is difficult to rationalize unless no other options are available. Patients tend to continue with medical management, and unfortunately a significant portion of these patients further deteriorate, become too unstable for surgery, and eventually succumb to their disease. The introduction of FMT to this subset of patients not only constitutes a new treatment modality but may also stabilize partial responders to FMT such that they are better candidates for surgery. As such, FMT should now be considered the next line of therapy for those with severe and fulminant CDI after 48 to 72 hours of maximum medical therapy, particularly as there are generally fewer risks and decreased postoperative recovery time compared with surgery.

Beyond improved cure rates, FMT may result in decreased rates of CDI-related colectomy and bloodstream infection and may be associated with better survival in this critically ill patient population. In a single-center study, while the number of patients hospitalized for CDI and related colectomy rates increased steadily from 54 to 268 between 2010 and 2014, introduction of inpatient FMT in 2013 led to a significant decline in the number of CDI-related colectomies (zero). ³⁴ Another single-center retrospective cohort study also reported dramatic decreases in rates of CDI-related colectomy from 6.8 to 2.7% ( p  = 0.042) and in 30-day mortality from 10.2 to 4.5% ( p  = 0.021) after integration of an inpatient sequential FMT program. ³⁵ In this study, in a subgroup of patients with severe or fulminant CDI that were refractory to medical therapy (defined as continued worsening and/or nonresponse to at least 5 days of oral vancomycin), FMT was associated with even higher absolute risk reduction in mortality (43.2 vs. 12.1%, p  < 0.001) and colectomy (31.8 vs. 7.6%, p  = 0.001). ^{35 36} Within this study, 32 patients with refractory severe or fulminant CDI were also determined to be too ill to undergo colectomy by the surgical team. Seventeen of these patients continued medical therapy, while 15 entered the sequential FMT protocol. Patients who received FMT had significantly decreased CDI-related mortality (20.0 vs. 82.4%, p  = 0.001). ³³ In a French hospital, where infectious disease specialists recommended early FMT for hospitalized patients with CDI, among 111 patients, the 90-day mortality was 12.1% in the FMT group compared with 42.2% in the standard antibiotic group ( p  < 0.0001), with no patients undergoing surgery. ³⁷ The authors suggested that just two patients with severe CDI would need treatment with FMT to save one life. A retrospective, matched cohort study of 48 patients with severe or fulminant CDI requiring intensive unit care showed 77% decrease in odds of dying, and the estimated number needed to treat to prevent one death was three. ³⁸ Beyond survival benefit, Ianiro et al showed that FMT can lower the incidence of bloodstream infection in patients hospitalized with CDI who are at high risk of sepsis. In a cohort of propensity score–matched 114 patients, the 90-day mortality was 11% in those receiving FMT compared with 39% in those receiving anti-CDI antimicrobials alone. ³⁹ The incidence of fungal sepsis was zero in the FMT group compared with 12% in controls, and bacteremia occurred in 4% in the FMT group compared with 14% in the control group. These results underscore the important role commensal gut microbiota may play in stabilizing the gut barrier.

While data from these retrospective studies are compelling, randomized controlled trials are lacking and unlikely to be conducted in the future for multiple reasons. Many experts believe that such trials in patients with fulminant infection would be unethical given high rates of mortality and the lack of better alternative therapies. FMT showed an excellent safety profile in the critically ill population. ⁴⁰ Comparison to a surgical arm would be difficult given the fact that a significant number of patients would not be surgical candidates. Standardizing the timing of surgery would be challenging. Late intervention would place patients at risk of progression toward medical nonresponsiveness, hemodynamic instability, perforation, and ischemia, while surgery prior to determining if patients respond to medical therapy would unnecessarily expose patients to the high rates of colectomy-associated morbidity.

Emerging FMT Indications

The success of FMT in CDI generated intense interest in the role of gut microbiota in health and disease and boosted the impetus to try FMT for other diseases that are associated with dysbiosis in the gut. A wide variety of diseases including gastrointestinal, cardiometabolic, neuropsychiatric, and immunologic disorders have been linked to abnormal gut microbiota, and many published and ongoing interventional trials applied FMT to treat them. ⁴¹

Among these, FMT trials in UC show the greatest promise. UC is an immune-mediated inflammatory disease that is rising in global prevalence, most likely due to the environmental effects on the gut microbiota. While the alteration of the gut microbiota is hypothesized to contribute to its pathogenesis, it is unclear whether the dysbiosis is a cause or an effect of the gut inflammation. The potential causal relationship between dysbiotic microbiota and UC is far more complex than in recurrent CDI, where the colonic microbiota is greatly decimated in both total mass and diversity, therefore presenting a fertile soil for engraftment. ⁴² In UC, the indigenous flora, which is abnormal but robust, will likely impede the transplanted flora from taking a foothold.

Nevertheless, out of five randomized controlled trials published to date, ^{43 44 45 46 47} four showed superior results with FMT compared with the placebo or autologous stool. ^{44 45 46 47} These trials enrolled patients mainly with mild to moderately severe UC, left-sided or pancolonic distribution, and most of them allowed stable concomitant immunosuppressive therapy. The study design was quite heterogenous between the studies. The route of administration varied from nasojejunal tube, ⁴³ rectal enema, ⁴⁴ and combination of colonoscopy and enema ^{45 46} to exclusive oral lyophilized capsules. ⁴⁷ Two studies pooled stool from up to seven different donors, ^{45 46} whereas the other three studies ^{43 44 47} administered FMT derived from individual donors. The number of FMT treatments in total varied between 2 and 40, and autologous FMT was used as the placebo arm in two of the studies but the other two used colored water or placebo capsule.

A Cochrane database review and meta-analysis ⁴⁸ of the first four trials ^{43 44 45 46} found that the overall clinical remission rate at 8 weeks was 37% ( n  = 52/140) in patients receiving FMT compared with 18% ( n  = 24/137) in controls (risk ratio: 2.03; 95% confidence interval [CI]: 1.07–3.86). Rates of endoscopic remission also improved significantly in patients who received FMT. The study that used anaerobic conditions for FMT preparation ⁴⁶ reported the highest rates of steroid-free remission suggesting that anaerobic preparation conditions may be an important factor in improving treatment efficacy. One study reported higher treatment success with a particular donor compared with the other donors, ⁴⁴ implying that if FMT proves to be beneficial in the therapy of UC, donor selection could be much more important in this scenario than is the case for CDI.

In a more recent study called the lyophilised oral faecal microbiota transplantation for ulcerative colitis (LOTUS) trial, Haifer et al ⁴⁷ reproduced the so-called super-donor phenomenon despite rationally selecting their donors. While the FMT product from one donor achieved the primary endpoint in 4 of 4 recipients, the FMT product from the other donor was successful only in 4 of 11 recipients. Microbiome analysis revealed differences in donor microbiome bacterial diversity driven by higher species evenness rather than richness and relative abundances in certain Bacteroides species. Furthermore, increases in the abundances of specific Bacteroides species in recipients correlated with treatment response. Perhaps the most important unknown that needs to be resolved in development of all microbiota therapeutics for UC, including FMT-based approaches, is selection of desired functionalities in donor microbiota. The LOTUS study was the first in the series of FMT for UC trials to apply pretreatment with broad-spectrum antibiotics, which, at least in part, might be responsible for their superior results. The composite outcome of steroid-free clinical remission with endoscopic remission or response at 8 weeks was achieved by 53% of patients on oral capsules with lyophilized microbiota capsules and 15% of patients on placebo (a 38% point difference). By 56 weeks, 100% of patients (4/4) receiving FMT were in endoscopic and histologic remission, while none (0/6) receiving placebo (100% point difference) were in endoscopic and histologic remission. Antibiotic pretreatment suppressed Fusobacterium spp., previously shown to diminish FMT's success. ⁴⁹

These findings strongly indicate that appropriate antibiotic preconditioning is likely to be an important component of future microbiota transplant regimens. Continued interventional trials accompanied by detailed microbiome analysis are needed to further optimize the treatment protocols, investigate the likely contribution of diet, and identify the best formulations for individual patients.

The Future of Microbiome Restoration Therapy: What's on the Horizon?

FMT is an investigational intervention and currently there are no FDA-approved agents on the market. The process of FMT material procurement is not standardized including donor recruitment and screening, stool collection, and processing, while the reporting on follow-up and outcomes vary a great deal between publications. ⁵⁰ Transmission of infectious agents such as ESBL (extended spectrum beta-lactamase) bacteremia, EPEC (enteropathogenic E. coli ), and STEC (Shiga toxin-producing E. coli ) from asymptomatic stool donors remains a significant concern. ⁵¹ More recently, the CoVID-19 epidemic augmented the hurdles associated with FMT being dependent on the procurement of stool from well-screened healthy donors. There is a need for better regulated, standardized, readily available product for microbiota restoration. Several live biotherapeutics aiming to restore the gut microbiome are in late phase of clinical trials. Donor-derived enema formulation includes RBX2660 ^{52 53} and donor-derived oral capsule formulation includes CP101 ⁵⁴ and SER-109, ⁵⁵ while VE303 ⁵⁶ represents a synthetic capsule formulation containing rationally defined bacterial consortium consisting of eight bacterial strains.

Conclusion

FMT has a well-defined role in the treatment of recurrent CDI, with evidence suggesting that it may also be effective in severe, fulminant, and refractory CDI resulting in survival benefit, decreased risk of sepsis and avoidance of surgery. Banked, ready-to-use material, low risk of adverse events, as well as high rates of efficacy with multiple infusions make it an attractive therapeutic option. Colectomy for refractory CDI will always be necessary particularly in cases of concurrent ischemia or perforation. However, where clinicians have traditionally faced the dilemma of choosing between continuing ineffective antibiotic therapy versus subjecting patients to surgery, we now have a promising treatment option in FMT. Among the emerging FMT indications, UC is the most promising therapeutic target, but not ready for prime time in clinical practice yet. FDA approval of live biotherapeutics in the near future is expected to greatly simplify the logistics of microbiome restoration.