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Abstract
Fecal microbiota transplantation (FMT) restores a balanced intestinal flora, which helps to cure recurrent Clostridium difficile infections (RCDI). FMT has also been used to treat other gastrointestinal diseases, including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and chronic constipation, as well as a variety of non-GI disorders. The purpose of this review is to discuss gut microbiota and FMT treatment of GI and non-GI diseases. An imbalanced gut microbiota is known to predispose one to Clostridium difficile infections (CDI), IBD, and IBS. However, the complex role of the gut microbiota in maintaining health is a newer concept that is being increasingly studied. The microbiome plays a major role in cellular immunity and metabolism and has been implicated in the pathogenesis of non-GI autoimmune diseases, chronic fatigue syndrome, obesity, and even some neuropsychiatric disorders. Many recent studies have reported that viral gastroenteritis can affect intestinal epithelial cells, and SARS-CoV-2 virus has been identified in the stool of infected patients. FMT is a highly effective cure for RCDI, but a better understanding of the gut microbiota in maintaining health and controlled studies of FMT in a variety of conditions are needed before FMT can be accepted and used clinically.
Keywords: Fecal microbiota transplantation, inflammatory bowel diseases, irritable bowel syndrome, obesity, recurrent clostridium difficile infections, SARS-CoV-2
How to cite this article: Introduction 
Fecal microbiota transplantation (FMT)
FMT is a fecal suspension from a selected healthy donor into the intestines of a diseased patient. It was introduced 1700 years ago in the fourth century by a Chinese scientist named Ge Hong, who administered suspensions orally with human feces to treat patients suffering from food poisoning or severe diarrhea.[1],[2] Much later, Ralph Lewin reported that “The Bedouin recommended the consumption of hot, fresh camel dung as a remedy for bacterial dysentery; its effectiveness was confirmed by German soldiers in Africa during World War II”.[3] In the sixteenth century, Li Shizhen described the use of a variety of recurrent Clostridium difficile infection (RCDI) treatments with success rates similar to fresh feces.[4] The success of FMT in modern medicine was first documented in 1958 by Eiseman et al.[5] (Surgeon of the U.S state of Colorado), when Denver physicians administered it to their patients with fulminant pseudomembranous enterocolitis and life-threatening disease.[6],[7] For years, FMT remained a rarely used, if not forgotten, therapy. The first documented case of confirmed Clostridium difficile infection (CDI) treated with FMT was reported in 1983.[8] The 2013 American College of Gastroenterology Guidelines for the Treatment of C. difficile also recommends FMT as an alternative therapy for recurrent cases of CDI that do not respond to a pulsed/reduced regimen of vancomycin.[9],[10] The progress and development process of FMT practice is shown in [Figure 1]. In this review we aim to discuss the gut microbiota and FMT treatment of gastrointestinal (GI) and non-GI diseases.
Figure 1: Advances in FMT from its inception to date. RCDI: Recurrent Clostridium difficile infections; FDA: Food and Drug Administration; USA: United States of America; ANSM: Agence Nationale pour la Securite du Medicament; NICE: National Institute for Health and Care Excellence; UK: United Kingdom; IABS: International Alliance for Biological Standardization.[13],[14],[15],[16],[17],[18],[19]Description of FMT
Transplanting the fecal microbiota from a healthy donor to a person with CDI can restore a healthy gut microbiota in the patient's diseased colon, resulting in resolution of symptoms. The complete mechanism that achieved this normalization remains unclear.[11] It is possible that the reconstruction and features of the intestinal microbiota are of paramount importance, as it is a critical resistance thing in opposition to CDI and different pathogens, with mechanisms along with resistance to bacterial colonization and immune stimulation. FMT refers to the instillation of a liquid stool suspension from a healthy donor into the patient's GI tract.[12] FMT can be viewed as a form of “organ transplantation.” The idea of a human microbial organ is a novel concept well supported by modern science.[11] Without a doubt, FMT is easier to perform than other organ transplants without the need for donor-recipient immunological compatibility or post-procedure immunosuppression. FMT can be performed in a number of ways, depending on what is considered safer for the individual patient: nasogastric or nasojejunal tube, upper tract endoscopy, retention enema, colonoscopy.[11] Disorders related to changes in the gut microbiota that could be treated with FMT are shown in [Figure 2].
Figure 2: FMT targeting gut microbiota has recently been successfully applied to UC. According to the results of studies, FMT might reduce Candida abundance and restrict pro-inflammatory immunity during intestinal inflammation. FMT: Fecal microbiota transplantation,[17],[21] UC: Ulcerative colitisThe role of microbiota in the treatment of the GI tract diseases
The gut microbiota consists of a variety of microorganisms that play important roles in metabolism, immune function, and intestinal homeostasis.[20],[21] Dysbiosis, or abnormal changes in the composition or diversity of the gut microbiota, has been linked to a variety of diseases, including CDI, inflammatory bowel disease (IBD), and irritable bowel syndrome (IBS).[22] FMT can affect GI and non-GI diseases in humans, as shown in [Figure 3].
Figure 3: Disorders associated with alterations to the intestinal microbiota that could be treated by FMTApplication of FMT for the treatment of CDI
The prevalence, severity, and mortality of CDI and RCDI have increased over the past decade.[23] The annual cost of CDI in USA was estimated at $4.8 billion for acute care facilities in 2008, and the estimated epidemiological burden in 2011 to be 434,000 infections and 29,000 deaths.[23],[24]
Further analysis of 2013 RCDI costs indicated CDI-associated costs of $34,104 per patient and a 2013 national estimate of $2.8 billion for RCDI alone.[25] FMT has emerged as a highly effective and cost-effective therapeutic option for RCDI, with average cure rates of approximately 90% (recipient disease requires optimization of donor selection and detection of potentially transmissible infections and other disorders associated with gut microbiota function).[25]
CDI causes severe diarrhea, intestinal inflammation, and cell death due to toxin-mediated infection by pathogenic bacteria. In recent years, C. difficile–associated diarrhea (CDAD) has become more common, more severe, more refractory to standard therapy, and more likely to relapse.[26],[27],[28]
This pattern is widespread in Canada, USA, and Europe, and is attributed to a new, more virulent CD strain called NAP1/B1/027. Patients are usually treated with antibiotics, which not only eliminate the pathogenic CD, but also show activity against the phyla of the dominant gut microbiota. Standard first-line treatment includes the option of using vancomycin or metronidazole, with eradication rates of 97% and 87%, respectively.[23],[24],[29]
However, after initial therapeutic success, between 20% and 35% of treated patients experience an initial recurrence of infection, which occurs as a result of spore persistence or reinfection which require longer antibiotic therapies. Continued disruption of the normal colonic microflora by repeated antibiotic therapies used to treat recurrent CDI increases the risk of recurrences. Sixty percent to 65% of patients have multiple recurrences. Recurrences are more common in long-term in-patients older than 65 years. RCDIs carry a high risk of serious complications (septic shock, perforation).[22]
One of the factors that has contributed to the increase in cases of CDI is the presence of a new strain that is more virulent and resistant to quinolones, producing 16 times more of toxin A and 23 times more of toxin B, in addition to a third toxin which has enterotoxigenic activity in vitro. However, one of the challenging aspects of treating patients with CDI is disease recurrence after successful treatment. Recurrence is considered if symptoms reappear within the first eight weeks after stopping treatment. The recurrence rates after treatment with metronidazole and vancomycin are similar (20.2% and 18.4%, respectively).[30]
Since the turn of the century, there has been an alarming increase in the incidence and severity of CDI. Such cases have nearly doubled from 98,000 in 1996 to 178,000 in 2003, and the unadjusted mortality rate increased from 1.2% in 2000 to 2.3% in 2004. Mortality is now approaching 30,000 deaths per year.[2]
It is now estimated that between 500,000 and 700,000 cases of CDI occur annually in US hospitals and long-term care facilities, with an estimated additional hospital care cost of approximately US$3.2 billion.[6],[31]
The first randomized controlled FMT study for RCDI enrolled 43 patients.[32] The study compared FMT via a nasoduodenal tube after four to five days of oral vancomycin to 14 days of vancomycin alone and 14 days of vancomycin with enema. Symptoms resolved within three months in 81% of patients receiving FMT, in 31% of patients receiving vancomycin alone, and in 23% of patients receiving vancomycin plus colonic irrigation. A second randomized controlled trial compared FMT administered via a nasogastric tube to colonoscopy.[33] Symptoms resolved in 70% of patients after FMT; the nasogastric group had a 60% cure and the colonoscopy group had an 80% cure. The usual cure rate was 90% after retreatment.[6]
A systematic review published in 2011 included 317 RCDI patients treated with FMT. Symptoms resolved in 92% of the patients; 89% after one treatment and 5% more after re-treatment.[14] Another systematic review showed that FMT was successful in 85% of RCDI and 55% of refractory CDI, compared to medical success rates of 30% to 80%.[11] Currently, the evidence supporting the use of FMT for RCDI is more compelling than for fulminant or refractory CDI. Studies have not yet supported FMT as a first-line treatment for CDI. Future randomized controlled trials on the use of FMT as first-line treatment or in fulminant and refractory CDI are needed. Studies are also now investigating different types of therapies for FMT.[6] A recent study reported successful results in two RCDI patients treated with a stool substitute composed of 33 different gut bacteria isolated in pure culture from a single donor after repeated courses of antibiotics had failed.[29] Another study showed that FMT with a volunteer's frozen inoculum was as effective as fresh feces in treating RCDI. Finally, a proof-of-concept study used frozen stool capsules prepared by healthy donors to treat 20 RCDI patients and found an overall response rate of 90% within one or two treatment cycles.[6]
Mechanisms underlying the decreased fitness of C. difficile after FMT remain elusive but likely include niche exclusion, competition for nutrients, and the creation of a nutrient environment unfavorable for growth—the ability of members of the healthy gut microbiota to produce antimicrobial agents—which inhibit the growth of C. difficile, and an elevation in secondary bile acid production. An important factor determining the success of stool transplantation is the recovery of microbial diversity after treatment.[11],[34],[35]
Infectious CDI is associated with high mortality and morbidity, with approximately 22% of patients experiencing recurrent disease. Current interest in FMT for recurrent CDI is based on its good outcomes, apparent safety, and cost-effectiveness. In this case, it was hypothesized that FMT might fail in subjects re-infected from their environment or from residual spores in the gut and that a single FMT might not be robust enough to prevent this in certain hosts. By repeating the FMT, the intestinal flora would be strengthened enough for C. difficile to gain a foothold again.[10]
Application of FMT for the treatment of chronic fatigue syndrome
Chronic fatigue syndrome (CFS) is a multisystem disease, associated with disabling fatigue, cognitive dysfunction, and sleep disturbance. In 1992, the World Health Organization (WHO) approved the term “chronic fatigue syndrome” and recognized the disorder as a neurological disease. Recent developments favor gastrointestinal and neurotoxic causes of immune dysfunction. Importantly, findings in recent years support the idea that CFS is associated with an imbalance in the gut microbiome.[3]
Application of FMT for the treatment of IBD
The GI tract houses the largest population of commensal organisms in the human body, and as such, hosts a unique set of immunoregulatory mechanisms that prevent unnecessary activation of the immune system against harmless antigens, including those expressed by the microbiota.[36] Failure of these overlapping regulatory mechanisms leads to the accumulation of chronic inflammatory conditions collectively known as IBD. The relationship between mucosal immune dysfunction and IBD is illustrated by the fact that both Crohn's disease (CD)[12] and ulcerative colitis (UC)[11] are associated with genes critical for maintaining the epithelial barrier and regulating innate and adaptive immune responses.[37] The etiology of IBD is complex and is thought to result from genetic factors, the host immune system, and environmental factors such as the microbiota.[38] It has also been suggested that stress factors such as infections contribute to the induction of these disorders.[39]
Although the microbial basis of IBD is much more complex and variable than that of relapsed/refractory CDI, microbiome-based therapies are an important area of investigation for these chronic and debilitating diseases. As early as 1900, physicians recognized that bacteria can play a vital role in colitis.[40] With over a century of research and advancements, we are only beginning to understand the microbiological basis of IBD and how FMT and other microbial therapies can help IBD. Advanced molecular techniques have revealed fundamental differences in both microbial composition and function in patients with IBD.[41],[42],[43] A small number of these case reports also reported endoscopic and histological remission. A recent systematic review and meta-analysis of 18 studies involving 122 patients with IBD undergoing FMT found a clinical remission rate of 45%. However, the remission rate fell to 36.2% when case series were excluded to minimize publication bias. Two randomized, placebo-controlled trials of FMT in IBD have recently been reported.[10],[44]
Application of FMT for the treatment of IBS
IBS is a common chronic GI disease affecting nearly 20% of the North American population and is associated with significant healthcare costs and morbidity. The underlying pathophysiology of IBS symptoms is not well defined, though both central and peripheral mechanisms are involved.[45] Different studies have identified changes in the gut microbiome in patients with IBS.[46],[47] Some early studies reported improvement in IBS patients after FMT. For example, in one study reported in abstract form, nearly 90% of patients treated with FMT had improved bowel evacuation and less bloating after FMT, and 60% showed a long-term benefit of 9 to 19 months.[48]
Application of FMT for the treatment of UC
The first case report of FMT for UC was published in January 1989 by Justin Bennet and Brinkman. Bennet himself suffered from UC and experimented with FMT himself. He had endoscopically and histologically confirmed UC refractory to sulfasalazine and steroids for seven years,[49] achieving both clinical and histological remission after administration of donor microbiota via fecal enemas. FMT not only offers a potentially effective therapy, but also an ideal human model to specifically study the influence of microbiota modulation on UC.[34] In a study by Moayyedi et al.[44], 75 patients with active UC were randomized to weekly FMT or water enema for six weeks; there was a statistically significant difference in remission, the primary endpoint, between the two groups. Remission (complete Mayo score <3 and complete mucosal healing) was achieved in 24% of patients after FMT and 5% with placebo; stool from patients receiving FMT showed greater microbial diversity than those from patients receiving placebo.[44]
The second study, conducted in Amsterdam, recruited 50 patients with mild-to-moderate active UC and randomized them to receive donor stool or an autologous fecal transplant via a nasoduodenal tube. FMT was administered at the start of the study and again three weeks later. Only 37 patients completed assessment of the primary endpoint (clinical remission associated with a 1-point decrease in Mayo Endoscopic Score in week 12). There was no statistically significant difference in clinical and endoscopic remission between the two groups. It is likely that this study was underpowered to detect these differences.[10] However, only a subset of patients responds to FMT, and there is a pressing need for biomarkers of responsiveness. Fungi (Mycobiota) represent a highly immunologically reactive component of the gut microbiota. We analyzed samples from a large randomized controlled trial of FMT for UC.[50] High Candida abundance pre-FMT was associated with a clinical response, whereas decreased Candida abundance post-FMT was indicative of ameliorated disease severity. High pre-FMT Candida was associated with increased bacterial diversity post FMT, and the presence of genera was linked to FMT responsiveness. Although we detected elevated anti-Candida antibodies in placebo recipients, this increase was abrogated in FMT recipients. Our data suggest that FMT might reduce Candida to contain pro-inflammatory immunity during intestinal disease and highlight the utility of microbiota-focused approaches to identify FMT responders prior to therapy initiation,[50] as shown in [Figure 2].
Application of FMT for the treatment of CD
CD is a chronic inflammatory disease thought to result from a complex interplay between genetic susceptibility, environmental factors, and alterations in the gut microbiota. The therapeutic potential of FMT in CD has recently been demonstrated. However, management of CD is mostly individualized and patients may receive multiple treatments. Integrative treatments called step-up FMT strategies consist of single or multiple FMTs in combination with steroids, immunomodulatory agents, and exclusive enteral nutrition.
Application of FMT for the treatment of obesity
Obesity is recognized as a worldwide epidemic.[51] The lack of effective non-surgical therapies has led to investigation of possible factors contributing to the development of obesity. Several lines of evidence support a role for gut microbiota in obesity. Lean and obese individuals show marked differences in the gut microbiome.[52] The precise mechanism by which the gut microbiota influences obesity remains to be elucidated, though recent data from animal models provide valuable insight. The gut microbiota can ferment carbohydrates and short chain fatty acids in the diet and provide extra energy for the host body. A recent, double-blind, randomized, controlled study examined the effect of gut microbiota transfer from lean to obese subjects and found better insulin sensitivity and gut microbial diversity with higher butyrate producers after transplantation.[53]
Safety of FMT
Some of the short-term side effects of transplantation include: flatulence, diarrhea, constipation, borborygmus, vomiting, and transient serious events.[10],[15],[54],[55] More serious adverse events related to the method of administration of FMT can occur, though they are rare. These include endoscopic complications such as perforation and bleeding, as well as sedation-related side effects such as aspiration.[34]
However, there were two deaths, including an aspiration event, related to the procedure used to administer FMT, and 17% of IBD patients experienced a flare after FMT. The other patient died 13 days after FMT from progressive pneumonia for which he was treated with antibiotics before and after FMT. This death was not thought to be related to FMT.[34] Potential long-term adverse events, the main concern about FMT, relates to long-term safety. These risks include the possible transmission of infectious agents through FMT or the development of diseases/conditions related to changes in the gut microbiota.[34]
Work flow of FMT during the COVID-19 pandemic
The coronavirus disease 2019 (COVID-19) outbreak, caused by the novel coronavirus SARS-CoV-2, has rapidly become a global pandemic. Several recent studies have reported that the virus can infect intestinal epithelial cells and the ribonucleic acid virus SARS-CoV-2 has been identified in the stool of infected patients.[56],[57] It is assumed that SARS-CoV-2 can be transmitted by FMT. According to previous studies, safety is an important issue in FMT.[58],[59],[60] Timely recommendations on the safety of FMT amid the pandemic have been published.[61] On March 16, 2020, an international group of experts on FMT and stool banking called for reverse transcriptase-polymerase chain reaction RT-PCR assay to be considered in all donors, even if they are asymptomatic or do not have a history of high-risk travel or contact.[61] Shortly thereafter, on March 23 and April 9 of the same year, the Food and Drug Administration (FDA) issued safety alerts warning of the potential risk of transmission of SARS-CoV-2 through FMT and recommended the use of FMT products that are made from stool donated on or before December 1, 2019. If FMT products are not available prior to this date, providers must test donors for COVID-19 and obtain a new informed consent that highlights the potential risks of transmission of the virus through FMT. As a result, many banks or FMT centers have suspended active recruitment of new donors and updated the FMT protocols.[62],[63]
FMT in multiple sclerosis (MS)
Case 1: A 30-year-old man had constipation, dizziness, reduced concentration, and a concurrent history of MS and trigeminal neuralgia. Neurological symptoms included severe leg weakness and required a wheelchair and an indwelling urinary catheter. Previous failed treatments included mexiletine, trytanol, and interferon beta. The patient underwent five infusions of FMT for his constipation, with its complete resolution.[64]
Interestingly, his MS also progressively improved; he was able to walk again and had his catheter removed more easily. Originally considered a “remission”, the patient remained healthy without relapse 15 years after FMT.
Case 2: A 29-year-old man in a wheelchair had an “atypical diagnosis of MS and severe chronic constipation.” He reported paresthesia and muscle weakness in the legs. The patient received FMT infusions for 10 days, which cleared his constipation. He also noticed a progressive improvement in neurological symptoms and was able to walk again after the paresthesia in his legs slowly subsided. Three years later, the patient maintained normal motor, urinary, and GI function.[64]
Case 3: An 80-year-old woman with severe chronic constipation, transient proctalgia, and severe muscle weakness, causing difficulty in walking was diagnosed as “atypical” MS. She received five FMT infusions with rapid improvement in constipation and increased energy levels. After eight months, she reported complete elimination of bowel symptoms and neurological improvement, and can walk long distances unassisted. Two years after FMT, the patient was asymptomatic.
The above cases highlight the reversal of key neurological symptoms in three patients after FMT for their underlying GI symptoms. Because MS can have a relapsing-remitting course, this unexpected finding was not reported earlier until considerable time had elapsed to confirm prolonged remission. It is tempting to speculate that FMT has managed to eradicate a hidden GI pathogen that causes MS symptoms. Their finding that FMT can reverse MS-like symptoms suggests a GI infection underlying these disorders. It is hoped that such fortuitous findings can stimulate a new direction in neurological research.[64]
Future clinical perspectives
As a result of the studies, it became possible to use the FMT method and produce oral capsules. A bright future for FMT can be envisioned. Encapsulation technology requires a safe and nonaggressive attitude to cells. To capture and protect probiotics, the following techniques were used: spray drying, lyophilization, and fluid-bed drying. The use of encapsulated, orally administered FMTs expands patient access and simplifies the design of placebo-controlled studies. Recently, the use of capsule-based FMT has been shown to be a clinically effective approach to restore gut microbiota composition. FMT can be administered in a variety of ways, including through colonoscopy, enema, or capsule containing lyophilized material. Zain et al.[65] provided the first detailed description of a good, manufacturing practice–compliant, freeze-dried FMT capsule formulation, manufactured in the UK under medicines and healthcare products regulatory agency and investigational medicinal products license. The use of such preparations has the potential to provide patients with broader access to FMT. Additionally, without the invasive route of administration required for FMT suspension formulations, treatment can be expected to save costs and overcome logistical barriers.[65]
Limitations of FMT use in humans
An important barrier to the integration of FMT into regular clinical practice is the heterogeneity and lack of standardization. The apparent lack of adequate reproducible evidence for the efficacy of FMT in most indications, including gastrointestinal and extra-gastrointestinal diseases, may stem from a number of concepts and methodologies.
Conclusion FMT restores a balanced gut microbiota. The complexity of the fecal microbiota is being defined and recent studies have shown that the pathogenesis of many diseases, GI and non-GI, results from dysregulation linked to the microbiota. FMT is likely to achieve widespread therapeutic benefits for a variety of diseases in the future.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
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