List of Abbreviations
Clostridium difficile infection
Data Monitoring and Safety Committee
The Food and Drug Administration
Fecal microbiota transplantation
Inflammatory bowel disease
Nucleotide-binding oligomerization domain-containing protein 2/caspase recruitment domain-containing protein 15
Randomized controlled trial
Short-chain fatty acid
Tumor necrosis factor
Ulcerative Colitis Endoscopic Index of Severity
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic relapsing condition. There are approximately 1.6 million Americans currently living with IBD, and as many as 70,000 new cases of IBD are diagnosed each year. Although the exact pathogenesis of IBD remains unclear, it is thought to be caused by a combination of genetic, environmental, and immunologic factors. There is a pathologic immune response in genetically susceptible individuals driven by an altered host gut microbiota (dysbiosis). Current medical therapy is aimed at suppressing the host immune system with medications such as steroids, immunosuppressant therapy, and biologics. Despite advances in medical treatment, many patients continue to live with active symptoms that affect their quality of life.
The commensal human intestinal microbiota is a complex ecosystem involved in a number of physiologic functions including production of nutrients, regulation of metabolism, and immune function. Alterations may contribute to chronic inflammatory and autoimmune diseases. Fecal microbiota therapy (FMT), also known as fecal microbiota transplantation, refers to the delivery of stool from a healthy individual into the intestines of a diseased individual with the hope to restore the intestinal microbiota and potentially cure a specific disease. FMT is a highly effective and safe method for the treatment of refractory and recurrent Clostridium difficile infection (CDI), with cure rates over 90% with a single infusion. Because of its high success for treating CDI, there has been increasing interest to study FMT for other gastrointestinal conditions associated with intestinal dysbiosis such as IBD. The aim of this chapter is to review the current literature on using FMT products in clinical practice for IBD patients.
Human Microbiota and Inflammatory Bowel Disease
The human intestinal microbiota is comprised of microorganisms that include bacteria, archaea, viruses, and some unicellular eukaryotes. There are over 1200 different species that can colonize the human gut, which is equivalent to 1–2 kg of total body weight. A much greater understanding in the composition, function, genetics, and metabolic profile of human gut microbiota has come about over the past 20 years through advances in 16 s rRNA gene sequencing techniques of variable regions of bacteria. Most of the current understanding of the microbiota is derived from studies such as the Human Microbiome Project.
Both extrinsic and intrinsic factors play a role in composition of microbes that an individual will have. This includes host genetics, nutrition and diet, geographical location, and early microbial exposure in life. Some of the early factors in microbial development include mode of delivery (vaginal vs. cesarean birth), diet (formula vs. breast-feeding), medications, and living conditions. In a healthy state, microbial diversity increases in the first few years of life and remains relatively stable and resilient in adulthood. However, environmental perturbations can affect the microbiome; such as dietary changes, medications (i.e., antibiotics, gastric acid suppressive medications, nonsteroidal medications), and illnesses (i.e., infections). In the elderly, the gut microbiome has less diversity with alterations in the relative proportions of certain phyla. This may contribute in some way to the physiological aging process and comorbidities associated with aging.
Four main bacterial phyla are found in the human gut: Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria with Bacteroidetes and Firmicutes being the predominant species in a healthy host. There is a spatial distribution of gut microbiota with the majority residing in the colon, where the highest intestinal bacterial concentrations are found and where there is a predominance of anaerobes. The human gut microbiota serves many vital functions including food digestion, synthesis of vitamins, fat storage, angiogenesis regulation, development of the host immune system and as an intestinal epithelial barrier. Microbes that are located along the intestinal epithelium appear to have more influence on the immune system, whereas those located within the lumen appear to play an important role in energy and metabolism. Perturbations of the intestinal microbial population creates an imbalance of harmful versus protective bacterial species. This promotes inflammation and can lead to IBD. Dysbiosis has been linked to a number of chronic inflammatory diseases such as IBD, diabetes, colorectal cancer, atherosclerosis, and nonalcoholic fatty liver disease.
Studies on the microbiome in IBD patients show altered microbial composition when compared to healthy individuals. There is a reduced biodiversity of intestinal flora; for example, a decrease in the antiinflammatory phyla of Bacteroides and Firmicutes. Firmicutes are the major producers of short-chain fatty acids (SCFAs) which are the substrates with immunoregulatory properties but also play an important role in providing energy source for intestinal epithelial cells and maintaining colonic homeostasis. There is even evidence that the depletion of a single species (i.e., Faecalibacterium prausnitzii which belongs to Firmicutis phylum ), can lead to the development of IBD. A decrease in other protective species (Lachnospiraceae, Bifidobacterium , Roseburia , and Sutterella ) has also been observed in patients with IBD. There is an expansion of presumably aggressive groups of species including Proteobacteria, Fusobacterium , Ruminococcus gnavus , and Desulfovibrio spp. There may be an increase in invasive mucosal-adherent bacteria such as Escherichia coli , which can adhere to and invade intestinal epithelial cells. Several studies have demonstrated increases in adherent/invasive E. coli in terminal ileum of patients with CD. Klebsiella spp. has been found to provoke moderate pancolitis while Bifidobacterium animalis tends to cause mild inflammation in the distal colon and duodenum. Genes associated with IBD susceptibility (NOD2/CARD15) may encode for proteins that either regulate the microbiota or control the host response (through IL-12 – IL23R pathway or autophagy). Essentially, the dysregulation of mucosal homeostasis may drive aggressive T-cell–mediated immune response to specific components of intestinal microbiota in genetically susceptible hosts. On the other hand, data exist showing evidence that dysbiosis of the intestinal microbiota may be a response to inflammation. Chronic inflammation leads to increased oxygen concentration and consequent hyperemia, increased vascular and mucosal permeability, electrolyte imbalance (secondary to altered sodium/hydrogen exchange system), and the production of alternative electron acceptors that promote respiration of facultative anaerobes. Furthermore, inflammation alters epithelial defenses, mucus composition, and viscosity, leading to tissue damage with ulceration allowing access for invasive oxygen-tolerant bacteria. This could account for increased association of E. coli bacteria with mucosa seen in patients with IBD. Defects in Paneth cells can potentially lead to reduced antimicrobial peptide production, resulting in dysbiosis. Conversely, IBD therapies may help to improve microbial diversity and promote protective strains. For example, F. prausnitizii was noted to be more abundant in antitumor necrosis factor (anti-TNF)-therapy responders versus nonresponders. F. prausnitzii is an antiinflammatory commensal bacterium identified by gut microbiota analysis of CD patients. In summary, there is increasing evidence for microbial dysbiosis in the pathogenesis of IBD. Despite the studies available, it still remains unclear whether dysbiosis is a consequence or a cause of inflammation.
Background on Fecal Microbiota Therapy
As previously stated, FMT refers to the transfer of intestinal fecal material from a healthy donor to a diseased individual with an altered gut microbiota. Although interest in FMT has been growing rapidly, this technique is not new. There are reports dating back to the fourth century when the Chinese physician Ge Hong recorded the use of a human fecal suspension for the treatment of diarrhea. In the 16th century, Li Shizhen composed the classic medical compendium, Ben Cao Gung Mu, which describes a series of prescriptions using “fermented fecal solution, fresh fecal suspension, dry feces, or infant feces for effective treatment of abdominal diseases with severe diarrhea, fever, pain, vomiting, and constipation.” In 1958, Eiseman et al. reported in a case series using fecal enemas for the treatment of pseudomembranous colitis in four patients who were consequently cured. These patients were critically ill and had a “dramatic” improvement of symptoms within 24–48 h. At that time, C. difficile was not yet known to be a cause of pseudomembranous colitis. The first use of FMT for confirmed CDI was in 1983 by Schwan et al., which was followed by a number of case reports and series. Over the past few decades, there has been considerable interest in FMT, as it has repeatedly shown to be an effective therapy for recurrent CDI, resulting in the correction of the dysbiosis associated with CDI, A recent systematic review found cure rates of ∼91% with FMT in patients with recurrent or refractory CDI. In a pivotal randomized clinical trial, van Nood et al. compared FMT, vancomycin and bowel lavage, and vancomycin alone. There was an overall 94% cure rate (15/16 patients) observed for the FMT group, with 81% (13/16 patients) being cured after the first FMT, compared to 23% and 31% cure rates in the vancomycin-bowel lavage and vancomycin alone groups. Another recent randomized clinical trial compared the efficacy of vancomycin against FMT via colonoscopy. The trial was halted at the 1-year interim analysis when it was found that 90% of the patients receiving FMT had resolution of symptoms compared to only 26% of the patients receiving vancomycin. Current published guidelines recommend FMT for the treatment of recurrent CDI. The European guidelines recommend FMT be considered after a second recurrence of CDI, while guidelines from the American College of Gastroenterology recommend to consider FMT after a third recurrence, following a pulsed vancomycin regimen.
Current methodology for FMT, and donor selection and screening, has been published by the FMT Working Group ( Table 28.1 ). Requirements for FMT donors include an informed consent, detailed history, physical examination, and stool as well as serological testing. Most of this information comes from experience with FMT for CDI. Potential donors often have a close relationship to the recipients, and previously it has been reported that related donors may provide a better long-term outcome, although more recent reports have not found this to be the case. There may be an advantage to having unrelated donors for diseases in which genetics may play a role such as in IBD. In general, donors should be healthy individuals with no risk factors for transmittable infectious disease, and no gastrointestinal comorbidities such as IBD, irritable bowel syndrome, chronic constipation, and GI malignancies. Other exclusion criteria include history of autoimmune disease, metabolic syndrome, atopy, and history of malignancy. Because of the possibility of transmitting infectious agents, donors are screened for a number of infections including C. difficile toxin A/B testing, stool culture for enteric bacterial pathogens, ova, and parasites. Blood is screened for antibodies such as Hepatitis A IgM, Hepatitis B surface antigen, antibodies to Hepatitis B surface antigen, Hepatitis C antibody, HIV 1 and 2 antibody, and Treponema pallidum ( Table 28.2 ). Checking for Helicobacter pylori is advised when a nasoenteric route of administration is being considered. A donor questionnaire similar to current protocols for screening blood donors can be followed. Ideally, testing should be done within 4 weeks of donation. Donors should not take any antibiotics for at least 3 months prior to stool donation, as this can change the intestinal microflora. Donors should not ingest foods that the recipient is allergic to within 5 days before the FMT. Fresh donor feces samples are used for FMT (ideally within 6 h from defecation). It is helpful to have the donor take a gentle laxative the evening before. Prior to FMT for CDI, recipients discontinue all antibiotics (at least 48 h prior to the procedure). Recipients will undergo a large bowel lavage with 3–4 L of polyethylene glycol solution. It is important to make sure that the prep is very complete with no residual stool. Although the amount of stool to be used for FMT has not been standardized, most reports describe approximately 50 g of stool mixed with a diluting agent (typically sterile saline 0.9%, however other dilatants have been used including yogurt and milk). Stool samples are mixed with nonbacteriostatic saline to a homogenized consistency. This can be done by either hand stirring or with a mechanical blender. The mixture is then filtered to remove any particulate matter. Universal precautions are always used when preparing the FMT donor sample. The stool mixed with diluting agent can be aspirated into 60-mL syringes. There are various routes by which FMT can be administered, including a lower GI route via colonoscopy, flexible sigmoidoscopy, or retention enema. An upper GI route can be performed as well using nasogastric/nasointestinal tubes or gastroduodenoscopy. For colonic administration, ∼300 mL is administered in the cecal region. For duodenal administration, ∼60 mL is administered. Proton pump inhibitors are given to patients following an upper approach. Once the FMT is completed via colonoscopy, patients are asked to hold the fecal sample for at least 6 h. Loperamide can be given before and after the procedure to assist with stool retention (with total recommended dose of Loperamide up to 8 mg). In the event of treatment failure, FMT can be repeated, typically with a different donor. Treatment success rates for FMT in CDI are reported to be as high as 80% when administered by duodenal route, and greater than 90% when administered from below via colonoscopy. Not only is this treatment efficacious, it is also very safe.
|Absolute Exclusion Criteria||Relative Exclusion Criteria|
|Failure to give informed consent||History of major GI surgery|
|Microbial infections||Metabolic syndrome|
|Current communicable diseases||Diabetes|
|Malignancy||Systemic autoimmune disease|
|GI polyposis syndromes||Chronic pain syndromes|
|Chronic gastrointestinal disorders||Neuropsychiatric disorders|
|Inflammatory bowel disease|
|Use of immunosuppressive agents|
|High risk lifestyles|
|Donor Screening: Blood||Donor Screening: Stool|
|Hepatitis A, B, C||Enteric pathogens:|
|HIV 1 and 2||C. difficile PCR|
|Syphilis||Ova and Parasites|
|Cytomegalovirus||Acid fast stain |
Cyclospora and Isospora
|Epstein–Barr virus||Giardia Ag|
There are number of potential safety issues surrounding FMT and the use of a live stool mixture of microbes. Endoscopic routes (such as colonoscopy) can carry procedural risks, but they are usually well tolerated and allow for the examination of the colonic mucosa. A number of publications have shown a low incidence of adverse events associated with FMT with this route of administration. Potential adverse effects from upper administration approach include vomiting, aspiration, and the possibility of bacterial overgrowth. More serious adverse effects may include the transfer of viral or bacterial infections not screened for prior to FMT. Other long-term adverse effects theoretically include the development of diseases that are associated with altered gut microbiota such as diabetes, obesity, nonalcoholic fatty liver disease, irritable bowel syndrome, IBD flares, and asthma. This is because FMT raises a concern of transporting not only antiinflammatory active bacteria and their products but potentially transmitting other diseases including autoimmune disorders, metabolic syndrome, and cancer. At the time of this publication, the US Food and Drug Administration (FDA) considers stool to be a biological product and requires physicians to obtain an investigational new drug application to perform FMT. In regards to CDI and FMT, the FDA has stated that it will implement an “enforcement discretion.” The FDA draft states that FMT product must be obtained from a donor known to the patient or the licensed health care provider treating the patient. Physicians must obtain informed consent, explain all risks and benefits of the procedure, and note that this is an investigational treatment. The position statement of the FDA on this matter is likely to modify over time especially if preparation of stool in stool banks is approved and becomes commercially available. An advantage of stool banks is that they may reduce screening costs and improve screening efficiency.
There are several limitations when it comes to using FMT in clinical practice as described above, including finding a suitable donor, the preparation of fresh fecal samples (which can be arduous and time consuming), and the lack of standardized treatment regimens. To overcome these challenges, there has been a development of new delivery methods including frozen stool samples, frozen filtered capsules as a lyophilized powder within delayed-release capsules, and encapsulated spore-specific combinations. An advantage of preparations such as frozen inoculate is that it can be screened in advance, stored, and in turn can expedite the FMT procedure. Studies on frozen preparation of stool from healthy volunteers (unrelated donors) have shown similar success rates when compared to fresh stool groups. In a study of 23 patients that had FMT using this technique compared to fresh donors, the success rate was 96% with no significant side effects. The study used two healthy volunteers that acted as universal donors. Total of 42 patients were followed up for 1 year post-FMT and found to have a successful response to therapy of 88% in both fresh and frozen fecal groups. Lee et al. compared free-thawed (n = 114) versus fresh samples (n = 118) for FMT in CDI. There was no significant difference between rates of clinical resolution without recurrence up to 13 weeks. A recent open-label feasibility study looked at the effect of frozen oral, capsulized fecal samples from unrelated donors for treating 20 patients. Participants with recurrent CDI were given 15 capsules to ingest over a 2-day period. They were offered retreatment if symptoms continued 72 h later (6 patients). There was an overall 90% success rate with no significant complications reported (such as vomiting or aspiration). Thus, oral administration of frozen donor samples may be a viable alternative to the current practice of administering fecal material via endoscopic routes. Petrof et al. recently studied a stool substitute made of a preparation of 33 different intestinal bacteria isolated from a single donor used to successfully treat 2 patients with refractory CDI. It is likely that traditional FMT will be replaced by the use of defined microbial consortia prepared under laboratory conditions where defined combinations of microbes would likely have outcomes that are more predictable with less adverse events (reducing the risk for pathogen transmission). Thus, the future may be in manufactured oral preparations that replicate human stool, and the use of standard fecal stool may even become obsolete.