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Gastroenterology & Hepatology
Inflammatory bowel diseases represent a complex array of diseases of incompletely known etiology that led to gastrointestinal tract chronic inflammation. In inflammatory bowel disease, a promising method of treatment is represented by fecal microbiota transplantation (FMT). As the use, safety and effectiveness of FMT for recurrent Clostridioides difficile infection (CDI) has increased in recent years, it has also demonstrated real clinical benefits for treating SARS-CoV-2 and CDI co-infection. As a result of immune dysregulation, Crohn's disease and ulcerative colitis cause damage to the digestive tract.
- microbiota transplantation
- inflammatory bowel disease
- fecal microbiota transplantation
1. Introduction
Fecal microbiota transplantation (FMT), a therapy based on the microbiome, has acquired widespread interest in the scientific, clinical and lay communities in recent years [1]. Through the use of various techniques and modalities, FMT is a cumbersome procedure that restores a balanced intestinal flora through feces infusion from healthy donors into a diseased gastrointestinal tract (GI) to cure a specific condition. FMT has been successfully used for both non-GI diseases and GI-diseases, the second being represented by idiopathic constipation, recurrent Clostridioides difficile infection (CDI), inflammatory bowel disease (IBD) and irritable bowel syndrome [2,3,4,5]. FMT is not a new therapeutic concept, but one that has felt an increasing interest in recent years, with evolving methodology and clinical indications [6]. Many patients may find FMT distasteful and unimaginable, but the concept has been around for decades and the procedure has been proven to be effective [7].
The human gastrointestinal tract contains a wide diversity of microorganisms, of which the bacterial community, made up of at least 1014 predominantly anaerobic bacteria, is the dominant one. It should be mentioned that not all species of GI bacteria have been yet cultivated [8]. Bacteroides, Firmicutes phyla, Actinobacteria phyla and Fusobacteria are some of the 1000 species that describe the normal gut microbiota and are genetically imprinted from birth [9]. There are different bacterial communities in the proximal and distal intestine, with most intestinal microbes being hosted by the colon, which plays a critical role in health and illness [10]. The proximal one contributes to the production, absorption and distribution of micronutrients and vitamins; regulation of metabolism and metabolism of xenobiotics; and the renewal of intestinal epithelial cells, but also to the immune system development and protective measures against pathogens. The disruption of the intestinal microbiota, now called dysbiosis, is a state that is believed to be involved in a range of diseases, including irritable bowel syndrome, IBD, enteric infections, colorectal cancer, asthma, atopic diseases, obesity and metabolic syndrome [11]. Genetically susceptible individuals develop IBD when their immune systems respond inappropriately to intestinal microbes. Dysbiosis is also associated with abscesses, surgery at a young age and worsening symptoms in patients with Crohn’s disease (CD) [9].
The severity of IBD and complications have a positive correlation with an overpopulation of pathogenic bacteria (Coprobacillus, Clostridium ramosum, Clostridium hathewayi), and a decrease in the beneficial anti-inflammatory bacteria Faecalibacterium prausnitzll, which are beneficial bacteria in the gut that regulate the immune system of the host. Protective bacteria have a role in immunosuppression, preventing induction of cytokines and potential intestinal damage [2,11]. In patients with CD, their microbiota presented a predominance of Actinomyces spp., increased Veillonella spp. E. Coli and Intestinibacter spp. The gut microbiota of patients with UC are specified by an increase of Eubacterium rectum, E. Coli and Ruminococcus gnavus, microbes that maintain and induce cell inflammation [2].
In cases of IBD, levels of Eubacterium rectale, Faecalibacterium prausnitzii, and Roseburia intestinalis as well as other healthy bacteria were more reduced in comparison with healthy microbiota from control groups [2].
The intestinal flora composition can be altered by slight, temporary changes due to diet and probiotics or by significant changes due to antibiotics [12]. The majority of risk factors for IBD identified so far are related to the microbiome and include smoking, diet, hygiene hypothesis, exposure to gastroenteritis and early antibiotic use [13]. An important issue is the diet, patients with IBD should receive nutritional recommendations, a diet rich in vegetables and fruits is associated with a decreased risk of developing IBD. On the other hand, ultra-processed food and carboxymethylcellulose predispose patients to IBD development or flares despite proper treatment [12].
The immune system is known to be usually concessive to commensal microbes colonizing in the GI tract. As a potential pathogenic mechanism of IBD, the intestinal microbiota’s imbalance may stimulate an abnormal immune response [14]. Studies with several mutant mouse strains demonstrated the impact of the innate immune system on the intestinal microbiota and the development of gut inflammation, metagenomic analyses of the gut microbiota outlined the co-dependence between intestinal microbes and inflammatory diseases of the gut. Furthermore, studies on mice emphasized that T- and B-cell-deficient mice lacking the T-bet transcription factor developed colitis with an altered microbiota that, upon transfer to wild-type-recipient mice, induced bowel inflammation [13,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30]. Mycobacterium avium subspecies paratuberculosis and Fusobacterium varium are some of the few specific bacteria that have been associated with IBD. However, specific pathogens that fulfill Koch’s postulates have not yet been identified, Koch’s postulates required that the identified organism be present in all cases of the disease, isolated from diseased patients and cause disease when reintroduced to a healthy susceptible animal. However, due to the various triggers involved in CD and UC, Koch’s theory (a pathogen for a disease) is not enough in order to explain the unbalanced immune response of the microbiota in case of IBD [13].
2. History of FMT
Historically, FMT’s first use in a human patient was reported in the IVth century by Ge Hong in China when it was first administered orally to a patient for food poisoning or severe diarrhea [16]. Li Shizhen described how stool products were used for treating GI symptoms such as constipation, abdominal pain, diarrhea, vomiting and fever during the XVIth century [17]. Fabricius Acquapendente, an Italian anatomist, recounted in the XVIIth century: “I have heard of animals which lost the capacity to ruminate, which, when one puts into their mouth a portion of the materials from the mouth of another ruminant which that animal has already chewed, they immediately start chewing and regain their other health” [18]. FMT then began to be used in veterinary medicine, later being called “transfaunation”. Fecal transplants have been performed for the treatment of horses with diarrhea by administering healthy feces in the rectums of the sick horses. Rumen fluid has also been used to treat cows and alpacas suffering from various gastrointestinal disorders [19].
Eiseman et al. performed and reported the first human fecal transplant in 1958 to treat cases of pseudomembranous colitis. In four patients with refractory infections who failed to respond to antibiotics, fecal retention enemas were found to be effective [20]. A second series of pseudomembranous colitis cases was added in 1981 by Bowden et al., with 16 patients successfully treated with retention enemas as well [21]. Further, a CDI case was treated with FMT for the first time in 1983 and was reported by Schwan et al. [22]. Almost 40 years later, in 2021, microbiota transplantation as a treatment in a large number of CDI patients, recorded very low rates of recurrence [23]. Previous studies on patients with CDI and SARS-CoV-2 co-infection recorded a statistically significant correlation between FMT and the reduction of abdominal pain for the patients at discharge (91.3%, p < 0.005) as well as normalization of inflammatory markers: CRP mean 5.67 mg/dL, WBC mean 7695 cells/mL and fibrinogen 420 mg/dL in FMT patients (p < 0.05). On the same topic, the study realized by Konturek et al. outlined a significant CRP reduction after FMT therapy in all treated patients. FMT proved its benefits in recurrent CDI, being considered a salvatory option for patients that developed severe and recurrent CDI infection, despite proper antibiotic use [23,24,25,26,27,28,29,30].
Moreover, we aim to outline that very few adverse effects are generally directly attributable to the FMT procedure. Most reported adverse events in the literature have been self-limiting gastrointestinal symptoms comprising abdominal cramps, nausea and constipation. Fever, Gram-negative bacteremia and bowel perforation are very rare adverse effects. Furthermore, in order to improve the safety of FMT, recent studies describe new technics such as washed microbiota preparation, which is based on the use of an automatic microfiltration machine and subsequent repeated centrifugation. In a study with patients who underwent either washed microbiota transplantation (WMT) or crude FMT, in the same FMT center with the same indications, fewer adverse effects were recorded in the WMT group [31].
Up to date studies on FMT outlined its benefits in antibiotic-refractory CDI, autoimmune diseases, behavioral diseases, metabolic disorders and organic diseases. Furthermore, the review realized by Yuanyuan Zhao opened new perspectives, showing progress of fecal microbiota transplantation in liver diseases, through the gut–liver axis [30].
3. Inflammatory Bowel Disease
The GI tract is affected by inflammatory bowel disease (IBD), an ongoing chronic recurrent condition that involves chronic remitting and relapsing inflammation [24]. A genetically susceptible individual’s dysregulated immune response to environmental factors is believed to be at the heart of IBD’s etiology [25]. The etiology is still incompletely known, but the dominant hypothesis holds that a pathogenic or altered microbiota in a genetically susceptible individual leads to the inflammation in IBD. Considerable efforts have been made to understand the genetic and immunological basis that determines this disease, and medical treatments are used to remit the patient’s inflammatory response. The medication is represented by amino salicylates, steroids, tumor necrosis factor modulating agents, thiopurines and other immunosuppressants.
The response to treatment is often limited or unsatisfactory due to side effects, infections or even lack of response [11,26]. By understanding the role played by the microbiota in this pathology, new and innovative treatment options can be developed that modulate the gut bacteria [11].
Despite several attempts to identify the bacterial, fungal or viral origins of IBD, as well as the general imbalance of the gut microbiota, the majority of the potential candidates have been rejected due to a lack of valid scientific evidence. Mycobacterium avium subspecies Paratuberculosis and Escherichia Coli (E. Coli) are the specific microorganisms still actively being studied thoroughly [27].
IBD, a chronic recurrent inflammation of the GI tract, is defined by two pathologies: ulcerative colitis (UC), affecting only the colon and its mucosa, or Crohn’s disease (CD), involving any section of the GI tract [11,14].
There is an increasing prevalence of UC as a chronic inflammation of the colonic mucosa caused by contact between luminal content and the mucosal immune system. It has a high prevalence of persistent or recurrent symptoms, including anemia with bloody diarrhea and abdominal pain [28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54].
CD is a chronic relapsing IBD that has not yet been fully understood, but is thought to be caused by excessive GI immune responses against the microbiota in the gut of genetically susceptible individuals or under an environmental influence [30,31,32,33]. Several studies have indicated that these patients have a dysbiosis of their intestinal microbiota, including an increase in bacteria that can cause inflammation, such as E. Coli, and a reduction in bacteria that prevent inflammation, such as Faecalibacterium prausnitzii [30,31,32,33]. Recent clinical trials mention the role of FMT in inflammatory bowel disease (IBD), multiple sclerosis and Parkinson’s disease. This suggests not only a local modulating intestinal effect but also a systemic immunological response to FMT with an impact on the gut–lung, gut–liver and gut–brain axes [25,29,30].
Immunological response after FMT was associated with a substantial reduction in the colonic mucosal CD8+ T cell density and a decrease in serum concentrations of IL-6 and IP-10. Serum levels of IL-6 and VCAM-1 were all significantly correlated with CRP and ESR, as has been highlighted in the study by Yanzhi et. al. on FMT’s role in ulcerative colitis treatment [29]. Additionally, it is considered that FMT has an important role in decreasing gut inflammation via the induction of IL-10 and TGF-β, cytokines critical for T-reg accumulation in the intestine. Moreover, FMT is involved in the inhibition of pathogenic TH-17 cells, through induced IL-10+ T-regs in patients with IBD or Crohn’s disease [29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55].
4. Evolution of IBD Cases Treated with FMT
FMT was first published about for IBD treatment in 1989, in which the author stated he had suffered with UC for 7 years despite receiving sulfasalazine and steroids. After 6 months since the FMT procedure by retention enemas from a healthy donor, he remained asymptomatic [55].
A study conducted in 2006 by Borody and his colleagues found that daily FMT enemas were effective in treating severe UC in 6 adults. They observed clinical improvement earlier than 1 week after the procedure, with complete symptomatic remission for all patients during the first 4 months after the procedure [56].
According to Kunde et al., 10 young adults with mild to moderate UC were treated via FMT in March 2013 by enemas for 5 days daily in the first series of pediatric patients with IBD treated with FMT. At the end of this one-month small pilot study, three of the nine patients were in remission and six of them had a sustained clinical response despite the lack of follow-up [57].
A total of 133 subjects were treated with FMT in a 2014 study (77 with UC, 53 with CD and 3 with indefinite IBD), most of whom were resistant to therapy or dependent on medication. Among all included subjects, 57 (43%) (25 with UC, 31 with CD and 1 with undefined IBD) suffered from a difficult or recurrent CDI. FMT has not been adequately evaluated in clinical trials evaluating its effectiveness in restoring disturbed intestinal microbiota due to poor quality studies and insufficient endpoints and inclusion criteria. From the evaluated data, FMT obtained a reduction of 71% in symptoms of the treated patients. The rate of symptom relief remains constant even when CDI is excluded from our analysis (69%). It should be noted that the exact procedures for FMT in the study were not fully recorded. Nevertheless, most patients were treated with polyethylene glycol lavage or antibiotics that were not specified prior to FMT. A total of 42 patients received FMT via upper routes (nasogastric or naso-jejunal tube and gastroscopy), 20 patients through enema, 23 through colonoscopy and 11 patients had FMT infusions via both upper and lower routes [3].
Another analysis conducted in 2014 analyzed 122 patients with IBD with the note that 3 were excluded from study the because of the FMT enema intolerance. As a result of the cumulative analysis, 119 patients were categorized between mild, moderate and severe. A total of 27 (23%) had mild or mild/moderate disease, 16 (13%) had moderate/severe disease, and 19 (16%) were severe disease patients. Refractory therapy occurred in 10 cases (8%) whereas active disease occurred in 44 cases (37%) and refractory pouching occurred in 5 cases (4%). The clinical remission rate was 45% (54 out of 119). Finally, 12 out of the 16 patients (75%) experienced mucosal healing [58].
A cohort in 2017 that included 30 patients with refractory midgut CD demonstrated a clinical remission of 77% after one month after only one nasoduodenal FMT [59,60].
A group of 555 patients with UC were evaluated in 42 studies reporting on FMT in 2017 (9 case reports, 4 randomized controlled trials, 5 case series and 24 prospective cohort studies out of which 20 were uncontrolled and 4 were controlled). The clinical remission rate was 36% (201 patients out of 555) [61]. In a meta-analysis of 24 cohort studies with 307 individuals, the pooled proportion of individuals with UC achieving clinical remission was moderately heterogeneous (54%) [61].
UC response to FMT was analyzed in 2019 to identify bacterial species and metabolic pathways. In patients who experienced remission, the system contained Eubacterium, Roseburia and short-chain fatty acids, as well as secondary bile acid biosynthesis, whereas in patients who did not experience remission, the system contained Fusobacterium, Sutterella and Escherichia species. Bacteroides in donor stool were associated with remission in patients receiving FMT, and Streptococcus species in donor stool was associated with no response to FMT [62].
It was reported in 2020 that autologous FMT (a-FMT) had similar benefits to heterologous FMT (h-FMT). The purpose of a-FMT is to re-establish the gut microbial community after disturbances have occurred using one’s own feces in a healthy state. IBD and other infectious diseases can be treated with h-FMT in which feces are transplanted into the sick person from a healthy donor. It is preferable to use a-FMT over h-FMT in order to avoid infectious complications; however, it is important to determine which stool samples are functionally optimal in order to prevent complications related to inflammation in IBD.
This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11041016
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