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At first glance, fecal microbiota transplantation (FMT) appears to be a far-fetched procedure devised as a slapstick plot for a sit-com series. However, this innovative technique may revolutionize the future of medical treatments for a host of maladies including autoimmune and allergic diseases as well as autism spectrum disorder
The Demise of the Microbe-Fearing Paradigm
Following the advent of germ theory, microorganisms were demonized as the causative agents behind all manner of human suffering, which led to the glorification of antibiotics and other magic bullet pharmaceuticals as harbingers to the eventual end of human disease. Pill-for-every-ill pharmaceutical remedies led the masses to worship at the altar of the biomedical paradigm and to herald an era of better living through chemistry. Physicians were anointed with almost deity-like reverence and became elevated in the collective consciousness as the gatekeepers of a sacred body of privileged knowledge.
However, with the emergence of more research and the advancement of the scientific enterprise, the vilification of microbial entities has been increasingly found to be misguided and to have disastrous implications for human health. The exquisitely fine-tuned symphony of bacterial interactions that occurs within the confines of our corporeal bodies is susceptible to disruption by many of the medical interventions of modernity, including antibiotics, non-steroidal anti-inflammatory drugs, vaccinations, and proton pump inhibitors, as well as the inevitable encroachment of Westernized nutrient-poor dietary patterns that accompanies an increasingly globalized economy (1, 2, 3, 4, 5, 6, 7).
Even on his death bed, the founder of immunization and pasteurization, Louis Pasteur, confessed his short-sightedness in his acquiescing that it was the terrain, or the prevailing gut bacterial milieu and physiological environment, that mattered rather than the virulence of the invading pathogen (8). When the overarching needs of the human organism are met--that is, micronutrient sufficiency, freedom from toxicity, effective sanitation infrastructure, and a harmonious gut ecology--we are less vulnerable to infection.
The Centrality of the Microbiota to Human Health
Although the quantification of commensal bacteria is still debated, the human intestinal tract has been estimated to harbor one hundred trillion microbes, representing ten-fold the number of human cells in the body (9). In a poetic revision, more recent studies have proposed that we harbor an equivalent number of bacterial cells and human cells, suggesting an elegant balance between our microbial inhabitants and those basic elements of self (10).
Due to this mutualistic relationship, human physiology represents the culmination of human-microbe co-metabolism (9). In fact, premiere Stanford scientist Dr. Justin Sonnenberg encapsulates the essentiality of our microbial counterparts to our very existence with his speculation that human beings may merely be elaborate vessels designed for the propagation of bacterial colonies (10).
The gut microbiota occupies a pivotal role in educating and entraining the immune system in order to establish self-tolerance and to prevent the self-directed immune reactions that comprise autoimmune disease. In fact, that the acquisition of the microbiota in evolutionary history coincided with the development of distinct arms of the immune system lends credence to the notion that the machinery of the immune system was in part an adaptation to maintain symbiotic relationships with sophisticated microbial communities (11). According to researchers, "When operating optimally, the immune system - microbiota alliance interweaves the innate and adaptive arms of immunity in a dialogue that selects, calibrates and terminates responses in the most appropriate manner" (11).
Importantly, the microbiota inhibit the overgrowth of pathogenic organisms by competing for attachment sites (12). In addition, our commensal microflora is integral to nutrient assimilation and metabolism, as well as to production of essential mucosal nutrients (12). For instance, gut microbes ferment indigestible fiber, also known as microbiota accessible carbohydrates, into short-chain fatty acids such as butyrate, which in turn reinforce the gut lining and prevent development of pathologic leaky gut syndrome (12).
This regulation of the barrier function of the gut by the microbiota is pivotal in preventing aberrant autoimmune reactions. Violation of mucosal barrier integrity of the gastrointestinal tract is the precursor to all autoimmune disorders, since it invites the translocation of undigested food proteins, microbial byproducts, microorganisms, and toxicants into systemic circulation where immune responses are incited (13).
Debunking Mythology: Probiotics Cannot Reinoculate the Gut
Due to the convoluted and interdependent relationship between the microbiota and the host immune system, dysbiosis, or microbial imbalance, can have dire consequences. Cesarean section, bottle feeding, and hyper-sanitized conditions have all irreparably transformed our microbiotas. As articulated by researchers, "Alteration of the composition and function of the microbiota as a result of antibiotic use, diet evolution and recent elimination of constitutive partners such as helminth worms has transformed our microbial allies into potential liabilities" (11).
Dysbiosis has been implicated in gastrointestinal disorders such as Crohn’s disease and ulcerative colitis, as well as other autoimmune conditions (14), allergic disorders (15), metabolic disease (16, 17), and neuropsychiatric illness (18). Because microbial imbalance is implicated in the etiology of these disorders, restoration of a healthy microbial community may arrest these underlying disease processes and alleviate symptomatology.
Despite the marketing hype, no strain of commercial probiotic has ever been demonstrated to permanently colonize the gastrointestinal tract, such that regimens based upon reinoculation revolve around a fundamentally flawed premise. Rather than repopulating species extinguished due to antibiotic use, probiotics from supplements and fermented foods exert temporary and transient benefits as they pass through our digestive systems, affecting the metabolism of indigenous glut flora and modulating our immune system, the bulk of which directly interfaces with our gut (19). At present, fecal microbiota transplant (FMT) is the only means by which we can permanently recover lost strains.
Fecal Microbiota Transplant: Resurgence of An Old Technology
Essentially, FMT represents the transfer of the fecal microbiota from a healthy donor to a diseased recipient in order to restore a balanced gut microbial ecology and in turn, foster the resolution of symptoms (20). A liquid suspension of homogenized stool is instilled into the gastrointestinal tract of the patient by various modes of administration, including nasogastric tube, nasojejunal tube, or upper tract endoscopy from the proximal side of the digestive tract, or via a retention enema or colonoscopy from the distal end (21, 22, 23).
The notion of a fecal transplant as a therapeutic intervention is not new, as this procedure was first performed almost two millennia ago by a Chinese medical scientist named Ge Hong (24). Later in 1958, it was reported that rapid remission of antibiotic-associated diarrhea occurred in patients treated with fecal enemas (25). With over a 90% cure rate, FMT became established as an effective therapy for antibiotic-associated pseudomembranous colitis caused by Clostridium difficile infection, so much so that it is now recommended as the standard of care after a third recurrence following a pulsed regimen of vancomycin (26).
Compared to probiotics, which act temporarily, "the satisfactory outcome of treatment with FMT suggests that feces contain a superior combination of intestinal bacterial strains and is more favorable for repairing disrupted native microbiota by introducing a complete, stable community of intestinal micro-organisms"(19). Likewise, feces contains other factors such as proteins, vitamins, and bile acids which may enhance gut recovery (27).
Mechanism of Action for Fecal Transplant in Inflammatory Bowel Disease
Scientific literature supports the notion that FMT reinstalls depleted bacteria, as augmentation of donor-derived microbial strains as well as "normalization of the bowel function was accompanied by the engraftment of intestinal micro-organisms from a healthy donor" (19). Restoration of bacterial populations in turn promotes immunomodulatory effects, which engenders equilibrium in the immune system and prevent aberrant autoimmune responses.
One rationale for use of FMT in inflammatory bowel disease (IBD) is that patients with Crohn’s disease and ulcerative colitis, the two subtypes of IBD, have compromised bacterial diversity and alterations in taxa abundance, as illustrated by metagenomic sequencing studies which show 25% fewer genes in IBD microbiota and significantly diminished bacterial counts (28). IBD cohorts have prominent reductions in the bacterial phyla Firmicutes and Bacteroidetes, which appear robustly in healthy controls, as well as lower levels of Bacteroidales and Clostridiales (29, 30, 31). In contrast, IBD often presents with abnormal elevations in Enterobacteriaceae and Fusobacteriaceae (31).
Other IBD-associated microbial signatures include more virulent strains of Escherichia coli (E. coli), an increase in Proteobacteria, and decreased counts of bifidobacteria and Faecalibacterium prausnitzii, both of which are instrumental in ensuring integrity of the gut barrier (32, 33, 34, 35, 36).
The role of the microbiota in IBD is further illustrated by an immunomodulatory bacterial molecule called polysaccharide A or symbiosis factor, which accompanies the species Bacteroides fragilis (37). Symbiosis factor can prevent and cure IBD by inducing production of the anti-inflammatory cytokine, or signaling molecule, known as interleukin-10 (IL-10), and by promoting activity of immune-balancing regulatory T cells (Tregs) (37). By a similar Treg-upregulating mechanism, the phylum Firmicutes can reduce intestinal inflammation in animal models of ulcerative colitis (38).
At a larger scale, post-FMT improvement in histology, or the microscopic anatomy of cells, has been witnessed in cases of Crohn’s colitis treated with FMT (39). This FMT-elicited improvement encompassed both total mucosal healing evident upon colonoscopy as well as normalization of levels of fecal calprotectin, a marker of intestinal inflammation which can predict relapse in quiescent IBD patients (39, 40). Taken cumulatively, this research "provides evidence of the untapped power of the normal luminal flora to inhibit even the most severe inflammation of Crohn’s colitis" (41).
Efficacy of Fecal Transplant in Inflammatory Bowel Disease and other Intestinal Disorders
In the late 1980s, an initial report was published on the efficacy of FMT infused through retention enema in inducing complete clinical remission in ulcerative colitis (42). Thereafter, a series of case reports documented the success of FMT in promoting IBD remission, lasting up to 13 years (41). Although FMT treatments in IBD did not procure the near-ubiquitous success rates observed in Clostridium difficile, one systematic review revealed that most IBD patients who underwent FMT exhibited symptomatic reduction, medication cessation, and disease remission (43).
For IBD, a systematic review and meta-analysis of 18 studies, which represents the highest quality peer-reviewed research, demonstrated that 45% of subjects achieved clinical remission with FMT (44). Another study concluded that FMT has a 34.1% cure rate and 68.2% improvement rate for ulcerative colitis, and a 30.0% cure rate and 60.0% improvement rate for Crohn’s (45). According to Borody and colleagues (2014), ulcerative colitis is more responsive to FMT than Crohn’s disease, and multiple infusions are required in most cases to maintain remission (41). They likewise speculate that FMT may be more efficacious in cases of IBD where antibiotic use is implicated in onset, and that certain dysbiotic profiles of IBD may be more susceptible to rapid reversal after fecal transplant (41).
Regarding other gut-centered disorders, studies have shown a 85.2% cure rate and 95.1% improvement rate for Clostridium difficile, a 46.7% cure rate and 73.3% improvement rate for irritable bowel syndrome (IBS), and a 40.2% cure rate and 67.4% improvement rate for constipation (45).
Future Clinical Applications
Because the microbiota is so instrumental to the immune system, and because immune perturbations are implicated in the pathophysiology of so many diseases, the sky is the limit when it comes to the clinical utility of fecal transplants. As articulated by Xu and colleagues (2015), "Case reports of FMT have also shown favorable outcomes in Parkinson's disease, multiple sclerosis, myoclonus dystonia, chronic fatigue syndrome, and idiopathic thrombocytopenic purpura," several of which will be explored in further detail below (19).
The gut-brain axis, or the bidirectional communication system between the gut and brain which operates through neuroendocrine, neuroimmune, and autonomic pathways, is the means through which the gut microbiota influences brain development and higher-order behaviors (45). Thus, the gut dysfunction which often accompanies autism spectrum disorders (ASD) may contribute to its neurological symptomatology. Compared to controls, children with autism exhibit higher fecal counts of Clostridium and Ruminococcus species, as well as non-spore-forming anaerobes and microaerophilic bacteria (46).
In one open-label trial, 18 children with autism underwent two-week antibiotic treatment followed by a bowel cleanse and FMT consisting of a high loading dose and lower maintenance doses for two months (47). The researchers observed an 80% reduction in gastrointestinal symptoms such as altered bowel movements, abdominal pain, and indigestion, which persisted when re-tested two months later (47). These gastrointestinal improvements were concomitant with expansion of bacteria taxa such as Bifidobacterium, Prevotella, and Desulfovibrio as well as overall bacterial diversity, which continued upon re-measurement two months later (47).
Importantly, the transplant elicited significant improvement in ASD symptoms, such as aberrant speech, hyperactivity, irritability, lethargy, stereotypy, communication, and socialization, with an average developmental age increasing by 1.4 years (47). The use of FMT in ASD is also supported by case studies of improvements in autism when children are given FMT or administered cultures of Bacteroidetes and Clostridia (48).
Dysregulation of tight junctions, or the dynamic cytoskeletal architectural protein between intestinal cells, which regulate the trafficking of molecules across the gut barrier, is prerequisite to the development of all autoimmune diseases (13). Dysbiosis can interfere with tight junctions, leading to the passage of antigenic food particles, toxic agents, microorganisms, and bacterial byproducts across the gut lumen, inciting immune responses that can become self-directed and culminate in autoimmunity (13). Therefore, restoring an equilibrium in the gut microbiota, which can in turn promote repair of the mucosal barrier, is a feasible strategy to arrest autoimmune responses.
For instance, in both Sjögren’s syndrome and systemic lupus erythematosus (SLE), one of the main intracellular self-antigens against which auto-antibodies are produced is Sjögren’s syndrome antigen A, also known as Ro60, which consists of a ribonucleoprotein-RNA complex (19, 49). Ro60 is associated with symptom severity and sun sensitivity in the aforementioned disorders (19). T lymphocytes which perpetuate immune responses against this auto-antigen are activated by a protein expressed by a gut resident, Escherichia coli (E. coli) (50). Accordingly, "immune responses to the gut microbiota may play a pivotal role in the initiation of autoimmunity in SLE and SS," which points to a possible role for FMT (19).
In another instance, FMT was shown to eliminate symptoms of the autoimmune disease idiopathic thrombocytopenic purpura (ITP), as well as normalize levels of platelets, the cells which facilitate blood clotting and are the target of immune attack in this condition (51). Likewise, three multiple sclerosis (MS) patients who received FMT for chronic constipation achieved normal defecation, marked improvements in motor symptoms which enabled them to walk, and restoration of urinary function such that indwelling catheters were no longer needed (48). Similarly, another report chronicles a patient who had experienced myoclonus dystonia for 22 years, a movement disorder of rapid muscular contractions, repetitive movements, and abnormal postures. After FMT, she experienced 90% improvement, "allowing her to resume employment and execute fine motor tasks, such as drinking from a cup, fastening buttons, and dressing" (48).
These results may have applicability to other autoimmune diseases as well, since increased intestinal permeability has been demonstrated to be a trigger for every autoimmune disease in which it has been studied, including rheumatoid arthritis, inflammatory bowel disease, celiac disease, insulin-dependent diabetes, multiple sclerosis, and ankylosing spondylitis (13). In addition, there is a well-elucidated connection between gut pathogens and the onset of autoimmune disorders, such as Yersinia enterocolitica and Prevotella copri in Hashimoto’s thyroiditis and rheumatoid arthritis, respectively (52, 53).
Similar to the hygiene hypothesis, the microflora hypothesis of allergic disease postulates that antibiotic- and diet-induced alterations in the commensal microflora in industrialized countries has led to increased incidence of allergic airway disease (54). This theory is tenable since the microbiota is essential in shaping development of the immune system and establishment of immunological tolerance in mucosa (54). It is supported by research that early-life antibiotic exposure, Cesarean section, and bottle feeding, all of which alter normal colonization of the gastrointestinal tract with microorganisms, are correlated with development of atopic diseases such as allergies, asthma, and food reactions (55, 56).
According to animal studies, "the presence of commensal bacteria is critical for ensuring normal cellular maturation, recruitment, and control of allergic airway inflammation" (57, p. 198). In mice that have not been naturally colonized by gut microbiota, known as germ-free or gnotobiotic mice, allergen exposure results in a greater number of infiltrating white blood cells such as eosinophils as well as increased local production of inflammatory cytokines and allergen-associated antibodies, indicating a greater immune response and more severe allergic disease (57). Therefore, with respect to allergic disease, Xu and colleagues (2015) propose that "the use of FMT seems promising in restoring immune homeostasis by transferring a complex community of bacteria which is more stable and harbors a greater ability to colonize" (19).
Safety and Issues in Fecal Microbiota Transplant
Currently, the crude process of donor selection operates on the premise of exclusion rather than inclusion, with disqualification of donors who present with risk factors for dysbiosis, comorbid diseases, or contagious infections (41). Some donors are better than others, but the optimal donor characteristics and microbial ecosystem remain to be elucidated (41). In the future, donors and recipients may be screened for compatible enterotypes, or particular profiles of gut flora (41). Case reports of recipients adopting personality traits of donors have surfaced as well, highlighting the need for further research.
Despite the unappealing nature of fecal transplant, surveys have illuminated that the majority (85%) of respondents indicate that they would be willing to undergo the procedure instead of receiving antibiotics for recurrent Clostridium difficile, demonstrating that public perception is improving (58). Professional education on the merits of FMT for a spectrum of disorders is essential since 94% of those polled endorsed statements that they would be willing to receive FMT if their physician recommended it (58).
Compared to immunosuppressant drugs, biologic agents, and steroid therapy, often prescribed to treat autoimmune diseases, the adverse sequelae of fecal transplant are mild and self-limiting, and have been documented to include fever, abdominal cramping, bloating, and fullness, gas, diarrhea, and blood in stool (Kunde et al., 2013). Although FMT is not a panacea, it represents a viable alternative or adjunctive approach for those patients who do not respond to less-invasive measures of gut healing such as an anti-inflammatory diet, facto-fermented and prebiotic foods, antimicrobial herbs, and probiotic supplementation.
This research remains is in its infancy, yet it holds promise for people suffering from a wide spectrum of debilitating diseases due to the centrality of the microbiota in either imparting health or engendering illness.
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