Intestinal dysbiosis is now known to be a complication in a myriad of diseases. Fecal microbiota transplantation (FMT), as a microbiota-target therapy, is arguably very effective for curing Clostridium difficile infection and has good outcomes in other intestinal diseases. New insights have raised an interest in FMT for the management of extra-intestinal disorders associated with gut microbiota. This review shows that it is an exciting time in the burgeoning science of FMT application in previously unexpected areas, including metabolic diseases, neuropsychiatric disorders, autoimmune diseases, allergic disorders, and tumors. A randomized controlled trial was conducted on FMT in metabolic syndrome by infusing microbiota from lean donors or from self-collected feces, with the resultant findings showing that the lean donor feces group displayed increased insulin sensitivity, along with increased levels of butyrate-producing intestinal microbiota. Case reports of FMT have also shown favorable outcomes in Parkinson’s disease, multiple sclerosis, myoclonus dystonia, chronic fatigue syndrome, and idiopathic thrombocytopenic purpura. FMT is a promising approach in the manipulation of the intestinal microbiota and has potential applications in a variety of extra-intestinal conditions associated with intestinal dysbiosis.

The human intestinal tract is home to up to 10¹⁴ microbes, outnumbering human cells within our bodies by tenfold[1,2]. The number and diversity of bacteria differ according to the different anatomical areas, ranging from the proximal to the distal gastrointestinal tract, with the colon harboring most of the intestinal microbiota[3]. Such an environment developed by host-bacteria associations is termed as being mutualistic. Four predominant bacterial phyla are identified in the human intestine: Bacteroidetes, Firmicutes, Actinobacteria, and Proteobacteria[4].

Rather than simply occupying space in our bodies, the intestinal microbiota is essential to nutrient metabolism, opportunistic pathogens defense[5], immune system development, and intestinal-barrier function regulation[3,6,7]. The specific balance of intestinal microbial diversity differs by individual according to variations (such as sanitation, social behaviors, and genetics)[8,9]. The beneficial balance of the intestinal microbial ecosystem can be disrupted by a series of factors, which includes antimicrobial drugs, vaccination, and dietary shifts[3]. Previous studies have suggested that intestinal microbiota alterations have been implicated in many gastrointestinal diseases and even systemic illnesses, such as metabolic diseases[10,11], neuropsychiatric conditions[12], autoimmune diseases[13], allergic disorders[14], and tumors[15].

Fecal microbiota transplantation (FMT) is a technique in which intestinal microbiota are transferred from a healthy donor to the patient, with the goal being to introduce or restore a stable microbial community in the gut. The first use of feces in such a manner was described, according to the Handbook of Emergency Medicine, approximately 1700 years ago by a Chinese medical scientist named Ge Hong[16]. It was first published in the English language by Eiseman et al[17] in 1958, when he reported a prompt response in patients with antibiotic-associated diarrhea treated with fecal enemas. Nevertheless, this practice was not well recognized until 1978, when investigators recognized Clostridium difficile infection (CDI) was the etiology of antibiotic-associated pseudomembranous colitis[18,19]. In the past few decades, the use of FMT for managing the increasing burdens of CDI has demonstrated it to be an effective therapeutic strategy for CDI[20-23]. In 2012, Borody et al[24] reported that more than 1200 cases have been treated in several centers. A total of 583 CDI patients treated with FMT produced a cumulative cure rate of more than 90% in 36 publications[25]. In addition, standardized frozen donor fecal bacterial preparations used in the treatment of recurrent CDI showed equal cure rates to fresh fecal samples[26]. 2013 guidelines for CDI have recommended that FMT should be considered if there is a third recurrence after a pulsed vancomycin regimen[27].

Although there are still many areas of uncertainty concerning this emerging technology, including transmission of infectious organisms, long-term sequelae, and even cost-effective evaluation, the United States Food and Drugs Administration have recently paid critical attention to FMT protocol in clinical applications. Borody et al[24] regarded the flora in feces as a special organ, and therefore considered the technique of FMT as a particular type of organ transplantation, regardless of the issue of immunological rejection. FMT has hence emerged as an important therapeutic modality in the manipulation of altered intestinal microbiota, with the indications of FMT possibly being expanded to even extra-intestinal conditions.

The exact mechanisms by which intestinal dysbiosis becomes involved in disease development are not completely elucidated. Alteration of metabolic activities induced by perturbed intestinal bacterial species leads to weakened defense of the gastrointestinal mucosa, which in turn leads to increasing intestinal permeability and toxic substances being absorbed into the systemic circulation. Prior work has observed disruption of the intestinal microbiota being evident at the phylum level, with marked depletion in levels of probiotics and a relative increase in the numbers of pathogens leading to complications in intestinal conditions[27]. The alteration of microbial communities in both inflammatory bowel disease (IBD) and CDI patients was characterized by a reduction in two phyla of bacteria, Firmicutes and Bacteroidetes, which are prominent in healthy controls[28,29]. Moreover, an increase in Proteobacteria such as Enterobacteriaceae is also found in individuals with IBD[30]. Bacteroides fragilis, the prominent human gut commensal, can prevent and cure inflammatory disease via the effect of its symbiosis factor (polysaccharide A, an immunomodulatory bacterial molecule) on the activation of the Toll-like receptor 2 pathway, inducing regulatory T cells and interleukin-10 production[31]. Dextran sodium sulfate-induced colitis in a mouse model demonstrated that spore-forming Firmicutes in clostridial clusters IV and XIVa reduced intestinal inflammation through regulatory T cells induction[32].

These studies highlight the role of microbiota-target therapy for reinstalling the depleted bacterial species associated with the disease. Probiotics somehow alter the metabolism of the indigenous gut flora, although the effect is largely restricted to limited bacterial species, and have a transient inhabitation effect on the intestine. Nevertheless, 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. Feces also harbors additional substances (proteins, bile acids, and vitamins) which might contribute to the recovery of gut function[20].

This scenario has in fact been documented in a recent study of FMT in recurrent CDI trying to elucidate the mechanism of action of fecal infusion[33]. The authors assessed the characteristics of fecal microbiota before, after, and during follow-up of FMT and found the intestinal microbiota changed persistently over time, from a less-diverse disease state (pre-FMT) to a more diverse ecosystem virtually resembling that of fecal donors (post-FMT). Such dynamic monitoring of the intestinal microbiota helps us to identify the key groups representing the ecosystem, as well as further illustrating that normalization of the bowel function was accompanied by the engraftment of intestinal micro-organisms from a healthy donor. Currently, there is significant interest in the area of FMT in IBD[34], especially with the evidence of an impressive curable effect in some ulcerative colitis (UC) patients[35,36]. A study was conducted to determine microbiota composition after FMT in 5 patients with UC by monitoring their fecal bacterial communities at multiple time points[37]. The results showed that one patient had a positive response to FMT, which was characterized by the augmentation of donor-derived microbiota, including Faecalibacterium prausnitzii, Rosebura faecis, and Bacteroides ovatus. According to Borody et al[38] Crohn’s disease (CD) is less responsive to FMT when compared with UC. Nonetheless, recent case reports have shown the promising future of FMT as a rescue therapy for CD[39-41]. Data on the application of FMT in irritable bowel syndrome (IBS) is limited to a case series of 55 patients which showed that 36% of patients were regarded as curable while 16% had symptoms reduced[42,43]. To better understand the role of the intestinal microbiota in the etiology and effective treatment of IBD and IBS, future controlled trials are necessary.

For this reason, the core mechanism for the efficacy of FMT is likely to be the establishment of intestinal bacterial strains and antimicrobial components (adhesin, immunomodulatory molecules, bacteriocin, etc.) produced by these associated strains. Adhesin molecules can compete for sites with pathogens, leading to them being prevented from colonizing in the intestine and rehabilitating the intestinal microbiota[5].

When FMT entered the medical community, it became a relatively hot therapeutic strategy, bringing with it both promise and controversy. According to published articles, transient adverse responses after FMT have been reported, including mild fever, abdominal pain, diarrhea, exhaust, flatulence, and fatigue[36]. However, these adverse effects are self-limiting. De Leon et al[22] reported a UC patient quiescent for more than 20 years who developed a flare of UC after FMT. This case gives us cautionary information concerning FMT being used to treat CDI with UC. Moreover, a recent paper reported a UC patient who had a cytomegalovirus infection after performing home FMT without donor screening[44]. As extracts of feces are mediators between the donor and recipient, FMT has the potential for transmitting occult infections even when strict donor screening is performed.

It seems to be serendipitous that the CDI epidemic facilitated the application of FMT to many other diseases (Table 1). The pathogenesis of gut microbiota in extra-intestinal diseases was inspired by massive studies in germ-free (GF) animals. Complete construction of the hypothalamic-pituitary-adrenal axis requires the participation of gut microbiota[45]. GF mice exhibit a dysregulation of the axis, thereby resulting in altered brain-derived hormones (e.g., norepinephrine and tryptophan) and increased caloric intake[45]. Aside from the crucial role of intestinal microbiota in central nervous system activity, another concept is emerging which was termed as “bidirectional brain-gut-microbiota axis”[46-48]. The destruction of the axis leads to altered behaviors and various neurologic conditions[49,50]. Identically, ample human studies have provided evidence for the critical role of the gut microbiota in extra-intestinal disorders.

A strong association has now been illustrated between the intestinal microbiota (e.g., Streptococcus bovis, Enterococcus spp, enterotoxigenic Bacteroides fragilis, pathogenic Escherichia coli, and Fusobacterium nucleatum) and colorectal cancer[108-110]. Recently, incremental data has suggested that the gut flora (namely Streptococcus bovis and Helicobacter hepaticus) might be involved in extra-intestinal tumors. Gold et al[15] reviewed 8 extraintestinal malignancies [3 pancreatic adenocarcinomas, 1 lung cancer, 1 ovarian cancer, 1 endometrial cancer, 2 non-solid-organ malignancies (1 chronic myelogenous leukemia with blast crisis and 1 chronic lymphocytic leukemia with end-stage liver disease)] in 45 cases with Streptococcus bovis bacteremia in a retrospective study, which suggested that extraintestinal malignancy might be warranted in patients with Streptococcus bovis. In addition, prior work has shown the gut microbiota is also involved in mammary tumors[111,112]. The authors infected recombination-activating gene 2-deficient multiple intestinal neoplasia (Apc^Min/+) mice with Helicobacter hepaticus and found the gut flora modulated the carcinogenesis of both mammary carcinoma and intestinal adenocarcinoma in females by triggering inflammatory responses. On a similar note, Rao et al[113] emphasized the question as to whether the gut bacteria should be examined in terms of prevention and treatment for mammary cancer.

In addition, Fox et al[114] used a mouse model to examine the hypothesis that specific intestinal bacteria were associated with hepatocarcinogenesis. The progress of hepatocellular carcinoma induced by aflatoxin and hepatitis C transgene was promoted by Helicobacter hepaticus colonization in the intestine through activation of the nuclear factor-κB pathway, which was associated with immunity in the intestine and liver. Surprisingly, neither hepatitis nor bacterial translocation to the liver was essential during this course. These results lead us to think of intestinal bacteria as an attractive therapeutic target.

More recently, Yamamoto et al[115] investigated the relationship between the gut microbiota and lymphoma. Using an Atm^-/- mouse model (mice with ataxia-telangiectasia, which can eventually developed into lymphoma), the authors compared the incidence of lymphoma in isogenic mice reared in 2 distinct housing conditions, and found that the gut microbiota acted as a potential contributor to lymphoma onset. Meanwhile, Lactobacillus johnsonii was identified to be abundant in more cancer-resistant mice and was further tested for its ability to confer reduced systemic inflammation and genotoxicity when re-established by oral transfer. Given that gut microbiota impact lymphoma incidence and latency, FMT holds promise for reducing lymphoma risk in susceptible individuals.

FMT is proven to be a well-established procedure and the most effective therapy for recurrent CDI to date. Case studies suggest that FMT also has potential clinical applications in treating a wide spectrum of other conditions associated with intestinal dysbiosis. However, additional high quality data are urgently needed to further establish the efficacy of FMT. It is expected that the standardization of FMT will be established in the coming years and its indications expanded. For this reason, besides conventional approaches, FMT is promising as an alternative therapy for many extra-intestinal disorders associated with gut microbiota.