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Faecal Microbiota Transplantation - Comprehensive analysis

Behaviour, Allergy, Digestion, Weight loss | September 8, 2015 | Author: The Super Pharmacist

Digestion

Faecal Microbiota Transplantation - Comprehensive analysis

The term “microbiome” was coined in 2001 by Nobel Prize-winning microbiologist, Joshua Lederberg, to signify the ecological community of microorganisms that literally share our body space. The human microbiome, also known as microbiota, consists of the collective microbes (microscopic organisms) including bacteria, fungi, protozoa and viruses that live inside and on the human body.

Microbes can be found anywhere the body has contact with the environment, including the skin, the nostrils and lungs, the vagina, and even on the surface of the eye. The skin, depending on the site, has between 100 and 10,000 organisms per square centimeter. The richest populations of microbes occur in the gastrointestinal tract, from the mouth to the anus. Saliva contains ten million organisms per milliliter. The colon contains the largest population of organisms, and about a third of the mass of faeces is microbes (100 billion microbes per gram).

The composition of microbes in different parts of the body can vary widely. Each person’s microbiome is different and can change with diet, illness, medication, geography, and age.

  • Microbes form a barrier between the body and the outside world
  • The microbes in our gut and on our skin and mucous membranes colonise those surfaces, preventing disease-causing organisms from gaining a foothold by competing for nutrients and blocking attachment sites.
  • Gut microbes break down nutrients such as complex carbohydrates and plant polysaccharides into smaller molecules which can then be absorbed and used for energy by human cells.
  • Gut microbes also produce nutrients that the human body could not get otherwise, such as vitamin B12 and vitamin K, an important blood-clotting factor.

The Human Microbiome Project was launched in 2007 by the US National Institutes of Health with the mission of characterising the normal microbial makeup of healthy humans. One of its main findings was that there are many different microbiomes that are considered healthy. Researchers also found that everyone routinely carries pathogens (microorganisms known to cause disease). In healthy individuals, however, pathogens cause no disease; they simply coexist with their host and the rest of the human microbiome. This and other projects such as the European-based Metagenomics of the Human Intestinal Tract have helped elucidate the crucial role of microbiota in health homeostasis as well as disease pathogenesis and have altered the way we perceive the gastrointestinal microbiota.

Gut microbiota were once considered pathogenic, but the concept of gut microbiota and their influence in human health has undergone a major transformation, as there is mounting evidence of their many relevant functions including the development and regulation of both local and systemic immunity, the modulation of several metabolic pathways, and their barrier action against foreign agents passing throughout the intestine.

What Is Faecal Microbiota Transplantation?

Faecal Microbiota Transplantation (FMT) refers to the injection of stools from a healthy subject into the gastrointestinal tract of another person to cure a specific disease. Ge Hong, a Chinese doctor from the 4th century, is credited as the first to use faecal transplantation in the form of a faecal suspension that was given by mouth to patients suffering from severe diarrhoea. In the 17th century, faecal infusion was applied by Fabricius Acquapendente in veterinary field. However, FMT made its first appearance into mainstream medicine only in 1958, when Eiseman successfully treated 4 patients with pseudomembranous colitis using faecal enemas. Previous terms for the procedure include faecal bacteriotherapy, faecal transfusion, faecal transplant, stool transplant, faecal enema, and human probiotic infusion.

FMT involves restoration of the colonic microflora by introducing healthy bacterial flora through infusion of stool, e.g. by enema, orogastric tube or orally in the form of a capsule containing freeze-dried material, obtained from a healthy donor.

Human babies are believed to be born with sterile gastro-intestinal tracts, but immediately upon birth colonisation of the gut by microbes begins. Mode of birth (vaginal delivery compared to caesarean section) has been shown to be the primary initial influence of the developing infant microbiome. Additionally, breast-fed vs formula-fed infants have very different trajectories of gut microbiome development. Caesarean deliveries encourage the growth of microbes from the mother’s skin, instead of from the birth canal, in the baby’s gut. Over the first years of life the gut microbiome is changing and remodeling, ultimately resembling an adult gut microbiome by year 3.This suggests there is a “core microbiome” that is the hallmark of a healthy individual.

What Are the Indications for FMT?

Digestive Diseases

Several lines of evidence suggest that the impairment of gut microbiota homeostasis can lead to the development of many digestive diseases.

1. Clostridium difficile Infection (CDI)

The composition of the microbiota is significantly affected by the use of antibiotics and certain diseases, causing microbial imbalances or “dysbiosis.” The increasing interest in FMT over the last several decades has to a certain extent paralleled the increasing prevalence of CDI and the desire to find better treatment options for those suffering from severe or refractory infection.

Difficile infection is generally treated with antibiotics such as metronidazole and oral vancomycin, which are effective against the bacterium but do not address the underlying dysbiosis which predisposes to the condition. Therefore recurrence of C. difficile infection is high, with up to a 10-20% recurrence rate after initial antibiotic therapy and up to 40-65% in patients who are retreated for a second episode. 

Difficile infections are a leading cause of antibiotic-associated and hospital-acquired diarrhoea. Despite effective antibiotic treatments, recurrent infections are common. With the recent emergence of hypervirulent isolates of C. difficile, CDI is a growing epidemic with higher rates of recurrence, increasing severity and mortality.

FMT is an alternative treatment for recurrent CDI

A better understanding of intestinal microbiota and its role in CDI has opened the door to this promising therapeutic approach. FMT is thought to resolve dysbiosis by restoring gut microbiota diversity thereby breaking the cycle of recurrent CDI. The most recent systematic review and meta-analysis showed that 245 of 273 patients (90%) experienced clinical resolution. A multi-centre long-term follow-up study of 77 patients who had undergone FMT for recurrent CDI at least 3 months prior (with a mean follow-up period of 17 months) reported a primary cure rate of 91%, with all late recurrences of CDI (in 15 of 77 patients, 19%) occurring in the setting of antimicrobial therapy for an infection unrelated to C. difficile.

2. Inflammatory Bowel Disease (IBD)

Increasing evidence supports a microbial influence in the pathogenesis of IBD, likely due to an inappropriate immune response toward a component or components of the microbiota. Alteration of gut microbiota is a main step in the development of IBD. Lower diversity and higher instability, as well as a decrease of Firmicutes and Bacteroides and a growth of Enterobacteriaceae and Actinobacteria distinguish gut microbiota composition of IBD subjects. 

Therefore, manipulation of the microbiota as a treatment for IBD has been investigated. The literature contains several case reports and case series, mainly about ulcerative colitis patients, but there have been no randomised, controlled trials of FMT as a therapy for IBD. One recent systematic review found 17 articles, representing 41 patients (27 ulcerative colitis, 12 Crohn’s disease, and 2 indeterminate) who had received FMT for management of IBD. The majority experienced a reduction of symptoms (19/25), cessation of IBD medications (13/17) and disease remission (15/24). Although the available evidence was limited, it did suggest that FMT has the potential to be a safe and effective treatment for IBD. FMT is considered a safe treatment, though a recent paper reported a case of a flare of UC (ulcerative colitis) in a patient who received FMT for CDI. IBD patients are more susceptible to CDI, which is associated with poor outcomes.

Recently a retrospective study from 16 medical centers in the United States reported their experience in FMT in 80 immunosuppressed patients with severe, recurrent or refractory CDI. The majority of the patients were immunosuppressed due to solid organ transplantation or treatment for IBD. The cure rate was 79% for the first time and 89% overall. There was a 15% incidence of serious adverse events within 12 wk. Five of the 36 IBD patients had post-FMT disease flare. Thus it appears that successful FMT is possible in immunosuppressed patients, although with a slightly reduced success rate and a higher rate of adverse events.

Two studies examining the efficacy and safety of FMT in ulcerative colitis (UC) were published in the July 2015 issue of Gastroenterology with different conclusions. The newly published studies are the first two randomised, controlled trials examining the efficacy of FMT treatment in active UC patients. In one study, 70 patients completed the study trial over a six-week period and were given six infusions, either placebo or FMT, through the lower gastrointestinal route. Researchers concluded that FMT induces remission in a significantly greater percentage of patients with active UC than placebo, with no difference in adverse events. The other study included 37 patients who were examined for a 12-week period, with two FMT infusions, either from healthy donors or from themselves (control), via the upper gastrointestinal route. Authors concluded that there was no statistically significant difference in clinical and endoscopic remission between patients with UC who received faecal transplants from healthy donors and those who received their own faecal microbiota. Authors did, however, point out that the differences in the microbiota of responders and non-responders warranted further study.

Irritable Bowel Syndrome (IBS)

Current figures suggest that 10-20% of the population may suffer from the disease and it is the most common gastrointestinal illness diagnosed by doctors in the western world. There is evidence linking dysbiosis to IBS, and thus, there is a question regarding the possibility of FMT for treatment. There have been reports of a favourable outcome after FMT in diarrhoea-predominant IBS. A recent report of single-center experience of 13 patients with IBS of whom 9 had diarrhoea-predominant, 3 constipation-predominant and one mixed-type found resolution or improvement in symptoms in 70% of the patients overall. Presumably, the small sample size prevented the reporting of the response rate in each group separately. This subject has recently been reviewed. Further research is needed to define the role of FMT in the treatment of this common condition.

Non-Digestive Diseases

Impairment of gut microbiota homeostasis has been implicated in obesity and metabolic syndrome, autism, and allergies.

1. Obesity and Metabolic Syndrome

meal replacement shake weight lossIt is now apparent that there is an interaction be­tween the microbiome of the intestinal tract and the metabolism of the human host and that there is a link to obesity. Although there are reports of changes in the ratio of Firmicutes/Bacteroides with human obesity other groups have not found such changes. 

There are reports in mice of the induction of a phenotype of the metabolic syndrome via faecal transplants. This complex subject has been reviewed. Furthermore in mice the intestinal microbiota plays a role in the development of non-alcoholic fatty liver disease. Recently stools from twins discordant for obesity has been shown to promote or impair the development of obesity in adult male germ-free mice. In humans, there is a single study reporting that FMT using stool from lean donors improves insulin sensitivity in obese male individuals concomitant with an increase in butyrate-producing intestinal bacteria.

2. Autism

Although research is needed to elucidate the relationship between feeding problems, dietary patterns and gut dysbiosis in autism spectrum disorder, it seems plausible that interventions aimed at restoring the microbial balance in the gut may improve behaviours (e.g. irritability, anxiety, and social withdrawal) documented to occur more frequently among a subgroup of individuals with autism spectrum disorder and gastrointestinal symptoms. Indeed, probiotics (i.e. microorganisms ingested through food or supplement consisting primarily of lactic acid-producing bacteria, such as lactobacilli, lactococci, bifidobacteria) have been shown to improve symptoms of irritable bowel syndrome, such as bloating, abdominal pain, and flatulence and suggested as a possible intervention to improve behavioural issues associated with gastrointestinal discomfort in autism spectrum disorder.

3. Allergies

Deviations in neonatal gut microflora, including more Clostridia and fewer Bifidobacterium, have also been shown to precede the later development of atopic sensitisation and subsequent atopic disease, providing additional evidence regarding the potential role of gut colonisation and commensal microflora in modulating immunity, including regulating hypersensitivity to food and/or other environmental elements.

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