Introduction
Recently, worldwide obesity prevalence has been raised rapidly and nearly doubled between 1980 and 2014, however in 2014 more than a half a billion of adult (18 years and older) were obese (11% men and 15% women) (WHO, 2014). Obesity and overweight are defined as excess body fat accumulation that leads to health risks and comorbidities. Adult weight can be classified based on the Body Mass Index. Hence, an individual having a BMI equal to or more than 25 is regarded as being overweight, while a person with a BMI equal to or more than 30 is considered obese (WHO, 2015). Different causative factors contribute and implicated to increase the prevalence of obesity, including genetics, family life style (family sharing similar habit of eating and physical activity), low level of physical activity, medications (e.g. antidepressant and steroid), and unhealthy food (diet lack in fruit and vegetables, and rich of high calories) (Mayo clinic, 2014). Moreover, recent researches found significant association between gut microbiome and obesity (Bäckhed et al., 2004; Ley et al., 2005). However, this raised in prevalence is associated with increased incidence of diabetes, metabolic syndrome, and cardiovascular disease (Collaborators, 2013). Despite our understanding of underlying pathophysiology and the diversity of treatment options, including diet and exercise, medication, and bariatric surgery, most patients not respond to treatment, and this opened the door to seek a new approaches for obesity treatment with emphasis on reduction of cost, social and health consequences of obesity comorbidities. Hence, fecal microbiota transplantation (FMT) is suggested to be an effective new method for changing the gut microbiome and consequently lead to favorable metabolic changes (Smits, et al., 2013). This review has an objective of summarizing the biological basis, procedure, benefits, current clinical trials, and potential adverse events associated with fecal microbiota transplantation (FMT) as potential therapeutic intervention for obesity.
Gut Microbiota
Although the microbiome composition in amniotic fluid circulation during pregnancy not examined thoroughly, but there presence before birth change the thought that fetuses are sterile in uteri, which supported when a samples of meconium were collected two hours after delivery of healthy neonates and they show number of microbes (e.g. E.coli, S. epidermidis) (Aagaard et al., 2014; Jiménez et al., 2008), in addition, the amniotic fluid isolated from healthy mothers gave a positive result of presence of circulating microbes (Li et al 2014) .
However, during delivery, the infant’s gut colonized with the mother and environmental bacteria immediately, and there are different factors that influence on the composition of this microbiota and make it widely vary from baby to baby, for instance, cesarean or vaginal delivery, gestational age, feeding by either formula or breastfeeding, and antibiotic use (Palmer et al., 2007). By age of one year, the microbiota will change as a result of various factors (e.g. introduction of solid food, genetics of the host, development of the gut environment), and more stable with nearly adult microbiota characteristics (two main phyla, Firmicutes and Bacteroidetes consist more than 90% of gut microbiome) is settled by nearly three year of age (Koenig, et al., 2011). At adult age, the gut microbiome slightly fluctuating but mainly they remain till the digestive and dietary habit change when getting older in age (Faith et al., 2013).
New Technique for Characterizing Gut Microbiota Composition
Diversity of factors affecting microbiome composition either at early age or later, like mode of delivery, gestational age, diet, antibiotic use, and geographical location make every individual own special kind of microbiome (The Human Microbiome Project Consortium, 2012; Ursell et al., 2012). Furthermore, within the individual the colonized microorganism in oral cavity, gastrointestinal and respiratory tract, are distinct and diverse (Ursell, et al., 2012). Focusing on gut microbiota, the composition not only different within the gut, but different epithelial layers has it is distinctive organism (Swidsinski, et al., 2005).
Culturing to identify and characterize the microbes is consider as a traditional technique and has a limit, for instance not all microorganisms are able to be cultured, so a new culture-independent technique was identified in 1980s based on sequencing the 16s RNA gene (Olsen et al., 1986). Fortunately, through the Human Microbiome Project, we entered a new era to the level which we can know the gene content of the bacteria by what is called metagenomics techniques (Frank, et al., 2008). Through this technique is expensive, however it helps to overcome the limitation with conventional techniques and allow better understand of the gut microbiota composition and functional genes expression (Verberkmoes et al., 2009)
Currently, Human Microbiome Project (HMP) consortium funded by the US National Institute of Health and the metagenomics of the human intestinal tract (Meta-HIT) funded by the European Commission are working on developing and applying the metagenomics technique, to understand the relationship between microbiome and diseases (Kim et al, 2013).
Gut Microbiota and Human Health
Gordon et al (2005) described gut microbiota in an excellent way as it is “a microbial organ positioned inside a host organ”. Gut microbiota have a multiple fundamental functions within our bodies, including energy storage, consuming and redistribution. Moreover, they can have the ability to self-replicate which give the vital feature of self-maintenance and repair when get injured. So, at yet we have a symbiotic relationship with this important component within our bodies, though our understanding of this relationship improved based on the tools and techniques available, but it is still limited (Backhed, et al., 2005). Additionally, imbalance in the arrangement of the gut microbiota (Dysbiosis) has been linked with intestinal (e.g. IBD, IBS, GI cancer) and non-intestinal dysfunction and diseases, including diabetes, cardiovascular, liver diseases, and obesity (Sun, et al., 2014).
Figure 1: Gut microbiota, Sun, et al., (2014).
Gut Microbiota and Obesity
Many articles have discussed the relationship among the gut microbiota and obesity based on indications from germ-free animal models, especially after the landmark studies initiated from Jeffery Gordon’s laboratory at Washington University, St. Louis, MO, USA, which facilitate the paradigm shift toward a special way of thinking and treating obesity and other diseases associated with gut microbiota. Although there are a limited data on human, and still many concerns and issues regarding the causal effect not addressed yet, but we can get the knowledge from the current trials done and encourage more clinical trials to figure out this relationship which will definitely help on finding an intervention to treat obesity by fecal microbiota transplantation (FMT) which will be discussed in detailed later in this review.
Firmicutes, Bacteroidetes, Proteobacteria, and Actionobacteria are the four major bacterial phyla located in the human gut (Khanna et al., 2014). However, two of them are dominant in the adult human gut, Firmicutes (∼30%) and Bacteroidetes (∼30%) ( Backhed, et al., 2005). Interestingly, the imbalance in the microbial composition (dysbiosis) can be associated with obesity, firstly in mice, where obese mice have a prominent reduction in Bacteroidetes and increased numbers of Firmicutes (Ley et al., 2005).
In addition, using 16S RNA gene sequencing to inspect the diversity of microbial composition between obese and lean human in initial research shows similar differences in the gut microbiota (i.e. more Firmicutes compared to Bacteroidetes in obese persons (Ley et al., 2006). Collectively, these studies in mice and in human suggested an association between obesity and microbiota which may help in initiating an intervention to manipulate the gut microbiota toward lean bacterial ratio (i.e. lower Firmicutes / Bacteroidetes ratio), although one major open question, which is difficult to answer, is whether the change in the gut microbiota happened before development of the obesity or does the obesity change the composition of the microbiota instead? So, emphasis on more clinical trials will be helpful to clarify this association and whether there is a causal relationship or not.
Possible Mechanisms of Association between Obesity and Microbiota
Figure 2: Obesity and Microbiota
Energy Harvest
The global obesity epidemic has stimulated efforts aimed at identifying the environmental aspects which affect energy balance. In this regard, relationships have been made of the distal gut microbiota of mice which are hereditarily obese and compared to their slender littermates. Studies have also compared obese and lean human volunteers and results point to a correlation between obesity and variations in the comparative abundance of two of the most prevailing bacterial separations – the Firmicutes and the Bacteroidetes. Metagenomic and biochemical investigates equally reveal that these changes have the capacity to affect the metabolic capacity of the microbiota in the gut of mice. A study by Yatsunenko, et al., (2012) indicates that obese microbiome has the potential of harvesting energy from diet and results also indicate that this trait can be passed on. Documented evidence from this research equally indicates that colonization by ‘obese microbiota’ of germ free mice will lead to a major upsurge in the entire body fat than when the germ free mice are colonized by ‘lean microbiota’ Consequentially, the gut microbiota is a contributor to the pathophysiology of obesity.
Research work by Devaraj, et al., (2013) aimed at determining whether microbial unrestricted gene content has linkages with and is a likely contributor to obesity involves the classification of the distal microbiomes of obese (ob/ob, ob/+) and lean mice (+/+) using random shotgun sequencing of the mice’ caecal microbial DNA. Mice where ideal for this experiment compared to humans since confounders such as diet, genotype and environmental factors were eliminated. Additionally, the caecum was selected as the sampling site for the gut habitat due to its anatomical distinction and its location between the colon and the ileum which are colonized by adequate numbers of readily available microbiota which can be used for metagenomic analysis.
Figure 3: microbiota transplantation experiments and Biochemical analysis results sanctioning that microbiome of obese mice (ob/ob) has an improved ability to harvest dietary energy
Metabolic Changes
Connections between microorganisms in a person’s gut and the onset of obesity among other metabolic conditions is getting clearer with advanced research work. However, owing to the complication of the microbial flora, the practical linkages are least grasped. However, commensurate research work involving mice suggests that there is an influence of gut micro biota on the metabolism of a host. Studies by Yatsunenko, et al., (2012) for instance indicates that gut microbiota can augment energy yields from the food and also modulates the diet of the compounds derived from the host which affect the metabolic pathway of the host.
Inflammation Induction
Obesity and related inflammation marks the onset of a state of insulin resistance. By secreting chemoattractants like IL-1β, MCP-1, TNF-α, and MIF and of cytokines IL-6, leads to the drawing of immune cells such as macrophages and T cells into the adipose tissue (Scott, et al. 2015). Consequentially, a dysfunctional adipose tissue lipid metabolism results in an increased circulation of fatty acids. This leads to inflammatory signal cascades in the community of infiltrating cells. A feedback loop of cytokines serves to aggravate this pathological condition leading to more infiltration of immune cells and the production of cytokine thus affecting the insulin signaling pathway. Therefore, therapeutic interventions such as the use of FMT offers some hope in mitigating against AT biology in relation to inflammation.
Gut and Fecal Microbiota Transplantation
Biological basis
Fecal substance has predominantly been labelled as waste. However, fecal microbial remedies reveal the potential of fecal donations. The use of fecal waste to treat some diseases dates back to the 4th century where it is documented that warm camel waste was used to treat diarrhea (Scott, et al., 2015). The fecal microbiota transplant (FMT) process involves the transplanting of fecal bacteria from a fit person to a beneficiary. Microflora of the colon is restored in the process by the introduction of healthy flora of bacteria by the infusion of stool through orogastric tubes or can be administered orally by using capsules that have freeze dried materials which are obtained from a healthy donor (Kelly, 2014). Some studies have indicated this process to be effectual in treating Clostridium difficile infection (CDI) (Kelly, 2014; Vestal, 2016).
Gut microbiota on the other hand is made up of complex microbes which dwell in the digestive tract of animals. This microbiota contains the biggest and the most varied pool of mutualistic microbes that are linked to animals. The mutual influence of the makeup of the gut flora and its mass is linked to discrepancies in the potential for taking up energy at diverse ratios for bacteroidetes and Firmicutes, more so in the digestion of polysaccharides and of fatty acids (Nieuwdorp, 2014). In experiments where the gut flora of obese mice were transferred in germ free mice serving as recipients, weight increment was documented despite a reduction in consumed food (Kelly, 2014). This result suggests that bacteria which are specific to obese and lean genes are potential weapons in combating the obesity problem.
Procedure and clinical application for fecal microbiota transplant
Presently, there exists two noninvasive and innovative methods of fecal microbial therapy which holds a bright future in curbing and treating obesity. These are the “synthetic fecal” transplantation (SFT) and the fecal microbiota transplantation (FMT). The FMT however will form the basis of this manuscripts discussion.
According to Kelly, (2014) the FMT is documented as having the capacity of reestablishing a recipient’s healthy microbiota and also in preserving approximately 1150 functional species of bacteria which are removed from a healthy donor (Zhang et al., 2014). According to Zhang, using FMT is not a new practice due to suggested evidence indicating that fecal slurries have been used to treat patients who have diarrhea in China. In such treatments, the results were easily regarded as miracles due to the dramatic improvements of patients’’ adverse conditions. However, no literature exists that addresses the use of fecal microbiota transplant in treating or preventing obesity.
Procedure
The FMT process involves the administration of fecal suspension to a recipient from a donor as Borody et al. (2014) opines. Donor selection thus is the first step in the technique. Here, a donor is carefully selected and screened. Donors with inherent conditions including presence of GIT infections are excluded. Close relatives are often used as donors according to Borody et al. (2014) but even in these cases, proper screening is required.
The specimen is then prepared and an approximate amount of 200 to 300 gm of fecal matter is used for treatment if optimum results are to be obtained. Frozen stools can be used however fresh stool have to be used within 6 hours (Nieuwdorp, 2014). In the specimen preparation process, documented evidence suggests that using water as opposed to saline results in a twofold likelihood of relapsing. Additionally, using infusions higher than 500ml yields. However, more research work needs to establish whether using some missing methods like using electric blender decreases the efficacy of treatment by destroying obligate anaerobes or by over oxygenating the solution.
Administration follows the preparation stage. To achieve this, various techniques are used in the installation process of FMT including colonoscopy, upper tract endoscopy, and the use of a nasojejunal tube and using nasogastric tube retention enema (Gough et al. 2011). However, Smits et al. (2013) submits that the most appropriate administration route must be established according to the anatomical location of the condition.
The autologous restoration of the gastrointestinal flora (ARG) follows the administration process of FMT. Here, an autologous sample of the fecal matter which is delivered by the patient afore medicinal usage using antibiotics begins is refrigerated. If the patient develops C. difficile, the stored specimen is then removed using saline and is then cleaned. This is then freeze dried and the subsequent solid sealed off in enteric covered capsules. According to Ince, et al., (2016), administering the capsules can restore the colons flora of the patient and fight C. difficile. Presently, only the management of Clostridium difficile and related diarrhea and has been proved to be managed using fecal transplantation therapy.
Fecal transplantation therapy in managing obesity
Critique of studies
Research work on the use of FMT in managing metabolic disease remains in infancy. Although trials are at initial stages, the application of FMT in managing obesity is a much awaited scientific breakthrough. The procedure has only been effective in managing C difficile hitherto. In this regard, Vrieze, et al., (2013) have made progress in its application in managing insulin resistance. According to Vrieze’s clinical trials observation, infusing microbiota donated by lean persons into obese individuals resulted in an improved sensitivity towards insulin. According to the researchers, the plausible explanation towards the improvement is the increased manufacture of butyrate by the microorganisms of the colon. Fecal displacement in this case was carried out in the duodenum which was considered a safe and effectual way of managing metabolic conditions.
Fecal microbiota transplant in managing obesity – Studies Critique
There is paucity of information and limited to no data regarding the application of fecal microbiota transplant in treating obesity. This is because of the inherent risks of using FMT including the plausible transfer of pathogens and the challenges in obtaining efficacious fecal matter from a ‘super fecal donor’
Figure 4: Functional interactions between the gut microbiota and host metabolism plausible cause of obesity (Tremaroli & Bäckhed, 2012)
Tel-Aviv Sourasky Medical Center has proposed a study that addresses Fecal Microbiota Transplantation for Diabetes Mellitus Type II in Obese Patients. The study stems from the fact that obesity raises the risk of comorbid conditions including type 2 diabetes mellitus (T2DM). Consequentially, insulin resistance is the underlying characteristic of the condition. Consequentially, even though Diabetes Mellitus Type II Obese Patients can be treated with alternative options such as bariatric surgery, the efficacy of fecal microbiota transplants has been considered. The study by Tel-Aviv Sourasky Medical Center thus seeks to use FMT from lean to Diabetes Mellitus Type II Obese Patients in managing the condition. The primary aim of the study is to decrease the resistance of insulin by up to 30% 6 weeks post baseline after FMT. A second FMT will then be carried out that aims to decrease the resistance further up to 40%.
Yu, (2016) documents a proposed clinical trial, a first of its kind involving human participants whereby management of metabolic condition- obesity is expected using FMT. Although in its infancy, the study aims at reducing body wright in the proposed 24 study participants, which will be recorded in an 18 week period and measured in a metabolic scale. Additionally, as a secondary outcome, body mass composition 12 weeks from baseline will be measure using dual energy X-Ray absorptiometry. This interventional study that involves the use of placebo capsules and FMT capsules to research participants commences April of this year (2016).
Comparison between cases 1 & 2
Conclusively, both cases present plausible ways of addressing obesity AND T2DM using FMT. Evidence from case 1 which proposes to use FMT in addressing insulin resistance and improving other anthropogenic measures such as a reduction of waist to hip ratio by up to 5%, suggests that FMT can be used to address obesity. Case 2 will thus be effectual in this regard and the project’s completion in 18 weeks’ time from baseline (April 2016) will definitely offer great insights.
Clinical Application and concerns for FMT in managing metabolic diseases
Since actual data on the use of FMT in managing obesity is nonexistent, adverse events are yet to be documented and are thus few. However, a major concern area in using FMT to manage obesity and related conditions is its safety. The absence of a homogenous treatment formula and encouraging of patients to use the cure at home minus direction possess a real danger (Silverman, 2010). Additionally, their lacks a proper screening test with regard to donors which can be used to screen for the carriage of pathogens. This means that the procedure is open to transmitting unknown microbes and as such it is a major concern for the FMT process.
Future perspective and Recommendations
It is evident that FMT only offers benefits when specific donors ‘super donors’ are used. Consequentially, its efficacy in managing obesity is doubtable (Nieuwdorp, et al., 2014). Furthermore, study (clinical trial) by Vrieze, et al., (2013), which offers the closest attempt to use FMT in managing obesity raises some concerns. In his trials, non-responders where present which was due to either the persons physiology or due to the lack of efficacy from the donors sample. Therefore, because research is yet to establish what an efficacious sample consists of, this is room for future research work.
Additionally, more research work needs to establish whether using some methods in the fecal sample preparation such as using electronic blender decreases the usefulness of cure by destroying obligate anaerobes or by over oxygenating the solution.
Summation and conclusion
In conclusion, the use of FMT in managing C. difficile has elicited excitement over its potential use in treating metabolic diseases including obesity. However, trial are still at the infancy stage in this regard. The inherent risks of using FMT including the plausible transfer of pathogens and the challenges in obtaining the ‘super fecal donor’ are hitherto stumbling blocks in efforts to use FMT to manage obesity. However, trials by Vrieze, et al., (2013) offer promise in the quest of therapeutic management of obesity. By effectively increasing insulin sensitivity in patients by infusing microbiota donated by lean persons into obese individuals, Vrieze, et al., (2013) works are but a precursor of similar future research work.
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