Biology

What is the potential of the intestinal microbiota as a target for treating obesity in comparison to current bariatric surgical procedures?

What is the potential of the intestinal microbiota as a target for treating obesity in comparison to current bariatric surgical procedures?

By Mohona Sengupta

Abstract

The purpose of this research is to investigate the role of the intestinal microbiome as a prospective treatment for obesity. In order to assess the potential of this bacterial ecology three main pathways that showcase bacterial sensitivity to alterations by the host will be explored. These areas are: Firmicutes and Bacteriodes bacteria; Microbiota-accessible carbohydrates and Toll-like receptors. I have additionally evaluated bariatric surgery alongside the microbiome, by means of comparing the viability of a microbial treatment as an alternative to surgery.

Through analysing current studies, I found that an increase of Firmicutes bacteria exposes you to increased fat through an enlarged capacity of energy harvesting from the diet; and a high species diversity reduces your triglyceride levels by approximately 25%. Moreover, the overall balance in the composition of the gut microbial community, as well as the presence or absence of key species, is a key factor in ensuring the maintenance of an interdependent relationship with the host to prevent an offset of a multitude of ailments.

I have concluded that a treatment centred around the microbiome has great potential in becoming a new option for obese individuals through observing the various ways in which modulations in this ecology correlates with obesity trends; however, further research is needed to fully understand the role of the microbiome and to begin testing beyond lab mice and limited study groups, and will involve a huge investment of time and money (to acquire advanced equipment and the necessary expertise .

With the trend of a current rise in obesity, it is becoming necessary for a treatment which combines efficiency of bariatric procedures alongside safety and practicality. In recent years the microbiome has opened up an exciting path of using your own bacteria to reduce fat. If successful, in the subsequent future we can increase weight loss treatment accessibility to the population and reduce the burden on the NHS to provide such expensive operations.

Introduction

I have produced a glossary and a list of abbreviations for technical words which are referred to throughout this dissertation. Please refer to this list if you are unsure about a term (page 16).

An escalating global epidemic of obesity is dominating many parts of the world today. This increase is driven mainly by the changes in the global food system, and although these outcomes are predictable due to the mass increase in consumerism, little effort is being put into creating policy action in the form of treatment. Thus, I chose to focus on the escalating topic of obesity.

In conjunction with this, I chose the subject area based on current medical breakthroughs and I was surprised to discover how the gut microbiome holds a symbiotic relationship with its host; and this in turn maintains normal bodily functionality, including weight regulation. This was intriguing as I had never considered bacteria to harbour such an important role within our bodies. Therefore, using the knowledge of how this unexplored ecology functions to make treatments will enable progression of medicine in the future, as well as being a potential milestone in eradicating the epidemic of obesity.

As mentioned, currently the only effective treatment for obesity is bariatric surgery, though it is normally used as a last resort for the severely obese. Whilst it has its enormous advantages in the form of substantial weight loss in a short period of time, disadvantages are brought about by the restriction of dietary intake and movement which the post-operative period brings 2.

It is widely debated whether it is right to use bacteria in treating disease,especially in manipulating your microbial composition, since we currently have a very preliminary understanding of what certain species do and thus cannot predict the long-term effects of altering such an important system of the body. Furthermore, every individual has a distinct composition of bacteria, raising the question of whether a ‘one-size-fits-all approach’ will be beneficial to the whole population. Only time will be able to answer these questions, but for now we must continue to study this ecology to establish concrete patterns between changes in the microbiome and the development of obesity.

Literature review

I have used a multitude of sources in this discussion which I have evaluated underneath my references. They are all of a high standard as they are mostly either peer-reviewed academic articles/journals that are well acknowledged (e.g. BBC Health News). Thus, the scientific information and data obtained are from credible and (mostly) unbiased sources- i.e. the author doesn’t explicitly put across his opinions, giving me the scope to correctly reference information and form a personal perspective.

As research is still very much in the preliminary stages, there is limited access to studies which contradict microbial capacity to treat obesity or provide any alternative arguments thus I chose to use bariatric surgery as a way of assessing microbial treatments and provide possible objections.

Introduction to the Intestinal microbiome

Fig. 1.

The intestinal microbiota is an assortment of over 3.3 million species of microorganisms inhabiting the length of the human gastrointestinal tract. The composition of this microbial community is host specific and susceptible to both exogenous and endogenous modifications. In recent years, it has provoked substantial interest in researchers (Figure 1. Christine, 2010) as it has been recognised that disturbances in this community are linked to various infections and disorders.

During pregnancy, an infant’s intestinal tract is sterile; up until birth, when it is exposed to maternal vaginal microbes whilst travelling down the birth canal. From then on, the composition of this community is modified constantly depending on internal and external factors such as genetics, diet and lifestyle3.

Recently, research has shown that a newborn’s weight can be determined from their type of delivery. Studies show that babies born via Caesarean section (C-section) are more likely to be obese and develop additionalhealth risks than babies born vaginally. This is because as babies travel down the birth canal, they acquire a multitude of bacteria that promote good health, which isn’t received through C-section4. One of these bacterial species is called Bacteriodes, (explained later in this dissertation), which are predominantly present in the microbiome of thin individuals; strongly corroborating with the evidence that Caesarean births result in an increased risk of obesity.

Introduction to obesity

Obesity is defined as excessive fat tissue accumulation caused by an energy imbalance between the numbers of calories consumed and calories expended. Current reports show that over 1.9 billion adults worldwide are overweight with over 600 million of these obese.5 The reason why this epidemic is so threatening is because it rises with metabolic syndrome,a collection of symptoms that correlate with obesity e.g. type 2 diabetes (insulin resistance), cardiovascular disease and hypertension (abnormally high blood sugar levels) 6 .

[1]

There are three types of bariatric surgery: Roux-en-Y gastric bypass, Laparoscopic Gastric band and Laparoscopic Sleeve gastrectomy. All these types of surgery aim to reroute the intestinal area to restrict the capacity of the stomach, causing malabsorption of nutrients via various mechanisms8.

Laparoscopic Roux-en-Y gastric bypass (Figure 2: Dirksen, 2012) – This procedure involves creating a small stomach pouch approximately 30 millilitres in volume by stapling a small upper section from the larger section underneath. Then, as for the bypass aspect, the surgeon connects the lower part of your small intestine (jejunum) to the newly created pouch to redirect the soluble products of digestion. The procedure is completed by connecting the lower stomach to the small intestine further down so that the stomach acids and digestive enzymes from the bypassed stomach eventually mix like usual 2. Image result for gastric bypass

Laparoscopic Gastric band (Figure 3: WLSA, no date) – This surgery is less invasive and involves placing an inflatable band around the upper portion of the stomach creating a significantly smaller upper pouch and a larger bottom one. The band acts as a restrictive tool, leading to the absorption of less nutrients with the same feeling of satiety.

[2]

Laparoscopic Sleeve gastrectomy (Figure 4: UCLA gastric sleeve, 2017) – This procedure is largely irreversible and involves surgically removing approximately 80% of the stomach to leave a tubular pouch which holds about 50-100mL of fluid.

From dietary interventions and nutritional counselling to commercial weight loss programmes, there have been hundreds of claimed remedies to promote fat breakdown and most importantly restore your BMI (body mass index). However, it has been evident that weight gain and loss aren’t merely a reflection of dietary intake as many of us fail to burn fat despite eating a balanced diet and exercising regularly. Knowing this, it has to be questioned whether there is something else playing a pivotal role in how our bodies process fat and reduce the symptoms of metabolic syndrome 8.

[3]

Intestinal microbiome and obesity

With the availability of high throughput gene sequencing technology, study of the gut microbiota currently consists of two stages: (1) 16S ribosomal RNA based sequencing and (2) shotgun sequencing, which both enable analysis of whole complex microbial communities. Even though the definition of a ‘normal’ gut microbiota is still largely undefined, healthy gut microbes are consistently dominated by two predominant bacterial groups, Bacteriodes and Firmicutes.

Firmicutes and Bacteriodes

The first study to determine whether a correlation exists between the ratio of these two bacteria and obesity, was conducted by Ley et al (2006). 12 obese participants were randomly assigned to either a fat-restricted (FAT-R) or to a carbohydrate-restricted (CARB-R) low-calorie diet. The composition of their microbes was monitored over the period of 1 year by analysing stool samples. The resulting data set of 18,348 bacterial sequences revealed that the ratio of these dominant species changed over the course of the study (Figure 5: Ley et al. 2006) 9. Before dietary restriction, all the obese participants had a lower ratio of Bacteriodes: Firmicutes compared to the thin group. Over time, the relative abundance of Bacteriodes substantially increased, from around 5% to 20% of total sequences, whilst the abundance of Firmicutes decreased. These results were made even more significant due to the fact that this trend was present in all mice.

To further explore this correlation, the researchers next conducted a similar experiment whereby germ-free mice (without bacteria in the intestinal tract) were given a microbiome from obese or thin donors. The results showed that the transplanted mice with an obese microbiome had a greater relative abundance of Firmicutes and, in addition, exhibited a significantly greater percentage increase in body fat over two weeks as compared to mice colonized with an obese microbiome. This lead to conclude that the microbial community adapts its abundance of certain bacteria to variations in food consumption, which in turn presents its effects on its host’s BMI. From these two studies, it can be established that increased Firmicutes is associated with a diet high in fats and carbohydrates resulting in increased obesity whereas a depletion of Firmicutes is due to decreased levels of fats/carbohydrates, thereby reducing fat 10.

The microbiomes of the obese mice had less energy left over in the faeces, meaning Firmicutes are better adapted for energy harvesting from the diet which results in more fat accumulation in tissues and less energy output. From the first study, it can be concluded that alterations in the efficiency of energy harvesting from the diet does not have to be great to contribute to obesity, given that small changes in energy balance over the course of a year can result in significant changes in body weight. Additionally, the fact that there were no differences in food consumption between the microbiome of thin and obese donors promotes the idea that the mechanisms behind the changes in microbial composition are self-perpetuating and not an effect of the diet given. Thus, this shows that our microbiome encodes capacities that the host has not yet evolved with; making it a potential new pathway to find a therapeutic target for people with obesity 10.

On the contrary, when considering the limitations of the studies, the obese mice were leptin-deficient which was in fact the primary cause of obesity in the obese mouse model, also explaining the increased food consumption. Although this model provides experimental evidence that one type of obesity-induced gut microbiome has an increased capacity for energy harvest from the diet, it is questionable whether a similar response would be enacted by the microbiome if all causations of obesity were to be applied.

Microbiota-accessible carbohydrates

Microbiota-accessible carbohydrates (MACs) highlight the importance of microbiome diversity in maintaining homeostasis. MACs are dietary fibres that are resistant to absorption by the host. They solely provide energy and nourishment for the microbial community. These dietary MACs may come from a variety of sources including plants, animal tissue, or food microbe;s however they must be metabolized by the microbiota and not the host to qualify as a MAC.

[4]

[5]Recent exploration has shown that obesity is linked to the effects of dietary MAC alterations on microbiota diversity. These MACs are notably reduced in Western diets (high in fat and simple carbohydrates, low in fibre) compared to a more traditional diet, correlating with the fact that modernization is causing an increase in obesity [6].

Although the mechanisms enabling an increase in dietary MACs to exert its impact on the hosts BMI has yet to be elucidated; it has been discovered that the products of MAC fermentation: short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate predispose the body to anti-inflammation and insulin sensitivity 11. The microbiome is equipped with a specialized collection of enzymes called glycoside hydrolases, which can break down the complex carbohydrate bonds in MACs into consumable monosaccharides 8. The end products of this carbohydrate fermentation are short-chain fatty acids, which are absorbed into our circulation and have anti-inflammatory effects whilst increasing microbial diversity, in turn reducing weight gain. ../Desktop/Screen%20Shot%202017-05-01%20at%2014.10.01.png

To investigate whether this pattern was representative within a population, a group of researchers conducted a study which proved dietary MACs have a direct impact on obesity via changes in microbial diversity. 341 participants comprised of obese, overweight and healthy individuals exhibited a distribution of microbiota species diversity brought about by varying levels of MAC diet over 12 weeks. Those given a high MAC diet displayed a high diversity; likewise, individuals given a low MAC diet showed a low diversity. As predicted, it was seen over the course of the study that the latter group were more insulin sensitive and had lower markers of inflammation relative to the former group. This indicates that microbial diversity decreases the symptoms of metabolic syndrome.

Knowing this, it must be questioned whether these characteristics in the gut microbiota last through generations or have the malleability to be easily reversable from sudden shifts in the diet. So, to test this, Sonnenburg et al. (2014) conducted a study on a group of mice which were fed a diet rich in MACs for 6 weeks; they were then switched to a low-MAC diet for 7 weeks before again returning to the high-MAC diet for 6 weeks, for the purpose of observing the recovery of microbial species in response to sudden shifts in MAC diet 12 . The control group, on the other hand, were maintained on the high-MAC diet.

The results showed that the microbial composition from both groups of mice was initially indistinguishable. The diet-switching mice, while consuming the low-MAC diet had a lower microbiota diversity relative to the control – 60% of bacteria (124 out 208) decreased in abundance compared to only 11% of the control group. Weeks after returning to the high-MAC diet, the diversity again increased – 34% of bacteria were lost (71 out of the 208), with the control group not changing significantly. These data reveal two divergent qualities of the microbiota. Firstly, 25% of bacteria recovered with the reintroduction of MACs illustrating microbiota resilience over short time scales. However, the low-MAC diet induced “scars” on the microbiota conveying the susceptibility it has had from alterations by the host.

To determine whether the carbohydrate degrading capacity had been lost, the researchers next inputed glycoside hydrolases between the initial and final stages of the study in the diet-switching group. Twenty-two glycoside hydrolase families showed a reduction in abundance, which shows that in addition to the loss of important bacteria, there is a loss in glycoside hydrolases over time; this would prevent the efficiency of carbohydrate fermentation in the future if a high dietary MAC were to be reintroduced. Notably, most of the bacteria lost are Bacteriodes, important because of the direct correlation between obesity and a low frequency of Bacteriodes. The unrecoverable species shows that the diversity loss would only be enlarged over generations, even if a high MAC diet was to be reintroduced.Possibly, the only way of restoring previous MAC fermentation would be to re-introduce extinct species and enzymes (thereby replicating the microbiome of a thin individual who has a high MAC diet); subsequently exerting positive effects on the host’s weight.

This model, however, does not allow us to address the natural microbial adaptations that may have occurred as humans evolved through time with changes in environment and lifestyle, potentially contributing to some of the patterns seen. Nevertheless, the data is an indicator of bacterial susceptibility throughout history, making the microbiome a promising target in future treatments.

Toll-like receptor

In addition to showing the symbiotic relationship of the microbiome with the host, it is important to establish the negative impacts that alterations of this community can have on the body.

The Toll-like receptor is expressed on the surface of most intestinal cells and plays a huge role in pathogen recognition. It does this by recognising pathogen-associated substances (i.e. recognising ‘Flagellin’- the structural component of bacterial flagella, which is secreted by bacteria for mobility). By recognising bacteria, the receptor controls the mass of bacterial pathogens living in the intestine so the gut microbiota doesn’t over flourish.8 An external file that holds a picture, illustration, etc.
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To study the role of Toll-like receptor 5 in obesity, Gewritz et al. (2014) bred knockout mice without this receptor (T5KO mice) and compared these to germ-free wild-type (WT) mice (WT-mice with the receptor). Over the period of 20 weeks, T5KO mice had 20% greater body masses and fat pads that were double the size than WT mice; a further finding was that T5KO mice hadhigh levels of triglycerides and cholesterol in the blood.

This study showed that the Toll-like receptor is an important part of the intestinal microbiome and without it, there is a direct effect on the host’s weight. Bacteria expand in number which lead the microbiome into an inflammatory state. Given that previous experiments have shown powerful anti-inflammatory effects of insulin, a failure of the receptor to regulate the balance between responding to inflammatory factors and insulin can lead to the desensitization of either process, resulting in the emergence of metabolic syndrome. This relationship adds to the evidence that the microbiome encodes capacities of its own which have a significant role in controlling many of the host’s biochemical processes13 .

Microbiome vs. bariatric procedures

The past decade has seen a tremendous increase in the number of morbidly obese patients. Presently, bariatric surgery is the most effective treatment for obesity with the number of bariatric surgeries increasing from 82,000 in 2002 to 179,000 in 2013. Every year 6,000 operations are conducted in the UK. This costs the National Health Service (NHS) on average £5.1 billion every year and this figure is predicted to be raised to £10-12 billion by 2030 1. Ultimately, bariatric surgery is not a cure for obesity given the enormous growth in number of severely obese patients and the financial status of the NHS .

Fortunately, it has been observed that the surgery alters various aspects of host physiology given the marked improvements in glucose homeostasis, insulin sensitivity and short-chain fatty acid production. These significant changes cannot simply be attributed to decreased dietary consumption via rerouting of the intestinal tract.

Current research focuses on the intestinal microbiota as a biomarker for many of the physiological changes seen after surgery. To analyse surgical changes on the microbiome, Liou et al. (2013) fed obese mice a high fat diet for 6 weeks, for them to develop high blood sugar and insulin resistance. Then they were given laparoscopic Roux-en-Y surgery (RYGB). As a control, a group of mice were given a sham operated (SHAM – fake) surgery to rule out any false results due to intestinal transection. Sequencing of the resulting microbiomes saw that RYGB mice had far more varied bacterial groups with a higher abundance of Bacteriodes (red – figure 9: (Liou et al.2013)) in comparison to SHAM mice whose microbial ecology had a higher ratio of Firmicutes (blue- figure 9: (Liou et al. 2013)). The RYGB microbiome correlates to that of thin individuals, suggesting that following surgery, the microbiome adapts to that of a thin individual hence providing the host with many of the physiological benefits seen after surgery 14 . ../../../../../Desktop/Screen%20Shot%202017-05-20%20at%2016.02

However, it could be argued that these changes in microbial ecology are an effect rather than a cause of the surgery; therefore, it is important to determine whether any of these benefits could be directly influenced by the RYGB microbiota. This was done by transplanting the microbiota from RYGB and SHAM donors into sterile mice. During the first 2 weeks, the RYGB mice exhibited significant decreases in body weight -10% ± 1.8% whereas SHAM mice exhibited no substantial differences, whilst consuming the same caloric intake. This signifies the microbiome as transmissible and sufficient to trigger host weight without surgery. To analyze the long-term effects of the transplanted microbiome on the host’s physiology 15, observations were carried out over an extended period of time and changes were seen taking place even 5 weeks post-surgery. At that point RYGB mice continued to show marked changes in terms of improved insulin sensitivity. Additionally, a significantly higher proportion of acetate and butyrate was found in these mice in the ratio of 73:13 as compared to in SHAM mice 62:11, correlating with the fact that a higher production of SCFA’s reduces body fat. These clear trends assure us of a promising, new target in treating obesity. Having seen that the microbiome can individually trigger an effect on its host’s weight to an extent similar to surgery gives hope to a future involving the replication of such an ecology without such an invasive procedure . In conclusion, these studies have shown that to a large extent the success of bariatric surgery can substantially be attributed to the changes in microbiome. This includes a reduction of the ability to harvest energy from the diet, and the induction of a number of inflammatory target-related genes to increase insulin sensitivity and maintain glucose homeostasis.[7]

Having provided study-based evidence of the potential of altering the microbiome, I will now evaluate the advantages and disadvantages of both types of treatment for further assessment.

Firstly, it is apparent that the invasiveness of surgery brings an array of risks. These include dilation of the oesophagus if the patient overeats, bowel obstruction and symptomatic cholelithiasis (development of gallstones which are lumps of cholesterol that form in gallbladder). The prevalence of serious early complications after gastric surgery are at 5%, with mortality rates at 0.1%1. Even though these statistics may seem underrepresented within the wider context, it highlights the impact that this form of treatment can have on an individual. Comparatively, microbial treatments would likely perform via the consumption of a pill which are authorised as safer means because they have the ability to be taken intothe body by an oral route. Additionally, they wouldn’t require incisions and hence are not physically permanent, so this potentially may provide a much higher success rate in part due to a lower complication rate.

Secondly, the strict criteria for weight loss surgery initiated by the National Institute for Health and Care Excellence (NICE) only allows surgery for the morbidly obese (those who have a BMI 40+), meaning that thousands of patients who are at risk of increasing obesity and/or have various symptoms of metabolic syndrome including type 2 diabetes are denied the chance of life-saving surgery 2. Approximately 15% these sufferers who are of ‘normal’ weight therefore don’t qualify for this treatment-considering the outstanding costs per operation varying between £3,000-6,000. Following on from this, child obesity rates are steadily increasing , and currently there are scarcely any operations performed on children under the age of 18, due to concerns over nutritional deficiencies and linear growth disruptions 10 . Being at the stage of manipulating the microbiome in lab mice, there haven’t been any detrimental consequences recorded, therefore in this respect there is no reason why we cannot offer microbial treatments to the whole population. A treatment involving alteration of the intestinal microbiome is relatively safer and more unaggressive, and hence it could be potentially distributed to individuals of a wider range of ages and BMI’s (who are currently being denied surgery). On the other hand, as we are in the process of researching and testing, the costs involved with developing and distributing this form of treatment are currently unclear; therefore, it is difficult to assess whether or not such a treatment would be accessible to the whole market, or whether companies would be as selective as they were in the case of bariatric operations. At this stage though, one aspect on which we can confidently conclude is the effectiveness and safety in manipulating microbial populations on a variety of microbiomes, irrespective of the economical limitations imposed by the implementation within a larger community16.

From a practical standpoint, given the vast number of patients who are currently awaiting but being denied surgery, there is an insufficient number of surgeons with the necessary expertise to be able to effectively provide surgery when considering how quickly the obesity epidemic is growing. Because surgery cannot be fully automated as of yet, safety of the surgical procedure is largely dependent on the quality of manual labour.The need for manual implementation, on the other hand, is negated with the mechanisms of a microbial treatment. This means that the frequency of successful treatments conducted could be increased as the switch from manual surgery to automated surgery reduces waiting time..

[8]As with any novel treatment, the long-term consequences are unclear . There have not yet been any host- negative impacts via alteration of the microbiome (from studies already done) but if there were to be any consequences, e.g. a bacterial mutation, one would predict a large effect on the body. As seen with prior unsuccessful antibiotic treatments, they have not been targeted specifically hence explaining the observation of exogenous bacteria attacking host body cells. In regard to the microbiome, theoretically if the host were to recognize the inserted bacteria as ‘foreign’ and attack against its own microbial ecology, one may witness the depletion of important species – perhaps adversely offsetting many infections and symptoms of metabolic syndrome 6.

It is debateable whether microbial treatments will have the depth to be able to replace bariatric surgery or simply be an adjuvant therapy to be used alongside other obesity treatments. As mentioned earlier, Ley et al (2016) conducted a study whereby obese mice were put on a fat or carbohydrate-restricted diet, with teh observation that there was an increase in Bacteriodes over time . However, the percentage increase was not statistically significant, with an increase of 3% every 12 weeks. Similar results in weight loss were seen in the RYGB transplanted mice. Whether these alterations would be replicable or even more significant in humans is unknown as of yet; but it does raise concerns in terms of whether or not these patterns being identified in studies are notable enough to form the basis of an effective treatment.

Conclusion

From the evidence presented in studies we can conclude upon two things: 1) the microbiome possesses its own capacities which are different from the host; and 2) these capacities have a prominent contribution to host health.

This is evident from the fact that all the studies distinguished between the microbiomes of thin and obese individuals. The first study characterized an increase in Firmicutes species that correlated well with an individual who had increased obesity. In another study, this species was found to increase energy expenditure from the diet thus resulting in the accumulation of fat in the liver; highlighting species–level functions on host health. This finding was reinforced by the Microbiota-accessible carbohydrate (MAC) studies which showed the benefits of microbial diversity on SCFA production; and more importantly, pointed evidence to the microbiome as a major reason for the rise in the obesity epidemic over the last decade.

To answer the question “What is the potential of the intestinal microbiota as a therapeutic target for treating obesity in comparison to current bariatric surgical procedures?”, I have concluded that at the present time the technologies and methods are not advanced enough to show that the microbiome has the capacity to be a standalone treatment for obesity 17. However, from the direct and positive correlations between microbial alterations and weight loss on the host, I am confident of a future where the replication of beneficial bacterial species and enzymes (seen in a thin individual) into obese individuals is a viable alternative to operations.

When conversing on the general success of bariatric surgery, it is important to realise that the magnitude of the desired postoperative weight loss is highly dependent on the patient’s’ motivation to follow strict, long-term dietary restrictions 10. Many times, are poor outcomes are brought about by the development of psychological disorders such as depression and binge eating, leading to relapse and weight gain. This highlights that surgery can occasionally bring additional detrimental consequences to a patient’s health than rewards; and given the huge burden on the NHS to provide such surgeries, the need for an alternative treatment that is much less invasive,widely accessible (and scores better on the cost-benefit analysis scale) is proving to be more necessary than ever before; and data from microbial studies gives me the confidence that targeting the intestinal microbiota is the gateway for an effective treatment in the future.

Evaluation

The aim of this dissertation was to find out about the complexity of how the microbiome maintains a symbiotic relationship with its host. To a large extent I have achieved this goal whilst enjoying the research process, although, occasionally there were times where I felt I could have researched deeper into the microbiome (but was restricted due to the inaccessibility of a few articles). Due to the novelty of this area of research, there haven’t been many chronologically developed studies as of yet; consequently, I encountered myself interpreting some of the data which could have resulted in some fallible assumptions. To maximise the chance of this not occurring, I spent time in the researching process ensuring that I had read various academics’ interpretations of the data to help stimulate my thoughts and avoid making unjustifiable conclusions.

The microbiome being so varied across individuals is the consequence of a complex interplay between age, environment, diet and host genetics. Therefore, further work may need to consider these factors, by conducting studies with people of similar ages and lifestyles to acquire more reliable results and elucidating whether or not this would have an impact on efficacy of (intestinal microbiota) treatment.

Additionally, if I were to carry out this research project again, I would explore the financial viability of microbial treatments, assessing their start-up and selling costs on the NHS in comparison to bariatric surgeries; which is facet in assessing the possibility of bringing these treatments onto the market. Additionally, I would look at potential future human studies (which are currently unavailable) over mouse models, as they would act as a better indicator with regards to the actual response of the host to microbial alterations.

Everyone inhabits a unique collection of microbial species making a ‘one-size-fits-all’ approach impossible; making this treatment effective for all requires contributions from the also-burgeoning field of personalized (precision) medicine (an area of medicine designed to optimize efficiency of care by tailoring treatments to certain individuals using molecular gene profiling), whereby each person would, for example, take a bacterial supplement of bacteria needed to reduce their obesity-related issues relating to their own microbiota 10. . This is an effective yet costly and laborious approach; but may well be the future of treating obesity.

Glossary and abbreviations

Laboratory terms:

16S ribosomal RNA sequencing – 16S ribosomal RNA is a component of prokaryotic ribosomes. Its gene is used to reconstruct bacterial sequences for studying them.

Shotgun sequencing – A method used for sequencing DNA strands for analysis. This is approached by ‘shredding’ the strands into smaller fragments of DNA.

Germ-free mice – Mice that have been bred in labs (sterile conditions) to have no microorganisms living within them. They are raised in germ-free isolators for use in studies of probiotic research that requires careful control of outside contaminants.

Leptin deficiency – ‘Leptin’ a hormone made by adipose cells that help regulate energy balance by inhibiting hunger. A deficit of this hormone is normally induced in mice to make them ob/ob.

Control group – A group used in a study as a benchmark to compare responses by other tested subjects, to ensure that the experimental results are actually caused by the given treatment and no other factors.

Wild-type – This term refers to alleles that are the most common in a particular population, therefore not as a result of a mutation.

Donor mice – Mice which have their desired characteristics experimentally donated to another group of mice for scientific purposes.

Surgical terms:

Laparoscopic – A type of surgical procedure that allows a surgeon to perform an operation in the inside of the abdomen and pelvis without having to make large incisions on the skin.

Intestinal transection – A division/ cutting of the intestinal area.

SHAM surgery – A fake surgical operation that omits the steps thought to be necessary however doesn’t complete the required operation to produce valid results. These are carried out as a scientific control.

Scientific terms:

Inflammatory bowel disease – Chronic inflammation on the lining of your digestive tract.

Short-chain fatty acids – These are produced when dietary fibre is fermented in the colon, which thereby induce the secretion of chemicals such as propionate, acetate and butyrate.

Insulin sensitivity – The term used to describe the sensitivity of an individual to insulin. The more sensitive a person is, the less insulin is required to lower abnormally high glucose levels.

Glycoside hydrolases – These are enzymes that catalyse the hydrolysis of the glyosidic bonds in glycosides (a component of Microbiota-accessible carbohydrates).

Polysaccharide hydrolases – These are the enzymes which catalyse the breakdown of polysaccharides (a chain of glucose molecules found in Microbiota-accessible carbohydrates).

Oligosaccharides / monosaccharides – The simplest monomers which compose carbohydrates (sugars). Oligosaccharides are composed of a relatively small number of monosaccharide units.

Pathogen – A bacterium/virus/microorganism that causes disease.

Inflammatory-related target genes – Genes that are involved in controlling inflammatory responses by the host.

Epididymal fat pads – Accumulation of fat tissue in the epididymis, which is an elongated organ on the surface of the testis which stores sperm.

Homeostasis – The maintenance of a constant internal environment within the host, whereby all physiological processes are relatively stable and in equilibrium.

Host physiology – The branch of biology that studies the normal functions of the body and its chemical interactions.

Abbreviations:

MAC – Microbiota-accessible carbohydrates

SCFA – Short chain fatty acids

TLR – Toll-like receptor

WT – Wild type

T5KO – Mice without toll-like receptor 5

RYGB – Roux-en-Y surgery

SHAM – sham operated mice (fake operation)

NICE – National institute for health and care excellence

Bibliography (alphabetical order)

I used this article to research on the correlations in obesity patterns of those born through vaginal delivery compared to caesarean to increase my knowledge on another aspect in which the microbiome causes obesity. The article was published by ‘The Scientist’ which is a credible magazine for life science professionals- a publication dedicated to covering a wide range of scientific topics. The articles are written by prominent scientists and professional journalists so are credible and to a high standard.

This source was used to access some recent statistics on the obesity epidemic and NHS costs. These provided evidence to the growing seriousness of obesity and its the burden on the NHS. The author is Finkelstein who has written may articles on obesity so he is well informed in this respect. This article is published on ‘PubMed’ which is a respected and widely recognised scientific publishing website therefore the information is valid and reliable. Additionally, references are provided at the end of the article thus it is possible to check for accuracy of data.

This source is very reliable as it comes from BBC Health where the articles are peer reviewed and updated every few years to ensure data is up to date. The website has many statistics on diabetes rates and the consequent burden on the NHS which are sourced from NICE, a nationally respected body who provide national governance information to improve health and social care. Additionally, the article contains a mixture of viewpoints from academics who are pioneers of the weight loss industry. This has stimulated my thinking on the importance of this issue and has given me the scope to develop a personal perspective.

  • Gerard E, Mullin, MD. (2013) The Gut Balance Revolution. NOT FOUND. Oxford University Press. pg. 1-5, 12-15

This was the first source I read which introduced me to the new field of microbiota research and of the great potential of the microbiome to determine your weight compared to the hosts abilities. This source is relevant as it, in simple terms, covers the general principles of the microbiome and the ways in which the gut maintains a symbiotic relationship with its host. The sections on the future of microbiome research has given me the knowledge to think ahead into the viabilities of a microbial treatment. Dr Mullin is board-certified in internal medicine, gastroenterology, integrative medicine, functional medicine and nutrition. He is an associate editor for several nutrition and integrative medicine journals. He has been presented with the Goldsmith award (acknowledges scientists for significant achievements in the field of nutrition). Therefore, his knowledge is undoubtable. As he is so successful I don’t believe it is in his interests to promote a book that may tarnish his public image therefore I don’t think there is any bias or misuse of information. Unfortunately, books do go through a long haul of drafting and editing, meaning some information may be outdated.

This source looked at the influence of probiotics/exogenous bacteria on microbiota diversity, allowing me to question the ethical and safety issues concerning a bacterial treatment (e.g. bacterial mutations, antibiotic resistance etc.) The article was published on ‘NCBI’-National Institute for Biotechnology Information so articles have been peer-reviewed and all sources have been referenced at the end so it is possible to check for the truthfulness of the information. Gerritsen is a respected author, publishing numerous times on the uses and implications of probiotics and antibiotics on various diseases so he is well informed on this topic thus we can trust that his conclusions are reliable.

This source covered a wide spectrum of truths concerning the microbiome and its role within our bodies including the genomic sequencing technologies used to study molecular patterns. From this, I realised that although we have advanced our understanding of this ecology, we still currently face many barriers in ensuring a potential treatment. This article was found on ‘PubMed’ which is an internationally respected medical publishing site. This article has been published from the findings of a variety of authors therefore information and data present has been peer-reviewed thus can be trusted.

This source is reliable as it comes from a very respectable international journal ‘Nature’. They publish articles on emerging areas of research so their information is trustworthy and relevant. Also, the text is credible as it is published by Ley and Turnbaugh who are the two leading academics in microbiota research. This source is similar to the previous ‘Nature’ study but this extends further to show the impacts of a fat/carbohydrate restricted diet on the abundance of Firmicutes and Bacteriodes adding extra evidence on the potential of the microbiome to treat obesity.

This source contributed to most of the section on toll-like receptors. This page not only described the function of toll-like receptors but contained studies on TK5O and WT mice showing the impacts microbial disruption can have on host weight. This article is published on the ‘PMC- National Library of Medicine’ and the article contains large group studies with many researchers involved therefore the information reliable.

When reading this article I noticed there was a gap in the treatments available for the majority who are concerned about their weight and/or have symptoms of metabolic syndrome but do not qualify for surgery; thus, inspiring me to write an EPQ on this topic. The NHS is a respectable website so their information is unbiased in respect to persuading the public/ supporting a point of view. Pages are reviewed every 3 years so we can trust that the data is recent and accurate.

The information on the NHS website is intended to truthfully inform readers regarding various ailments therefore information is valid. Pages are reviewed every 3 years so we can trust that the website contains recent data. Through this website I gained knowledge on the criteria needed to qualify for weight loss surgery in the UK as well as the aftercare and risks post-surgery. This opened my eyes into the enormity of this form of treatment due to the impacts it can have on a patient’s quality of life. This encouraged the purpose of my EPQ, convincing me that it is become more necessary to have an alternative form of treatment that is less restrictive.

This article was very in depth and gave me a general overview on all aspects of the microbiome; from the growth of microbiota related research over the years to the involvement of the microbiome in the development of diseases and disorders such as autism, inflammatory bowel disease and depression. It has stimulated my thinking beyond the limitations posed by my question and has thus helped me consider future research. This article was published on APS (American physiological society) whose Director is Dennis Brown (a professor of Medicine at Harvard Medical School in Biology) therefore he is knowledgeable and educated in this subject field and so is unlikely to tarnish his name by providing any false and biased (persuasive) information.

I have used this source as an introduction to the obesity pandemic and the human gastrointestinal tract (including bacterial colonisation, predominant bacterial groups etc.). This source also introduced me to the current research on the role on toll-like receptor 5 in altering weight through inflammatory target genes and insulin sensitivity. From this source, I gained a basic knowledge of understanding which I explored through other reliable sources. This source isn’t very credible because the authors are students of Slonczewski, Kenyon College so even though they are studying microbiology they don’t have advanced scholarly expertise so some of the information could be misinterpreted. Also, the text isn’t peer reviewed so of questionable reliability but as the sources are referenced it is possible to check whether the information is accurate.

This source informed me of the importance of a high MAC diet through the discussion of the effects a diet deficient in MACs (e.g. causing inflammation and decreased production of SCFA’s). So this further supported my EPQ, for the need of a treatment to restore specific bacteria and enzymes to lower obesity. This article was published on ‘NCBI’- the National Center for Biotechnology Information which provides biomedical and genomic information. Therefore, the data present is of a reliable standard. Sonnenburg is an author who has published a number of articles on the importance of a surplus in MACs in nourishing the microbiome so he is trustworthy and a well-informed individual.

This source opened my eyes to a new path of research, into the role of dietary MAC’s and their degrading capacity. A study aimed to replicate a loss of a high MAC diet over an extended period of time, showed a permanent loss of taxa over generations suggesting the need for a potential treatment which aims to restore the lost bacteria and enzymes present in a high MAC diet. This article is published on ‘Nature’, a critically acclaimed and respected scientific publishing journal that posts on the current advancements in the scientific field. Therefore, the information in this article is reliable and credible. Sonnenburg works at the department of Microbiology at Stanford University School of Medicine so is a respected and well-informed researcher.

This source further explored the inter-relationship between diet, microbial ecology and energy harvesting using mouse models. Transplantation of the microbiome from diet-induced obese mice to lean germ-free mice, showed a significantly greater growth in fat tissue- supporting the idea that the microbiome encodes its own capacities which play a pivotal role in weight regulation. This article was published on ‘NCBI’-National Institute for Biotechnology Information so articles come from a well-known and reliable source. The articles have also been peer-reviewed and all sources have been referenced at the end so it is possible to check for the accuracy of information. One of the main authors – Turnbaugh is a well-respected researcher in the microbiome field who has published many articles concerning my EPQ therefore he is very knowledgeable and doesn’t explicitly have any vested interest as his main aim is to inform readers of current advancements. Also, he has added diagrams and graphs for visual aid showing the validity of his research.

Personally, I found this article one of the most useful as it contains studies that are very relevant to my EPQ question. For example, it showed that obesity is associated with two dominant bacterial divisions- Firmicutes and Bacteriodes which play a role in energy harvesting from the diet. Thus, this article provides scientific evidence that alterations in the gut microbiome contribute to host obesity. This source is reliable as it comes from a very respectable international journal named ‘Nature’. They publish material on emerging research so their information is trustworthy and relevant. This article is especially important as it was written by Ley and Turnbaugh who are the two leading academics in microbiota research.

I have used this article as an introduction to bariatric surgery. As well as simply explaining the procedures involved in the three main types of gastric surgery, the article outlines the pros and cons of each operation, giving me the scope to form a debate. The article appears on Medical News Today (MNT) which is owned by a leading healthcare company. They source information from evidence-based, peer-reviewed studies, along with accurate, unbiased organisations (e.g. FDA, NHS), medical societies, royal colleges, professional associations, pharmaceutical and biotech companies etc. The article itself has vested interest in persuading readers to choose bariatric surgery as their treatment for obesity, however still aims to provide an insightful outlook on the realities of the surgery. This source has advanced my knowledge on the procedure and actually made me believe that bariatric surgery is becoming a lot more unique to each patient, so there are less complications in the future.

Figure Acknowledgements

Figure 1: Christine (2010) N.A. [Accessed: 28 March 2017]

Figure 2: Dirksen C, Jorgensen NB et al. Mechanisms of improved glycaemic control after Roux-en-Y Gastric BypassDiabetologia. < https://www.intechopen.com/books/type-2-diabetes/understanding-the-effects-of-roux-en-y-gastric-bypass-rygb-surgery-on-type-2-diabetes-mellitus >2012;55:1890-1901. [Accessed 05 May 2017]

Figure 3: WLSA (N.D) Laparoscopic adjustable gastric banding < http://www.wlsa.com.au/laparoscopic-gastric-banding/ > [Accessed: 06 May 2017]

Figure 4: UCLA gastric sleeve (2017) Gastric sleeve surgery-14 ways it will affect you < http://www.bariatric-surgery-source.com/gastric-sleeve-surgery.html > [Accessed: 05 May 2017]

Figure 5: Ley et al. (2006) Microbial ecology: human gut microbes associated with obesity < https://www.ncbi.nlm.nih.gov/pubmed/17183309> [Accessed: 02 April 2017]

Figure 6: Sonnenburg. NCBI (2014) Starving our microbial self: The deleterious consequences of a diet deficient in Microbiota-Accessible Carbohydrates < https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896489/ > [Accessed: 15 March 2017]

Figure 7: Gewritz, A. et al. (2014) Intestinal Epithelial Cell Toll-like Receptor 5 Regulates the Intestinal Microbiota to Prevent Low-Grade Inflammation and Metabolic Syndrome in Mice. < https://www.ncbi.nlm.nih.gov/pubmed/25172014 > [Accessed: 11 April 2017]

Figure 8: Gewritz, A. et al. (2014) Intestinal Epithelial Cell Toll-like Receptor 5 Regulates the Intestinal Microbiota to Prevent Low-Grade Inflammation and Metabolic Syndrome in Mice. < https://www.ncbi.nlm.nih.gov/pubmed/25172014 > [Accessed: 11 April 2017]

Figure 9: Liou et al. (2013) Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity < https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652229/ > [Accessed: 03 April 2017]

    • 13 Gerard E, Mullin, MD. (2013) The Gut Balance Revolution. NOT FOUND. Oxford University Press. pg. 1-5, 12-15
    • 14 Whiteman ,H. Medical News Today (2013) Weight loss surgery: do the benefits really outweigh the risks? [Online] Available from: http://www.medicalnewstoday.com/articles/269487.php [Accessed: 22 March 2017]
    • 15 Liou et al. (2013) Conserved shifts in the gut microbiota due to gastric bypass reduce host weight and adiposity [online] Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652229/ [Accessed: 03 April 2017

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