How do we benefit from the microorganisms that live within us?

Abstract

Microorganisms help to form the human microbiome, which is the aggregate of all the microbiota that reside in our body. This paper aims to determine the potential benefits of the microbes in our bodies. In this paper, the roles of the microorganisms of the body in diet and health and immunity were reviewed and the potential for their uses as treatment options for cancer and other diseases were discussed. The advantages of the human microbiome are significant – it can improve the efficacy of fat reducing surgeries, boost immune system function and help to regulate the metabolic reactions in our bodies. It is an individual’s second genome and a simple shift in its diversity (for instance, through diet) can cause severe health problems. Knowledge of the human microbiome is still in its primitive stages and there is still so much to discover about the organisms inhabiting in the human body.

Introduction

The word ‘microorganisms’ or ‘microbes’, has associated them with diseases such as those that caused the Ebola outbreak in 2014, to flesh-eating bacteria. However, the average healthy adult has 10 times as many microbial cells as normal cells in their bodies. These cells collectively form what is known as the human microbiome, which is the full array of microorganisms that live in and on the human body. Body surfaces such as the skin, digestive system, and the lining of the nose, are covered with microbes collectively called the normal body flora. Some of the bacteria found on the normal body flora are commensal, whereby they have a relationship with the human body and derive food from our bodies without helping or hindering the body.
The human microbiome is thought to be formed as early as in the womb with the method of delivery (caesarean or natural) then affecting the composition of bacteria in our bodies. An incorrect combination of bacterial species then has the ability to increase the risk of various diseases like asthma and pneumonia. Therefore, shifts in the bacterial populations can provoke the development of diseases.
It has been shown that 85% [1] of the human microbiome actually positively impacts processes such as the regulation of blood glucose and therefore helps in preventing the development of Type 2 Diabetes and obesity through the production of short chain fatty acids. These molecules then stimulate ghrelin and leptin which are the ‘hunger hormones’ of the body , to increase or decrease the appetite depending on the circumstances. So the bacterial populations can be seen to instigate the whole process of glucose regulation.
The future may include research delving into how bacterial populations have the potential to be used as treatment options for cancer and gastrointestinal diseases, with faecal microbiota transplantation already being used to restore healthy bacteria in the colon by introducing stool from healthy human donors by colonoscopy or enema.
Therefore this essay will explore the benefits of the microorganisms in our bodies and question whether they outweigh the risks involved.

Diet and Health:

The human microbiome plays a crucial role in our digestive system. Firstly, microbes in the gut make vitamins that our bodies cannot make by themselves. Examples include B vitamins which are coenzymes, (compounds that aid in the functioning of enzymes), involved in the formation and repair of DNA. Similarly, B12 (helps to build healthy blood and brain tissue) and vitamin K (helps the blood to clot and so prevents any further pathogens entering the body through a wound) are also produced [8].
They also ferment and therefore breakdown, non-digestible molecules like fibres and mucus (a liquid used to protect cells from damage caused by harmful microbes). These then support the growth of specialist microbes that produce molecules such as short chain fatty acids (SCFAs) and gases (acetate, propionate and butyrate). Acetate combines with other molecules in chemical reactions to then act as a source of energy. Butyrate provides most of the energy required for epithelial cells (cells on the surface) of the colon (colonocytes), which induce programmed cell death (apoptosis) of colon cancer and activate the process of intestinal gluconeogenesis to produce glucose from non-carbohydrate compounds (IGN). IGN produces glucose from molecules which do not contain carbon, like amino acids [5]. Overall, IGN has beneficial effects on glucose and energy homeostasis which helps to maintain a relatively constant environment within the body. By activating gluconeogenesis, excess glucose in the body is converted to glycogen to be stored in the muscle and liver, lowering the blood glucose level in the body before it reaches dangerously high levels. The use of glycogen as a storage source of glucose is better for the body as glycogen (unlike glucose) is insoluble so will not affect the water balance of cells and cause damage. Comparatively, propionate activates IGN gene expression (the activation of the gene) through a gut-brain neural circuit involving the free fatty acid receptor 3 (FFAR3). Activation of FFAR3 leads to an increased expression and secretion of hormones released by the cells in the wall of the gut (such as glucagon-like-peptide 1 or peptide YY which cause satiety and so helps to reduce obesity) [2]. Additionally, SCFAs can improve insulin signalling in the body. Control trials [3] have shown that a higher production of these short chain fatty acids results in a positive correlation with reduced insulin resistance (which causes Type 2 diabetes). However the sample size used was small and therefore the results may not be representative of the whole population. This means that these microbes are considered to reduce the risk of diabetes as glucose levels would remain balanced. However, low levels of glucose in the body has the potential to cause weakness and dizziness so it is vital that the glucose level in the body is not lowered to an extreme.
Microbiota in the gut also affects the way through which humans store fat, balance glucose levels and how they interact with the hormones ghrelin and leptin, to bring about these changes. These hormones have been shown to play a role in increasing or decreasing an individual’s appetite, and are controlled by Butyrate and Propionate (SCFAs produced by our microbiome) by a feedback loop^[4]. When nutrient levels are low in the body, ghrelin acts to increase the appetite and with the aim to increase the nutrients in the body whereas the opposite occurs with the stimulation of leptin. Individuals with lower BMIs also tend to have a wider diversity of bacteria, more specifically Bacteroidetes which are microbes that help to break down starches and polysaccharides – long chain carbohydrate chains into monosaccharides (small molecules) like glucose, which can then be used as an energy source. ^[5]
In a study conducted on twins by Goodrich JK et al ^[6], it was found that the bacteria Christensenella, was found in lower quantities in the gut of overweight individuals. This bacterium was also shown to help prevent weight gain in Germ Free (GF) or gnotobiotic mouse when administered. It can therefore be suggested that an incorrect mixture of Christensenella and Bacteroidetes in the gut can contribute to both weight gain and weight loss. Although most studies of overweight and obese people are characterised by the imbalance of gut microbiota it is also possible that any observed changes in the gut microbiota are the result of weight shifts [7] .
Overall, obese people have a higher proportion of Gram-negative to Gram-positive microbes in their gut^[8]. This increases the concentration of lipopolysaccharides (lipids), which has been shown to generate low level chronic inflammation in the fat tissues in mice and promote insulin resistance (a prediabetes condition). These results therefore identify gut microbiota and its diversity, to have a contributing factor to the pathophysiology or the progression^[9] of obesity and T2DM (Type 2 diabetes mellitus). This is helpful as it has provided scientists with a new target to reduce the risk of disease which is prevalent in Britain, affecting 90% of the population [10]. If the prevalence of the disease within the UK is reduced, the cost of the NHS to treat diabetic individuals would also decrease.
Bariatric surgery (a surgery used to reduce fat on obese people) is currently the most effective procedure for the treatment of obesity. Investigations into the long-term effects of bariatric surgery on the microbiome of patients showed altered levels of faecal and circulating metabolites (substances needed for body processes) when compared with obese controls. By colonizing GF mice with samples of faeces from the patients, it was demonstrated that the surgically altered microbiota encouraged reduced fat deposition in recipient mice and promoted the improvement in metabolic function. These mice also had a lower respiratory quotient, indicating decreased utilisation of carbohydrates as fuel. Therefore, these results suggest that gut microbiota may have a direct role in the reduction of adiposity (fat storage) observed after bariatric surgery^[10].The surgery itself carries some long-term risks for patients, such as low blood sugar and malnutrition, however they are rare. Comparatively, diabetes has been shown to resolve or improve in 86% of patients; high cholesterol improves in 70% or more and hypertension (abnormally high blood pressure) resolves in 62%. Probably because of these effects, a study that examined the long-term outcomes of almost 10,000 patients who had undergone gastric bypass surgery found that overall mortality was reduced in comparison with a matched control group of severely obese people who had not undergone surgery [11]. Therefore the benefits of the surgery can be seen to outweigh the risks.

Neonatal Immunology

A study carried out by Dominguez-Bello et.al. ^[12] found that babies who have been born by caesarean section (C-section) have different bacteria on their skin, noses, mouths and rectums compared to babies who have been born vaginally and that these babies have a higher chance of developing conditions such as – asthma, Type 1 diabetes and obesity ^[13] (compared to babies born via natural delivery). This is due to C-section babies not being exposed to microbes such as Lactobacillus (bacteria that aid in milk digestion) as they do not pass through the birth canal and so the transfer of microbiota from the mother to the baby does not occur. Rather, they are more likely to be colonised by a mixture of harmful bacteria such as Staphylococcus and Acinetobacter, typically found on the skin of the mother and in hospital environments. This is detrimental to the newborn as they now have an increased risk of developing boils, impetigo, cellulitis (all skin conditions) and pneumonia [14]. Therefore, the procedure of C-sections (in addition to other events such as breastfeeding) shifts a baby’s first bacterial community and affects the gut microbiota development ^[15] .
Whilst the delivery of a child may impact the microbiome, in fact studies suggest that the immune system is crafted in utero as a baby typically swallows 400 to 500 ml of amniotic fluid (the fluid surrounding the embryo) – some of which may contain the mother’s microbes. ^[16] These findings support the \’hygiene hypothesis,\’ which suggests that the dramatic increase in autoimmune (immune responses to own body cells or parts) and inflammatory diseases such as rheumatoid arthritis over the last 50 years has resulted from changes in our exposure to microbes due to the transition towards society favouring C-sections. But this comes at a cost to the composition of the microbiome population in the body. With an already underdeveloped immune system, the newborns now have an increased risk of developing conditions like obesity and pneumonia.

Immunity:

Studies by researchers have found that mice raised in sterile, germ-free environments have poorly developed immune systems due to their limited exposure to commensal (useful) bacteria. One of their primary functions is to boost the immune system, however as an added benefit, due to these microbes and our immune cells co-existing in our body, the immune system is also less likely to mistakenly attack our own cells.^[17]
Knight et. al ^[18] studied the spores from rod-shaped bacteria called Bacillus, found in the digestive system. Their studies demonstrate that when immune cells were exposed to Bacillus spores, the B-lymphocytes began to divide. This was because there were similar antigenic epitopes (markers) on the bacterial spores to the surface of the B-lymphocytes (B-cells). This binding to the receptors on the bacteria is what activates the B cells to divide and multiply. These findings suggest that bacterial spores could be used to treat people with weakened or undeveloped immune systems (e.g. newborns, the elderly and patients undergoing bone marrow transplants). In cancer patients, bacterial spores could perhaps boost the immune system to fight tumours^[19]. But there is always the risk that the microbes could mutate to more pathogenic and therefore disease inducing forms.
The bacteria on a body skin help to protect a host from becoming infected with more harmful microorganisms, by acting as a physical barrier. By colonising these linings, the microbes reduce the area available for pathogens to attach to and become established. An implication of this, is that pathogens must now compete with the normal body flora for nutrients. This competition now means that pathogens are less likely spread within the body and cause disease. Furthermore, gut-brain communication proposes that gut microbes may stimulate immune cells, which could then signal the brain. For example, gut microbes can prompt immune cells to produce and release small proteins called cytokines. Cytokines then travel through the bloodstream to the brain, where they play a role in the maturation and activation of microglia (the primary immune cells in the brain which when activated, perform functions such as removing damaged cells at a site of injury). This prevents the damaged cells releasing some or all of their contents into the extracellular environment, including proteases and nucleases which can degrade proteins or nucleic acids, oxidants, and other factors which can damage surrounding cells and trigger an inflammatory response [5].
Interestingly, a study conducted by the Hospital for Sick Children in Toronto (SickKids), has discovered that the varying composition of gut microbiota is responsible for females having a greater risk of autoimmune diseases, in comparison to males. Researchers found that when female mice (who were at high risk of Type 1 diabetes) were given normal gut bacteria from adult mice, they were strongly protected – only 25% of the females developed the disease after being given normal male gut microbes early in life. This could later be used to block the progression of insulin-dependent diabetes in children who have high genetic risk in the future.^[20] However, scientists unexpectedly saw an increase in testosterone (male hormones) levels of the female mice after being given normal gut microbes from the male. It can therefore be inferred that the testosterone levels may cause an imbalance in a female body system. Therefore the relationship between sex hormones and the composition of gut microbiota may be bidirectional. If that is so and with more research into the field, the future could include use the use of bacterial populations to help treat hormone imbalances [21].

Conclusion:

While the human microbiome and microbes in general, have the potential to cause harm, the benefits seem to outweigh the risks [22]. Admittedly, more research is needed within the field, but the presence of bacteria is essential in the human body for important biological processes such as digestion, immunity and blood glucose regulation. The advantage of the microbiome when regulating digestion is the control of weight gain and maintaining the blood sugar. Where immunity is concerned, the gut microbiome is able to regulate the host’s immune system to enable coexistence of both microbiomes. Often the absence of the bacteria from our bodies as seen in experiments containing ‘germ free’ species is more detrimental as it means that some processes which are vital to the functioning of our bodies such as the activation of B-cells involved in immune response, can no longer occur. However, there is always the risk of harm where the microbiome is concerned. Just as some cancers result from normal cell function gone awry, some diseases result from our microbiota gone awry.
In conclusion, the human body benefits significantly from the presence of microorganisms, with research now being centred on how to use the human microbiome for the treatment of different diseases that affect the gastrointestinal tract and for cancer.

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