The Human Microbiome And Preventive Medicine

The human body is host to hundreds of species of "friendly" bacteria, mainly residing in the gut, and we are only now beginning to understand the extent to which this so-called microbiome influences human health. Such is its importance that the role of the microbiome in the future of medicine and as a key component of preventive medicine is one of the hottest topics in current health research. In everything from immune function and inflammation, to obesity, diabetes and cancer, the microbiome is increasingly recognised as a significant factor in both preventing onset of disease and in pathogenesis. Indeed, it has been suggested that we should no longer consider ourselves as organisms, but as super-organisms, inextricably linked to our microbial companions as single, symbiotic functional units. We are effectively 90% bugs, 10% human.

Estimates as to number of species of bacteria in the human gastrointestinal tract range from several hundred to 1500, though declining with each generation with the use of antibiotics from upwards of 10,000 species 100 years ago, with untold impact on human health. Microbial genes still outnumber human genes by 100 to 1. We have co-existed with bacteria for millennia and evolved a perfectly synchronised metabolic partnership with our microbial residents. Nowhere is this relationship as vital in terms of future health as perhaps in fertility and embryogenesis, as gamete quality and early stages of development such as cell fating and foetal programming, are affected by environmental factors, including the maternal microbiome via changes in metabolism and nutritional status. Embryonic gene expression and organisation of emerging body systems in the foetus are especially susceptible to changes in the maternal environment. Pregnancy, therefore, can be viewed as a microcosm of a lifetime's predisposition to disease in the offspring, and is a key target for preventive medicine.

How exactly we harness the power of the microbiome is a question being considered by various research initiatives including, amongst others, the Human Microbiome Project, which is tasked with identifying and characterising the micro-organisms associated with both healthy and diseased humans. Of the many significant crises in health we are currently facing, obesity is perhaps the most often highlighted by the media. Evidence is increasingly demonstrating that dietary factors influence health and predisposition to disease on many levels. Indeed, diet and nutritional status are among the most important modifiable determinants of human health. And the nutritional value of food is influenced in part by an individual's gut microbial community. So as well as providing essential nutrients necessary to normal metabolism and embryonic development, diet, in conjunction with the microbiome, can exert influences beyond this.

The composition of gut flora affects weight and metabolism in many ways and is heritable. Obesity phenotypes have been shown to be transmissible via the gut microbiota in rodent models of obesity, for instance, whilst other studies demonstrate the microbiome's ability to act as a single causative agent in obesity. One study showed that enterobacter, an endotoxin-producing bacteria, taken from the gut of a morbidly obese adult, induced obesity and insulin resistance in healthy mice. In another study, a volunteer with an initial weight of 385lbs, enterobacter made up 35% of the gut bacteria. After a 23-week diet of whole grains, traditional Chinese medicinal foods and prebiotics, the volunteer lost 113lbs and all traces of enterobacter. The study concluded that this endotoxin-producing bacterium creates systemic inflammation that causes insulin resistance, resulting in weight gain. Further, recent studies indicate that differing species of gut flora can influence food cravings and that, conversely, what we eat alters the gut microbiome. Individuals who are chocolate desiring, for instance, have different microbial metabolites in their urine than chocolate indifferent individuals. Mechanisms for microbial control over eating behaviour include microbial influence on reward and satiety pathways, production of toxins that alter mood, changes to receptors including taste receptors, and hijacking of the vegas nerve, the neural axis between the gut and the brain.

Another key area of health that is influenced by the microbiota is immunity. We are still in the early stages of learning how the gut microbiome and the immune system co-evolve throughout life and how components of the microbiota impact the immune system. But this is an area that has been identified as of significant importance to immunity and human health through repeated studies and reviews. The link between, for example, the microbiome, nutrient metabolism and the immune system occurs at many levels, ranging from endocrine signalling to direct sensing of nutrients by immune cells. For example, leptin, a hormone that regulates appetite and fat storage in the body, maintains thymic output and cellularity, and affects the inter-relationship between different immune cells by promoting the dominance of Th1 cells over Th2 cells, whilst inhibiting proliferation of T-reg cells. Low levels of leptin, therefore, may account for decreased cellular immunity associated with periods of nutrient deprivation. Leptin levels are affected by the microbiome with observable species-dependent induced increase or decrease in serum levels of the hormone. Further, a 2014 study in mice showed that as well as influencing immune cell function, gut microbes also support the production of immune cells that form the first line of defence against infection. Other pathways linked to diet and microbiome prevent aberrant inflammatory responses via cytokine production, small protein molecules that are important in cell signalling and have a specific affect on the interaction between cells.

Given that the microbiome influences immunity and systemic inflammation, it is unsurprising then that it also plays a key role in the onset and prevention of cancer. Alterations of the microbiome through environmental changes (infection, antibiotics, diet and lifestyle) may disturb the symbiotic relationship between host and microbiota and promote disease. Studies have demonstrated significant differences in the relative abundance of certain microbes in cancer patients compared to controls, for instance. In addition, mouse models of cancer have been treated with antibiotics and shown to have either decreased or increased susceptibility to cancer depending on the composition of microbial species. Both the onset and progression of cancer are thought to be affected by the microbiome through diverse mechanisms involving the modulation of inflammation (as outlined above), influencing the genomic stability of host cells and producing metabolites that affect host gene expression. These studies add weight to the growing body of evidence to suggest that inclusion of dietary probiotics and prebiotics can be effective chemoprotective strategies.

Given the importance of the microbiome in human health, ensuring the microbiome is adequately seeded from infancy is therefore of prime significance in preventive medicine. It was thought that prior to birth, the foetus is sterile with no microflora, and through a vaginal birth, the emerging baby attracts its first colonies of bacteria from the birth canal. However, recent evidence suggests that maternal gut microbiota may be able to pass to the baby and placenta via the blood stream. In both cases, the maternal microbiome is the primary source of bacteria for the foetus and newborn baby, and the role of this microflora in neonatal health and immunity is increasingly recognised. Babies born by caesarean lack this primary exposure, something that is rarely discussed with expectant mothers opting for non-essential elective caesareans. Consequently, the risk of allergies and asthma is far higher for babies born by caesarean. The early postnatal environmental exposures play a very important role in determining the overall phylogenetic structure of an adult human gut microbiota, and assembly of the microbiota towards adult configuration occurs in the first three years of life. Martin Blaser, chairman of the Department of Medicine and professor of microbiology at the New York University School of Medicine, wrote an article in the BMJ in 1998 as part of a series on the future of medicine. He wrote that one day doctors would need to make sure that pregnant women have the appropriate microbial communities to pass on to their children. Therefore, optimising the maternal microbiome should be an important component of maternal-foetal health interventions as we move towards preventive medicine. Sixteen years later, this is not yet happening. Incorporating adequate dietary intake of both dietary pre- and probiotics into a preconception care package that can continue through pregnancy is an important first step towards that goal, something that is particularly important for women with a history of repeated treatment with antibiotics.

These developing bacterial colonies have been shown to influence health from early infancy. Infant colic, for instance, has been linked to lower microbiome diversity. Again, since the initial 'seeding' of the microbiota comes from the mother through pregnancy, vaginal birth, and then breastfeeding. Thus, preconception care and maintenance of the microbiome during pregnancy can have an immediate effect on health in the offspring, highlighting this as an early preventive measure. Further, a recent study published in Proceedings of the National Academy of Sciences demonstrated that the presence of a common gut microbe Clostridia protects mice against peanut sensitisation by preventing the allergens from entering the bloodstream. Food allergy rates amongst children are increasing, with studies indicating that changes in diet, hygiene and the use of antibiotics have altered the gut microbiome, increasing our susceptibility to food allergies.

Exactly how we tailor preventive interventions to optimise human health and avoid disease is still under investigation. Understanding the effects of both individual species, as well as the overall composition of the microbiome on metabolic biochemistry is key to being able to harness bacteria in the fight against disease. Microbes that reduce leptin levels, for instance, have been shown to protect against heart disease and aid recovery following cardiac arrest, as a direct result of reduction in leptin. Lower leptin levels, however, have been associated with decreased cellular immunity during times of nutrient deprivation, as outlined above. There is clearly a delicate balancing act in terms of species composition and different aspects of health to consider in administering bacteria as a treatment. Further, how the host and bacterial genomes influence each other, and whether particular human genes confer some kind of preference or ideal species composition is still open to question. Given the very limited exposure to nutritional science of medical students, let alone understanding of the microbiota, it seems we have some way to go before any tailored, sophisticated evidence-based microbiomic interventions are integrated in to modern medicine.

However, given the impact of the microbiome on these important areas of human health, the fact that antibiotics are routinely prescribed without any remedial measures taken whatsoever to restore the healthy microbial communities destroyed seems extraordinary, especially in hospitals where probiotic foods, at least, could easily be incorporated into menus. Patients in these scenarios are usually weakened by an initial infection or surgical intervention, sometimes also having experienced side effects from antibiotics, and are then further compromised by the destruction of gut flora and associated assault on immunity and digestion. The cumulative effect of this inaction epidemiologically is significant, both symptomatically and in terms of the declining number of species of gut microbes found in human gastrointestinal tracts over time. Easily implemented treatments such as the prescri ption of a probiotic supplement, or appropriate dietary guidelines to support the microbiome, in other scenarios where patients are symptomatic for inflammatory, immune system or digestive disorders are other key areas for change. This is especially relevant where studies have already identified appropriate species of bacteria to address the dysfunction, as is the case with obesity.

Modern medicine needs to harness the wealth of scientific evidence generated through revolutions in our understanding of human health in areas such as epigenetics and the microbiome. A dual approach is required whereby a preventive medicine system exists along side conventional pharmaceutical and surgical interventions. Indeed, the NHS has recently announced that we need to keep people healthy and prevent illness, rather than treating conditions once they arise, in order for health budgets to be sustainable in the future. A cultural shift towards preventive medicine is needed, and away from the dominance in modern healthcare of the pharmaceutical industry's propensity to medicate symptoms rather than address underlying causes. Further, combining the evidence for this kind of intervention with the power of the placebo effect into a 'lifestyle prescri ption', would leverage the efficacy of current conventional, drug-based treatment protocols. Having a written prescri ption from a doctor tailored to each individual for appropriate exercise, dietary guidance and mental well-being strategies is likely to increase patient adoption and adherence to lifestyle changes that collectively could bring about a significant shift in public health.

A key aspect of a future preventive medicine service as a vital component of the National Health Service would be to seed and protect the microbiome in all patients, inextricably linked to broader dietary guidance and interventions. Hippocrates' refrain 'let food be thy medicine and medicine be thy food', it seems, is borne out by current scientific evidence, where once it would have been derided and dismissed as pseudoscience.

Medical practice, it seems, has yet to catch on.

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