The incidence of chronic illness, metabolic disorders, autoimmune disease, inflammatory conditions and functionally depleting states are exponentially rising, presenting clinicians with increasingly complicated cases to manage and resolve. Genetic drift alone cannot account for the rapid increase in incidence, and lifestyle and environmental pressures are recognised as strong candidates for cause and resolution.
An organ of increasing importance in the propagation and resolution of these complaints is found inside the gastrointestinal tract; composed of bacteria, viruses, fungi and others, collectively referred to as the microbiome. Whilst not the human tissue structure seen in our well understood organs, their extraordinary complexity and range of effects has bestowed upon them the moniker of the ‘essential’ acquired organ.
These organisms have, through an extensive period of co-evolution with us, formed a mutually beneficial or tolerant relationship, providing many essential functions including:
- gleaning indigestible ingredients from food and synthesising nutritional factors, such as vitamins
- detoxifying the deleterious xenobiotics and affecting the host metabotypes
- developing a robust systemic and intestinal immune system
- providing signals for epithelial renewal and maintaining gut integrity
- secreting antimicrobial products, which negatively select against pathogenic
- bacteria through the development of colonisation resistance.
Their ratios and species range evolved not from a random insertion of organisms, but have been shaped by host factors such as pre- and postnatal transfer, diet, hygiene, exercise, medicines, smoking and food intake volume. Overconsumption of a westernised, high fat, high simple carbohydrate diet can have direct effects on host immunity, but it also causes dysbiosis characterised by shifts in the structure and function of the gut microbiota.[2-4]
A dysbiotic microbiota is typically reduced in taxonomic diversity and metabolic function, and can harbour pathobionts that exacerbate intestinal inflammation or manifest systemic disease.
The fundamental stability and nature of this evolutionary determined relationship is now being threatened by persistent changes in our environment, diet and lifestyle particularly over the last 50-100 years. These changes have had an effect on the collective human microbiome (and their extensive gene variations), yet corresponding adaptive changes in the collective human genome are unable to respond with such rapidity.
It is estimated that human genomic changes only occur at a molecular level at a rate of 0.5% every million years. This resulting mis-match between us as host and these organisms can result in a state of homeostatic chaos, including the promotion of para-inflammation, and are increasingly linked to the many complex and interrelated immune and functional disorders that plague people in the modern age.
Relationships between perturbed microflora and the host are often the result of conscious decisions or behavioural patterns, as well as inadvertent exposures to medicines, natural and pharmacological and may result in a state of dysbiosis that may not be limited to the gastrointestinal tract alone. The change in bacterial eubiosis can lead to inflammation through the emergence of pathobionts (these are commensals that due to a change in the ratio of bacteria become pro-inflammatory, rather than regulatory) and the declining volumes of tolerising commensal bacteria. Under these circumstances a series of viscous cycles may emerge that become difficult to break despite a variety of clinical interventions.
One of the emerging areas of interest is the conflated effect of a dysbiotic gut and damaged local mitochondria, found in epithelial cells and macrophages. The proteobacterium that founded our mitochondria retain enough of the bacterial genetic material to be subject to damage in the face of antibiotics, caloric over ingestion, age and other environmental triggers and also in the presence of dysbiosis related release of bacterial toxins and bacteriophage activity.
Thus, people with dysbiosis also develop problems with the membrane integrity of their mitochondria, causing a release of activated enzymes via the triggering of an intracellular environmental switch called the inflammasome. Whilst designed to function as part of our innate defence against microbial infection they can become agent provocateurs and are increasingly linked to persistent inflammation states that lead to a wide range of illnesses. Inflammasomes are signalling platforms that sense a diverse range of microbial products and also a number of stress and damage associated endogenous signals.
Once released these enzymes trigger the formation of potent inflammatory cytokines (IL-1 beta and IL-18), which in turn generate risk and maintenance of dysbiosis, creating a dynamic and problematic cycle of energy deficit, inflammation, dysbiosis and systemic dysfunction and disease.
Metabolic syndrome and type 2 diabetes, for example, are closely related to food selection, including volume, overeating and high levels of blood sugars; known triggers of inflammasome activation via mitochondrial oxidation.[11,12]
This process is known as ‘sterile’ inflammation, initially proposed by Polly Matzinger in her Danger Theory model, has subsequently gained greater understanding as the role of damage associated molecular patterns (DAMPS) are seen as primary triggers of many types of
chronic illness with the mitochondria being particularly sensitive to a number of agents.[13,14]
The gut of course is the organ most exposed to external antigens, primarily in the form of foods. As such, it is always under some condition of damage and danger, even more so during events or patterns of behaviour that create and generate dysbiosis and associated pathobionts and alterations on metabolic by-products. These disease promoting microbes produce metabolites and pro-inflammatory mediators that negatively impact on the intestine and other organ systems and tissues.
There is increasing and substantive evidence that the reach of gut microbes extends beyond the intestine, affecting systemic processes such as metabolism and organ functions of brain, cardiovascular system, liver and others. A number of metabolomic studies have identified hundreds of circulating compounds in blood specifically derived or dependent on the presence of gut microbes. These findings have enlarged further the consequences of the dysbiotic gut microbiome, particularly in influencing developmental processes and in the physiological regulation of a vast array of tissue and cell functions in the body.
The propagation of inflammation by bacterial pathobionts, the reduction in diversity and the decrease in metabolic activity contribute a rich environment suitable for clinical manipulation to enhance eubiosis and generate stable homeostasis.
The use of diet, food composition and quantity, bacteria and other microbes, enhancement or compression of transcription factors and genetics need to be mutually manipulated and leveraged to achieve the best outcomes possible. However, other elements of health promotion also have a role to play in the management of eubiosis and tolerance including exercise, empathy, the meaning response, sleep, love and pre- and postnatal experiences.
If we solely limit research and treatment to either the patient or their bacteria, only half of the effect required in using the digestive tracts capabilities is being seen. The symbiotic relationship of the host and resident microbiota must remain in delicate harmony to maintain a healthy body. Disruption of the microbial community can lead to an imbalance in homeostasis of the immune cells including T effector cells such as Th17, T regulatory, and innate lymphoid cells and immunoglobulins, which can influence susceptibility of the host to a variety of health disorders including rheumatoid arthritis, obesity, inflammatory bowel disease, Crohn’s disease, diabetes and ulcerative colitis among others.
As the number of mucosal immunology and microbiomic studies continue to grow, it is becoming increasingly clear that the host and microbiota do not operate alone. To understand the complete story, the interaction between the host immune and digestive function and bacterial systems needs to be considered through a more holistic, systematic approach both from research and from clinical practice. Functional medicine provides a working platform to pull these and other aspects of human health needs into a cohesive and multifactorial treatment through which prevention and resolution of chronic illness may be realistically managed.
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