Food, Bugs, Transcription Factors and Genetics In Gastrointestinal And (Mucosal) Immune Function: How to Leverage Our Current Understandings to Achieve Better Local and Systemic Health Outcomes.

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Mucosal_Wordle_3-300x167The incidence of chronic illness, autoimmune disease and multiple conditions that manifest as inflammatory driven and functionally depleting states are exponentially rising, presenting clinicians with increasingly complicated cases to manage and resolve. Yet 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.[1] Hence, it is increasingly rare that a single point of intervention of treatment or modality is adequate to mitigate risk or resolve problems of these illnesses and as such a multipoint approach is increasingly attractive and necessary.

An organ of increasing importance in the propagation and resolution of these complaints is found inside the gastrointestinal tract and is composed of bacteria, viruses fungi and others, collectively referred to as the microbiome.[2] 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: 1) gleaning indigestible ingredients from food and synthesising nutritional factors, such as vitamins; 2) detoxifying the deleterious xenobiotics and affecting the host metabotypes; 3) development of a robust systemic and intestinal immune system; 4) providing signals for epithelial renewal and maintaining gut integrity; and 5) secretion of anti-microbial 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 prenatal, and post natal transfer, diet, hygiene, exercise, medicines, smoking and food intake volume. Over consumption (i.e. excess caloric intake) 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.[3],[4],[5]

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 for example estimated that human genomic changes only occur at a molecular level at a rate of 0.5% every million years.[6] 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.[7]

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 the sustaining of 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.[8]

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, a highly abundant immune cell in the gut. 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.[9] 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.[10] 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 (IL1β and IL18) 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.[11]

Metabolic syndrome and diabetes (type 2) for example are closely related to food selection, including volume, overeating and high levels of blood sugars are known triggers of inflammasome activation via mitochondrial oxidation.[12],[13] This process is known as ‘sterile’ inflammation, and was initially proposed by Polly Matzinger in her Danger Theory model, and 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 .[14],[15] The gut of course is the organ most exposed to external antigens, primarily in the form of foods and as such it is always under some condition of damage and danger and 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.[16]

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.[17] 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.

Other intersecting elements, including the propagation of inflammation by bacterial pathobionts to favour the retention and domination of those species, 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.[18]

The use of diet, food composition and quantity, bacteria and other microbes as well as enhancement or compression of transcription factors, and genetics need to be mutually manipulated and leveraged to achieve the best outcomes possible. Identifying the best target for a heterogeneous collection of patients in whom diverse immunopathogenic mechanisms are activated requires multi-layered, iterative strategies to achieve safe effective outcomes. Whilst the focus of the presentations in the 2015 conference will be on the use of food concentrates, foods and bacteria, 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 prenatal and post natal 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.


[1] Hotamisligil GS. Inflammation and metabolic disorders. Nature, 444 (2006), pp 860-867

[3] Walter J, Ley R, The human gut microbiome: ecology and recent evolutionary changes Annu Rev Microbiol, 65 (2011), pp. 411–429

[4] Chan YK, Estaki M, Gibson DL. Clinical consequences of diet-induced dysbiosis. Ann Nutr Metab. 2013;63 Suppl 2:28-40.

[5] Power SE, O’Toole PW, Stanton C, Ross RP, Fitzgerald GF. Intestinal microbiota, diet and health. Br J Nutr. 2014 Feb;111(3):387-402.

[6] Kumar S. Molecular clocks: four decades of evolution. Nat Rev Genet. 2005 Aug;6(8):654-62.

[7] Medzhitov R. Inflammation 2010: new adventures of an old flame. Cell. 2010 Mar 19;140(6):771-6.

[8] Round J.L. Mazmanian S.K. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol, 9 (2009), pp 313-323

[9] Szklarczyk R, Huynen MA. Mosaic origin of the mitochondrial proteome. Proteomics. 2010 Nov;10(22):4012-24

[10] Bauernfeind F, Hornung V. Of inflammasomes and pathogens–sensing of microbes by the inflammasome. EMBO Mol Med. 2013 Jun;5(6):814-26.

[11] Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature. 2012 Feb 1;482(7384):179-85.

[12] O’Neill LA. Cardiolipin and the Nlrp3 inflammasome. Cell Metab. 2013 Nov 5;18(5):610-2.

[13] Tschopp J. Mitochondria: Sovereign of inflammation? Eur J Immunol. 2011 May;41(5):1196-202.

[14] Matzinger P. The evolution of the danger theory. Interview by Lauren Constable, Commissioning Editor. Expert Rev Clin Immunol. 2012 May;8(4):311-7

[15] Sutterwala FS, Haasken S, Cassel SL. Mechanism of NLRP3 inflammasome activation. Ann N Y Acad Sci. 2014 Jun;1319:82-95.

[16] Albenberg LG, Wu GD. Diet and the intestinal microbiome: associations, functions, and implications for health and disease. Gastroenterology. 2014 May;146(6):1564-72

[17] Swann JR, Want EJ, Geier FM, Spagou K, Wilson ID, Sidaway JE, Nicholson JK, Holmes E. Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1:4523-30.

[18] Stecher B, Maier L, Hardt WD. ‘Blooming’ in the gut: how dysbiosis might contribute to pathogen evolution. Nat Rev Microbiol. 2013 Apr;11(4):277-84

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