All Immunity is Mucosal – The GUT is No 1

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The Gut is The Formula 1 of Immunity

mi_cimageProperly regulated mucosal immunity is critical to overall health and well being. The cells found in the mucosal surfaces of the body meet on a daily basis, local challenges from foods, microbes and environmental pollutants. The result is a series of immunological decisions that on a single day exceed those made by the systemic immune system in a lifetime.

The immune system bound up in these tissues – mostly the ‘innate immune system’, must translate this infornatic onslaught to the ‘systemic immune system’  affecting the body as a whole. Immune tolerance or homeostasis in these tissues will help ensure adequate nourishment from passing ‘foreign’ food stuffs and so maintain bacterial/commensal balance. It is this bacterial balance that will ensure immunological tolerance so keeping the balance of power in the hands of health promoters (commensals) via this yin and yang relationship.

However, should mucosal tolerance be lost, damage can occur to tissues, not just locally due to an unregulated inflammatory response, but its effects can be seen throughout the body. This can manifest as autoimmune disease, allergy, depression and even cancer.

Commensals have a vital role to play.

Whilst the crucial role of bacteria in the development, activation and regulation of immunity has long been recognised, far less is understood about the role of specific bacterial species and of course their interactions amongst other species and the effect of local tissue health. The current growth of research into metagenomics continues to expand the understanding of  how our microbial friends colonise the mucosal surfaces increasing the interest in the role of our little friends and their effect on immunity via the wet surfaces of our bodies.

Nowhere is this more complex or fascinating than the gastrointestinal tract, with over 40,000 and counting individual species identified so far. It is also clear that their composition varies widely among individuals and apparent that changes in the balance of these organisms or ‘dysbiosis’ causes not only local inflammation but can induce significant collateral damage and cause systemic disease including autoimuune illness and depression.

Administration of cytokines including interferon (IFN)-alpha and cytokine inducers such as lipopolysaccharide (LPS) and typhoid vaccination have also been found to lead to a host of behavioural changes that overlap with those seen in depressed patients including depressed mood, anxiety, anorexia, fatigue, psychomotor retardation, impaired sleep and cognitive dysfunction. [1]

In the gastrointestinal tract, SIgA, and the families of regulatory T cells, essential for inflammation control, work together to produce specific IgA antibodies to limit challenging antigens capacity for damage. The combination of Treg-sIgA microbial homeostasis acts as a vital stabilser, a sort of ‘homeostatic glue’ that keeps the commensals content and so prevents inflammation and adherence by unwanted pathogens.

In mammals, the gut is populated with an extremely dense and diverse bacterial community. The colonisation of the intestine with bacteria is invariably associated with a prompt and abundant generation of immunoglobulin A (IgA) from the B cells present in the gut-associated lymphoid tissues. Upon secretion into the intestinal lumen, IgA provide protection against pathogens, and has a key role in selection and maintenance of gut microbiota. Thus, from studies in mice, it is thought that hypermutated high-affinity IgA neutralise toxins and drive diversification of bacterial communities, whereas nonmutated natural IgA limit the penetration of commensal bacteria below the intestinal epithelial surface.[2]

Another important chemical is the essential cytokine – TGFβ which in conjunction with the vitamin retinoic acid combines at differing concentrations to either increase inflammation by inducing TH17 cells or  induces tolerance via Treg cells. The role of nutrients in homeostasis of the gut are excellently represented by the role of vitamin A.

Other bacteria promote a reduction in inflammation via the induction of the cytokine IL-10. The probiotic LGG Culturelle adds an extra benefit by supporting the epithelial cell health reducing exposure of bacterial products to the sensitive submucosal immune cells.

Comment

However, it is also important to remember that even commensals can be a problem if the health of the tissues are compromised by trauma or antibiotics. The manipulation of the bacterial species represents an exciting area for nutritionally oriented clinicians to become involved in, as every meal of natural foods includes a healthy dose of microbial hitchikers!

[1]  Brydon et al., 2008 L. Brydon, N.A. Harrison, C. Walker, A. Steptoe and H.D. Critchley, Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans, Biol. Psychiatry 63 (2008), pp. 1022–1029 View Abstract

[2] Suzuki,K and Fagarasan,S . Diverse regulatory pathways for IgA synthesis in the gut Mucosal Immunology (2009) 2, 468–471; doi:10.1038/mi.2009.107; published online View Abstract

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