Gut-systemic inflammatory axis - “role of nutrition in fighting the modern plague of autoimmune and metabolic related diseases”

The incidence of autoimmune diseases has risen dramatically since the 1940’s with classical autoimmune diseases such as type 1 diabetes, celiac disease, inflammatory bowel disease, Multiple sclerosis, Amyotrophic lateral sclerosis (ALS), asthma, psoriasis and rheumatoid arthritis, now affecting about 5-10% of the global population depending on what diseases you include in the definition of AD’s. There is also a strong geographical distribution of these diseases, with increased prevalence in the richer areas of the world, or rather a strong socioeconomic component in the epidemiology of these diseases, with AD’s directly correlating with industrial development, urbanisation or Westernisation even in developing countries with historically low incidence of these diseases. AD’s are thought to derive from a combination of genetic predisposition and environment, or “bad genes and bad luck”. Diet is probably the most pervasive of environmental interactions with the human body, and diet too has changed dramatically since the 1940’s. The post-World War II diet which emerged in affluent countries in the 1950’s and became known as the Western-style diet, is typified by increased daily energy intake, high intake of refined carbohydrates especially sugars, high intake of fat, especially saturated fat, and animal protein and low intake of fresh fruit and vegetables, important sources of dietary fiber, polyphenols, minerals and vitamins. The Western diet too is typified by increased intake of highly processed foods, often energy dense but nutrient poor, leading to high intake of readily available energy sources and flavourings like sodium chloride and monosodium glutamate, but poor in minerals and vitamins as well as being low in fiber and phytochemicals. These biologically active compounds are emerging as important regulators of many mammalian physiological processes including those linked to immune tolerance and homeostasis, and are contributing to the recognised phenomenon of “nutrient malnutrition” alongside “energy over-nutrition”. Interestingly, AD’s are extremely rare in populations following traditional diets but this changes when indigenous peoples from rural areas following traditional lifestyles move to the cities and adopt Western-style lifestyles and diets. The Western-style diet too has been linked to the increased prevalence of other diseases with strong immunological and autoimmune components, including allergies, food allergies and atopic dermatitis and obesity and the diseases of obesity (type 2 diabetes, non-alcoholic fatty liver disease, coronary vascular disease and certain cancers), and since in most affluent, Westernised communities obesity is reaching about 30% of the population, the health burden of autoimmunity is sky-rocketing. Although not formally classed as autoimmune diseases, these common metabolic pathologies are characterised by persistent low grade systemic inflammation typified by elevated plasma CRP, IL-6, IL-1 and TNF-α, and are also associated with elevated blood levels of autoantibodies. Gut permeability to inflammatory bacterial lipopolysaccharide appears to be an important trigger for this low grade systemic inflammation, a processes directly impacted by the gut microbiota and their interaction with diet, especially fat and dietary fibers. In addition, certain members of the gut microbiota have been shown to induce mimics of human antigens and trigger autoantibodies responsible for aberrant immune responses to normal human proteins and hormones, an important consideration with the recent recognition of an “obese type” gut microbiome. Recently, metabolism of dietary phosphatidylcholine and L-carnitine, mainly provided by red meat and other animal products in the Western-style diet, has been shown to produce trimethylamine (TMA) which is further metabolised to trimethylamine-N-oxide (TMAO) by the liver and shown to play a direct role in CVD. TMAO modulates macrophage inflammatory status, reverse cholesterol metabolism, plasma bile acid concentrations and BA signalling through FXR. These CVD associated inflammatory and metabolic processes mediated by the gut microbiota were found to be induced by dietary red meat and down regulated in vegans. The adverse impact of the energy dense, nutrient poor Western-style diet on our gut microbiota and immune system, which have both been finely tuned and honed by high-fiber, high polyphenol traditional diets over the millennia, may therefore be an important contributor to the environmental stimuli which trigger these modern autoimmune and metabolic diseases of affluence. A possible starting point when discussing the underlying mechanisms by which diets rich in whole plant foods or fermentable fibers can impact on immune function and tolerance may be the recent demonstration that butyrate, an important fermentation end product produced by the gut microbiota from fiber, controls human dendritic cell maturation, a key process in immune homeostasis since dendritic cells are considered the “gate keepers” of our immune system. SCFA has also been shown to play a role in regulating other immune parameters, including neutrophil and macrophage activity, and the gut microbiota has also recently been shown to produce other immuno active compounds such as conjugated linoleic acid (CLA) and gamma-aminobutyric acid (GABA) with have anti-inflammatory potential. Similarly, up-regulating microbial activities within the enterohepatic circulation of bile acids, through bile acid receptors (e.g. GRP5) and nuclear receptors (especially FXR) and in combination with immune signalling via tole-like receptors, is emerging as an important communication highway linking the gut microbiota:host immune metabolic axis intimately with the environmental risk factors of autoimmune and metabolic disease. In this presentation, I will discuss how diet, through its interaction with the human microbiome, both microorganisms themselves and their metabolic output, may play a role in immune homeostasis both within the gut and systemically, and could possibly provide novel therapeutic options to help in the fight against the modern plague of autoimmune and metabolic disease.