Gut health and the immune system
Our digestive tract is a repository for a multitude of information processing cells, some of which are human and others not. Harbouring a diverse population of organisms in the human gut, including bacteria, fungi, viruses and sometimes parasites, means they interact with each other and with the immune system. In the last few years, next-generation sequencing (NGS) techniques have revealed that the genes of gut microbes outnumber human genes by ~150- fold and that the gut microbiota displays unique metabolic activities[1]. Meaning we are partners at a genetic and functional level with organisms resident in our gut.
When this relationship becomes dysfunctional various outcomes related to immune loss of tolerance can occur. The relationship between autoimmune disease (AD) and dysbiotic gastrointestinal contents and tissues has been an area of interest for many years. The May 2022 immunology Reviews Journal revisited and expanded this notion and pulled in numerous recent studies that continue to open a causal understanding of mechanistic triggering and potential therapeutic approaches to improve gut health[2].
Immune modulation in extra-intestinal ADs
A variety of immune cells, both innate and adaptive, participate in the autoimmune inflammatory responses in ADs. In addition, increases in intestinal permeability, which might allow abnormal passage of luminal antigens and bacterial products into the lamina propria, also play a pathogenic role in both intestinal and extra-intestinal ADs[3]. The link between innate and adaptive immune cells at the intestinal barrier of the host and the gut microbiota has been well summarised in other journals[4]. And whilst still being expounded upon, certain themes of activation and resolution are well understood.
One such paper in Frontiers in Immunology published in Jan 2022 qualified a causal relationship between the Bifidobacterium genus and Type 1 Diabetes and Coeliac Disease thus providing novel insights into the gut microbiota-mediated development mechanism of AD[5].
Understanding gut health and these interactions are an increasingly important component of clinical care for here in the UK alone, at least 4 million people have developed ADs, with some individuals suffering more than one. Internationally, it is now estimated that cases of autoimmune diseases are rising by between 3% and 9% a year. If the mechanistic triggers are not grasped and modified, the rate of AD development will soon impact every family.
Nutrition, Gut Health and AD
It has long been known that certain diet components including both nutrients and non-nutrient phytochemicals can modulate a variety of immune and inflammatory events, many of which are key players in the pathogenesis of ADs. Suggesting that nutritional intervention and paying attention the gut health may be a promising approach to prevent and mitigate autoimmune diseases.
It has been demonstrated in pre-clinical and clinical trials that dietary practices can influence immune tolerance and disease[6]. Indeed, dietary components, including micronutrients and macronutrients, can affect both innate physical defences such as epithelial barrier integrity, antimicrobial peptides, and pro/anti-inflammatory cytokines, as well as adaptive immune cell functionality, all components linked to immune tolerance management.
Dietary patterns that are mostly plant-based such as Mediterranean or Dietary Approaches to Stop Hypertension (DASH) diets have been shown to contain anti-inflammatory and antioxidant components that could impose and sustain protective effects against autoimmunity[7]. Among these, plant-derived phytochemicals including polyphenols such as flavonoids and isoflavones have been extensively investigated for healthful modulation and recovery from autoimmunity.
Micronutrients including vitamins (such as vitamins E, A, and D) and minerals (such as selenium, copper, and zinc) are also long known to possess capabilities to modulate immune responses. Micronutrients it seems can tone every aspect of both innate and adaptive responses[8].
Short-chain fatty acids
Inevitably one of the best understood (albeit incomplete) relationships between the gut, the related microbiota and food intake are the production of short-chain fatty acids. Short-chain fatty acids (SCFAs) are intestinal microbial metabolites that result from nutritional fibre digestion and also exert immune regulatory properties[9],[10]. A high fibre diet can produce approximately 400–800 mmol of SCFAs per day. The concentration and relative proportion of each of the induced SCFA in the intestine depends on the microbiota composition, substrate type, and gut transport time[11].
SCFAs are mainly absorbed by colonic epithelial cells and provide energy for their vital activities. A small proportion of SCFAs that are not absorbed by the intestinal epithelium may exert anti-inflammatory, anticancer, and immunomodulatory functions in the gut[12]. Unused SCFAs are excreted in the faeces and urine, although these are typically only about 5% of the total SCFAs.
Whilst the Mediterranean diet has an obvious association with a rich source of fibre and is to be considered a standard therapeutic approach to improve gut health, research is also being conducted on supplemental fibres to induce SCFAs and enhance immunomodulation of inflammatory conditions.
Researchers from Monash University published an experimental study in the Journal Microbiome in Jan 2022 where they utilised a high-amylose maize-resistant starch modified with acetate and butyrate (HAMSAB) to assess safety while monitoring changes in the gut microbiota in alignment with modulation of the immune system status[13]. The subjects were people with T1D and after consuming the supplement for the trial period their raised SCFA status enhanced glycaemic control and induced more regulatory phenotypical immune cells after just 6 weeks.
Treg Cells
Breakdown of immune tolerance as we know is a feature of many non-communicable diseases. Regulatory T cells (Tregs) are a subset of anti-inflammatory CD4+ T cells defined by their expression of the transcription factor FoxP3[14]. Tregs mediate immune tolerance, and their deficiency, or a defect in their function, leads to anomalous immune responses to innocuous food and commensal bacteria-derived antigens, as well as to self-antigens. Consequently, loss of Tregs results in various inflammatory disorders, including autoimmunity and allergies.
There are multiple means by which Treg differentiation can be regulated by both diet and the gut microbiota[15]. These include epigenetic changes, alteration to T cell metabolism, and the engagement of host receptors, such as Toll Like Receptors (TLRs) and aryl hydrocarbon receptors (AhR)[16],[17]. Diet can also influence other immune subsets and regulate physiological processes, such as bile acid biology, to regulate and sustain Treg biology.
The concerted contribution of these pathways may be required for optimal Treg induction and the maintenance of immune tolerance. All aspects of diets (macronutrients, micronutrients, and additives) have been shown to regulate Treg biology to varying extent, suggesting that Treg development is highly responsive to the nutritional status and selection of the host.
Indeed, defects in Treg development associated with the adoption of a western diet may underlie the increasing incidence of inflammatory diseases such as autoimmunity, allergies, poor gut health and inflammatory bowel disease in western countries.
Conclusion
It should be becoming clear that nutrition, metabolic state, microbiota, and autoimmunity are deeply interconnected. In addition to genetic factors, the Western diet characterised by high caloric intake in the form of processed food enriched in protein, sugar, fat and salt, is widely believed to contribute to the rise in autoimmune diseases in the last decades.
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