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. 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.
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. 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. 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.
Understanding these interactions is 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 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 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. 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. 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.
Inevitably one of the best understood (albeit incomplete) relationships between the gut, the related microbiota and food intake is 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,. 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.
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. 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, 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. 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.
Breakdown of immune tolerance 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. 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. 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),. 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 and inflammatory bowel disease in Western countries.
The art of inducing and maintaining Treg functionality via nutritional support represents a simple, safe and multi-layered opportunity to bring inflammatory conditions back under control. 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.
Dietary factors, via direct effects on immune cells, or by acting indirectly through modulation of the gut microbiota, may regulate Treg plasticity and function and, therefore, may have the potential to control disease outcomes. However, more research and tightly controlled studies are needed to assess the impact of specific dietary nutrients and bacteria or microbial metabolites on Tregs, autoimmunity, and human health.
 Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).
 Miyauchi E, Shimokawa C, Steimle A, Desai MS, Ohno H. The impact of the gut microbiome on extra-intestinal autoimmune diseases. Nat Rev Immunol. 2022 May 9.
 Fasano, A. Leaky gut and autoimmune diseases. Clin. Rev. Allergy Immunol. 42, 71–78 (2012).
 Zhang, X., Chen, B. D., Zhao, L. D. & Li, H. The gut microbiota: emerging evidence in autoimmune diseases. Trends Mol. Med. 26, 862–873 (2020).
 Xu Q, Ni J-J, Han B-X, Yan S-S, Wei X-T, Feng G-J, Zhang H, Zhang L, Li B and Pei Y-F (2022) Causal Relationship Between Gut Microbiota and Autoimmune Diseases: A Two-Sample Mendelian Randomization Study. Front. Immunol. 12:746998.
 Abdelhamid L and Luo XM (2022) Diet and Hygiene in Modulating Autoimmunity During the Pandemic Era. Front. Immunol. 12:749774.
 Pocovi-Gerardino G, Correa-Rodríguez M, Callejas-Rubio J-L, Ríos-Fernández R, Martín-Amada M, Cruz-Caparros M-G, et al. Beneficial Effect of Mediterranean Diet on Disease Activity and Cardiovascular Risk in Systemic Lupus Erythematosus Patients: A Cross-Sectional Study. Rheumatology (2021) 60(1):160–9.
 Gombart AF, Pierre A, Maggini S. A Review of Micronutrients and the Immune System–Working in Harmony to Reduce the Risk of Infection. Nutrients (2020) 12(1):236.
 Zaiss MM , Joyce Wu H-J , Mauro D , et al . The gut-joint axis in rheumatoid arthritis. Nat Rev Rheumatol 2021;17:224–37.
 Zhang, Z., Zhang, H., Chen, T. et al. Regulatory role of short-chain fatty acids in inflammatory bowel disease. Cell Commun Signal 20, 64 (2022).
 Macfarlane S, Macfarlane GT. Regulation of short-chain fatty acid production. Proc Nutr Soc. 2003;62:67–72.
 Yang Q, Ouyang J, Sun F, Yang J. Short-chain fatty acids: a soldier fighting against inflammation and protecting from tumorigenesis in people with diabetes. Front Immunol. 2020;11:590685
 Bell, K.J., Saad, S., Tillett, B.J. et al. Metabolite-based dietary supplementation in human type 1 diabetes is associated with microbiota and immune modulation. Microbiome 10, 9 (2022)
 Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. (2003) 299:1057–61.
 Tan J, Taitz J, Sun SM, Langford L, Ni D and Macia L (2022) Your Regulatory T Cells Are What You Eat: How Diet and Gut Microbiota Affect Regulatory T Cell Development. Front. Nutr. 9:878382.
 Vijay K. Toll-like receptors in immunity and inflammatory diseases: Past, present, and future [published correction appears in Int Immunopharmacol. 2018 Sep;62:338]. Int Immunopharmacol. 2018;59:391-412.
 Gutiérrez-Vázquez C, Quintana FJ. Regulation of the Immune Response by the Aryl Hydrocarbon Receptor. Immunity. 2018;48(1):19-33.
 Arroyo Hornero R, Hamad I, Côrte-Real B, Kleinewietfeld M. The Impact of Dietary Components on Regulatory T Cells and Disease. Front Immunol. 2020;11:253. Published 2020 Feb 21.