Approximately 10% of people in the UK are affected by autoimmune diseases, and the number appears to be rising 1. While theories behind this rise are inconclusive, it is known that the gut forms a critical interface between environmental exposure and immune regulation, suggesting that microbiome dysbiosis may play an important role in the development of autoimmune conditions 2.
This article explores the relationship between autoimmune disease and the gut microbiome, including the role of intestinal permeability, immune regulation, and emerging evidence-based microbiome-targeted interventions.
Autoimmune disease describes a diverse group of conditions where the loss of immune self-tolerance results in the immune system attacking the body’s own tissues and organs 3. When healthy, the immune system has tolerance mechanisms that regulate the immune system and suppress any self-attack 4.
However, autoimmune diseases result in the bypass of these tolerance mechanisms, enabling the escape of immune cells targeting the body’s cells. These cells cause the aberrant activation of the immune system, inflammation, and organ dysfunction 5.
Over 100 different autoimmune diseases have been recognised to date. These can be broadly categorised into organ-specific conditions, such as Hashimoto’s thyroiditis and Type 1 diabetes 6, and systemic conditions, such as Rheumatoid arthritis and Systemic lupus erythematosus 7.
While risk factors vary for different diseases, shared risk factors include both genetic predisposition and environmental triggers. Approximately 30% of autoimmune risk can be attributed to genetics, with 100s of genetic loci thought to increase the risk 5, 8. The remaining ~70% of autoimmune disease risk is thought to be due to environmental risks, including infections, smoking, toxin exposure, and gut microbiome dysbiosis – highlighting the growing importance of gut health in autoimmune disease development 9.
The gut microbiome has emerged as playing a fundamental role in immune homeostasis. It is thought that mammals and microorganisms found within the gut co-evolved to form a bidirectional relationship that is essential in the development and function of the immune system 10.
The microbiota is involved in immune regulation, with shifts in the composition of the microbiota and in metabolite release both modulating immune signalling networks 11.
Immune tolerance (the ability of the immune system to remain unreactive to triggers, including self-cells) can also be affected by the microbiome, with the microbiome contributing to important tolerance-supporting functions, including training the immune system and promoting regulatory cells 10. Beyond direct links between the gut microbiome and immune system within the gut, the microbiome also influences inflammation systemically 12.
Autoimmunity and gut barrier function are closely linked – microbiome dysbiosis results in gut barrier dysfunction and the leakage of bacterial fragments and metabolites into systemic circulation, causing systemic immune activation 12. The gut barrier is formed of multiple layers and tightly controls what passes between the gut and the rest of the body. A healthy microbiota helps to maintain and reinforce this barrier by stimulating mucus production and promoting tight junctions 13.
However, dysbiosis results in increased intestinal permeability (commonly referred to as a "leaky gut"), due to downregulated tight junction proteins and thinning of the mucus layer 14. When the barrier is compromised, substances that would normally be prevented from moving across the barrier can now enter systemic circulation. These include microbial metabolites such as lipopolysaccharide (LPS), which activate pattern recognition receptors and increase inflammation 15. Increasing evidence links a leaky gut and autoimmune conditions. The increased passage of microbial products into systemic circulation drives systemic inflammation, loss of tolerance, the priming of autoreactive immune cells, and molecular mimicry, all of which contribute to autoimmune disease development 16, 17.
Dysbiosis is commonly seen in autoimmune disorders, and the resulting inflammation and gut health disruption include a reduction in overall microbiome diversity, a reduction in anti-inflammatory species, and an increase in pro-inflammatory species 18. As a result, it has been implicated in the development of these disorders.
Studies have shown the expansion of Prevotella copri species in the gut microbiome of patients with RA, and a reduction in beneficial microbial species 19. This was thought to result in inflammation, molecular mimicry, and loss of barrier integrity, all of which could contribute to the development of RA 20.
A consistent increase in pro-inflammatory microbial species, including Bacteroides and Prevotella, and a reduction in protective anti-inflammatory species, including Bifidobacteria and Lactobacilli, has been seen in patient studies. This dysbiosis is thought to lead to a dysregulated immune response, which then contributes to coeliac development 21.
Gut dysbiosis has been identified in patients with multiple sclerosis. Altered bacteria include a reduction in short-chain fatty acid (SCFA)-producing bacteria, leading to chronic inflammation 22.
IBD has been consistently demonstrated to involve the reduction of beneficial, SCFA-producing bacteria and an increase in pro-inflammatory bacteria, and this dysbiosis is thought to exacerbate the progression of the disease 23.
While the evidence supporting dysbiosis in autoimmune diseases is strong, the evidence for a direct causative effect remains limited for many autoimmune conditions, although emerging data provide evidence for a potential causal effect in IBD and type 1 diabetes 24, 25. Researchers suggest that the relationship may be bidirectional, with dysbiosis both contributing to the development of autoimmune diseases while also occurring as a consequence 26.
Diet is the single largest driver of gut microbiome composition and diversity 27. Dietary patterns comprising high fibre, whole foods, low levels of ultra-processed foods, and fermented foods are linked to high microbial diversity and a greater presence of beneficial bacterial species 28–31.
Lifestyle factors can also impact the gut microbiome. Irregularity of meal timings 32, high stress 33, a lack of sleep 34, and limited physical exercise 35 have all been associated with gut dysbiosis and potential health impacts. Further effects on the microbiome may result from environmental factors, such as antibiotic intake or exposure to pollutants 36.
Probiotics are thought to impact the microbiome and, as a consequence, may have a therapeutic effect on autoimmune conditions by inducing regulatory immune cells, suppressing pro-inflammatory mechanisms, and restoring gut barrier integrity.
While evidence does exist for a protective effect in humans, it varies widely between different conditions, probiotics, and patient populations. For example, in two small RCTs in patients with RA, probiotic supplementation improved the Disease Activity Score in addition to decreasing inflammation 37, 38. Similar positive effects of probiotics have been seen in ulcerative colitis, with a systematic review concluding that probiotics in combination with conventional treatments improved remission rates among patients 39. These trials are often limited by small sample sizes and a short intervention duration, but the initial results are promising.
The relationship between gut health and autoimmune disease is an emerging and rapidly evolving area of research. The gut microbiome plays an important role in immune regulation, influencing immune tolerance, inflammation, and gut barrier integrity.
As research in this area continues, associations between gut dysbiosis and autoimmune conditions, including RA, coeliac disease, and IBD, are continuing to increase. However, the strength and nature of this evidence vary widely between conditions.
Diet and lifestyle remain the most easily implemented and evidence-supported strategies for improving the health and diversity of the gut microbiome, but microbiome-targeted therapies (such as probiotics) show early promise as supportive interventions for some autoimmune conditions. Nevertheless, clinical evidence remains limited, and larger trials are needed before therapeutic conclusions can be made.
Microbiome health is important in managing overall health, and while probiotics for autoimmune disease warrant continued scientific research and hold genuine promise for the future, current evidence suggests they are best viewed as a supportive tool alongside established lifestyle measures.
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