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Stress, intestinal barrier disruption, and autoimmune diseases

The role of intestinal barrier and dysbiosis in autoimmune diseases has been expanding over the years. (Image: Canva)

Mon. 25 December 2023

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At least 50% of the onset of autoimmune diseases is attributed to unknown causes (1). Many retrospective studies have shown that most autoimmune disease patients have negative anxiety symptoms before the onset of the disease (2). Selye first described stress in 1936 as a real (physical) or perceived (psychological) threat to homeostasis to which the body must respond with adaptive responses (3). Epidemiological studies reveal that stress can cause and worsen autoimmune diseases. This is a vicious cycle as autoimmune disease can cause stress in patients (4,5).

Psychological stress alters the intestinal barrier

Mental illness can alter the digestive system to respond differently. Stress may cause microbiome dysbiosis, intestinal hyperpermeability, and intestinal inflammation. Therefore, all these elements of the intestinal barrier interact with each other as well as alter each other. Microbiota dysbiosis is responsible for intestinal hyperpermeability and inflammation; alternatively, intestinal hyperpermeability and intestinal inflammation can result in microbiota dysbiosis. Finally, stress can also cause autoimmune diseases in the body (1).

A. Effect of intestinal microbiota dysbiosis on autoimmune diseases

Research on the connection between gut microbiota dysbiosis and autoimmune illnesses is ongoing, and while the precise processes behind this association are still being worked out, some broad conclusions have been drawn (1).

  1. Regulation of immune tolerance

Intestinal microbiota plays a crucial role in the development and regulation of the immune system. A balanced microbiome helps the immune system distinguish between harmless agents and harmful invaders. Dysbiosis can upset the balance and cause the body to respond inappropriately to self–antigens (6).

  1. Influence on T Regulatory Cells (Tregs)

Tregs are a part of the immune system that plays an important role in preventing autoimmunity by preventing excessive immune responses. The gut microbiota is known to influence the development and function of Tregs. Dysbiosis may promote autoimmune processes by altering the balance between regulatory and immune responses (7).

  1. Mucosal barrier integrity

The gut microbiota helps to maintain the integrity of the intestinal mucosal barrier. Dysbiosis disrupts the barrier function, causing increased permeability and translocation of bacteria products into the blood. This phenomenon is often called “collapse” and is associated with autoimmune diseases (8).

  1. Molecular mimicry

Some components of the gut microbiota show similar patterns as other tissues. In cases of dysbiosis, the immune system can produce antibodies against microbial antigens that interact with the tissues, leading to an autoimmune response. This concept is known as molecular mimicry (9).

  1. Short-chain fatty acids (SCFAs)

The gut microbiota produces metabolites, including short-chain fatty acids, through the fermentation of dietary fiber. SCFAs have immunomodulatory effects and help maintain the balance between the immune response and the immune system. Dysbiosis can modify the synthesis of these metabolites, thus affecting the immune system (10).

B. Effect of intestinal hyperpermeability on autoimmune diseases

In autoimmune diseases, intestinal hyperpermeability has been described, resulting in an increased entry of luminal antigens derived from food and/or intestinal microbiota or pathogens. The associated inflammation has been suggested to participate in autoimmune disease onset and/or exacerbation (1).

C. Effect of intestinal inflammation on autoimmune diseases

Stress may contribute to inflammation through various pathways. It can enhance the production of pro-inflammatory cytokines and modulate immune cell activity. In the context of autoimmune diseases, this heightened inflammation may exacerbate existing immune responses against self-antigens (1).

Following are the autoimmune diseases affected by the stress and intestinal disruption:

  1. Type 1 Diabetes (T1D)

T1D is related to microbial dysbiosis, intestinal hyperpermeability, expanded IL-17 emissions in the intestine and at a systemic level, and expanded myeloperoxidase (MPO) within the digestive tract. Thus, colonization by a complex microbiota is defensive from T1D(1).

  1. Systemic Lupus Erythematosus (SLE)

SLE is linked with microbiota dysbiosis and increased production at the intestinal level of IL-17 and IL-22 by T cells as well as IFN-α and IFN-β by dendritic cells. At the systemic level, there is increased emission of IL-6 and TNF-α by monocytes and macrophages in SLE. Hence, colonization by a complex microbiota is detrimental to the onset of SLE (1).

  1. Multiple Sclerosis (MS)

MS is connected with microbiota dysbiosis, intestinal hyperpermeability, and increased production of IL-17 and IFN-γ by T cells at the intestinal level. The increased number of innate lymphoid cells (ILC) was noticed in MS. Interestingly, colonization by a complex microbiota is deleterious for the onset of MS (1).

Conclusion

Stress is known to have long–term effects on the digestive system. Cross-sectional studies of autoimmune diseases, stress, and intestinal function might be useful and provide new insights into the pathophysiology of autoimmune diseases. Identifying the causes of intestinal stress dysfunction as an important factor in autoimmune diseases may lead to new potential therapeutic targets, particularly strategies for preventing an autoimmune disease. Clinical strategies indicate that probiotic therapy and fecal microbiota transplantation (FMT) may improve symptoms of autoimmune diseases, but preventive strategies still need to be investigated in high-risk groups (1).

References

  1. Ilchmann-Diounou H, Menard S. Psychological Stress, Intestinal Barrier Dysfunctions, and Autoimmune Disorders: An Overview. Front. Immunol 2022; 11:1823. doi: 10.3389/fimmu.2020.01823
  2. Stojanovich L, Marisavljevich D. Stress as a trigger of autoimmune disease. Autoimmun Rev 2008;7:209–13. doi: 10.1016/j.autrev.2007.11.007
  3. Selye H. Syndrome produced by diverse nocuous agents. Nature 1936;138:32. doi: 10.1038/138032a0
  4. Shepshelovich D, Shoenfeld Y. Prediction and prevention of autoimmune diseases: additional aspects of the mosaic of autoimmunity. Lupus 2006;15:183–90. doi: 10.1191/0961203306lu2274rr
  5. Huerta PT, Kowal C, DeGiorgio LA, Volpe BT, Diamond B. Immunity and behavior: antibodies alter emotion. Proc Natl Acad Sci USA. 2006; 103:678–83. doi: 10.1073/pnas.0510055103
  6. Yoo J Y, Groer M, Dutra S V O, Sarkar A, McSkimming D I. Gut Microbiota and Immune System Interactions. Microorganisms 2020; 8: 1587. doi:10.3390/microorganisms8101587
  7. Eggenhuizen PJ, Ng B H, Ooi J D. Treg Enhancing Therapies to Treat Autoimmune Diseases. Int. J. Mol. Sci. 2020, 21, 7015; doi:10.3390/ijms21197015
  8. An J, Liu Y, Wang Y, Fan R, Hu X, Zhang F, Yang J, and Chen J. The Role of Intestinal Mucosal Barrier in Autoimmune Disease: A Potential Target. Front. Immunol. 2022;13:871713. doi: 10.3389/fimmu.2022.871713
  9. English J, Patrick S, Stewart L D. The potential role of molecular mimicry by the anaerobic microbiota in the aetiology of autoimmune disease. Anaerobe 2023;80: 102721.
  10. Portincasa, P.; Bonfrate, L.; Vacca, M.; De Angelis, M.; Farella, I.; Lanza, E.; Khalil, M.; Wang, D.Q.-H.; Sperandio, M.; Di Ciaula, A. Gut Microbiota and Short Chain Fatty Acids: Implications in Glucose Homeostasis. Int. J. Mol. Sci. 2022; 23: 1105. https://doi.org/10.3390/ijms23031105

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