The role of gastrointestinal dysbiosis in the pathogenesis of systemic lupus erythematosus
Introduction & Background
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by widespread inflammation mediated by the body’s own antibodies, causing damage to tissues and organs. Most of the symptoms are nonspecific, involving fatigue, fever, and joint pain. One characteristic symptom of SLE is a “butterfly rash” across the cheeks and nose (1). Until the discovery of self-reactive antibodies in the mid-twentieth century, the mechanism of SLE was unknown. Today, it is still unclear exactly how systemic lupus erythematosus is acquired. The development of SLE is currently believed to be the result of the interaction of multiple genes with yet unidentified environmental factors; some of the proposed environmental factors include vitamin D deficiency, exposure to pesticides, Epstein-Barr virus, certain medications, and dysbiosis (2). This paper will explore the relationship between gastrointestinal dysbiosis and systemic lupus erythematosus.
Number of people with SLE
Demographic statistics
Effects of lupus
Definitions
Antinuclear antibody: an antibody that reacts to normal proteins within the nuclei of self-cells
Dysbiosis: an imbalance in the microbial composition of the host’s body, especially within the gastrointestinal system
Eubiosis: the state of balance in the host’s commensal and pathogenic microbiota; the opposite of dysbiosis
Human microbiome: the community of commensal and pathogenic microorganisms that normally inhabit our bodies
Hygiene hypothesis: the theory that the rise in autoimmune diseases and allergies in modern Western societies can be attributed to reduced exposure to microbes during childhood as a result of excessively clean environments
“Old Friends” hypothesis:
IgA: the immunoglobulin primarily responsible for immune responses in mucosal membranes
Antibiotic-induced gastrointestinal dysbiosis
Interactions between human hosts and microflora are known to be associated with certain disease states; according to the hygiene hypothesis, reduced exposure to microorganisms has contributed to the rise of allergies and autoimmune diseases in modern Western societies, in which over-sterilization has limited the diversity of our microbiomes and impaired our immune systems (4). When oral antibiotics are used to treat an infection, our natural bacterial populations within the gastrointestinal system are also affected. The gastrointestinal microbiome can be significantly reduced for a year or more after a single round of antibiotics, and these effects can be lifelong when antibiotic-induced dysbiosis is sustained within the first few years of life. The reduction in number and diversity of these bacteria is known as dysbiosis and can lead to a number of consequences, including infection and enzymatic deficiencies. For example, a reduction in Lactobacillus, which produce lactase, may result in transient or permanent lactose intolerance. Different antibiotics have been demonstrated to have differing effects on not only the composition of the gastrointestinal microbiome, but also on its ability to recover and return to eubiosis (5). New immunological research suggests that antibiotic-induced gastrointestinal dysbiosis can also have a profound effect on the immune system by killing off the bacteria that contribute to the production of IgA and interleukins the intestines (7).
Dysbiosis in systemic lupus erythematosus (SLE)
Gastrointestinal dysbiosis has been implicated in a number of intestinal autoimmune diseases, including Crohn’s disease and Irritable Bowel Disease (IBD). However, there is increasing evidence to suggest that gastrointestinal dysbiosis can affect the entire immune system and contribute to non-intestinal autoimmune diseases, such as multiple sclerosis (MS). Systemic lupus erythematosus is an autoimmune disease that affects many parts of the body, including the blood vessels, joints, and kidneys. Hevia et al.demonstrate that there are significant differences in gastrointestinal microbiota between patients with lupus and healthy controls, with SLE patients notably exhibiting a significantly smaller ratio of Firmicutes:Bacteroidetes (8). This study also revealed differences in the relative abundance of specific bacterial species and categories. Notably, SLE patients and healthy controls in similar studies were found to have no difference in Firmicutes:Bacteroidetes ratios, but SLE patients did exhibit higher concentrations of lipopolysaccharide-containing facultative anaerobic Gram-negative bacteria than healthy controls (9). 
Problems
The hypothesis that dysbiosis contributes to the development of systemic lupus erythematosus has encountered several problems. Firstly, it does not explain why there is such a marked sex bias in SLE patients. However, the sex bias towards females may be attributed to the genetic component of SLE rather than environmental or microbial factors; this could be supported by the fact that almost all autoimmune diseases affect more women than men. The hypothesis also fails to explain why some studies have found that certain antibiotics actually alleviate symptoms of systemic lupus erythematosus, whereas other antibiotics may contribute to the development or severity of the disease. This may be a result of the differential specificity of antibiotics; for example, I would expect antibiotics targeting lipopolysaccharide-containing facultative anaerobic Gram-negative bacteria to improve SLE symptoms resulting from gastrointestinal dysbiosis, whereas antibiotics that further reduce abundance of Firmicutes bacteria would exacerbate the dysbiosis. Finally, the antibiotic-induced gastrointestinal dysbiosis hypothesis cannot rule out that SLE causesdysbiosis, rather than dysbiosis contributing to the development of the SLE (10).
Discussion & Conclusions
Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease with no cure and limited information about its pathogenesis. It is believed to result from interactions between multiple genes and environmental factors. Dysbiosis secondary to oral antibiotics have been implicated in the development of intestinal autoimmune diseases; however, there a growing body of evidence to suggest that the gastrointestinal microbiome plays a significant role in the immune system as a whole and may contribute to extra-intestinal and multisystem autoimmune diseases, including SLE.
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The relationship between gastrointestinal dysbiosis and systemic lupus erythematosus has significant implications for the issue of antibiotic overuse as well as the treatment of SLE and other autoimmune diseases. If gastrointestinal dysbiosis resulting from administration of oral antibiotics is proven to contribute to autoimmune pathogenesis, physicians will need to further curb the prescription of antibiotics, especially to young children and those with family histories of autoimmune disease. Furthermore, administration of prebiotics and/or probiotics after a course of antibiotics may help the gastrointestinal microbiome and immune system recover more quickly. The use of prebiotics and/or probiotics may also prove useful in the treatment of some autoimmune diseases. Similarly, fecal transplantation could be another treatment option for these conditions. Hopefully, further research into the role of antibiotic-induced gastrointestinal dysbiosis in the pathogenesis of systemic lupus erythematosus and other autoimmune diseases will help elucidate contributory factors as well as provide direction for the development of future pharmaceutical and/or therapeutic treatments for these conditions.
References
- Lupus. (2017, October 25). Retrieved from https://www.mayoclinic.org/diseases-conditions/lupus/symptoms-causes/syc-20365789
- Kamen, D. L. (2014). Environmental influences on systemic lupus erythematosus expression. Rheumatic Disease Clinics, 40(3), 401-412.
- Velasquez-Manoff, M. (2012). An epidemic of absence: a new way of understanding allergies and autoimmune diseases. Simon and Schuster.
- Panda, S., El khader, I., Casellas, F., López Vivancos, J., García Cors, M., Santiago, A., Cuenca, S., Guarner, F., … Manichanh, C. (2014). Short-term effect of antibiotics on human gut microbiota. PloS one, 9(4)
- Zhang, M., Sun, K., Wu, Y., Yang, Y., Tso, P., & Wu, Z. (2017). Interactions between intestinal microbiota and host immune response in inflammatory bowel disease. Frontiers in immunology, 8, 942.
- Ubeda, C., & Pamer, E. G. (2012). Antibiotics, microbiota, and immune defense. Trends in immunology, 33(9), 459-466.
- Hevia, A., Milani, C., López, P., Cuervo, A., Arboleya, S., Duranti, S., … & Ventura, M. (2014). Intestinal dysbiosis associated with systemic lupus erythematosus. MBio, 5(5), e01548-14.
- Shi, N., Li, N., Duan, X., & Niu, H. (2017). Interaction between the gut microbiome and mucosal immune system. Military Medical Research, 4(1), 14.
- López, P., Sánchez, B., Margolles, A., & Suárez, A. (2016). Intestinal dysbiosis in systemic lupus erythematosus: cause or consequence?. Current opinion in rheumatology, 28(5), 515-522.
