Interaction of Intestinal Microorganisms with the Human Host in the Framework of Autoimmune Diseases

Abstract

Autoimmune diseases, such as systemic lupus erythematosus (SLE), are caused by a complex interaction of environmental-, genetic-, and sex-related factors. Although SLE has traditionally been considered independent from the microbiota, recent work published during the last 5 years suggests a strong connection between SLE and the composition of our gut commensals as one of the main environmental factors linked to this disease. Preliminary data have evidenced that (i) interaction of certain microbial-derived molecules with specific cell receptors and (ii) the influence of certain commensal microorganisms over specific immune cell subsets plays an important role in the pathogenesis of SLE and SLE-like diseases. In addition, epigenetic changes driven by certain microbial groups have been recently proposed as an additional link between gut microbiota and SLE. As immune responses elicited against commensal bacteria are deeply dependent on the composition of the latter, and as microbial populations can be modified by dietary interventions, identifying the precise gut microorganisms responsible for worsening the SLE symptoms is of crucial importance for this and other SLE-related diseases, including antiphospholipid syndrome or lupus nephritis. In this minireview, the current knowledge on the relationships between microbes and SLE and SLE-related diseases is compiled and discussed.

Keywords: dietary intervention; intestinal microbiota; molecular mimicry; systemic lupus erythematosus; toll-like receptors.

Figure 1

Evidences of the role of the commensal microbiota in SLE pathogenesis. (A) Antibody titers were increased in SLE patients, being those recognizing the gut microbiota decreased during the disease episodes, probably after binding to certain bacterial members (12). (B) Cell wall deficient forms (CWD) of commensal bacteria were isolated from skin lesions in LE patients (20), and Helicobacter pylori was isolated in the 67% of kidney biopsies from a LN cohort (25). (C) In the pristane animal model of SLE, production of autoantibodies was lower and delayed, in germ-free versus control mice (27). (D) Injection of LPS in mice induced production of anti-dsDNA antibodies (22).

Figure 2

Main mechanisms of potential influence of the intestinal microbiota in the framework of autoimmune diseases. (A) The immunomodulatory effect of the intestinal microbiota is highly dependent on its composition and on the immunological status of the host. Some bacteria trigger downstream effector responses, such as Th1, Th17, or Th2, whereas other acts by expanding the subset of regulatory T cells. Expression of certain receptors recognizing bacterial and viral DNA, mainly TLR7 and TLR9, is increased in the context of SLE. (B) Superantigens are molecules activating both innate (represented by a dendritic cell) and adaptative immunity (represented by a T-cell clone), being this the mechanism of action of some pathogens notably at the level of the upper respiratory tract. (C) Infection of the Epstein–Barr virus in B cells could be responsible for the increased levels of interferon gamma observed in the serum of certain SLE patients. IFNγ is produced mainly by natural killer and natural killer T cells during innate immune response and by CD4⁺ Th1 and CD8⁺ cytotoxic T lymphocyte cells during adaptative immune response. (D) Autoreactive B and T cells may be activated by antigens from bacterial origin leading to production of auto antibodies. This similarity between certain bacteria antigens, such as peptides (represented by the gray sphere) and autoantigens at the molecular level, is denominated molecular mimicry. Clearance of immune complexes is directly related to damages at the kidney level. In a context of autoimmunity, increased production of autoantibodies involves higher formation of such complexes.