Autoimmunity and the gut

Abstract

Autoimmune diseases have increased dramatically worldwide since World War II. This is coincidental with the increased production and use of chemicals both in industrial countries and agriculture, as well as the ease of travel from region to region and continent to continent, making the transfer of a pathogen or pathogens from one part of the world to another much easier than ever before. In this review, triggers of autoimmunity are examined, principally environmental. The number of possible environmental triggers is vast and includes chemicals, bacteria, viruses, and molds. Examples of these triggers are given and include the mechanism of action and method by which they bring about autoimmunity.

Figure 1

The triangle of autoimmune triggers. Gut dysbiosis and genetic and environmental factors play major roles in the development of autoimmune diseases.

Figure 2

The composition of the intestinal microbiota is involved in the regulation of immune homeostasis. (a) Signals from different components of the microbiota (different colored arrows) regulate different branches of mucosal T cell response (corresponding color immune cells) in the lamina propria. (b) Changes in the composition of commensal bacteria, for example, the introduction of segmented filamentous bacteria (SFB), effect a change in the immune homeostasis, in this case, increasing the signals mediating induction of Th17 cells (purple arrows). This changes the immunological fitness of the individual. In the case of SFB, the increased production of Th17 cell effector cytokines, for example, IL-17 and IL-22, and the consecutive increase in antimicrobial peptide production from epithelial cells (red circles) increase the ability of the host to fight off intestinal infections. However, this increase in proinflammatory cytokines may also render the host more susceptible to chronic autoimmune inflammation. In this way, differences in the composition of the commensal bacteria in the gut may account for differences in individual response in the face of similar environmental challenges. (Adapted from: Ivanov I, Littman D. Segmented filamentous bacteria take the stage. Mucosal Immunology, 3(3):209-12, 2010.).

Figure 3

Commensal bacteria induce CD4+ T cell differentiation. Naïve CD4+ T cells can differentiate into four major cell types: Th1, Th2, Tregs, and Th17. The differentiation of each lineage requires the induction of a transcription factor that is unique to each lineage. Once differentiated, each lineage secretes a special set of cytokines. Th1 cells play an important role in eliminating intracellular pathogens while Th2 function to control parasitic infection. The primary role of Th17 is to control infection, while that of Tregs is to regulate immune response. The type of bacteria species that has been shown to induce a particular T cell differentiation pathway is also shown. (Adapted from Wu H, Wu E. The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes 3 : 1, 4-14, 2012.).

Figure 4

How segmented filamentous bacteria (SFB) can change the ratio between Th17 and Tregs, leading to autoimmunity.

Figure 5

The interconnection of the gut, brain, and microbiota.

Figure 6

Impact of the gut microbiota on the gut-brain axis in health and disease. It is now generally accepted that a stable gut microbiota is essential for normal gut physiology and contributes to appropriate signaling along the gut-brain axis and, thereby, to the healthy status of the individual (a). On the other hand (b), intestinal dysbiosis can adversely influence gut physiology, leading to inappropriate gut-brain axis signaling and associated consequences for CNS functions and resulting in disease states. Conversely, stress at the level of the CNS can affect gut function and lead to perturbations of the microbiota. (Adapted from: Cryan J, Dinan T. Mind-altering microorganisms: the impact of the gut microbiota on brain and behavior. Nat Rev Neurosci., 13(10):701-12, 2012.).