The Gut Microbiota in Control of Autoimmunity

The microbiota is composed of bacteria, fungi, viruses, and other microbial and eukaryotic species which reside in different tissues and biofluids including gut, skin, lung, saliva, oral cavity, kidneys, and reproductive tracts. Of these, the gastrointestinal tract is home to the largest community of bacteria which is estimated to be about 100 trillion cells in humans and outnumbers the host's cells ten-fold.

The host maintains a homeostatic relationship with the microbiota by minimizing the contact between microorganisms and the gut epithelial cell surface. The intestinal epithelium provides a physical barrier between the intestinal lumen and the inside of the body. Goblet cells secrete mucins forming a mucus layer above the epithelial cell layer. In addition, epithelial cells are potent producers of antimicrobial peptides and cytokines.

By Peter Andrey Smith, Boston Globe
Recent studies have shown that microbiota play an important role in controlling different aspects of host physiology including immune responses. Advances in next-generation sequencing led to an understanding of the diversity of microbiota species in health and disease. These studies have shown that each individual harbors a unique microbiome consisting of genes derived from an average of 150 individual bacterial species, each of which includes about 200 strains.

The influence of microbiota on development and maturation of the immune system was demonstrated on germ-free mice which exhibit an underdeveloped immune system associated with reduction in size and number of secondary immune organs including Peyer's patches, altered crypt structure and reduced mucus production by goblet cells. Germ-free mice were further utilized as a model to study the effect of bacteria strains on development of the immune system.
Gut commensals can be subdivided into two major categories, inflammatory and immunoregulatory, depending on their effect on the immune system. Figure 1 describes how the anti-inflammatory or pro-inflammatory responses in the steady state, infection, or inflammation can influence disease formation and progression.

In the steady state, CD103+ mucosal DC cells sample commensal bacteria using pattern-recognition receptors (PRRs), like Toll-Like Receptors. Then CD103+ mucosal cells induce differentiation of Treg cells. In turn, Treg cells block the activation of T helper cells, like Th17 and Tfh cells, and help B cells to produce IgA, restricting the growth or inflammatory effects of commensals. Bacteria strains that have shown immunoregulatory capabilities include Clostridium, Bacteroides fragilis, and Bifidobacterium infantis.

Figure 1. The anti-inflammatory or pro-inflammatory responses
in the steady state or during infection or inflammation.

On the other hand, potentially proinflammatory bacteria strains, like Segmented Filamentous Bacteria (SFB) and Helicobacter hepaticus, can induce differentiation of inflammatory dendritic cells, resulting in expansion of Th1 and Th17 cells. This can lead to the induction of autoimmune diseases within the gut tissue, such as inflammatory bowel disease, Crohn's disease, and colitis, or in distal sites likely due to molecular mimicry between the bacterial and self antigens. Table 1 shows a correlation between some non-gut autoimmune diseases and microbiota.

Table 1. Alterations observed in the microbiota in non-intestinal autoimmune diseases.
Host microbiota are established by many factors including age of the host, genetics, antibiotic usage, sanitary living conditions, and dietary habits. Diet is one of the important factors affecting the composition of microbiota in humans, and therefore, can directly influence the function of the immune system.

Commensals harvest energy from non-digestable dietary components such as starch, cellulose, or xylans providing an additional source of energy for the host. End products of this process include Short Chain Fatty Acids (SCFAs) such as butyrate, propionate, acetate and pentanoate acids. SFCAs provide an energy source for colonic epithelial cells increasing the intestinal epithelial barrier integrity and influence the Treg differentiation as well as T cell cytokine production. Another regulator of lymphocyte response produced by bacteria or triggered upon host cell interaction with bacteria includes Retinoic acid (RA), plant-derived flavonoids and glucosinolates, and gluten.

Comic by Dzu-Doodles
In conclusion, we have discussed an interplay between the gut commensals and the immune system. As you can see, the changes in microbial composition affects host immunity and influences the formation and/or outcome of autoimmunity. A better understanding of human microbiome and its interaction with the host is important for understanding the pathophysiology of human diseases and developing more effective disease treatments.
Contributed by Ekaterina Zvezdova, PhD.
  1. Role of the microbiota in immunity and inflammation
  2. Immune-microbiota interactions in health and disease
  3. The interplay between the gut microbiota and the immune system
  4. The microbiome and innate immunity
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