Nishant Mehta Ph.D. candidate

The immune system is responsible for detecting and destroying foreign pathogens with the ultimate goal of protecting the host from harm. Through a stringent process of T cell selection, the human immune system is largely depleted of cells that could attack the host, preventing autoimmunity in healthy individuals. The immune cells that remain are ready to defend against foreign invaders such as bacteria, viruses, and fungi. This begs the question: since the human gut contains around 1014 bacteria[1], why does the immune system refrain from attacking these cells and clearing them from the digestive tract? At first glance, we would expect immune cells to constantly wage war with the billions of bacteria we ingest every day. Fortunately for us, humans have evolved intricate immune-mediated mechanisms to preserve and enrich the microbiota in our gut while still protecting the rest of the body from opportunistic invasion. The microbiota, in turn, play an integral role in regulating the immune system.

Microbes in the gut are essential for healthy digestion and therefore must be protected against immune system clearance. There are two main methods of microbiota protection: stratification and compartmentalization. Stratification is the physical separation of gut bacteria from areas of immune activity. Compartmentalization is the containment of immune responses to intestinal sites to prevent widespread, systemic immune activation. Successful stratification is dependent on gut anatomy. The intestinal lumen is the cavity that is exposed to digesting food and commensal bacteria. A layer of epithelial cells joined together via tight junctions lines the outside of the lumen and serves as a protective barrier between the gut and blood circulation of the host. In the large intestine, there are two mucus layers that serve as physical barriers between the lumen and epithelial cells.

Bacteria can penetrate the outer, looser mucus layer but rarely pass through the firm, inner layer[2]. In the small intestine, a single mucus layer impedes bacterial penetration of the epithelial cell layer[3]. Stratification also depends on the activity of dendritic cells (DCs), i.e., cells responsible for surveying the environment and notifying the immune system of threats. These dendritic cells reach across the epithelial cell layer and sample bacteria that have penetrated the inner mucus layer. By engulfing sample bacteria and displaying bacterial fragments to other immune cells in intestinal lymph nodes, these DCs induce the production of secretory IgA antibodies. Secretory IgA can cross the epithelial cell layer and bind to encroaching bacteria, thereby preventing their migration across the epithelial barrier[4].

Even with bacteria-resistant mucus layers and protective secretory IgA antibodies, a small number of bacteria can successfully traverse the epithelial cell blockade. In the event of bacterial infiltration, the immune system is locally stimulated to clear the invaders without inducing systemic inflammation that could be harmful to the organism. This compartmentalization of the immune response is achieved through local macrophages and lymphoid cells that reside in tissues just outside of the epithelial cell layer. Lamina propria macrophages can engulf bacteria and lymphoid cells release a molecule called IL-22 that prevents bacterial passage into the blood stream[5], [6].

In addition to controlling the location of gut bacteria, the immune system can also directly modulate microbial composition. Epithelial cells have been shown to secrete antibacterial peptides called α-defensins that can alter the species of microbes present in the gut[7]. The influence of immune system on microbiota is also demonstrated through experiments with immune-deficient mice. Mice that are missing an important transcription factor called T-bet and are without a functional adaptive immune system (T cells and antibodies) spontaneously develop ulcerative colitis. Microbes from these mice can then be passed on to mice with functioning immune systems and the disease is passed on along with the bacteria[8]. It is hypothesized that a functioning immune system is necessary to prevent the microbial community from becoming too dysbiotic, i.e., problematic enough to cause inflammatory bowel disease.

It is clear now that the immune system is structured to modulate and protect gut microbiota. Remarkably, new evidence also proves the inverse is true: bacteria in the gut directly influence the immune system. The gut is maintained through a system of checks and balances between proinflammatory cells that secrete immune-stimulating molecules and anti-inflammatory cells that turn down the immune response. Colonization of mice with segmented filamentous bacteria (SFB) results in an inflation of pro-inflammatory T cells [9], while colonization of mice with Clostridial bacterial strains results in an increase in immunosuppressive regulatory T cells (Tregs)[10]. These two experiments show how the ratio of individual strains of bacteria can alter the inflammatory signature of the gut. The balance between stimulation and down-regulation is especially critical in the intestines because a lopsided pro-inflammatory response can lead to inflammatory bowel disease[11].

In addition to influencing immune cells in and around the gut, commensal bacteria can also affect the immune system globally. Recent animal studies have shown that gut microbes contribute to systemic autoimmune diseases such as arthritis and experimental autoimmune encephalomyelitis (EAE, a mouse model of multiple sclerosis). Germ-free mice, or mice that lack commensal bacteria, have a significant decrease of disease in models of arthritis, EAE, and colitis [12], [13]. It is thought that autoimmune T cells are generated in the gut in response to the bacteria present. These auto-reactive cells can then enter the blood stream to induce disease in distal locations. Additionally, as discussed in a previous blog post about the hygiene hypothesis, commensal gut bacteria can have a significant impact on the allergic response. An altered diversity of microbes in the gut of young children has been linked with a heightened risk of allergy[14]. The mechanism is still unknown, but it is thought that strong immune activation against microbes in the gut during infancy can inhibit weaker immune responses against allergens simply due to resource allocation issues.

A healthy microbiome is essential for many aspects of overall health. In this article, we review some of the inherent connections between the immune system and microbes that live in the gut. Humans possess a highly evolved immune system that prevents the spread of gut bacteria while still allowing them to thrive inside the gut lumen. The composition and density of gut bacteria can, in turn, influence inflammatory signatures in the gut, drive autoimmunity, and even prevent allergic responses. The intricate relationship between immune system and gut bacteria is just another reason to prioritize the health of your own microbiome.

References:

[1] I. Koboziev, C. Reinoso Webb, K. L. Furr, and M. B. Grisham, “Role of the enteric microbiota in intestinal homeostasis and inflammation,” Free Radic. Biol. Med., vol. 68, pp. 122–133, Mar. 2014.

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[8] W. S. Garrett et al., “Communicable Ulcerative Colitis Induced by T-bet Deficiency in the Innate Immune System,” Cell, vol. 131, no. 1, pp. 33–45, Oct. 2007.

[9] V. Gaboriau-Routhiau et al., “The Key Role of Segmented Filamentous Bacteria in the Coordinated Maturation of Gut Helper T Cell Responses,” Immunity, vol. 31, no. 4, pp. 677–689, Oct. 2009.

[10] K. Atarashi et al., “Induction of Colonic Regulatory T Cells by Indigenous Clostridium Species,” Science, vol. 331, no. 6015, pp. 337–341, Jan. 2011.

[11] E.-O. Glocker et al., “Inflammatory Bowel Disease and Mutations Affecting the Interleukin- 10 Receptor,” N. Engl. J. Med., vol. 361, no. 21, pp. 2033–2045, Nov. 2009.

[12] Y. K. Lee, J. S. Menezes, Y. Umesaki, and S. K. Mazmanian, “Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis,” Proc. Natl. Acad. Sci., vol. 108, no. Supplement 1, pp. 4615–4622, Mar. 2011.

[13] H.-J. Wu et al., “Gut-Residing Segmented Filamentous Bacteria Drive Autoimmune Arthritis via T Helper 17 Cells,” Immunity, vol. 32, no. 6, pp. 815–827, Jun. 2010.

[14] J. Penders et al., “Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study,” Gut, vol. 56, no. 5, pp. 661–667, May 2007.