Role of the microbiota in immunity and inflammation

Abstract

The microbiota plays a fundamental role on the induction, training, and function of the host immune system. In return, the immune system has largely evolved as a means to maintain the symbiotic relationship of the host with these highly diverse and evolving microbes. When operating optimally, this immune system-microbiota alliance allows the induction of protective responses to pathogens and the maintenance of regulatory pathways involved in the maintenance of tolerance to innocuous antigens. However, in high-income countries, overuse of antibiotics, changes in diet, and elimination of constitutive partners, such as nematodes, may have selected for a microbiota that lack the resilience and diversity required to establish balanced immune responses. This phenomenon is proposed to account for some of the dramatic rise in autoimmune and inflammatory disorders in parts of the world where our symbiotic relationship with the microbiota has been the most affected.

Copyright © 2014 Elsevier Inc. All rights reserved.

Figures

Figure 1. The mucosal firewall

1) The mucus represents the primary barrier limiting contact between the microbiota and host tissue and preventing microbial translocation. 2) Epithelial cells produce antimicrobial peptides that also play a significant role in limiting exposure to the commensal microbiota. 3) Translocating commensals are rapidly eliminated by tissue resident macrophages. 4) Commensals can also be captured by CD103+ CD11b+ DCs that traffic to the mLN from the lamina propria but do not penetrate further. Presentation of commensal antigens by these DCs leads to the differentiation of commensal specific regulatory cells (Treg) Th17 cells and IgA producing B cells. Commensal specific lymphocytes traffic to the lamina propria and Peyer’s Patches. In the Peyer’s patches Treg can further promote class switching and IgA generation against commensals. The combination of the epithelial barrier, mucus layer, IgA and DCs and T cells comprises the ‘mucosal firewall’, which limits the passage and exposure of commensals to the Gut-Associated Lymphoid tissue preventing untoward activation and pathology.

Figure 2. Promotion of immune regulation by the microbiota during steady state and inflammation

1) Commensals promote the induction of regulatory T cells via direct sensing of microbial products or metabolites by T cells or dendritic cells. Further commensals promote the induction of Th17 cells that can regulate the function and homeostasis of epithelial cells. In the context of inflammation similar mechanisms may account for the regulatory role of the microbiota. 2) Commensal derived metabolites can have a systemic effect on inflammatory cells. For example, SCFA can inhibit neutrophil activation. Upon entrance in the tissue inflammatory monocytes can also respond to microbial derived ligands by producing mediators such as PGE2 that limit neutrophil activation and tissue damage.

Figure 3. Promotion of protective immunity by the microbiota

The symbiosis between the microbiota and its mammalian host encompasses multiple of relationships including mutualistic, parasitic and commensal. The capacity of a given microbe, including the ones composing the microbiota, to trigger or promote disease is highly contextual and most microbes can shift from mutualist to commensal to parasite according to the state of activation of the host, co-infection or localization. Commensals can control microbes with pathogenic potential (as normal constituent of the microbiota or acquired) via distinct mechanisms. Commensals can compete for nutrients, produce antimicrobial molecules and metabolites that affect the survival and virulence of pathogens. Commensals can promote the production of antimicrobial peptides by epithelial cells and reinforce tight junctions. Commensals can modulate the function of dendritic cells and other innate cells both locally and systemically in a manner that promotes the induction of effector T and B cells responses against pathogens. When uncontrolled, this adjuvant property of the microbiota can promote inflammatory and autoimmune disorders.

Figure 4. Interdependence of diet, immune and microbiota interactions

Evidence now exists for bidirectional communication between the three key factors in the GI tract: Diet, Immune and commensal microflora. Diet can have profound influence on the immune system (e.g. Vitamin A, Vitamin D, AHR), while the immune system can also affect dietary intake. Diet also has dominant influence on the composition and metabolic capacity of commensal bacteria, while this, in return, influences nutrient absorption. The immune system is able to exert control over both commensal composition and localization, while commensal signals are critical for development and function of the immune system.