Interaction between microbiota and immunity in health and disease

Abstract

The interplay between the commensal microbiota and the mammalian immune system development and function includes multifold interactions in homeostasis and disease. The microbiome plays critical roles in the training and development of major components of the host's innate and adaptive immune system, while the immune system orchestrates the maintenance of key features of host-microbe symbiosis. In a genetically susceptible host, imbalances in microbiota-immunity interactions under defined environmental contexts are believed to contribute to the pathogenesis of a multitude of immune-mediated disorders. Here, we review features of microbiome-immunity crosstalk and their roles in health and disease, while providing examples of molecular mechanisms orchestrating these interactions in the intestine and extra-intestinal organs. We highlight aspects of the current knowledge, challenges and limitations in achieving causal understanding of host immune-microbiome interactions, as well as their impact on immune-mediated diseases, and discuss how these insights may translate towards future development of microbiome-targeted therapeutic interventions.

Fig. 1. Intestinal microbiota-immunity interplay in homeostasis.

Selected mechanistically well-characterized microbiota-immune system interactions are depicted. Microbiome-derived TLR and NOD ligands and metabolites (e.g., SCFA, AhR ligands) act directly on enterocytes and intestinal immune cells, but can also reach remote tissues via the systemic circulation to modulate immunity. Foxp3⁺ Treg cells and Tfh/ex-Th17 cells localize in Peyer’s patches to promote class switch of B cells and production of secretory (s)IgA. These contribute to compartmentalization of commensal microbiota and regulate homeostatic microbiota composition. Intestinal colonization by SFB and many other commensals promotes differentiation of CD4⁺ Th17 cells. Moreover, SFB colonization elicits signaling via the ILC3/IL-22/SAA1/2 axis to induce IL-17A production by RORγt⁺ Th17 cells. ILC3-derived IL-22 contributes to containment of specific microbiota members by promoting IL-17A production by Th17 cells. Furthermore, deletion of ILC3-expressed MHCII activates commensal-specific CD4⁺ T cells to prevent an immune response against harmless colonizers. Early-life microbial colonization limits the expansion of iNKT cells, in part via production of sphingolipids, to prevent potential disease-promoting activity within the intestinal lamina propria and the lungs. Colonization with Bacteroides fragilis, a prominent member of mammalian intestinal microbiota, is able to promote CD4⁺ T cell differentiation and to balance Th1 and Th2 populations, an effect that relies on its PSA. PSA is taken up by lamina propria DCs through a TLR2-dependent mechanism and presented to naïve CD4⁺ T cells. In the simultaneous presence of activated TGF-β, these cells can differentiate to regulatory T cells (iTreg). IL-10 produced by these cells promotes immune homeostasis. Contrarily, IL-23 licensed through the same cascade promotes expansion of pro-inflammatory Th17 cells.

Fig. 2. Dysregulation of microbiome-immunity interaction in disease.

Under the influence of certain environmental factors and host genetic susceptibility, aberrant interactions between the microbiome and the host’s immune system contribute to the development of various immune-mediated disorders. In IBD as an example, antibiotic use or dietary changes, in the presence of genetic susceptibility (e.g., NOD2 mutation), may lead to alterations of the gut microbiome configuration, including decreased richness and perturbed taxonomic and metabolite composition. These microbiome alterations are strongly associated with aberrant mucosal immune responses, including upregulated Th17, Th1 and Th2 type responses, downregulated T regulatory cells, and dysregulated humoral immunity. This may finally result in chronic, clinically-overt intestinal inflammation and tissue injury.

Fig. 3. Microbiome-immunity interaction in extra-intestinal organs.

The gut microbiome and microbiome-associated metabolites translocate from the intestinal lumen to various organs (e.g., liver, brain or lung) through the circulatory system, and subsequently induce tissue-specific local immune responses. In the liver, bacterial LPS is recognized by TLR4 in different cell types, leading to upregulation of various pro-inflammatory chemokines and adhesion molecules. MAMPs influence the number, function and maturation of Kupffer cells, and glycolipid antigen-containing probiotics can activate hepatic NKT cells. The gut-resident pathobiont Klebsiella pneumoniae can translocate and induce Th17 cell responses in the liver. In the CNS, microbiome-derived SCFAs regulate microglial homeostasis, and promote regulatory T cells to counter-regulate CNS autoimmunity. In the lung, SCFA-induced primed myeloid cells translocate to the lung and shape the pulmonary immunological landscape. Clostridium orbiscindens-derived product desaminotyrosine modulates type I IFN signaling. In addition, exposure to different lung-resident microbes (e.g., Pseudomonas, Lactobacillus, pneumotypeSPT) is associated with an enhanced Th17 type response.