Role of the commensal microbiota in normal and pathogenic host immune responses

Abstract

The commensal microbiota that inhabit different parts of the gastrointestinal (GI) tract have been shaped by coevolution with the host species. The symbiotic relationship of the hundreds of microbial species with the host requires a tuned response that prevents host damage, e.g., inflammation, while tolerating the presence of the potentially beneficial microbes. Recent studies have begun to shed light on immunological processes that participate in maintenance of homeostasis with the microbiota and on how disturbance of host immunity or the microbial ecosystem can result in disease-provoking dysbiosis. Our growing appreciation of this delicate host-microbe relationship promises to influence our understanding of inflammatory diseases and infection by microbial pathogens and to provide new therapeutic opportunities.

Figure 1. Schematic of intestinal immune system cells discussed in this review

Cryptopatches consist of RORγt⁺ lymphoid tissue inducer cells (that comprise one of the subsets of ILCs) and dendritic cells (whose precise phenotype has not been determined). Signals transmitted from microbiota to cryptopatches result in influx of B lymphocytes, to form isolated lymphoid follicles (not shown in the figure). Induced Treg cells control the expansion and effector activity of Th1 and Th17 cells as well as ILCs. TCRγδ cells are not shown, but also contribute to inflammatory cytokine production.

Figure 2. Examples of how commensal or pathogenic microbiota can influence immune homeostasis in the gut

SFB and various clostridia can induce accumulation of Th17 or iTreg, respectively. Commensal bacteria like Prevotella do not associate with the epithelium unless there is dysbiosis, as observed in mice with mutations in NLRP6 or IL18. Such bacteria may elicit antigen-specific iTreg cells, preserving immune tolerance to the microbiota. It is hypothesized that displacement of the bacteria to the epithelial surface results in inflammatory signals and changes in the epithelial permeability. Invasive bacteria like Klebsiella or Citrobacter are typically held in check by the host immune system, but can breach the epithelium when pathways related to Th17 cells or ILCs are compromised.

Figure 3. Factors involved in maintenance or disruption of the mutualistic balance of host functions and the microbiota

The schematic depicts the homeostasis that exists between microbiota (including both commensals and ‘pathobionts’), components of host immunity and the host tissue (represented with blue arrows). This homeostasis can be disturbed and dysbiosis introduced (represented by black arrows) by extrinsic factors, including antibiotics, diet, environments toxins and acute enteric pathogens, and intrinsic factors such as the host’s genetic makeup. Understanding and manipulating these parameters to reset homeostasis could be exploited as strategies to reverse the deleterious consequences of infection with pathogens or antibiotic-induced dysbiosis.