Regulation of lung immunity and host defense by the intestinal microbiota

Abstract

Every year in the United States approximately 200,000 people die from pulmonary infections, such as influenza and pneumonia, or from lung disease that is exacerbated by pulmonary infection. In addition, respiratory diseases such as, asthma, affect 300 million people worldwide. Therefore, understanding the mechanistic basis for host defense against infection and regulation of immune processes involved in asthma are crucial for the development of novel therapeutic strategies. The identification, characterization, and manipulation of immune regulatory networks in the lung represents one of the biggest challenges in treatment of lung associated disease. Recent evidence suggests that the gastrointestinal (GI) microbiota plays a key role in immune adaptation and initiation in the GI tract as well as at other distal mucosal sites, such as the lung. This review explores the current research describing the role of the GI microbiota in the regulation of pulmonary immune responses. Specific focus is given to understanding how intestinal "dysbiosis" affects lung health.

Keywords: Gut-Lung Axis; dysbiosis; immunology; intestinal microbiota; pulmonary immunology; pulmonary infections.

Figure 1

The intestinal microbiota and the host immune system. Interaction between the immune system and the intestinal microbiota. Multiple immune effectors function together to minimize bacterial-epithelial invasion. These include the mucus layer, epithelial antibacterial proteins, and IgA secreted by lamina propria plasma cells. Compartmentalization is accomplished by unique anatomic adaptations that limit commensal bacterial exposure to the immune system. Some microbes are sampled by intestinal DCs. The loaded DCs traffic to the mesenteric lymph nodes through the intestinal lymphatic but do not migrate to distal tissues. This compartmentalizes live bacteria and induction of immune responses to the mucosal immune system. Induced B cells and T cell subsets recirculate through the lymphatic and the bloodstream back to mucosal sites, where B cells differentiate into IgA-secreting plasma cells. Thus, the intestinal microbiota shapes host mucosal as well as systemic immunity. ILFs, isolated lymphoid follicles.

Figure 2

Intestinal dysbiosis affects systemic immune responses. A model for the regulatory influence of the gastrointestinal microbiota on systemic immune responses. Antigens are processed by GI tract dendritic cells (DC). The DC then promote the proliferation and expansion of various T cell subsets in response to antigens. T cells then home to sites of infection or antigen exposure. Optimal inflammatory/non-inflammatory conditions and the production of various bacterial metabolites are affected by the composition of the intestinal microbiota. Disruptions in the intestinal microbiota (dysbiosis) lead to impaired proliferation and expansion of T cell subsets, increased inflammation, and loss or imbalance of bacterial metabolites, all of which can have a negative impact on health and systemic immune response.

Figure 3

Conceptual figure of the gut-lung axis. Proposed model for the regulatory influence of the gastrointestinal microbiota on the immunology of the lung. Microbes in the intestine are sampled by DCs either directly from the lumen or following translocation through M cells to the GALT. A combination of signals from the microbes results in phenotypic changes in the DCs and migration to the draining lymph node. DCs promote the activation of various T cell subsets within the MLN and the production of various regulatory cytokines such as IL-10, TGF-β, INFγ, and IL-6. T cell subsets then acquire immune homing molecules (i.e., CCR9, CCR4, and CCR9). Following immune challenge in the airway, cells activated in the GALT and MLN traffic to the respiratory mucosa via CCR4 or CCR6 where they promote protective and anti-inflammatory responses. In addition, bacterial derived products such as LPS can bind to TLR present on both intestinal epithelial cells and macrophages, leading to the production of various cytokines and chemokines. TLR activation also includes the expression of NF-kB in macrophages. Production of various bacterial metabolites (e.g., SCFAs) also affect the gut-lung axis, as these products are transported to the lung, where they can alter the levels of inflammation.