Exploring the immunomodulatory potential of microbial-associated molecular patterns derived from the enteric bacterial microbiota

Abstract

The human intestinal lumen represents one of the most densely populated microbial niches in the biological world and, as a result, the intestinal innate immune system exists in a constant state of stimulation. A key component in the innate defence system is the intestinal epithelial layer, which acts not only as a physical barrier, but also as an immune sensor. The expression of pattern recognition receptors, such as Toll-like receptors, in epithelial cells allows innate recognition of a wide range of highly conserved bacterial moieties, termed microbial-associated molecular patterns (MAMPs), from both pathogenic and non-pathogenic bacteria. To date, studies of epithelial immunity have largely concentrated on inflammatory pathogenic antigens; however, this review discusses the major types of MAMPs likely to be produced by the enteric bacterial microbiota and, using data from in vitro studies, animal model systems and clinical observations, speculates on their immunomodulatory potential. IntroductionThe intestine represents the body's largest mucosal surface, with the adult human intestine estimated to cover an area of about 250 m 2 (Artis, 2008). The highly folded luminal surface of the intestinal wall significantly increases absorption efficiency and, as such, is the largest surface area of the body exposed to the environment and its high microbial load (DeSesso & Jacobson, 2001). Humans have co-evolved with indigenous microbial populations, termed microbiota, which inhabit various niches of the body (Hooper et al., 2012) and the adult intestine is one of the most densely populated microbial habitations in the biological world (Artis, 2008). The enteric microbiota predominantly consists of bacteria, with estimated populations of~10 14 bacteria, with up to 500 species represented (Gill et al., 2006;Guarner & Malagelada, 2003); however, methanogenic archaea, eukaryotes (yeasts) and viruses (mainly bacteriophages) are also present (Lozupone et al., 2012). Due to the vast expanse of intestinal tissue exposed to the microbiota, the local innate immune system is in a constant state of stimulation, and a chronic, low-level proinflammatory response is characteristic of enteric immune homeostasis (Macpherson & Harris, 2004;Artis, 2008).The intestinal epithelium plays an active role in innate immunity, and pattern recognition receptors (PRRs) are utilized to detect the presence of bacteria and their associated antigens. PRRs are germline-encoded, sensory molecules which recognize a range of highly conserved bacterial motifs, termed 'pathogen-associated molecular patterns' (PAMPs) (Medzhitov, 2001). However, the ability of PRRs to recognize these bacterial moieties is not limited to just pathogens, and so the term 'microbial-associated molecular patterns' (MAMPs) may be more accurate (Medzhitov, 2001; Sanderson & Walker, 2007) and will be used throughout this review. Epithelium-associated, enteric immune cells, such as macrophages, dendritic cells, T-cells and B-cells, differentially express two major groups of PRRs, th...

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