Microbial activation of gut dendritic cells and the control of mucosal immunity

Abstract

Current data support a role for gut colonization in maintaining balanced mucosal and systemic immune responses and have suggested aberrant innate immune recognition of enteric bacteria as an initiator of the adaptive immune damage associated with inflammatory bowel disease (Crohn's disease and ulcerative colitis). In fact, data from human studies and experimental mouse models have implicated transformation of the gut microbiota from a beneficial symbiotic state to one of imbalance or "dysbiosis" in the pathogenesis of several autoinflammatory diseases, including allergic skin and respiratory disorders, rheumatoid arthritis, type I diabetes, and colorectal cancer. The host has evolved to co-exist and maintain a mutualistic relationship with the commensal microbes of the gut, and it is the function of the host innate immune system to initiate and maintain this homeostasis, while retaining the ability to respond appropriately to pathogenic organisms. In this review, we discuss the molecular and cellular interactions of the mucosal immune system that decide this delicate balance of mutualism. Furthermore, we will highlight the role of dendritic cells in preserving this precarious balance and how gene products of commensal microbes may play an integral role in re-establishing this balance once it has gone awry.

FIG. 1.

Composition of intestinal microbiome in the gastrointestinal tract. The estimated numbers of colony-forming units of bacteria/gram of luminal contents and most prevalent bacterial phyla in that location are shown. The numbers are low in the gastric juices of the stomach and then steadily increase abroad, with the highest numbers found in the colon (Hakansson and Molin 2011).

FIG. 2.

Differential activation of dendritic cells (DCs) by microbial communities. DCs can be activated by pathogenic bacteria to induce protective immunity via Th1/Th17 polarization; conversely, beneficial bacteria or their gene products can activate DCs to induce the development of Tregs, which will control the functions of protective Th1 and Th17 immune responses.

FIG. 3.

Overview of dysfunctional homeostasis that occurs during inflammatory bowel diseases (IBD). Microbial dysbiosis in IBD can be elicited by a reduced prevalence of putative beneficial bifidobacteria with concomitant increase in sulfate-reducing bacteria. The respiration of human colonocytes is dependent on butyrate oxidation. H₂S impairs this oxidation of butyrate, leading to pathologic changes, including increased epithelial permeability and leakage, by which increased numbers of bacteria and their gene products (e.g., lipopolysaccharide [LPS]) enter the lamina propria, which demonstrates immune dysfunction due, in part, to low levels of IgA. Insufficient bacterial clearance may result in pattern recognition receptor (e.g., TLR, C-type lectins, NOD) stimulation, and increased levels of pro-inflammatory cytokines and stimulatory molecules in innate immune cells, which then activate pathogenic T-cell responses. In addition, dysfunctional regulatory responses that are dictated by regulatory DCs and Tregs lead to breakdown of immune tolerance, amplifying the recruitment of neutrophils and pro-inflammatory T-cell subsets (Th1, Th17, pro-inflammatory Tregs), all of which result in devastating disease progression.