Microbiota-immune system interaction: an uneasy alliance

Abstract

An estimated 100 trillion microbes colonize human beings, with the majority of organisms residing in the intestines. This microbiota impacts host nutrition, protection, and gut development. Alterations in microbiota composition are associated with susceptibility to various infectious and inflammatory gut diseases. The mucosal surface is not a static barrier that simply prevents microbial invasion but a critical interface for microbiota-immune system interactions. Recent work suggests that dynamic interactions between microbes and the host immune system at the mucosal surface inform immune responses both locally and systemically. This review focuses on intestinal microbiota-immune interactions leading to intestinal homeostasis, and show that these interactions at the GI mucosal surface are critical for driving both protective and pathological immune responses systemically.

Figure 1. Mechanisms of host-bacterial sensing at the intestinal mucosal surface

The host uses several mechanisms to sense and respond to the microbiota. Anatomically, a single epithelial layer separated the host from the intestinal lumen contents, which include food, microbes and microbial antigens. The epithelium secretes a protective mucus layer. The dense inner layer excludes most bacteria, but specific species may penetrate this protection and directly contact the epithelium. Dendritic cells underlay the epithelial surface and can sample antigen delivered by M-cells (not shown), or extend their dendrites into the lumen for direct antigen sampling. Dendritic cells, Paneth cells, and enterocytes express pattern recognition receptors on their surfaces and intracellularly, to detect microbial associated molecular patterns such as LPS, MDP, and CpG DNA.

Figure 2. Bacteria-AMP feedback loops maintain intestinal homeostasis

Several bacterial-host feedback loops function at mucosal surfaces to maintain homeostasis. A. Bacterial colonization of the intestinal tract stimulates pattern recognition receptors on intestinal epithelial cells, including Paneth cells. Stimulation of MyD88 dependent TLR pathways results in induction of epithelial AMPs, which then act to prevent bacterial translocation. B. Paneth cell AMPs regulate SFB (and other bacterial species) abundance. SFB colonization triggers DC-dependent Th17 differentiation. IL22, a Th17 cytokine, acts on intestinal epithelial cells and Paneth cells to increase expression of AMPs. AMPs then act to modulate abundance of SFB. Imbalance in this regulatory loop can skew the regulatory/inflammatory balance, resulting in loss of homeostasis, and increased pro-inflammatory responsiveness both locally and systemically.

Figure 2. Bacteria-AMP feedback loops maintain intestinal homeostasis

Several bacterial-host feedback loops function at mucosal surfaces to maintain homeostasis. A. Bacterial colonization of the intestinal tract stimulates pattern recognition receptors on intestinal epithelial cells, including Paneth cells. Stimulation of MyD88 dependent TLR pathways results in induction of epithelial AMPs, which then act to prevent bacterial translocation. B. Paneth cell AMPs regulate SFB (and other bacterial species) abundance. SFB colonization triggers DC-dependent Th17 differentiation. IL22, a Th17 cytokine, acts on intestinal epithelial cells and Paneth cells to increase expression of AMPs. AMPs then act to modulate abundance of SFB. Imbalance in this regulatory loop can skew the regulatory/inflammatory balance, resulting in loss of homeostasis, and increased pro-inflammatory responsiveness both locally and systemically.