Intestinal bacteria and the regulation of immune cell homeostasis

Abstract

The human intestine is colonized by an estimated 100 trillion bacteria. Some of these bacteria are essential for normal physiology, whereas others have been implicated in the pathogenesis of multiple inflammatory diseases including IBD and asthma. This review examines the influence of signals from intestinal bacteria on the homeostasis of the mammalian immune system in the context of health and disease. We review the bacterial composition of the mammalian intestine, known bacterial-derived immunoregulatory molecules, and the mammalian innate immune receptors that recognize them. We discuss the influence of bacterial-derived signals on immune cell function and the mechanisms by which these signals modulate the development and progression of inflammatory disease. We conclude with an examination of successes and future challenges in using bacterial communities or their products in the prevention or treatment of human disease.

Figure 1

Intestinal bacteria in mammalian health and disease. Schematic of the known influences of intestinal bacteria on normal mammalian physiology and inflammatory disease states.

Figure 2

The composition of bacterial communities along the length and between luminal and mucosal compartments of the mammalian intestine. Stool pellet, luminal content, or mucosal-associated communities were sterilely collected. Total sample DNA was extracted and bacterial 16S rRNA gene fragments were PCR amplified with bar code–tagged primers and subjected to pyrosequencing, and taxonomic assignments for each sequence were obtained using RDP Classifier. (a) Commonly found bacteria in the murine colon. (b) Relative frequencies and distribution of bacteria along the length of the murine colon and in murine stool samples. (c) Relative frequencies and distribution of bacteria between luminal and mucosal-associated compartments of the murine colon. Adapted from Reference .

Figure 3

Innate receptors and signaling cascades of mammalian intestinal epithelial cells (IECs). Schematic shows the location of innate pattern-recognition receptors and their signaling cascades in mammalian IEC. Innate pattern-recognition receptors converge on a common NF-κB signaling cascade to regulate transcription of proinflammatory cytokines and chemokines.

Figure 4

The mucosal immune system of the mammalian intestine. Innate recognition of signals from intestinal bacteria takes place at the intestinal epithelium, in the lamina propria, and in gut-associated lymphoid tissues such as Peyer’s patches and isolated lymphoid follicles. Specialized intestinal epithelial cells known as M (microfold) cells overlie Peyer’s patches and lymphoid follicles to facilitate luminal sampling and to transport microbial components to professional antigen-presenting cells present in the subepithelial dome (SED). Dendritic cells (DCs) in the SED and perifollicular area (PFA) acquire antigens and influence adaptive responses. Additionally, specialized DC subsets directly sample luminal antigens. Intestinal DCs transport antigens to mesenteric lymph nodes through the afferent lymphatic system. DCs in the mesenteric lymph node promote differentiation of regulatory and effector T lymphocytes, as well as class switching of B lymphocytes, which then exit through the efferent lymph into the systemic circulation. Some of these cells home back to the intestine, where they exert their effector functions.