MicroRNAs and the regulation of intestinal homeostasis

Abstract

The mammalian intestinal tract is a unique site in which a large portion of our immune system and the 10(14) commensal organisms that make up the microbiota reside in intimate contact with each other. Despite the potential for inflammatory immune responses, this complex interface contains host immune cells and epithelial cells interacting with the microbiota in a manner that promotes symbiosis. Due to the complexity of the cell types and microorganisms involved, this process requires elaborate regulatory mechanisms to ensure mutualism and prevent disease. While many studies have described critical roles for protein regulators of intestinal homeostasis, recent reports indicate that non-coding RNAs are also major contributors to optimal host-commensal interactions. In particular, there is emerging evidence that microRNAs (miRNAs) have evolved to fine tune host gene expression networks and signaling pathways that modulate cellular physiology in the intestinal tract. Here, we review our present knowledge of the influence miRNAs have on both immune and epithelial cell biology in the mammalian intestines and the impact this has on the microbiota. We also discuss a need for further studies to decipher the functions of specific miRNAs within the gut to better understand cellular mechanisms that promote intestinal homeostasis and to identify potential molecular targets underlying diseases such as inflammatory bowel disease and colorectal cancer.

Keywords: homeostasis; host-commensal; immune system; intestine; microRNAs; microbiota.

FIGURE 1

MicroRNAs play important roles within the complex intestinal immune system. They can be expressed within hematopoietic cells in response to inflammatory signals from pattern recognition receptors (PRR) and antigen receptors (AR). In this way, miRNAs can regulate immune responses, including secretion of cytokines, chemokines, and antibodies, all of which affect intestinal homeostasis. Within intestinal epithelial cells (IECs) and other non-hematopoietic intestinal cells, miRNAs are expressed in and regulate pathways involved in secretion of antimicrobial peptides, cell renewal, and barrier permeability, among others. They also may mediate host responses to microbial metabolites, which signal to host cells via metabolite receptors (MR). Many immune signals that induce miRNAs and immune responses within the gut come from the microbiota. Altered commensal populations may mediate different miRNA responses and functions within the intestinal tract.