Gut Barrier: Innate Immunity

27.1

Introduction

The gastrointestinal barrier is more than a tissue with physiological function. As reviewed by others, it is now recognized as a complex ecosystem that requires a delicate homeostatic balance in order for the tissue to remain healthy and functional. The niche involves a multifaceted and dynamic mixture of host cells and molecules; microbes and their metabolites; as well as environmental factors that may reflect diet or contamination with toxins. Furthermore, gene expression in the host can modulate transcription in microbes resulting in changes in the metabolic profile and local immune responses that resonate throughout the body. Thus, these biological spheres are highly interconnected. A more recent and important concept is that the microbial-host interactions that begin in the digestive tract not only impact gastrointestinal inflammation and risks of local cancer, but they also affect the hosťs susceptibility to conditions ranging from diabetes, obesity to various neurological conditions.

Part of the role of the barrier is to confer innate immunity to protect the host from “danger” such as that threatened by a microbial challenge. This immunity entails a physical barrier as well as host responses that are either produced constitutively or induced in response to changes in the local ecosystem. While innate immunity may have evolved to protect the host from infection, its responses transition to adaptive immunity that enhances the health of the gastrointestinal tissues. However, sometimes protection is misguided to immune-mediated disease.

27.2

Composition of the Barrier

We propose a broader definition of the “barrier” than the single epithelial cell layer on the luminal surface of the gut. Overlying the epithelium is a biofilm—a mixed community of microbes that live in a complex relationship with the host and each other. This film is found adjacent to the apical surface and presumably thrives there due to the nutrients provided, in part, by the host and neighboring organisms. Protective microbes within the biofilm can occupy the niche and block colonization by pathogens or inhibit the growth of other organisms through the production of various antibiosis molecules. The important role for commensal organisms is illustrated by the increase in disease in mice treated with streptomycin and infected with Salmonella typhimurium. Further, the chronic diarrhea caused by C. difficile in humans after prolonged antimicrobial therapy is often effectively treated by restoring the microbiota with a fecal transplant while gastric microbiota in children have been suggested to limit the inflammation induced by infection with H. pylori. Mucus is another important element that contributes to the barrier. It provides a physical impediment to particle entry as well as serving as an “antiseptic paint” containing antimicrobial factors produced by the host. For example, mucus secretions contain antimicrobial peptides (defensins) from Paneth cells (PC) ; secretory IgA transported by epithelial cells ; and other protective molecules including lactoferrin and lysozyme.

Some microbes negotiate their way past the biofilm and mucus to become juxtaposed next to the epithelial layer. Indeed, this migration allows H. pylori to escape the harsh acidity in the lumen of the stomach by colonizing the more comfortable pH sanctuary under the mucus. In this niche, the gastric epithelium can alter gene expression in H. pylori to favor their colonization and subsequent molecular interactions affecting the sensing and the bi-directional interactions that define the relationship.

An important consideration, as covered elsewhere in this text, is the multiple lineages of epithelial cells including absorptive and secretory cells, goblet cells, enterochrommaffin cells, as well as more regionally limited, and highly specialized cells such as Paneth and parietal cells. All of these subsets contribute to the barrier and have been implicated, in one way or another, in innate immunity. This heterogeneity, along with the microbial diversity and complex metabolic profile in the lumen and adjacent tissue, contributes to the breadth of the innate responses that can be induced in the gut barrier.