Interplay between inflammation, immune system and neuronal pathways: effect on gastrointestinal motility

Abstract

Sepsis is a systemic inflammatory response representing the leading cause of death in critically ill patients, mostly due to multiple organ failure. The gastrointestinal tract plays a pivotal role in the pathogenesis of sepsis-induced multiple organ failure through intestinal barrier dysfunction, bacterial translocation and ileus. In this review we address the role of the gastrointestinal tract, the mediators, cell types and transduction pathways involved, based on experimental data obtained from models of inflammation-induced ileus and (preliminary) clinical data. The complex interplay within the gastrointestinal wall between mast cells, residential macrophages and glial cells on the one hand, and neurons and smooth muscle cells on the other hand, involves intracellular signaling pathways, Toll-like receptors and a plethora of neuroactive substances such as nitric oxide, prostaglandins, cytokines, chemokines, growth factors, tryptases and hormones. Multidirectional signaling between the different components in the gastrointestinal wall, the spinal cord and central nervous system impacts inflammation and its consequences. We propose that novel therapeutic strategies should target inflammation on the one hand and gastrointestinal motility, gastrointestinal sensitivity and even pain signaling on the other hand, for instance by impeding afferent neuronal signaling, by activation of the vagal anti-inflammatory pathway or by the use of pharmacological agents such as ghrelin and ghrelin agonists or drugs interfering with the endocannabinoid system.

Figure 1

Hypothetical scheme of the complex interplay between, on the one hand residential macrophages (red), mast cells (blue), glial cells (green) and the recruitment of inflammatory cells (yellow), and on the other hand the activation of neuronal reflex pathways (black). Mediators involved in the different cell populations are marked in the same color as the cell type involved. NO: Nitric oxide; PG: Prostaglandins; SP: Substance P; CGRP: Calcitonin gene-related peptide; GABA: γ-aminobutyric acid; NGF: Neuropeptides, growth factors; PAF: Platelet-activating factor; TRPV: Transient receptor potential channel of the vanilloid subtype; nAChR: Nicotinic acetylcholine receptor.