The mucosal immune system: master regulator of bidirectional gut–brain communications

Abstract

Communication between the brain and gut is not one-way, but a bidirectional highway whereby reciprocal signals between the two organ systems are exchanged to coordinate function. The messengers of this complex dialogue include neural, metabolic, endocrine and immune mediators responsive to diverse environmental cues, including nutrients and components of the intestinal microbiota (microbiota-gut-brain axis). We are now starting to understand how perturbation of these systems affects transition between health and disease. The pathological repercussions of disordered gut-brain dialogue are probably especially pertinent in functional gastrointestinal diseases, including IBS and functional dyspepsia. New insights into these pathways might lead to novel treatment strategies in these common gastrointestinal diseases. In this Review, we consider the role of the immune system as the gatekeeper and master regulator of brain-gut and gut-brain communications. Although adaptive immunity (T cells in particular) participates in this process, there is an emerging role for cells of the innate immune compartment (including innate lymphoid cells and cells of the mononuclear phagocyte system). We will also consider how these key immune cells interact with the specific components of the enteric and central nervous systems, and rapidly respond to environmental variables, including the microbiota, to alter gut homeostasis.

Functional dyspepsia

“…Increased CD4 + T helper 2 (T H 2) cell response is a potent producer of key cytokines (IL-4, IL-5 and IL-13) that are involved in recruiting and activating eosinophils and mast cells 97 . Eosinophil and mast cell numbers are increased in the submucosal plexus of the duodenum in patients with functional dyspepsia, and this finding was accompanied by a clear impairment of nerve excitability in the duodenal submucosal plexus -a decreased calcium response to depolarization and electrical stimulation -and could also implicate the central nervous system 54,92 . Blood-borne cytokines from the gut can also signal in the brain, thereby enabling cross-talk between the immune system, brain and gut 54 .…”

“…Innervation of the gastrointestinal tract regulates secretions, sphincter control, motility, blood flow and enteroendocrine function, and the enteric nervous system also communicates with the intestinal barrier via neuroendocrine and mucosal immune cells 54,56 . We discuss these different putative pathophysiological mechanisms in more detail in the following sections.…”

“…Communication between the central nervous system and the enteric nervous system has been recognized for over a century, but the fact that brain-gut communications are bi-directional has only been appreciated more recently 54,55 . Innervation of the gastrointestinal tract regulates secretions, sphincter control, motility, blood flow and enteroendocrine function, and the enteric nervous system also communicates with the intestinal barrier via neuroendocrine and mucosal immune cells 54,56 .…”

“…Eosinophils and mast cells that degranulate next to enteric neurons provide a mechanism for sensory excitation, which can be perceived by the enteric and central nervous systems 54 . Immune activation can still occur in the absence of eosino philia; in this case, only the number of degranulated eosinophils is increased 93 .…”

“…pylori-related dyspepsia is considered a separate entity. However, other prior gastrointestinal infections have been described as triggers of functional dyspepsia, by impairing gastric accommodation (a vagally mediated reflex that occurs postprandially and results in a reduction of smooth muscle tone; the stomach relaxes and provides a reservoir for the meal), possibly via immune mechanisms [51][52][53] .Communication between the central nervous system and the enteric nervous system has been recognized for over a century, but the fact that brain-gut communications are bi-directional has only been appreciated more recently 54,55 . Innervation of the gastrointestinal tract regulates secretions, sphincter control, motility, blood flow and enteroendocrine function, and the enteric nervous system also communicates with the intestinal barrier via neuroendocrine and mucosal immune cells 54,56 .…”