The Mucosal Immune System: Master Regulator of Bidirectional Gut–Brain Communications

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 Immune System as Gatekeeper

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). 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.

Pathological Gut–Brain Interactions

The pathological repercussions of disordered gut–brain dialogue are probably especially pertinent in functional gastrointestinal diseases, including IBS and functional dyspepsia. Common gastrointestinal diseases, such as IBS, functional dyspepsia and IBD, are closely linked to psychological morbidity. This link is driven in part through bidirectional signalling between the brain and gut, which reciprocally regulate each other. Growing evidence implicates the importance of immune activation, which might be overt or more subtle in pathological gut–brain interactions.

Comparison of Immune Activation in Gastrointestinal Diseases

According to the evidence, immune activation varies by condition:

• Inflammatory Bowel Disease (IBD): Characterized by overt immune activation.
• Irritable Bowel Syndrome (IBS): Characterized by more subtle immune activation.
• Functional Dyspepsia: Characterized by more subtle immune activation.

Microbiota and Therapeutic Targeting

The composition of the intestinal microbiota affects behaviour and mood, which could in part rely on selective activation of distinct host cytokine responses. Furthermore, the gut microbiota directly influences T-cell differentiation. New insights into these pathways might lead to novel treatment strategies in these common gastrointestinal diseases. Therapeutic targeting of gut microorganisms, host immunity or psychological symptoms could hold the key to uncoupling pathological interactions between the gut and brain.