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, 594 (20), 5771-5780

The Intestinal Cholinergic Anti-Inflammatory Pathway


The Intestinal Cholinergic Anti-Inflammatory Pathway

Gera Goverse et al. J Physiol.


The main task of the immune system is to distinguish and respond accordingly to 'danger' or 'non-danger' signals. This is of critical importance in the gastrointestinal tract in which immune cells are constantly in contact with food antigens, symbiotic microflora and potential pathogens. This complex mixture of food antigens and symbionts are essential for providing vital nutrients, so they must be tolerated by the intestinal immune system to prevent aberrant inflammation. Therefore, in the gut the balance between immune activation and tolerance should be tightly regulated to maintain intestinal homeostasis and to prevent hypersensitivity to harmless luminal antigens. Loss of this delicate equilibrium can lead to abnormal activation of the intestinal immune system resulting in devastating gastrointestinal disorders such as inflammatory bowel disease (IBD). Recent evidence supports the idea that the central nervous system interacts dynamically via the vagus nerve with the intestinal immune system to modulate inflammation through humoral and neural pathways, using a mechanism also referred to as the intestinal cholinergic anti-inflammatory pathway. In this review, we will focus on the current understanding of the mechanisms and neuronal circuits involved in the intestinal cholinergic anti-inflammatory pathway. Further investigation on the crosstalk between the nervous and intestinal immune system will hopefully provide new insights leading to the identification of innovative therapeutic approaches to treat intestinal inflammatory diseases.


Figure 1
Figure 1. Schematic overview of the crosstalk between the nervous and immune system in the gastrointestinal tract
The gastrointestinal tract has extensive innervation provided by the enteric nervous system and by extrinsic fibres from the sympathetic and parasympathetic nervous system. A, schematic representation of the intestinal wall with its different layers, showing the distribution of the intrinsic and extrinsic innervation and their relationship with the intestinal immune cells. Parasympathetic efferent fibres innervate the intestinal wall by contacting exclusively the enteric neurons located in the myenteric plexus region. Instead, sympathetic efferent fibres are also in direct contact with the mucosa and with intestinal immune cells located in the submucosal and mucosal compartment. B, in the mucosal villi, several immune cells such as macrophages, dendritic cells and T cells are affected by the release of neurotransmitters, such as ACh, produced by neuronal fibres. C, in the myenteric plexus, close proximity between enteric neurons and resident macrophages has been described in several publications. Based on anatomical and functional evidence, it has been hypothesized that secretion of ACh by cholinergic enteric neurons influences the phenotype of resident macrophages resulting in inhibition of TNF‐α and induction of regulatory T cells.

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