Therapeutic Potential of Vagus Nerve Stimulation for Inflammatory Bowel Diseases

Abstract

The vagus nerve is a mixed nerve, comprising 80% afferent fibers and 20% efferent fibers. It allows a bidirectional communication between the central nervous system and the digestive tract. It has a dual anti-inflammatory properties via activation of the hypothalamic pituitary adrenal axis, by its afferents, but also through a vago-vagal inflammatory reflex involving an afferent (vagal) and an efferent (vagal) arm, called the cholinergic anti-inflammatory pathway. Indeed, the release of acetylcholine at the end of its efferent fibers is able to inhibit the release of tumor necrosis factor (TNF) alpha by macrophages via an interneuron of the enteric nervous system synapsing between the efferent vagal endings and the macrophages and releasing acetylcholine. The vagus nerve also synapses with the splenic sympathetic nerve to inhibit the release of TNF-alpha by splenic macrophages. It can also activate the spinal sympathetic system after central integration of its afferents. This anti-TNF-alpha effect of the vagus nerve can be used in the treatment of chronic inflammatory bowel diseases, represented by Crohn’s disease and ulcerative colitis where this cytokine plays a key role. Bioelectronic medicine, via vagus nerve stimulation, may have an interest in this non-drug therapeutic approach as an alternative to conventional anti-TNF-alpha drugs, which are not devoid of side effects feared by patients.

A Review on the Vagus Nerve and Autonomic Nervous System During Fetal Development: Searching for Critical Windows

“…We have shown how alterations in CAN activity and sensorimotor behaviors can give hints about the developing ANS function. Similar hints can also be gained by monitoring organ development due to the research regarding the CAP and the systemic interactions of the vagus nerve (Bonaz et al, 2021 ).…”

“…It is noteworthy that all the adaptations required to pass from intrauterine to extrauterine life seem to rely on cortisol, whose release is markedly reduced in case of preterm birth or lack of labor (Hillman et al, 2012 ; Morton and Brodsky, 2016 ). Since cortisol is an efferent agent in anti-inflammatory neural reflexes like the CAP (Bonaz et al, 2021 ), its reduced production may alter the CAP development itself. Indeed, low cortisol levels could fail in regulating postnatal inflammation, e.g., necrotizing enterocolitis (NEC), which could induce cell death in the vagal brainstem centers (Fritze et al, 2014 ).…”

“…Many postnatal pathologies—e.g., hyperbilirubinemia, congenital heart disease, respiratory distress syndrome, respiratory syncytial virus, NEC, and sepsis—can lead to ANS impairment, probably due to inflammatory cytokines and toxins that can bypass the brain-blood barrier and induce neural death in areas paramount to ANS control (Fritze et al, 2014 ; Al-Shargabi et al, 2017 ; Bonaz et al, 2021 ).…”

“…Regarding the PNS, the vagus nerve has been recognized as a fundamental afferent pathway for sensing the milieu interior in peripheral tissues, thus allowing the organism to respond by activating complex networks involving the whole ANS, endocrine, metabolic, innate, and adaptive immune systems (Frasch et al, 2018b ; Bonaz et al, 2021 ).…”

“…One of such responses, able to perform homeokinetic adjustments, is the cholinergic anti-inflammatory pathway (CAP). Briefly, through the vagus nerve, the brain receives information about the body's inflammatory milieu and, thus, activates neuroimmune responses to dampen the detected inflammation (Garzoni et al, 2013 ; Frasch, 2020 ; Bonaz et al, 2021 ). Very little is known, however, about the central representation, the information processing network, of the vagus nerve.…”