Vagus Nerve Stimulation: A Personalized Therapeutic Approach for Crohn’s and Other Inflammatory Bowel Diseases

Figures

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  Figure 1. Immune response. Schematic representation of the key components of the innate (immediate and early induced) and the acquired response of the immune system. Immediate innate immunity is based on (1) the activity of circulating enzymes and peptides with anti-microbic action, including complement, (2) the integrity of the anatomic epithelia, and (3) the antagonism of resident host microbiota. Lately, early induced innate immunity is cell-dependent, modulated by the activity of leukocytes, phagocytes, and natural killer cells. Finally, adaptive immunity is lymphocyte-dependent: antigen is presented to B/T lymphocytes by antigen-presenting cells, which become active, proliferate, and differentiate into B cells producing antibodies, T cells CD4+ (T helper) or CD8+ (CTL, cytotoxic T lymphocytes) and B/T memory cells.

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  Figure 2. Gut nervous system. Intestine is heavily innervated by an intrinsic dense neural network (intrinsic nervous system) and by an extrinsic nervous system formed by the sensory and motor nerves of the central, sympathetic, and parasympathetic nervous systems. The enteric nervous system is composed of two complex neural plexuses, the myenteric, lying between the two muscles of the intestine, and the submucosal, placed between the longitudinal muscle and the mucosa. There is bidirectional communication between the intrinsic and the extrinsic system, and both of them communicate/interact with bacteria and immune system cells.

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  Figure 3. The enteric nervous system is mainly devoted to the modulation of the motility of the intestine (left) and to the modulation of the inflammatory processes that take place in this organ (right). In motility regulation, chemical and mechanical stimuli excite IPAN, intrinsic primary afferent sensory neurons (1). IPAN synapse with proxima-ascending (2) and distal-descending (3) interneurons, which, in turn, activate excitatory (4) or inhibitory motoneurons (5). IPAN produces substance P and calcitonin gen-related peptide; interneurons employ several neurotransmitters, including ACh; excitatory motneurons are ACh-ergic or neuropeptidergic, and inhibitory motoneurons are purinergic, NO-producing, etc., neurons. Inflammation regulation is carried out thanks to a tri-partite unit formed by the intercommunicating mucosa, gut nervous system, and immune system. Communication between intestinal epithelium and neural system is performed through the mucosa enteroendocrine cells secreting peptidic hormones (CCK, YY peptide, glucagon-like peptides, etc.) and neurotransmitters, especially glutammate; immune system mainly employs cytokines; enteric glial cells respond to several neurotransmitters…

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  Figure 4. Vagus nerve afferent terminals are mechanoreceptors, chemoreceptors, and thermoreceptors. They are stimulated by muscular tension and stretching, hormones, nutrients, enteroendocrine cells’ neurotransmitters, and inflammatory mediators and are sensitive to osmolarity and pH changes. Their bodies are in the nodose ganglia and transmit information to the nucleus of the solitary tract. The efferent pathways reach the myenteric plexus, where they communicate with (1) enteric neurons that regulate motility and inflammation, (2) with cholinergic neurons that contact macrophages (anti-inflammatory pathway) or (3) with the sympathetic adrenergic system (inflammatory pathway).

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  Figure 5. Once the polyphenols are ingested, a minimal part is metabolized in the small intestine and the majority in the large intestine. These are absorbed and passed to the liver, from where they can return to the intestine, be eliminated in the urine, or be distributed to different tissues or organs. In case of dysbiosis, polyphenols can help promote normal microbiota, thus reducing inflammatory mechanisms and sensitization of vagus nerve endings.

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  Figure 6. Immune-mediated process and inflammation in Crohn’s disease. The innate immune response acts as the first defense in the gastrointestinal tract. Specific cells of the immune system (macrophages, dendritic cells) can recognize these antigens and trigger an immune response, producing proinflammatory mediators that attract other immune cells to the site of inflammation and induce differentiation of undifferentiated T cells into Th1 or Th17. In Crohn’s disease, this response is triggered by: (1) increased permeability of the intestinal epithelium, (2) dysfunction of Paneth cells, which normally secrete antimicrobial peptides to maintain the microbiota, (3) decreased tolerance of dendritic cells and macrophages to antigens found in the intestinal lumen. Under normal conditions, the cells of the immune system communicate with the commensal microbiota through molecular recognition patterns (MAMPs) recognized by specialized receptors (4) dysbiosis of the gut microbiota. The acquired immune response is characterized by an imbalance of lymphocytes due to an increased number of Th cells in the mucosal lamina propria. Th lymphocytes generate pro-inflammatory molecules that, in turn, cause…

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  Figure 7. Vagus nerve stimulation-induced modulation of intestine immune responses. Artificial vagus nerve stimulation, both cervical (aVNS) and auricular (aVNS), directly excites brainstem relay neurons of the solitary tract nucleus (STN) and the spinal nucleus of the trigeminal complex (SpV), thus activating the visceral afferent, cholinergic anti-inflammatory and splenic nerve afferent pathways as well as the hypothalamic–pituitary–adrenal axis. DMx, dorsal motor nucleus of the vagus nerve; STN, solitary tract nucleus; SpV, spinal nucleus of the trigeminal complex; LC, locus coeruleus; HTh, hypothalamus; PG, pituitary gland.