Enteric neuroplasticity and dysmotility in inflammatory disease: key players and possible therapeutic targets

Abstract

Intestinal functions, including motility and secretion, are locally controlled by enteric neural networks housed within the wall of the gut. The fidelity of these functions depends on the precision of intercellular signaling among cellular elements, including enteric neurons, epithelial cells, immune cells, and glia, all of which are vulnerable to disruptive influences during inflammatory events. This review article describes current knowledge regarding inflammation-induced neuroplasticity along key elements of enteric neural circuits, what is known about the causes of these changes, and possible therapeutic targets for protecting and/or repairing the integrity of intrinsic enteric neurotransmission. Changes that have been detected in response to inflammation include increased epithelial serotonin availability, hyperexcitability of intrinsic primary afferent neurons, facilitation of synaptic activity among enteric neurons, and attenuated purinergic neuromuscular transmission. Dysfunctional propulsive motility has been detected in models of colitis, where causes include the changes described above, and in models of multiple sclerosis and other autoimmune conditions, where autoantibodies are thought to mediate dysmotility. Other cells implicated in inflammation-induced neuroplasticity include muscularis macrophages and enteric glia. Targeted treatments that are discussed include 5-hydroxytryptamine receptor 4 agonists, cyclooxygenase inhibitors, antioxidants, B cell depletion therapy, and activation of anti-inflammatory pathways.

Oxidized phospholipids affect small intestine neuromuscular transmission and serotonergic pathways in juvenile mice

“…They are known to modulate the release of nitric oxide from inhibitory nitrergic neurons, to counteract contraction, and the production of acetylcholine from myenteric excitatory cholinergic neurons, to ensure smooth muscle contraction, sustaining GI motility 46 . In the gut, 5‐HT is produced from the metabolism of the essential amino acid TRP, which under direct or indirect control of the microbiota may give origin to several other compounds, such as KYN, tryptamine, and indolic compounds, participating in the microbiota‐gut‐brain communication in health and disease states 25‐27 . OxPAPC treatment induced a significant increase in 5‐HTP and a reduction in 5‐HT ileal tissue levels, suggesting that blockade of TLR2 and TLR4 signaling affects TRP metabolism.…”

“…The administration of 5‐HT 3 receptor antagonists to IBS patients has been shown to ameliorate motor dysfunction and visceral hypersensitivity 23,24 . In the gut, 5‐HT is produced from the metabolism of the essential amino acid tryptophan (TRP) which may give origin to several other compounds, such as kynurenine (KYN), tryptamine, and indolic compounds, participating in the microbiota‐gut‐brain communication in health and disease states 25‐27 . Under normal conditions, approximately 3% of the assumed TRP is metabolized into 5‐HT, whereas about 90% is catabolized into KYN, through the KYN pathway, and the remaining is degraded by the gut microbiota in order to produce indole and its derivatives 28 .…”

Autoimmune gastrointestinal dysmotility: the interface between clinical immunology and neurogastroenterology

“…Spear and Mawe indicated the key players in dysmotility and ENS-related therapeutic targets [91], which are as follows: (1) changes in serotonin signaling, protective actions of 5-hydroxytryptamine receptor 4 activation, and proinflammatory actions of serotonin; (2) inflammation-induced enteric neuroplasticity; (3) purinergic neuromuscular transmission; (4) antibody-mediated GI dysmotility; (5) muscularis macrophages, which include cholinergic anti-inflammatory pathway and macrophage b 2adrenergic receptors; (6) enteric glia. In addition, they mentioned the use of cyclooxygenase inhibitors, free radical scavengers, and B cell depletion, as well as the cholinergic anti-inflammatory pathway stimulation and 5-HT4 agonist treatment as potential treatment strategies.…”

AAV Targeting of Glial Cell Types in the Central and Peripheral Nervous System and Relevance to Human Gene Therapy

“…As well as their role in normal physiological functions of the nervous system, glia are activated under pathological conditions and contribute significantly to disease pathology in many neurodegenerative diseases, neurotrauma, peripheral neuropathies and gut inflammation. Glial cells are therefore a potential cell target for several therapeutic approaches to treat diseases of the nervous system ( Ahmed et al, 2017 ; Spear and Mawe, 2019 ; Eastlake et al, 2020 ).…”