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The Enteric Nervous System and Its Emerging Role as a Therapeutic Target.

ABSTRACT: The gastrointestinal (GI) tract is innervated by the enteric nervous system (ENS), an extensive neuronal network that traverses along its walls. Due to local reflex circuits, the ENS is capable of functioning with and without input from the central nervous system. The functions of the ENS range from the propulsion of food to nutrient handling, blood flow regulation, and immunological defense. Records of it first being studied emerged in the early 19th century when the submucosal and myenteric plexuses were discovered. This was followed by extensive research and further delineation of its development, anatomy, and function during the next two centuries. The morbidity and mortality associated with the underdevelopment, infection, or inflammation of the ENS highlight its importance and the need for us to completely understand its normal function. This review will provide a general overview of the ENS to date and connect specific GI diseases including short bowel syndrome with neuronal pathophysiology and current therapies. Exciting opportunities in which the ENS could be used as a therapeutic target for common GI diseases will also be highlighted, as the further unlocking of such mechanisms could open the door to more therapy-related advances and ultimately change our treatment approach.

SUBMITTER: Fleming MA

PROVIDER: S-EPMC7495222 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Enteric Nervous System and Its Emerging Role as a Therapeutic Target.

Fleming Mark A MA Ehsan Lubaina L Moore Sean R SR Levin Daniel E DE

Gastroenterology research and practice 20200908

The gastrointestinal (GI) tract is innervated by the enteric nervous system (ENS), an extensive neuronal network that traverses along its walls. Due to local reflex circuits, the ENS is capable of functioning with and without input from the central nervous system. The functions of the ENS range from the propulsion of food to nutrient handling, blood flow regulation, and immunological defense. Records of it first being studied emerged in the early 19<sup>th</sup> century when the submucosal and m ...[more]

PMID: 32963521

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Project description:Besides symptoms caused by central nervous system (CNS) lesions, the majority of patients with multiple sclerosis (MS) also exhibit gastrointestinal dysfunction that has frequently been noted, but was not directly linked to the autoimmune etiology of the disease.We studied the enteric nervous system (ENS) in a murine model of MS by histology and electron microscopy. Serum IgG against enteric neurons and enteroglia was measured by ELISA and binding to the ENS was confirmed by immunohistochemistry. Target antigens were identified by mass spectrometry. Gastrointestinal dysfunction was determined by measuring dye transit time. RNA expression profiling was conducted with small intestines of MP4-immunized and control-immunized mice. Data from the mouse model were confirmed in MS patients by immunohistochemistry of the ENS in bowel resectates. In addition, ELISA was performed on plasma samples to detect antibodies against four specific target antigens as identified in the mouse model. ENS degeneration was evident already before the onset of clinical disease in the mouse model. Pathology was predominantly antibody-mediated and caused a significant decrease in gastrointestinal transit, which was associated with severe gliosis of the ENS. Unlike the dense infiltrates that developed in the perivascular compartments of the CNS of MP4-immunized mice, the infiltrates in the ENS consisted of single cells scattered throughout the tissue. RNA expression profiling could support these results, as the expression of inflammatory markers in the small intestine was similar between MP4-immunized and HEL-immunized mice. We identified four specific target antigens derived from enteric neurons and/or enteroglia. Antibodies against all four target antigens were present in MS patients. MS patients also showed gliosis and signs of ENS degeneration in the small intestine. For the first time, this study establishes a pathomechanistic link between the well-established autoimmune attack on the CNS and the ENS in MS. The presence of ENS pathology prior to CNS degeneration introduces entirely novel ways to explain MS etiology and immunopathogenesis.

Project description:The autonomic nervous system (ANS) regulates the cardiovascular system. A growing body of experimental and clinical evidence confirms significant dysfunction of this regulation during sepsis and septic shock. Clinical guidelines do not currently include any evaluation of ANS function during the resuscitation phase of septic shock despite the fact that the severity and persistence of ANS dysfunction are correlated with worse clinical outcomes. In the critical care setting, the clinical use of ANS-related hemodynamic indices is currently limited to preliminary investigations trying to predict and anticipate imminent clinical deterioration. In this review, we discuss the evidence supporting the concept that, in septic shock, restoration of ANS-mediated control of the cardiovascular system or alleviation of the clinical consequences induced by its dysfunction (e.g., excessive tachycardia, etc.), may be an important therapeutic goal, in combination with traditional resuscitation targets. Recent studies, which have used standard and advanced monitoring methods and mathematical models to investigate the ANS-mediated mechanisms of physiological regulation, have shown the feasibility and importance of monitoring ANS hemodynamic indices at the bedside, based on the acquisition of simple signals, such as heart rate and arterial blood pressure fluctuations. During the early phase of septic shock, experimental and/or clinical studies have shown the efficacy of negative-chronotropic agents (i.e., beta-blockers or ivabradine) in controlling persistent tachycardia despite adequate resuscitation. Central α-2 agonists have been shown to prevent peripheral adrenergic receptor desensitization by reducing catecholamine exposure. Whether these new therapeutic approaches can safely improve clinical outcomes remains to be confirmed in larger clinical trials. New technological solutions are now available to non-invasively modulate ANS outflow, such as transcutaneous vagal stimulation, with initial pre-clinical studies showing promising results and paving the way for ANS modulation to be considered as a new potential therapeutic target in patients with septic shock.

Dataset Information

The Enteric Nervous System and Its Emerging Role as a Therapeutic Target.

Publications

The Enteric Nervous System and Its Emerging Role as a Therapeutic Target.

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