Gastrointestinal motility disorders in neurologic disease

Camilleri, Michael

doi:10.1172/jci143771

Cited by 95 publications

(83 citation statements)

References 149 publications

(122 reference statements)

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“…In line with this view, other studies performed on SAMP8 and AβPP/PS1 transgenic AD mouse models observed the accumulation of intestinal Aβ and amyloid precursor protein, enteric inflammation, mitochondrial dysfunction along with enteric glial activation and gut dysbiosis in the early stages of AD before the full development of brain pathology ( Joachim et al, 1989 ; Puig et al, 2015 ; Piccarducci et al, 2019 ; Pellegrini et al, 2020 ). Bowel motor disturbances in AD patients contribute significantly to AD morbidity and complicate their clinical management ( Puig et al, 2015 ; Doi et al, 2019 ; Camilleri, 2021 ). In this regard, no specific treatments are currently available to manage gut alterations occurring in such patients and, therefore, the identification of novel pharmacological entities able to prevent or alleviate gut dysfunctions associated with AD represents an area of interest to the scientific community.…”

Section: Introductionmentioning

confidence: 99%

Palmitoylethanolamide Counteracts Enteric Inflammation and Bowel Motor Dysfunctions in a Mouse Model of Alzheimer’s Disease

et al. 2021

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Palmitoylethanolamide (PEA), an endogenous lipid mediator, is emerging as a promising pharmacological agent in multiple neurodegenerative disorders for its anti-inflammatory and neuroprotective properties. However, its effects on enteric inflammation and colonic dysmotility associated with Alzheimer’s disease (AD) are lacking. This study was designed to investigate the beneficial effect of PEA administration in counteracting the enteric inflammation and relieving the bowel motor dysfunctions in an AD mouse model, SAMP8 mice. In addition, the ability of PEA in modulating the activation of enteric glial cells (EGCs), pivotally involved in the pathophysiology of bowel dysfunctions associated with inflammatory conditions, has also been examined. SAMP8 mice at 4 months of age were treated orally with PEA (5 mg/kg/day) for 2 months. SAMR1 animals were employed as controls. At the end of treatment, parameters dealing with colonic motility, inflammation, barrier integrity and AD protein accumulation were evaluated. The effect of PEA on EGCs was tested in cultured cells treated with lipopolysaccharide (LPS) plus β-amyloid 1–42 (Aβ). SAMP8 treated with PEA displayed: 1) an improvement of in vitro colonic motor activity, citrate synthase activity and intestinal epithelial barrier integrity and 2) a decrease in colonic Aβ and α-synuclein (α-syn) accumulation, S100-β expression as well as enteric IL-1β and circulating LPS levels, as compared with untreated SAMP8 mice. In EGCs, treatment with PEA counteracted the increment of S100-β, TLR-4, NF-κB p65 and IL-1β release induced by LPS and Aβ. These results suggest that PEA, under a condition of cognitive decline, prevents the enteric glial hyperactivation, reduces AD protein accumulation and counteracts the onset and progression of colonic inflammatory condition, as well as relieves intestinal motor dysfunctions and improves the intestinal epithelial barrier integrity. Therefore, PEA represents a viable approach for the management of the enteric inflammation and motor contractile abnormalities associated with AD.

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Section: Introductionmentioning

confidence: 99%

Palmitoylethanolamide Counteracts Enteric Inflammation and Bowel Motor Dysfunctions in a Mouse Model of Alzheimer’s Disease

et al. 2021

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“…The ENS is a complex network of enteric neurons and glia that controls all aspects of GI physiology (Long-Smith et al, 2020; Schneider et al, 2019; Yoo and Mazmanian, 2017) and plays a central role in initiation and progression of enteric neuropathies and diseases of the gut-brain axis (Camilleri, 2021; Niesler et al, 2021; Pesce et al, 2018). Nevertheless, our understanding of the ENS has been disproportionately affected by long standing technical challenges.…”

Section: Discussionmentioning

confidence: 99%

hPSC-Derived Enteric Ganglioids Model Human ENS Development and Function

Majd

Samuel

Ramirez

et al. 2022

Preprint

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The enteric nervous system (ENS) plays a central role in gut physiology and mediating the crosstalk between the gastrointestinal (GI) tract and other organs. The human ENS has remained elusive, highlighting the need for an in vitro modeling and mapping blueprint. Here we map out the developmental and functional features of the human ENS, by establishing robust and scalable 2D ENS cultures and 3D enteric ganglioids from human pluripotent stem cells (hPSCs). These models recapitulate the remarkable neuronal and glial diversity found in primary tissue and enable comprehensive molecular analyses that uncover functional and developmental relationships within these lineages. As a salient example of the power of this system, we performed in-depth characterization of enteric nitrergic neurons (NO neurons) which are implicated in a wide range of GI motility disorders. We conducted an unbiased screen and identified drug candidates that modulate the activity of NO neurons and demonstrated their potential in promoting motility in mouse colonic tissue ex vivo. We established a high-throughput strategy to define the developmental programs involved in NO neuron specification and discovered that PDGFR inhibition boosts the induction of NO neurons in enteric ganglioids. Transplantation of these ganglioids in the colon of NO neuron-deficient mice results in extensive tissue engraftment, providing a xenograft model for the study of human ENS in vivo and the development of cell-based therapies for neurodegenerative GI disorders. These studies provide a framework for deciphering fundamental features of the human ENS and designing effective strategies to treat enteric neuropathies.

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“…Pandysautonomia can affect both sympathetic and parasympathetic nerves, leading to gastrointestinal symptoms. 15 Selective cholinergic dysautonomia can result in gastrointestinal dysmotility and occurs after infection with Epstein-Barr Virus (EBV) or influenza. 15 Idiopathic orthostatic hypotension can be associated with gastrointestinal motor dysfunction, such as fecal incontinence.…”

Section: Discussionmentioning

confidence: 99%

A case of parasympathetic hyperactivity and associated Parry–Romberg syndrome

Clapp

Hohler

2021

SAGE Open Medical Case Reports

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This case report describes a 46-year-old female with a history of multiple endocrine neoplasia type 1 syndrome status post-parathyroidectomy, thymectomy via robotic video-assisted thoracoscopic surgery, and pituitary adenoma resection presenting with parasympathetic hyperactivity and Parry–Romberg syndrome. Parry–Romberg syndrome is a rare disorder that manifests as facial hemiatrophy. Reported symptoms include cognitive dysfunction, olfactory hallucinations, and parasympathetic hyperactivity: miosis of the right eye, anhidrosis, diarrhea, urinary incontinence, bowel incontinence, and orthostatic hypotension. Previous reports have noted associations between Parry–Romberg syndrome and sympathetic hyperactivity and dysregulation. This case report focuses on an association between Parry–Romberg syndrome and unopposed parasympathetic activity.

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Gastrointestinal motility disorders in neurologic disease

Cited by 95 publications

References 149 publications

Palmitoylethanolamide Counteracts Enteric Inflammation and Bowel Motor Dysfunctions in a Mouse Model of Alzheimer’s Disease

Palmitoylethanolamide Counteracts Enteric Inflammation and Bowel Motor Dysfunctions in a Mouse Model of Alzheimer’s Disease

hPSC-Derived Enteric Ganglioids Model Human ENS Development and Function

A case of parasympathetic hyperactivity and associated Parry–Romberg syndrome

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