Anatomy and Neuroscience - Research Publications
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ItemNo Preview AvailableThe role of the gastrointestinal barrier in obesity-associated systemic inflammation(WILEY, 2024-03)Systemic inflammation is a key contributor to the onset and progression of several obesity-associated diseases and is thought to predominantly arise from the hyperplasia and hypertrophy of white adipose tissue. However, a growing body of works suggests that early changes in the gastrointestinal (GI) barrier may contribute to both local, within the GI lining, and systemic inflammation in obesity. Intestinal barrier dysfunction is well-characterized in inflammatory GI disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) and is known to contribute to systemic inflammation. Thus, drawing parallels between GI disorders, where intestinal permeability and systemic inflammation are prominent features, and obesity-induced GI manifestations may provide insights into the potential role of the intestinal barrier in systemic inflammation in obesity. This review summarizes the current literature surrounding intestinal barrier dysfunction in obesity and explores the potential role of intestinal hyperpermeability and intestinal barrier dysfunction in the development of systemic inflammation and GI dysfunction in obesity.
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ItemNo Preview AvailableUnderstanding the potential causes of gastrointestinal dysfunctions in multiple system atrophy(Elsevier, 2023-10-15)Multiple system atrophy (MSA) is a rare, progressive neurodegenerative disorder characterised by autonomic, pyramidal, parkinsonian and/or cerebellar dysfunction. Autonomic symptoms of MSA include deficits associated with the gastrointestinal (GI) system, such as difficulty swallowing, abdominal pain and bloating, nausea, delayed gastric emptying, and constipation. To date, studies assessing GI dysfunctions in MSA have primarily focused on alterations of the gut microbiome, however growing evidence indicates other structural components of the GI tract, such as the enteric nervous system, the intestinal barrier, GI hormones, and the GI-driven immune response may contribute to MSA-related GI symptoms. Here, we provide an in-depth exploration of the physiological, structural, and immunological changes theorised to underpin GI dysfunction in MSA patients and highlight areas for future research in order to identify more suitable pharmaceutical treatments for GI symptoms in patients with MSA.
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ItemMolecular Targets to Alleviate Enteric Neuropathy and Gastrointestinal Dysfunction(SPRINGER INTERNATIONAL PUBLISHING AG, 2022)Enteric neuropathy underlies long-term gastrointestinal (GI) dysfunction associated with several pathological conditions. Our previous studies have demonstrated that structural and functional changes in the enteric nervous system (ENS) result in persistent alterations of intestinal functions long after the acute insult. These changes lead to aberrant immune response and chronic dysregulation of the epithelial barrier. Damage to the ENS is prognostic of disease progression and plays an important role in the recurrence of clinical manifestations. This suggests that the ENS is a viable therapeutic target to alleviate chronic intestinal dysfunction. Our recent studies in preclinical animal models have progressed into the development of novel therapeutic strategies for the treatment of enteric neuropathy in various chronic GI disorders. We have tested the anti-inflammatory and neuroprotective efficacy of novel compounds targeting specific molecular pathways. Ex vivo studies in human tissues freshly collected after resection surgeries provide an understanding of the molecular mechanisms involved in enteric neuropathy. In vivo treatments in animal models provide data on the efficacy and the mechanisms of actions of the novel compounds and their combinations with clinically used therapies. These novel findings provide avenues for the development of safe, cost-effective, and highly efficacious treatments of GI disorders.
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ItemNo Preview AvailableIvacaftor Alters Macrophage and Lymphocyte Infiltration in the Lungs Following Lipopolysaccharide Exposure(AMER CHEMICAL SOC, 2022-06-10)Background and purpose: Cystic fibrosis (CF) is associated with a myriad of respiratory complications including increased susceptibility to lung infections and inflammation. Progressive inflammatory insults lead to airway damage and remodeling, resulting in compromised lung function. Treatment with ivacaftor significantly improves respiratory function and reduces the incidence of pulmonary exacerbations; however, its effect on lung inflammation is yet to be fully elucidated. Experimental approach: This study investigates the effects of ivacaftor on lung inflammation in a lipopolysaccharide (LPS) exposure mouse model (C57BL/6). All groups received intratracheal (IT) administration of LPS (10 μg). Prophylactic treatment involved intraperitoneal injections of ivacaftor (40 mg/kg) once a day beginning 4 days prior to LPS challenge. The therapeutic group received a single intraperitoneal ivacaftor injection (40 mg/kg) directly after LPS. Mice were culled either 24 or 72 h after LPS challenge, and serum, bronchoalveolar lavage fluid (BALF), and lung tissue samples were collected. The degree of inflammation was assessed through cell infiltration, cytokine expression, and histological analysis. Key results: Ivacaftor did not decrease the total number of immune cells within the BALF; however, prophylactic treatment did significantly reduce macrophage and lymphocyte infiltration. Prophylactic treatment exhibited a significant negative correlation between the immune cell number and ivacaftor concentrations in BALF; however, no significant changes in the cytokine expression or histological parameters were determined. Conclusions and implications: Ivacaftor possesses some inherent immunomodulatory effects within the lungs following LPS inoculation; however, further analysis of larger sample sizes is required to confirm the results.
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ItemGastrointestinal consequences of lipopolysaccharide-induced lung inflammation(SPRINGER BASEL AG, 2023-01)BACKGROUND: Respiratory inflammation is the body's response to lung infection, trauma or hypersensitivity and is often accompanied by comorbidities, including gastrointestinal (GI) symptoms. Why respiratory inflammation is accompanied by GI dysfunction remains unclear. Here, we investigate the effect of lipopolysaccharide (LPS)-induced lung inflammation on intestinal barrier integrity, tight-junctions, enteric neurons and inflammatory marker expression. METHODS: Female C57bl/6 mice (6-8 weeks) were intratracheally administered LPS (5 µg) or sterile saline, and assessed after either 24 or 72 h. Total and differential cell counts in bronchoalveolar lavage fluid (BALF) were used to evaluate lung inflammation. Intestinal barrier integrity was assessed via cross sectional immunohistochemistry of tight junction markers claudin-1, claudin-4 and EpCAM. Changes in the enteric nervous system (ENS) and inflammation in the intestine were quantified immunohistochemically using neuronal markers Hu + and nNOS, glial markers GFAP and S100β and pan leukocyte marker CD45. RESULTS: Intratracheal LPS significantly increased the number of neutrophils in BALF at 24 and 72 h. These changes were associated with an increase in CD45 + cells in the ileal mucosa at 24 and 72 h, increased goblet cell expression at 24 h, and increased expression of EpCAM at 72 h. LPS had no effect on the expression of GFAP, S100β, nor the number of Hu + neurons or proportion of nNOS neurons in the myenteric plexus. CONCLUSIONS: Intratracheal LPS administration induces inflammation in the ileum that is associated with enhanced expression of EpCAM, decreased claudin-4 expression and increased goblet cell density, these changes may contribute to systemic inflammation that is known to accompany many inflammatory diseases of the lung.
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ItemA Critical Analysis of Intestinal Enteric Neuron Loss and Constipation in Parkinson's Disease(IOS PRESS, 2022)Constipation afflicts many patients with Parkinson's disease (PD) and significantly impacts on patient quality of life. PD-related constipation is caused by intestinal dysfunction, but the etiology of this dysfunction in patients is unknown. One possible cause is neuron loss within the enteric nervous system (ENS) of the intestine. This review aims to 1) Critically evaluate the evidence for and against intestinal enteric neuron loss in PD patients, 2) Justify why PD-related constipation must be objectively measured, 3) Explore the potential link between loss of enteric neurons in the intestine and constipation in PD, 4) Provide potential explanations for disparities in the literature, and 5) Outline data and study design considerations to improve future research. Before the connection between intestinal enteric neuron loss and PD-related constipation can be confidently described, future research must use sufficiently large samples representative of the patient population (majority diagnosed with idiopathic PD for at least 5 years), implement a consistent neuronal quantification method and study design, including standardized patient recruitment criteria, objectively quantify intestinal dysfunctions, publish with a high degree of data transparency and account for potential PD heterogeneity. Further investigation into other potential influencers of PD-related constipation is also required, including changes in the function, connectivity, mitochondria and/or α-synuclein proteins of enteric neurons and their extrinsic innervation. The connection between enteric neuron loss and other PD-related gastrointestinal (GI) issues, including gastroparesis and dysphagia, as well as changes in nutrient absorption and the microbiome, should be explored in future research.
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ItemSqualamine Restores the Function of the Enteric Nervous System in Mouse Models of Parkinson's Disease(IOS Press, 2020-10-27)Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder thought to be caused by accumulation of α-synuclein (α-syn) within the brain, autonomic nerves, and the enteric nervous system (ENS). Involvement of the ENS in PD often precedes the onset of the classic motor signs of PD by many years at a time when severe constipation represents a major morbidity. Studies conducted in vitro and in vivo, have shown that squalamine, a zwitterionic amphipathic aminosterol, originally isolated from the liver of the dogfish shark, effectively displaces membrane-bound α-syn. Objective: Here we explore the electrophysiological effect of squalamine on the gastrointestinal (GI) tract of mouse models of PD engineered to express the highly aggregating A53T human α-syn mutant. Methods: GI motility and in vivo response to oral squalamine in PD model mice and controls were assessed using an in vitro tissue motility protocol and via fecal pellet output. Vagal afferent response to squalamine was measured using extracellular mesenteric nerve recordings from the jejunum. Whole cell patch clamp was performed to measure response to squalamine in the myenteric plexus. Results: Squalamine effectively restores disordered colonic motility in vivo and within minutes of local application to the bowel. We show that topical squalamine exposure to intrinsic primary afferent neurons (IPANs) of the ENS rapidly restores excitability. Conclusion: These observations may help to explain how squalamine may promote gut propulsive activity through local effects on IPANs in the ENS, and further support its possible utility in the treatment of constipation in patients with PD.
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ItemATH434 Reverses Colorectal Dysfunction in the A53T Mouse Model of Parkinson's Disease(IOS PRESS, 2021)BACKGROUND: Gastrointestinal (GI) complications, that severely impact patient quality of life, are a common occurrence in patients with Parkinson's disease (PD). Damage to enteric neurons and the accumulation of alpha-synuclein in the enteric nervous system (ENS) are thought to contribute to this phenotype. Copper or iron chelators, that bind excess or labile metal ions, can prevent aggregation of alpha-synuclein in the brain and alleviate motor-symptoms in preclinical models of PD. OBJECTIVE: We investigated the effect of ATH434 (formally PBT434), a small molecule, orally bioavailable, moderate-affinity iron chelator, on colonic propulsion and whole gut transit in A53T alpha-synuclein transgenic mice. METHODS: Mice were fed ATH434 (30 mg/kg/day) for either 4 months (beginning at ∼15 months of age), after the onset of slowed propulsion ("treatment group"), or for 3 months (beginning at ∼12 months of age), prior to slowed propulsion ("prevention group"). RESULTS: ATH434, given after dysfunction was established, resulted in a reversal of slowed colonic propulsion and gut transit deficits in A53T mice to WT levels. In addition, ATH434 administered from 12 months prevented the slowed bead expulsion at 15 months but did not alter deficits in gut transit time when compared to vehicle-treated A53T mice. The proportion of neurons with nuclear Hu+ translocation, an indicator of neuronal stress in the ENS, was significantly greater in A53T than WT mice, and was reduced in both groups when ATH434 was administered. CONCLUSION: ATH434 can reverse some of the GI deficits and enteric neuropathy that occur in a mouse model of PD, and thus may have potential clinical benefit in alleviating the GI dysfunctions associated with PD.
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ItemChronic isolation stress is associated with increased colonic and motor symptoms in the A53T mouse model of Parkinson's disease(WILEY, 2020-03)BACKGROUND: Chronic stress exacerbates motor deficits and increases dopaminergic cell loss in several rodent models of Parkinson's disease (PD). However, little is known about effects of stress on gastrointestinal (GI) dysfunction, a common non-motor symptom of PD. We aimed to determine whether chronic stress exacerbates GI dysfunction in the A53T mouse model of PD and whether this relates to changes in α-synuclein distribution. METHODS: Chronic isolation stress was induced by single-housing WT and homozygote A53T mice between 5 and 15 months of age. GI and motor function were compared with mice that had been group-housed. KEY RESULTS: Chronic isolation stress increased plasma corticosterone and exacerbated deficits in colonic propulsion and whole-gut transit in A53T mice and also increased motor deficits. However, our results indicated that the novel environment-induced defecation response, a common method used to evaluate colorectal function, was not a useful test to measure exacerbation of GI dysfunction, most likely because of the reported reduced level of anxiety in A53T mice. A53T mice had lower corticosterone levels than WT mice under both housing conditions, but single-housing increased levels for both genotypes. Enteric neuropathy was observed in aging A53T mice and A53T mice had a greater accumulation of alpha-synuclein (αsyn) in myenteric ganglia under both housing conditions. CONCLUSIONS & INFERENCES: Chronic isolation stress exacerbates PD-associated GI dysfunction, in addition to increasing motor deficits. However, these changes in GI symptoms are not directly related to corticosterone levels, worsened enteric neuropathy, or enteric αsyn accumulation.
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ItemMuscarinic receptor 1 allosteric modulators stimulate colorectal emptying in dog, mouse and rat and resolve constipation(WILEY, 2019-11)BACKGROUND: Because M1 muscarinic receptors are expressed by enteric neurons, we investigated whether positive allosteric modulators of these receptors (M1PAMs) would enhance colorectal propulsion and defecation in dogs, mice, and rats. METHODS: The potencies of the M1PAMs, T662 or T523, were investigated using M1 receptor-expressing CHO cells. Effectiveness of M1PAMs on defecation was investigated by oral administration in mice and rats, by recording propulsive contractions in anaesthetized rats and by recording high amplitude propagating contractions in dogs. KEY RESULTS: PAM EC50 values in M1 receptor-expressing CHO cells were 0.7-1.8 nmol/L for T662 and 8-10 nmol/L for T523. The compounds had 1000-fold lower potencies as agonists. In anesthetized rats, both compounds elicited propulsive colorectal contractions, and in dogs, mice, and rats, oral administration increased fecal output. No adverse effects were observed in conscious animals. M1PAMs triggered propagated high amplitude contractions and caused defecation in dogs. Nerve-mediated contractions were enhanced in the isolated mouse colon. M1PAMs were equi-effective in rats with or without the pelvic nerves being severed. In two models of constipation in mice, opiate-induced constipation and constipation of aging, defecation was induced and constipation was reversed. CONCLUSION AND INFERENCES: M1PAMs act at targets sites in the colorectum to enhance colorectal propulsion. They are effective across species, and they reverse experimentally induced constipation. Previous studies have shown that they are safe in human. Because they provide an enhancement of physiological control rather than being direct agonists, they are predicted to provide effective treatment for constipation.