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  • 1
    Online Resource
    Online Resource
    American Physiological Society ; 2022
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 323, No. 5 ( 2022-11-01), p. G477-G487
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 323, No. 5 ( 2022-11-01), p. G477-G487
    Abstract: Gastrointestinal motility is crucial to gut health and has been associated with different disorders such as inflammatory bowel diseases and postoperative ileus. Despite rat and mouse being the two animal models most widely used in gastrointestinal research, minimal studies in rats have investigated gastrointestinal motility. Therefore, our study provides a comparison of colonic motility in the mouse and rat to clarify species differences and assess the relative effectiveness of each animal model for colonic motility research. We describe the protocol modifications and optimization undertaken to enable video imaging of colonic motility in the rat. Apart from the broad difference in terms of gastrointestinal diameter and length, we identified differences in the fundamental histology of the proximal colon such that the rat had larger villus height-to-width and villus height-to-crypt depth ratios compared with mouse. Since gut motility is tightly regulated by the enteric nervous system (ENS), we investigated how colonic contractile activity within each rodent species responds to modulation of the ENS inhibitory neuronal network. Here we used N ω ‐nitro‐l‐arginine (l-NNA), an inhibitor of nitric oxide synthase (NOS) to assess proximal colon responses to the stimulatory effect of blocking the major inhibitory neurotransmitter, nitric oxide (NO). In rats, the frequency of proximal colonic contractions increased in the presence of l-NNA (vs. control levels) to a greater extent than in mice. This is despite a similar number of NOS-expressing neurons in the myenteric plexus across species. Given this increase in colonic contraction frequency, the rat represents another relevant animal model for investigating how gastrointestinal motility is regulated by the inhibitory neuronal network of the ENS. NEW & NOTEWORTHY Mice and rats are widely used in gastrointestinal research but have fundamental differences that make them important as different models for different questions. We found that mice have a higher villi length-to-width and villi length-to-crypt depth ratio than rat in proximal colon. Using the ex vivo video imaging technique, we observed that rat colon has more prominent response to blockade of major inhibitory neurotransmitter (nitric oxide) in myenteric plexus than mouse colon.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2022
    detail.hit.zdb_id: 1477329-6
    SSG: 12
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  • 2
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 14 ( 2023-10-5)
    Abstract: Intestinal macrophages are well-studied for their conventional roles in the immune response against pathogens and protecting the gut from chronic inflammation. However, these macrophages may also have additional functional roles in gastrointestinal motility under typical conditions. This is likely to occur via both direct and indirect influences on gastrointestinal motility through interaction with myenteric neurons that contribute to the gut-brain axis, but this mechanism is yet to be properly characterised. The CX3CR1 chemokine receptor is expressed in the majority of intestinal macrophages, so we used a conditional knockout Cx3cr1-Dtr (diphtheria toxin receptor) rat model to transiently ablate these cells. We then utilized ex vivo video imaging to evaluate colonic motility. Our previous studies in brain suggested that Cx3cr1 -expressing cells repopulate by 7 days after depletion in this model, so we performed our experiments at both the 48 hr (macrophage depletion) and 7-day (macrophage repopulation) time points. We also investigated whether inhibitory neuronal input driven by nitric oxide from the enteric nervous system is required for the regulation of colonic motility by intestinal macrophages. Our results demonstrated that CD163-positive resident intestinal macrophages are important in regulating colonic motility in the absence of this major inhibitory neuronal input. In addition, we show that intestinal macrophages are indispensable in maintaining a healthy intestinal structure. Our study provides a novel understanding of the interplay between the enteric nervous system and intestinal macrophages in colonic motility. We highlight intestinal macrophages as a potential therapeutic target for gastrointestinal motility disorders when inhibitory neuronal input is suppressed.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2606827-8
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  • 3
    In: Clinical Science, Portland Press Ltd., Vol. 134, No. 22 ( 2020-11-27), p. 2943-2957
    Abstract: Gastrointestinal (GI) dysfunction is a common comorbidity of chronic obstructive pulmonary disease (COPD) for which a major cause is cigarette smoking (CS). The underlying mechanisms and precise effects of CS on gut contractility, however, are not fully characterised. Therefore, the aim of the present study was to investigate whether CS impacts GI function and structure in a mouse model of CS-induced COPD. We also aimed to investigate GI function in the presence of ebselen, an antioxidant that has shown beneficial effects on lung inflammation resulting from CS exposure. Mice were exposed to CS for 2 or 6 months. GI structure was analysed by histology and immunofluorescence. After 2 months of CS exposure, ex vivo gut motility was analysed using video-imaging techniques to examine changes in colonic migrating motor complexes (CMMCs). CS decreased colon length in mice. Mice exposed to CS for 2 months had a higher frequency of CMMCs and a reduced resting colonic diameter but no change in enteric neuron numbers. Ten days cessation after 2 months CS reversed CMMC frequency changes but not the reduced colonic diameter phenotype. Ebselen treatment reversed the CS-induced reduction in colonic diameter. After 6 months CS, the number of myenteric nitric-oxide producing neurons was significantly reduced. This is the first evidence of colonic dysmotility in a mouse model of CS-induced COPD. Dysmotility after 2 months CS is not due to altered neuron numbers; however, prolonged CS-exposure significantly reduced enteric neuron numbers in mice. Further research is needed to assess potential therapeutic applications of ebselen in GI dysfunction in COPD.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2020
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  • 4
    Online Resource
    Online Resource
    Elsevier BV ; 2021
    In:  Cellular and Molecular Gastroenterology and Hepatology Vol. 12, No. 5 ( 2021), p. 1701-1718
    In: Cellular and Molecular Gastroenterology and Hepatology, Elsevier BV, Vol. 12, No. 5 ( 2021), p. 1701-1718
    Type of Medium: Online Resource
    ISSN: 2352-345X
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2819778-1
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  • 5
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2017
    In:  Current Developmental Disorders Reports Vol. 4, No. 2 ( 2017-06), p. 28-36
    In: Current Developmental Disorders Reports, Springer Science and Business Media LLC, Vol. 4, No. 2 ( 2017-06), p. 28-36
    Abstract: Individuals with autism spectrum disorders (ASD) commonly also suffer from gastrointestinal (GI) dysfunction; however, few animal model studies have systematically examined both ASD and GI dysfunction. In this review, we highlight studies investigating GI dysfunction and alterations in gut microbiota in animal models of ASD with the aim of determining if routinely used microbiology and enteric neurophysiology assays could expand our understanding of the link between the two. Recent Findings Gut–brain axis research is expanding, and several ASD models demonstrate GI dysfunction. The integration of well-established assays for detecting GI dysfunction into standard behavioural testing batteries is needed. Summary Advances in understanding the role of the gut–brain axis in ASD are emerging; however, we outline standard assays for investigating gut–brain axis function in rodents to strengthen future phenotyping studies. Integrating these findings to the field of animal behaviour is one of the next major challenges in autism research.
    Type of Medium: Online Resource
    ISSN: 2196-2987
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2760283-7
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  • 6
    In: The Journal of Physiology, Wiley, Vol. 594, No. 15 ( 2016-08), p. 4325-4338
    Abstract: Cholera causes more than 100,000 deaths each year as a result of severe diarrhoea, vomiting and dehydration due to the actions of cholera toxin; more females than males are affected. Cholera toxin induces hypersecretion via release of mucosal serotonin and over‐activation of enteric neurons, but its effects on gastrointestinal motility are not well characterized. We found that cholera toxin rapidly and reversibly reduces colonic motility in female mice in oestrus, but not in males or females in prooestrus, an effect mediated by 5‐HT in the colonic mucosa and by 5‐HT 3 receptors. We show that the number of mucosal enterochromaffin cells containing 5‐HT changes with the oestrous cycle in mice. These findings indicate that cholera toxin's effects on motility are rapid and depend on the oestrous cycle and therefore can help us better understand differences in responses in males and female patients.
    Type of Medium: Online Resource
    ISSN: 0022-3751 , 1469-7793
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 1475290-6
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Frontiers Media SA ; 2021
    In:  Frontiers in Neuroscience Vol. 15 ( 2021-9-29)
    In: Frontiers in Neuroscience, Frontiers Media SA, Vol. 15 ( 2021-9-29)
    Abstract: Women are more susceptible to functional bowel disorders than men and the severity of their symptoms such as diarrhea, constipation, abdominal pain and bloating changes over the menstrual cycle, suggesting a role for sex hormones in gastrointestinal function. Nitric oxide (NO) is a major inhibitory neurotransmitter in the gut and blockade of nitric oxide synthase (NOS; responsible for NO synthesis) increases colonic motility in male mice ex vivo . We assessed the effects of NOS inhibition on colonic motility in female mice using video imaging analysis of colonic motor complexes (CMCs). To understand interactions between NO and estrogen in the gut, we also quantified neuronal NOS and estrogen receptor alpha (ERα)-expressing myenteric neurons in estrus and proestrus female mice using immunofluorescence. Mice in estrus had fewer CMCs under control conditions (6 ± 1 per 15 min, n = 22) compared to proestrus (8 ± 1 per 15 min, n = 22, One-way ANOVA, p = 0.041). During proestrus, the NOS antagonist N-nitro-L-arginine (NOLA) increased CMC numbers compared to controls (189 ± 46%). In contrast, NOLA had no significant effect on CMC numbers during estrus. During estrus, we observed more NOS-expressing myenteric neurons (48 ± 2%) than during proestrus (39 ± 1%, n = 3, p = 0.035). Increased nuclear expression of ERα was observed in estrus which coincided with an altered motility response to NOLA in contrast with proestrus when ERα was largely cytoplasmic. In conclusion, we confirm a cyclic and sexually dimorphic effect of NOS activity in female mouse colon, which could be due to genomic effects of estrogens via ERα.
    Type of Medium: Online Resource
    ISSN: 1662-453X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2411902-7
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  • 8
    In: Autism Research, Wiley, Vol. 13, No. 5 ( 2020-05), p. 691-701
    Abstract: Gastrointestinal (GI) dysfunction is commonly reported by people diagnosed with autism spectrum disorder (ASD; autism) but the cause is unknown. Mutations in genes encoding synaptic proteins including Neuroligin‐3 are associated with autism. Mice lacking Neuroligin‐3 (Nlgn3 −/− ) have altered brain function, but whether the enteric nervous system (ENS) is altered remains unknown. We assessed for changes in GI structure and function in Nlgn3 −/− mice. We found no significant morphological differences in villus height or crypt depth in the jejunum or colon between wildtype (WT) and Nlgn3 −/− mice. To determine whether deletion of Nlgn3 affects enteric neurons, we stained for neural markers in the myenteric plexus. Nlgn3 −/− mice had similar numbers of neurons expressing the pan‐neuronal marker Hu in the jejunum, proximal mid, and distal colon regions. We also found no differences in the number of neuronal nitric oxide synthase (nNOS+) or calretinin (CalR+) motor neurons and interneurons between WT and Nlgn3 −/− mice. We used ex vivo video imaging analysis to assess colonic motility under baseline conditions and observed faster colonic migrating motor complexes (CMMCs) and an increased colonic diameter in Nlgn3 −/− mice, although CMMC frequency was unchanged. At baseline, CMMCs were faster in Nlgn3 −/− mice compared to WT. Although the numbers of neuronal subsets are conserved in Nlgn3 −/− mice, these findings suggest that Neuroligin‐3 modulates inhibitory neural pathways in the ENS and may contribute to mechanisms underlying GI disorders in autism. Autism Res 2020, 13: 691–701 . © 2019 The Authors. Autism Research published by International Society for Autism Research published byWiley Periodicals, Inc. Lay Summary People with autism commonly experience gut problems. Many gene mutations associated with autism affect neuronal activity. We studied mice in which the autism‐associated Neuroligin‐3 gene is deleted to determine whether this impacts gut neuronal numbers or motility. We found that although mutant mice had similar gut structure and numbers of neurons in all gut regions examined, they had distended colons and faster colonic muscle contractions. Further work is needed to understand how Neuroligin‐3 affects neuron connectivity in the gastrointestinal tract.
    Type of Medium: Online Resource
    ISSN: 1939-3792 , 1939-3806
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2418112-2
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  • 9
    In: Gastroenterology, Elsevier BV, Vol. 162, No. 7 ( 2022-05), p. S-178-
    Type of Medium: Online Resource
    ISSN: 0016-5085
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
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  • 10
    In: Autism Research, Wiley, Vol. 12, No. 7 ( 2019-07), p. 1043-1056
    Abstract: Gastrointestinal (GI) problems constitute an important comorbidity in many patients with autism. Multiple mutations in the neuroligin family of synaptic adhesion molecules are implicated in autism, however whether they are expressed and impact GI function via changes in the enteric nervous system is unknown. We report the GI symptoms of two brothers with autism and an R451C mutation in Nlgn3 encoding the synaptic adhesion protein, neuroligin‐3. We confirm the presence of an array of synaptic genes in the murine GI tract and investigate the impact of impaired synaptic protein expression in mice carrying the human neuroligin‐3 R451C missense mutation (NL3 R451C ). Assessing in vivo gut dysfunction, we report faster small intestinal transit in NL3 R451C compared to wild‐type mice. Using an ex vivo colonic motility assay, we show increased sensitivity to GABA A receptor modulation in NL3 R451C mice, a well‐established Central Nervous System (CNS) feature associated with this mutation. We further show increased numbers of small intestine myenteric neurons in NL3 R451C mice. Although we observed altered sensitivity to GABA A receptor modulators in the colon, there was no change in colonic neuronal numbers including the number of GABA‐immunoreactive myenteric neurons. We further identified altered fecal microbial communities in NL3 R451C mice. These results suggest that the R451C mutation affects small intestinal and colonic function and alter neuronal numbers in the small intestine as well as impact fecal microbes. Our findings identify a novel GI phenotype associated with the R451C mutation and highlight NL3 R451C mice as a useful preclinical model of GI dysfunction in autism. Autism Res 2019, 12: 1043–1056 . © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary People with autism commonly experience gastrointestinal problems, however the cause is unknown. We report gut symptoms in patients with the autism‐associated R451C mutation encoding the neuroligin‐3 protein. We show that many of the genes implicated in autism are expressed in mouse gut. The neuroligin‐3 R451C mutation alters the enteric nervous system, causes gastrointestinal dysfunction, and disrupts gut microbe populations in mice. Gut dysfunction in autism could be due to mutations that affect neuronal communication.
    Type of Medium: Online Resource
    ISSN: 1939-3792 , 1939-3806
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2418112-2
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