Browsing by Author "Nasser, Yasmin"

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    Enteric glial cells play a role in neuronal signalling and in inflammation in the gastrointestinal tract
    (2007) Nasser, Yasmin; Sharkey, Keith A.
    The functions of glial cells in the enteric nervous system remain poorly understood. We hypothesized that enteric glia play a role in enteric neurotransmission and in intestinal inflammation. Enteric glia may participate in neurotransmission as we observed that these cells expressed receptors for neurotransmitters, such as the metabotropic glutamate receptors (mGluR) 2/3 and 5, the a2a-adrenergic receptor and the somatostatin 2A (SSTR2A) receptor. Glial receptor expression was altered during colitis. We observed a redistribution in mGluR immunoreactivity in both trinitrobenzene sulphonic acid (TNBS) colitis in guinea pigs and dextran sodium sulphate (OSS) colitis in mice, while mGluR expression was decreased in the inflamed colons of interleukin-10 gene-deficient (I L-10-1-) mice. SSTR2A immunoreactivity was redistributed in mice given DSS but unchanged in IL-10-1- mice. No changes to enteric ganglia or glial fibrillary acidic protein expression were observed in DSS and IL-10_,_ mice. Stimulation of glial mGluR5 receptors increased the expression of the early immediate gene product, Fos, as well as the phosphorylated form of the extracellular signal-regulated kinase 1/2 (pERK1/2), but did not alter intracellular calcium, demonstrating that glial receptors were functionally activated. Studies in cultured enteric glia proved inconclusive, as their phenotype no longer resembled that in situ. The gliotoxin fluorocitrate specifically stimulated pERK1/2 expression in enteric glia and reduced ilea! motility in vitro and gastrointestinal transit in vivo. No changes in colonic transit or ion transport were observed, nor were there any signs of inflammation, suggesting that glia modulate the enteric neural circuits underlying gastrointestinal motility. Enteric glia of the mouse colon constitutively expressed the inducible nitric oxide synthase, likely due to "physiological" inflammation. The nitric oxide precursor, L-arginine was localized to neurons and glia in the mouse, suggesting that glial cells were not the sole source of L-arginine. No changes in gut transit or in the distribution of glial and neuronal markers were observed in mice deficient for the inducible L-arginine transporter. Taken together, these data demonstrate that enteric glia play a role in enteric neurotransmission, particularly in gastrointestinal motility and that changes in glial receptor expression are a feature of colitis.
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    Evaluating Yoga Therapy for Irritable Bowel Syndrome
    (2022-06-21) D'Silva, Adrijana; Raman, Maitreyi; Marshall, Deborah; Nasser, Yasmin; Vallance, Jeff
    Background: Irritable bowel syndrome (IBS) is a chronic disease of the brain-gut axis. Mind-body therapies such as yoga target the central nervous system, autonomic nervous system, immune and endocrine systems involved in the brain-gut axis to improve IBS symptoms and other patient outcomes such as mental health and quality of life. Virtually delivered yoga programming has not been tested nor have the experiences of participants in these programs been explored. Further, we are unaware of the beliefs and attitudes of IBS patients and gastroenterologists towards yoga. Objectives: This thesis had four objectives and they were to: 1) identify patients’ attitudes, subjective norms, perceived behavioural control for yoga, and underlying beliefs and intentions to practice yoga; 2) identify gastroenterologists’ attitudes, perceived supports, barriers and facilitators and intention to recommend a yoga program as part of routine medical care for patients with IBS; 3) explore the feasibility and efficacy of an eight-week virtual yoga program on IBS symptom severity and other patient-reported outcomes compared to an advice-only control group; and 4) explore and describe participants’ experiences in a virtual yoga program, and its impact. Methods: Using mixed-methods, cross-sectional surveys were used to answer aims 1 and 2. A randomized clinical trial answered objective 3 and semi-structured interviews answered objective 4. Results: Patients (N=109) reported controllability, self-efficacy, and affective attitude predicted their intention to practice yoga. Gastroenterologists (N=79) reported they were ten times more likely to recommend yoga if they agreed yoga improves IBS symptoms, however, most were not recommending yoga due to lack of confidence and scientific evidence. The randomized controlled trial (N=79) found virtually delivered yoga was safe, feasible, and efficacious in improving IBS symptoms, quality of life, stress, and fatigue. The interviews revealed the participants had overwhelmingly positive experiences in the program. Conclusions: Virtually delivered yoga programming is acceptable, safe, feasible, and efficacious in the treatment of IBS. Future research is needed to explore how virtually delivered yoga may be positioned as a therapy in the management of IBS.
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    Examining the activation of xenobiotic receptors using microbial metabolites and chemical ligands
    (2024-09-18) Shenoda, Eva Ibrahim Gorgy; Hirota, Simon; Nasser, Yasmin; McCafferty, Donna-Marie
    The aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) are key xenobiotic receptors involved in regulating chemical metabolism and detoxification. Traditionally, these receptors were known for mediating toxic responses by sensing and responding to chemicals. Recent research shows their role in maintaining gut homeostasis and regulating inflammation. However, the mechanisms by which they induce these responses are not clear. This thesis examines whether the activation of AhR and PXR in epithelial cells by microbial metabolites versus chemical ligands drives unique transcriptional responses and could explain differences in beneficial versus deleterious biological outcomes in the host. PXR and AhR were activated with indole-3-propionic acid (IPA) and indole-3-pyruvic acid (IPyA) as microbial metabolites, and pregnenolone 16α-carbonitrile (PCN) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as chemical ligands, respectively. We compared responses to these ligands, revealing significant gene expression differences. Further analysis showed both IPyA and TCDD activated genes involved in hypoxia-inducible factor (HIF) signaling and metabolism. IPyA upregulated genes for ATP synthesis and purine biosynthesis, while TCDD promoted genes related to cell cycle, cancer, and apoptosis. Given that AhR translocates to the nucleus upon activation, we hypothesized that the differences in transcriptomic responses and gene induction might be attributed to differences in nuclear translocation of AhR, with TCDD potentially inducing greater nuclear translocation compared to IPyA. To test this hypothesis, we established a cellular fractionation protocol for organoids. However, our results revealed no significant difference in AhR nuclear translocation between the two treatments, suggesting that other factors may affect gene expression in the AhR pathway. These findings highlight AhR and PXR's complex roles in gut health and inflammation, suggesting receptor activation can have both adverse and beneficial effects. This research enhances our understanding of AhR and PXR mechanisms and their potential for therapeutic strategies targeting gut disorders and inflammation.
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    Investigating the Sexual Dimorphism of Disease Tolerance in Sepsis
    (2023-12-04) Dobson, Breenna; McDonald, Braedon; Jenne, Craig; Nasser, Yasmin
    Sepsis is a dysregulated immune response to infection, with mortality rates as high as 30%, however, there are currently no disease-modifying treatments for this disease. One of the reasons why preclinical sepsis discoveries have failed to translate into effective human therapies is that interindividual heterogeneity has historically been neglected in preclinical sepsis research, including the fundamental contributions of biological sex on disease pathogenesis and treatment response. Epidemiologic studies have observed that males have a higher incidence, severity and mortality rate than females in sepsis, however, the mechanisms underlying this bias have not yet been established. This thesis aims to examine potential underlying mediators of the sexual dimorphism within sepsis illness severity. We investigated the impact of biological sex on host defence using a well-established mouse model of sepsis induced by fecal peritonitis. We used this model to study three principal mediators of sex- based immune response differences: the gut microbiota, sex chromosomes and sex hormones. To uncover differences in these mediators we used a transgenic and germ-free mouse model. Further, we aimed to understand the sex-based influence on infection tolerance and resistance. Lastly, we completed preliminary studies on sex-based differences in infection tolerance using a tetracycline antibiotic as a potentiator of mitochondrial tolerance. This project addressed a critical gap within sepsis research and revealed biological sex differences in infection tolerance and potential therapeutic implications.
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    Microbial dysbiosis alters serotonin signalling in a post-inflammatory murine model of visceral pain
    (2024-07-10) Roth, Timothy Douglas; Sharkey, Keith; Nasser, Yasmin; Altier, Christophe
    Inflammatory bowel disease (IBD) is a chronic disorder characterized by inflammation of the gastrointestinal tract, affecting a growing number of individuals worldwide. Despite achieving endoscopic remission, many IBD patients continue to experience visceral pain, suggesting underlying mechanisms beyond inflammation. One hypothesis implicates alterations in gut microbiota post-inflammation, leading to dysregulated serotonin (5-HT) signalling within the gut and heightened pain sensitivity. This thesis investigated this hypothesis using a mouse model of IBD in remission associated with visceral pain to explore changes in enterochromaffin cell populations, gene expression related to 5-HT synthesis, transport, and degradation, as well as 5-HT concentration and its metabolites. Additionally, fecal microbiota transplant (FMT) experiments were performed using stool from DSS-treated mice, alongside comparative analyses with germ-free (GF) mice, to delineate the impact of the microbiota on post-inflammatory pain in IBD and establish a baseline for gut microbiota effects on 5-HT signalling. High-performance liquid chromatography (HPLC) was utilized to assess 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) tissue concentrations, and enzyme-linked immunosorbent assay (ELISA) was employed to determine 5-HT release dynamics in the gut. Our findings revealed region-specific differences in 5-HT release in the terminal ileum, proximal colon, and distal colon, suggesting localized alterations in 5-HT signalling post-inflammation. Additionally, GF mice displayed distinct patterns of altered gene expression and 5-HT/5-HIAA concentration compared to conventionally colonized counterparts, underscoring the pivotal role of gut microbiota in modulating 5-HT metabolism and signalling. FMT experiments allowed us to assess the impact of dysbiotic microbiota on post-inflammatory pain. Surprisingly, we found no significant differences in gene expression between control and DSS-treated FMT groups, suggesting resilience of the host to changes in microbiota composition. However, we observed differences in 5-HT release dynamics between FMT groups, indicating potential microbiota-driven alterations in neuronal signalling pathways. Overall, we found alterations in 5-HT signalling in the recovery model of DSS-induced colitis. These findings enhance our understanding of the pathophysiology of IBD-related pain, highlighting the complex interplay between gut microbiota and 5-HT signalling after a period of intestinal inflammation.
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    Non-Psychotropic cannabinoids attenuate visceral pain in colitis
    (2023-05-25) Svendsen, Kristofer; Altier, Christophe; Sharkey, Keith; Nasser, Yasmin; Trang, Tuan; Ma, Chris
    The inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, are complex chronic diseases that affect an increasing proportion of the population. Abdominal pain is a major clinical symptom, but current treatments are limited and a source of frustration for patients, many of whom seek alternatives such as cannabis. Cannabis contains many compounds with therapeutic potential that do not have the prohibitive psychotropic effects of tetrahydrocannabinol (THC). These non-psychotropic cannabinoids (npCBs) have a variety of effects including analgesia and anti-inflammatory actions and show potentiating effects when administered in combination. This project explored the analgesic effects of cannabichromene (CBC), cannabidiol (CBD), cannabidivarin (CBDV), and cannabigerol (CBG), individually and in combination, in the treatment of colitis-evoked visceral hypersensitivity use the acute dextran sulfate sodium model. Abdominal pain was quantified by electromyographic recordings of the reflexive contraction of the external oblique muscle in response to colorectal distension using an animal of experimental colitis. Activation of the spinal cord was assessed using immunohistochemistry to the neuronal activity marker c-Fos in neurons of the lumbosacral dorsal horn. A single injection intraperitoneal injection of 10 mg/kg of either CBD or CBG was found to reduce both nocifensive behaviors in the functional assay and c-Fos activity in spinal cord in animals with colitis. Similarly, a combination of npCBs consisting of 5 m/kg CBD with 1 m/kg each CBC, CBDV, and CBG—all sub-therapeutic dosages—reduced both measures to the level of untreated control animals. Investigations of mechanism of actions via whole-cell patchclamp electrophysiology of primary dorsal root ganglia neurons revealed CBD to act via a voltage-gated calcium channel with preliminary evidence indicating a high-voltage activated isoform. Preliminary data also suggest that the mixture of npCBs may act through a similar mechanism. These results suggest CBD, CBG, and a mixture of npCBs may be beneficial in managing pain associated with IBD.
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    The role of serotonin in the immunoregulation by the helminth parasite Hymenolepis diminuta
    (2019-12-19) Wang, Susan Joanne; McKay, Derek Mark; Sharkey, Keith A.; Nasser, Yasmin; Geuking, Markus B.
    While infection with parasitic helminths remains a major concern for a quarter of the worlds’ population in non-westernized societies, the incidence of infection has significantly reduced in westernized societies. Simultaneously, the incidence of autoimmune diseases, such as inflammatory bowel disease, is on the rise in the industrialized-west. Studies of infection with various helminths, including the rat tapeworm, Hymenolepis diminuta, in murine models of inflammatory disease reveal the potential of helminth-based therapeutics. Serotonin (5-hydroxytryptamine, 5-HT) has previously been shown to be responsive to infection with a helminth. It has a variety of immunomodulatory actions in the gastrointestinal tract, yet its potential role in helminth expulsion and helminth therapy is largely unknown. Thus, the research presented in this thesis sought to test the hypothesis that infection with H. diminuta evokes increases in mucosal serotonin levels, important for fine-tuning type 2 (Th2) immunity and are involved in H. diminuta-mediated inhibition of dinitrobenzene sulphonic acid (DNBS)-induced colitis. Three specific aims were: (1) assess changes in murine intestinal serotonin following infection with H. diminuta, (2) determine if serotonin was important in the expulsion of H. diminuta from its non-permissive mouse host; and, (3) evaluate if manipulation of the enteric serotonergic system affected H. diminuta-evoked suppression of murine colitis caused by DNBS. This study did not find evidence of an increase in serotonin in the small intestine of H. diminuta-infected male BALB/c mice, and the extrinsic manipulation of the serotoninergic system via systemic delivery of a tryptophan hydroxylase inhibitor (para-chlorophenylalanine), 5-HT7 receptor antagonist (SB269970), or selective serotonin reuptake transporter inhibitor (fluoxetine) had negligible effects on worm expulsion or systemic Th2 events post-infection. Thus, the data do not support the hypothesis that enteric serotonin is a major influence of the immune response to infection with H. diminuta. Preliminary findings, however, suggest that the stress response to consecutive daily handling and i.p. injections may abrogate the helminth-evoked suppression of DNBS-induced colitis in mice, highlighting the neuro-immune axis and stress component of experimental design when studying inflammatory disorders.
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    Sex differences in the post-inflammatory gut microbiota play a role in chronic visceral pain in inflammatory bowel diseases
    (2023-06) Arzamendi, Maria Jose; Nasser, Yasmin; Geuking, Markus; Altier, Christophe; Sharkey, Keith; Trang, Tuan
    Despite achieving endoscopic remission, a substantial number of patients with inflammatory bowel disease (IBD), particularly females, continue to experience chronic abdominal pain. The mecha- nisms underlying these sex differences in pain perception remain unclear, but the gut microbiota and sex hormones are potential factors influencing pain sensitivity. The study utilizes a post- inflammatory DSS mouse model of IBD to examine sex-specific differences in the gut microbiota and visceral pain. We hypothesized that the gut microbiota plays a crucial role in modulating chronic visceral pain in females, leading to increased pain compared to ovariectomized females and male mice. Male and female mice were given DSS to induce colitis and thereafter allowed to recover to achieve a post-inflammatory state. Visceral pain was assessed using the visceral motor reflex (VMR) to colorectal distention (CRD). The results demonstrate that cycling female mice exhibit increased visceral pain compared to males and ovariectomized females, despite dis- playing decreased colitis severity compared to males. DSS-induced colitis altered the gut mi- crobial community in both male and cycling female mice, with sex-specific differences observed in metabolic profiles. Short-chain fatty acid (SCFA) levels were increased in post-inflammatory male mice but decreased in females. Furthermore, specific metabolite levels, such as adenine and d-tryptophan, exhibit sex-specific differences in post-inflammatory mice. Using fecal micro- biota transplant (FMT) to colonize germ-free mice with sex-hormone-appropriate and opposite sex-hormone microbiota, showed that the female post-inflammatory microbiota increased visceral hypersensitivity in both female and male recipient mice. These findings highlight the importance of sex-specific differences in the post-inflammatory gut microbiota and their influence on chronic pain. Understanding role of these differences in post-inflammatory visceral pain in IBD is crucial and may lead to the development of novel therapeutic approaches for managing chronic pain.