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Juvenile SDS induced colonic visceral hyperalgesia. (A) Representative electromyographic recordings of control and SDS model (stress) mice. (B) Visceromotor response (VMR) to colorectal distension (CRD) in control and SDS model mice. Data are presented as the mean ± SEM (n = 6-8 mice per group). *p < 0.05 compared with the control group.
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Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder. Traumatic stress during adolescence increases the risk of IBS in adults. The aim of this study was to characterize the juvenile social defeat stress (SDS)-associated IBS model in mice. Juvenile mice were exposed to an aggressor mouse for 10 min once daily for 10...
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... SDS increased visceral sensitivity to colorectal distension. We next investigated the effect of juvenile stress on visceral hyperalgesia (Fig. 3). The amplitude of the electromyographic recordings indicated a significant stimulus effect (F = 7.1, p = 0.0007). There was no significant group effect (F = 2.9) or group × stimulus interaction effect (F = 2.3). The visceromotor response to colorectal distension was significantly increased in mice exposed to juvenile SDS compared with ...
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... проведено исследование на мышах постнатального периода, отлученных от матери. В ответ на длительный стресс у мышей появлялись изменения перистальтики кишечника и нарушения показателей висцеральной чувствительности (ВЧ), аналогичные клиническим симптомам СРК у людей [2]. В последней, IV версии Римских критериев впервые введено понятие перекреста (overlap syndrome) функциональных заболеваний ЖКТ, связанных с общим патогенетическим механизмом развития. ...
Background. Stress, individual characteristics of each patient, visceral hypersensitivity and intestinal motility have the key importance in the pathogenesis of irritable bowel syndrome (IBS). In recent years, there has been growing interest in the use of selective serotonin and norepinephrine reuptake inhibitors (SNRIs) in the complex therapy of IBS patients with somatoform disorders. Aim. To examine the effectiveness of the SNRIs antidepressant therapy in the treatment of patients with IBS and diarrhea (IBS-D) with extraintestinal manifestations. Materials and methods. 42 patients with severe IBS and diarrhea (IBS-D) were examined, among them 22 female with a median age of 32 years old (22; 38), and 20 male with a median age of 31 years old (25; 35). Treatment with duloxetine 60 mg/day was prescribed. The effectiveness of the therapy was assessed after eight weeks. The IBS clinical symptoms dynamics were assessed by the intensity of pain syndrome and bloating, which were determined using Visual Analogue Pain Scale (VAS), stool frequency and shape based on the Bristol stool scale; Visceral sensitivity threshold was assessed according to the Balloon dilatation test. There was studied the effect of the duloxetine on the extraintestinal manifestations of IBS. The psycho-emotional state was assessed using the Beck scale of anxiety and depression and the SpielbergerKhanin scale by psychiatrist, neurologist-vegetol. Results. All patients showed positive dynamics after eight weeks duloxetine treatment: the decrease of pain syndrome from 9 (9; 10) to 2 (2; 3) points, bloating from 8 (8; 9) points to 2,5 (1; 3) points according to VAS, and defecation frequency from 10 (9; 12) to 2 (1; 2) times a day; the change of stool consistency from 6th (6; 7) to 3rd (3; 4) type. The visceral sensitivity threshold increased: the time of appearance of the first urge to defecate increased from 56 (34; 74) ml to 95 (80; 98) ml. Significantly decreased extraintestinal manifestations of IBS. In reassessing each patients individual characteristics there were the decrease of the depression level according to the Beck scale from 26 (23; 32) to 11.5 (10; 13) points and personal personal anxiety level according to the SpielbergerKhanin scale from 42.5 (35; 53) to 22 (20; 24) points, as well as the decrease of situational anxiety from 40 (37; 49) to 22 (21; 36) points. Conclusion. The severe course of IBS-D is mainly associated with the patients individual characteristics and anxiety or anxiety-depressive syndromes. The positive impact of duloxetine therapy in severe IBS-D with extraintestinal manifestations is associated with the regulation of serotonergic and noradrenergic activity of the central.
... Recently, the chronic social defeat stress (cSDS) and chronic vicarious social defeat stress (cVSDS) models have been regarded as widely valid animal models of MDD and PTSD that also presents anxiety-and anhedonia-like phenotypes (Kudryavtseva et al., 1991;Rygula et al., 2005Rygula et al., , 2006Warren et al., 2013;Iñiguez et al., 2019). Notably, we previously reported the induction by the juvenile cSDS paradigm in mice of IBS-like symptoms in their adulthood (Matsumoto et al., 2021). While cSDS model mice (hereinafter referred to as "physical stress (PS) mice, " as in previous reports) are submitted to repeated physical attacks from the other mouse, cVSDS model mice ["emotional stress (ES) mice"] receive emotional stress only through witnessing PS mice (Sial et al., 2016). ...
... We evaluated intestinal permeability as described previously (Matsumoto et al., 2021). In brief, we collected blood from the submandibular vein of mice 1 h after the oral administration of 200 µL of FITC-dextran (MW 4000) solution (50 mg/mL; Merck KGaA, Darmstadt, Germany). ...
... We determined the sample size by referring to previous reports (Eijkelkamp et al., 2007;Warren et al., 2013;Matsumoto et al., 2021;Yoshioka et al., 2022). Data were acquired from at least two divided experiments. ...
Increasing evidence has demonstrated that emotional states and intestinal conditions are inter-connected in so-called “brain–gut interactions.” Indeed, many psychiatric disorders are accompanied by gastrointestinal symptoms, such as the irritable bowel syndrome (IBS). However, the functional connection remains elusive, partly because there are few useful experimental animal models. Here, we focused on a highly validated animal model of stress-induced psychiatric disorders, such as depression, known as the chronic vicarious social defeat stress (cVSDS) model mice, which we prepared using exposure to repeated psychological stress, thereafter examining their intestinal conditions. In the charcoal meal test and the capsaicin-induced hyperalgesia test, cVSDS model mice showed a significantly higher intestinal transit ratio and increased visceral pain-related behaviors, respectively. These changes persisted over one month after the stress session. On the other hand, the pathological evaluations of the histological and inflammatory scores of naive and cVSDS model mice did not differ. Furthermore, keishikashakuyakuto—a kampo medicine clinically used for the treatment of IBS—normalized the intestinal motility change in cVSDS model mice. Our results indicate that cVSDS model mice present IBS-like symptoms such as chronic intestinal peristaltic changes and abdominal hyperalgesia without organic lesion. We therefore propose the cVSDS paradigm as a novel animal model of IBS with wide validity, elucidating the correlation between depressive states and intestinal abnormalities.
... Распространенность СРК в мире варьирует от 30 до 55% [1,2]. СРК -это болезнь молодого населения, встречается преимущественно у женщин [3]. ...
Background:
Irritable bowel syndrome (IBS) is a biopsychosocial model based on the malfunction of "brain-intestinal linking".
Aim:
To improve diagnostics of the severe IBS accompanied with somatoform disorders by using balloon dilatation test (BDT) and optimize the therapy by using antidepressants from the serotonin and noradrenaline reuptake inhibitor type.
Materials and methods:
61 patients with severe IBS and diarrhea were examined, among them 29 female with a median age of 31 years old (24; 36), and 31 male with a median age of 31 (24; 36) years old. All patients were randomized into two groups, group 1 consisted of 30 patients (15 female, 15 male), group 2 consisted of 31 patients (15 female, 16 male). The symptoms of all patients were assessed using the Visual Analogue Pain Scale (VAS Pain), visceral sensitivity index (VIS) was assessed according to the J. Labus questionnaire (2007) and visceral sensitivity threshold was assessed according to the BDT, the psycho-emotional state was assessed using the Beck scale of anxiety and depression and the Spielberger-Khanin scale. Both group patients underwent a comparative effectiveness evaluation between the therapy based on the use of Trimebutine at a dose of 600 mg per day and the SNRI-Duloxetine therapy at a dose of 60 mg per day for 8 weeks.
Results:
Patients from group with severe IBS and diarrhea who had undergone the antidepressant therapy showed the decrease of pain syndrome from 7 (5; 7) to 2.5 (2; 3) points according to VAS Pain; normalization of stool frequency from 7 (6; 9) to 2 (1; 2) times a day; normalization of stool consistency from 6 (6; 7) to 3 (3; 4) type; and decrease of VIS: first urge from 56 (34; 74) to 95 (80; 98) ml.; as well as the decrease of the depression level (Beck scale) from 26 (23; 32) to 11.5 (10; 13) points and anxiety according to Beck scale from 38 (31; 45) to 11 (10; 12), the decrease of personal anxiety level (Spielberger-Khanin scale) from 42.5 (35; 53) to 22 (20; 24) points, and the decrease of situational anxiety from 40 (37; 49) to 22 (21; 36) points. During the trimebutine therapy in group 1, the clinical symptoms of IBS have persisted. According to the BDT, the visceral sensitivity (HF) threshold remained at a low level. And the indicators of anxiety and depression remained at a high level according to the psychometric scales.
Conclusion:
The insufficient effect of the trimebutine therapy can be explained by the somatoform disorders persistence in patients from group 1. Meanwhile SNRI-duloxetine therapy in group 2 showed a clinical remission of IBS: such as a reliable relief from pain and diarrheal syndrome, as well as an increase in the HF threshold. Thus, Duloxetine is a promising treatment for severe IBS with somatoform disorders. BDT can be used as an objective criterion to diagnose and evaluate the effectiveness of therapy in patients with IBS.
... Earlier studies have reported different effects of social defeat stress on spontaneous motor activity. There are reports that social defeat of mice and 80-85 days old Sprague-Dawley rats do not alter the line-crossing index in the open field [32][33][34][35]. On the other hand, others reported that social defeat reduces motor activity in mice and rats [22,36,37]. ...
Early life stress (ELS) is an important factor in programing the brain for future response to stress, and resilience or vulnerability to stress-induced emotional disorders. The hippocampal formation, with essential roles in both regulating the stress circuitry and emotionality, contributes to this adaptive programing. Here, we examined the effects of early handling (EH) and maternal deprivation (MD) as mild and intense postnatal stressors, respectively, on the behavioural responses to social defeat stress in young adulthood. We also evaluated the interaction of mild and intense ELS with later social defeat (SD) stress on the morphology and dendritic spine density of Golgi-cox-stained CA3 hippocampal neurons. SD stress in adult rats, as expected, increased anxiety and depressive-like behaviours in the open field, elevated plus-maze and forced swimming test. These effects were associated with reduction of dendritic spines and soma size of CA3 neurons. Both behavioural and structural alterations were significantly ameliorated in socially defeated rats that experienced early handling (EH-SD). Basal dendrites of CA3 neurons in EH-SD rats also showed longer dendrites and more intersections with Sholl circles in the distal portion, compared to both control and SD rats. On the other hand, in socially defeated rats with maternal deprivation experience (MD-SD) the stress-induced behavioural and structural alterations were generally intensified compared to SD rats. In MD-SD rats, apical dendrites of CA3 neurons demonstrated remarkable retraction; an effect that was not detected in SD rats. The reduction of dendritic spines density on the apical dendrites of CA3 neurons was also more pronounced in MD-SD rats compared to SD rats. Dendritic arbors and spines comprise the major neuronal substrate for the circuit connectivity, and cell region-specific alterations of dendrites and spines in CA3 neurons reveal plausible mechanisms that can underlie the impact of different ELSs on risk for affective disorders in response to social stress in adulthood.
... One of the di culties in elucidating the pathophysiology of IBS is the paucity of useful animal models. Recently, the chronic social defeat stress (cSDS) and chronic vicarious social defeat stress (cVSDS) models have been regarded as widely valid animal models of MDD and PTSD that also presents anxietyand anhedonia-like phenotypes [12][13][14][15][16]. Notably, we previously reported the induction by the juvenile cSDS paradigm in mice of IBS-like symptoms in their adulthood [17]. While cSDS model mice (hereinafter referred to as "physical stress (PS) mice," as in previous reports) are submitted to repeated physical attacks from the other mouse, cVSDS model mice ("emotional stress (ES) mice") receive emotional stress only through witnessing PS mice [18]. ...
... We determined each sample size by reference to previous reports [15,17,19,21], and the data was acquired in at least 2 divided experiments. Investigators were blinded to animal groups and/or drug administration information during testing. ...
... Here, we revealed that repeated psychological stress-induced IBS-D-like symptoms without morphological changes and in ammations of the intestine, conferring on this cVSDS paradigm higher constructive and face validities. Previously, we reported that cSDS in juvenile mice causes IBS-like symptoms in their adulthood, an animal model of IBS now regarded as both novel and highly validated [17]. We consider both the cSDS and the cVSDS paradigms to be very useful animal models of IBS in the elucidation of the pathophysiological conditions and the design of therapeutic drugs. ...
Increasing evidence has demonstrated that emotional states and intestinal conditions are inter-connected in so-called “brain–gut interactions.” Indeed, many psychiatric disorders are accompanied by gastrointestinal symptoms, such as the irritable bowel syndrome (IBS). However, the functional connection remains elusive, partly because there are few useful experimental animal models. Here, we focused on a highly validated animal model of stress-induced psychiatric disorders, such as depression, known as the chronic vicarious social defeat stress (cVSDS) model mice, which we prepared using exposure to repeated psychological stress, thereafter examining their intestinal conditions. In the charcoal meal test and the capsaicin-induced hyperalgesia test, cVSDS model mice showed a significantly higher intestinal transit ratio and increased visceral pain-related behaviors, respectively. These changes persisted over one month after the stress session. On the other hand, the pathological evaluations of the histological and inflammatory scores of naive and cVSDS model mice did not differ. Furthermore, keishikashakuyakuto—a kampo medicine clinically used for the treatment of IBS—normalized the intestinal motility change in cVSDS model mice. Our results indicate that cVSDS model mice present IBS-like symptoms such as chronic intestinal peristaltic changes and abdominal hyperalgesia without organic lesion. We therefore propose the cVSDS paradigm as a novel animal model of IBS with wide validity, elucidating the correlation between depressive states and intestinal abnormalities.
Irritable bowel syndrome (IBS), which is characterized by chronic abdominal pain, has a high global prevalence. The anterior cingulate cortex (ACC), which is a pivotal region involved in pain processing, should be further investigated regarding its role in the regulation of visceral sensitivity and mental disorders. A C57BL/6J mouse model for IBS was established using chronic acute combining stress (CACS). IBS‐like symptoms were assessed using behavioral tests, intestinal motility measurements, and abdominal withdrawal reflex scores. Fluoro‐Gold retrograde tracing and immunohistochemistry techniques were employed to investigate the projection of ACC gamma‐aminobutyric acid‐producing (GABAergic) neurons to the lateral hypothalamus area (LHA). Chemogenetic approaches enabled the selective activation or inhibition of the ACC–LHA GABAergic pathway. Enzyme‐linked immunosorbent assay (ELISA) and western blot analyses were conducted to determine the expression of histamine, 5‐hydroxytryptamine (5‐HT), and transient receptor potential vanilloid 4 (TRPV4). Our findings suggest that CACS induced IBS‐like symptoms in mice. The GABA type A receptors (GABAAR) within LHA played a regulatory role in modulating IBS‐like symptoms. The chemogenetic activation of ACC–LHA GABAergic neurons elicited anxiety‐like behaviors, intestinal dysfunction, and visceral hypersensitivity in normal mice; however, these effects were effectively reversed by the administration of the GABAAR antagonist Bicuculline. Conversely, the chemogenetic inhibition of ACC–LHA GABAergic neurons alleviated anxiety‐like behaviors, intestinal dysfunction, and visceral hypersensitivity in the mouse model for IBS. These results highlight the crucial involvement of the ACC–LHA GABAergic pathway in modulating anxiety‐like behaviors, intestinal motility alterations, and visceral hypersensitivity, suggesting a potential therapeutic strategy for alleviating IBS‐like symptoms. image
Background. According to UNESCO data for 2018, every third student is involved in bullying. To study the impact of social conflicts the state of the nervous system the K.Micek model of chronic social stress was used, but the study of the effects of chronic social stress on prepubertal animals has not been conducted. The aim of the study is to analyze the effect of chronic stress in infant age period to the behavioral phenotype of C57Bl/6 mice in early and long-term periods. Materials and methods. The objects of the study were male C57Bl/6 mice, n=48. For bullying modeling we chose chronic social stress in infant age period according to the "resident-intruder" scheme. Mice were divided into two subgroups to study the early and long-term consequences of chronic social stress. For the behavioral phenotyping we used the following tests: open field test, three-chamber social test, object recognition test, passive avoidance task and Barnes maze. Results. Bullying modeling led to the changes in the behavioral phenotype both in infant age and in adulthood. The behavioral phenotype in infant age period was characterized by increased social activity and recognition, high anxiety, decreased locomotor and exploratory activity, impaired recognition of inanimate objects, but good characteristics of learning, working and long-term memory. In adulthood, the behavioral phenotype of mice retained high anxiety, low level of exploratory activity, good learning and memory characteristics, decline in social recognition in three-chamber test, while the recognition of inanimate objects was preserved at the same level. Conclusion. Chronic social stress in infant age in a mouse model of bullying causes disruption of the behavioral phenotype in infant and adult age. Features of the behavioral phenotype of mice after bullying were an increase in anxiety and social isolation against the background of the ability to learn and good memory.
Reliable biomarkers for common disorders of gut–brain interaction characterized by abdominal pain, including irritable bowel syndrome (IBS), are critically needed to enhance care and develop individualized therapies. The dynamic and heterogeneous nature of the pathophysiological mechanisms that underlie visceral hypersensitivity have challenged successful biomarker development. Consequently, effective therapies for pain in IBS are lacking. However, recent advances in modern omics technologies offer new opportunities to acquire deep biological insights into mechanisms of pain and nociception. Newer methods for large-scale data integration of complementary omics approaches have further expanded our ability to build a holistic understanding of complex biological networks and their co-contributions to abdominal pain. Here, we review the mechanisms of visceral hypersensitivity, focusing on IBS. We discuss candidate biomarkers for pain in IBS identified through single omics studies and summarize emerging multi-omics approaches for developing novel biomarkers that may transform clinical care for patients with IBS and abdominal pain.
Aims:
Animals involved in common laboratory procedures experience minor levels of stress. The direct effect of limited amounts of stress on gastrointestinal function has not been reported yet. Therefore, this study aimed to assess the effect of single-day and multi-day orogastric gavages on gut physiology in mice.
Main methods:
Twelve-week old female C57Bl6/J mice were randomized to receive a treatment with sterile water (200 µL) delivered by orogastric gavages twice daily for a total of 1 or 10 day(s). Control animals did not receive any treatment. Subsequently, gastrointestinal function was assessed by measuring fecal pellet production. Furthermore, ex vivo intestinal barrier and secretory function of the distal colon, proximal colon and terminal ileum were quantified in Ussing chambers.
Key findings:
In mice, single-day gavages did not influence corticosterone levels nor gastrointestinal function. In mice exposed to multi-day gavages, corticosterone levels were slightly but significantly increased compared to controls after 10 days of treatment. Gastrointestinal motor function was altered, as evidenced by increased fecal pellet counts and a small increase in fecal water content. However, exposure to repeated gavages did not lead to detectable alterations in gastrointestinal barrier function as quantified by the paracellular flux of the probe 4kDa FITC-dextran as well as transepithelial resistance measurements.
Significance:
The administration of drugs via single-day or multi-day orogastric gavages leads to no or minor stress in mice, respectively. In both cases, it does not hamper the study of the intestinal barrier function and therefore remains a valuable administration route in preclinical pharmacological research.
The limbic system plays a pivotal role in stress-induced anxiety and intestinal disorders, but how the functional circuits between nuclei within the limbic system are engaged in the processing is still unclear. In our study, the results of fluorescence gold retrograde tracing and fluorescence immunohistochemistry showed that the melanin-concentrating hormone (MCH) neurons of the lateral hypothalamic area (LHA) projected to the basolateral amygdala (BLA). Both chemogenetic activation of MCH neurons and microinjection of MCH into the BLA induced anxiety disorder in mice, which were reversed by intra-BLA microinjection of MCH receptor 1 (MCHR1) blocker SNAP-94847. In the chronic acute combining stress (CACS) stimulated mice, SNAP94847 administrated in the BLA ameliorated anxiety-like behaviors and improved intestinal dysfunction via reducing intestinal permeability and inflammation. In conclusion, MCHergic circuit from the LHA to the BLA participates in the regulation of anxiety-like behavior in mice, and this neural pathway is related to the intestinal dysfunction in CACS mice by regulating intestinal permeability and inflammation.
