[Objectives]To explore the mechanism of action of Tongxieyaofang ultrafine granular powder in treating visceral hypersensitivity in rats with diarrhea-predominant irritable bowel syndrome(IBS-D)based on enteric glial ...[Objectives]To explore the mechanism of action of Tongxieyaofang ultrafine granular powder in treating visceral hypersensitivity in rats with diarrhea-predominant irritable bowel syndrome(IBS-D)based on enteric glial cells(EGCs).[Methods]Eighty-four healthy male Wistar rats of SPF grade were selected and randomly assigned to seven groups,each comprising 12 rats:a normal control group,a model control group,a traditional Tongxieyaofang granular powder group(4.060 g/kg),three Tongxieyaofang ultrafine granular powder groups at low,medium,and high doses(1.015,2.030,and 4.060 g/kg of raw drug,respectively),and a pinaverium bromide group(0.018 g/kg).With the exception of the normal control group,all other groups were subjected to an IBS-D visceral hypersensitivity sensitivity model in rats developed by the chronic water avoidance stress method.Three days post modeling,the rats received continuous oral gavage administration for 8 d.Following the treatment period,serum and colon tissue samples were collected from each group.The BDNF level in the serum was quantified using ELISA.Additionally,the protein expression levels of GFAP,BDNF,and TrkB in colon tissues were assessed via Western blot assay.[Results]Compared to the normal control group,the serum BDNF levels in the model control group were significantly elevated(P<0.01).In contrast,each treatment group exhibited a significant reduction in serum BDNF levels relative to the model control group(P<0.01).Furthermore,the protein expression levels of GFAP,BDNF,and TrkB in colon tissue were significantly higher in the model control group compared to the normal control group(P<0.05,P<0.01).Conversely,these protein expressions were significantly decreased in each treatment group compared to the model control group(P<0.05,P<0.01).[Conclusions]Tongxieyaofang ultrafine granular powder effectively alleviates visceral sensitivity in IBS-D rats and inhibits the activation of EGCs,speculating that its mechanism of action involves the suppression of abnormal EGC activation.展开更多
Drug hypersensitivity reactions(DHRs),which produce symptoms from skin rash to anaphylaxis,are immune-mediated adverse reactions caused by drug formulations.The diagnosis of DHRs is challenging due to the lack of stan...Drug hypersensitivity reactions(DHRs),which produce symptoms from skin rash to anaphylaxis,are immune-mediated adverse reactions caused by drug formulations.The diagnosis of DHRs is challenging due to the lack of standardization for many drugs,and both underdiagnosis and overdiagnosis hamper the follow-up treatment of patients.Therefore,improved methods for diagnosing patients with suspected DHRs are needed.In this review,we analyzed traditional methods used to diagnose DHRs as well as new diagnostic advances made during the last 2 years.None of the diagnostic methods is perfect,as each exhibits varying sensitivities to different types of DHRs.Overall,our analysis indicates that the accuracy of DHR diagnosis can be improved by obtaining a detailed clinical history,physical examination,in vivo and in vitro testing.展开更多
OBJECTIVE:this study to investigate the mechanism underlying the electroacupuncture(EA)alleviates colorectal hypersensitivity,a feature of irritable bowel syndrome(IBS).METHODS:The colorectal hypersensitivity model wa...OBJECTIVE:this study to investigate the mechanism underlying the electroacupuncture(EA)alleviates colorectal hypersensitivity,a feature of irritable bowel syndrome(IBS).METHODS:The colorectal hypersensitivity model was established by treating mice with zymosan.Electrophysiological techniques,Western blotting and immunofluorescence staining were used to detect the changes of the sensitive state of the colorectum and the response in spinal ganglion and spinal cord after acupuncture intervention.RESULTS:colorectal distension studies revealed that repetitive applied electroacupuncture treatment on mice could significant alleviates colorectal intensity.Western blotting studies with nerve growth factor(NGF)in the colorectum,substance P(SP)in the spinal ganglion,protein kinase C gamma(PKCγ)in the spinal cord,and transient receptor potential vanilloid 1(TRPV1)showed that electroacupuncture suppressed zymosan-induced expression of TRPV1,NGF and SP in multiple tissues.Immunofluorescence labeling results showed that EA attenuated the expression of NGF in the colorectum,SP in the spinal ganglion,PKCγin the spinal cord,and TRPV1 in all three tissues in zymosan-treated mice.Moreover,the number of neurons double-positive for TRPV1/Isolectin B4(IB4)and TRPV1/Neurofilament(NF)200 was increased in the spinal ganglion.CONCLUSION:these results provide molecular-level evidence that EA alleviates zymosan-induced colorectal hypersensitivity by altering the expression of pain-associated proteins in the colorectum and spinal cord.EA has a potential to be therapeutic intervention option for IBS treatment.展开更多
BACKGROUND Reflux hypersensitivity(RH)constitutes roughly 14%of patients with heartburn and 34%of those with refractory heartburn,yet it is inadequately comprehended.AIM To investigate the clinical characteristics and...BACKGROUND Reflux hypersensitivity(RH)constitutes roughly 14%of patients with heartburn and 34%of those with refractory heartburn,yet it is inadequately comprehended.AIM To investigate the clinical characteristics and risk factors associated with RH.METHODS We conducted a retrospective analysis of 109 patients with RH and 384 healthy controls from three medical centers between January 2022 and December 2023.Comprehensive data encompassing symptoms,motility,impedance-pH monitoring,and psychological evaluations were collected.RESULTS RH patients encountered a greater frequency of weakly acidic reflux(WAR)events compared to acidic reflux or nonacidic reflux(NAR)events.Upright reflux time(1.22%)exceeds supine reflux time(0.54%)(P<0.05).Extraesophageal symptoms were more prevalent among younger patients and those with elevated NAR(P<0.05).The acidic reflux,WAR,NAR,and peristaltic contraction break length in male patients exceeded those in female patients(P<0.05).Age[odds ratio(OR)=5.633],hiatal hernia(OR=13.103),and anxiety(OR=17.342)constituted independent risk factors for RH.CONCLUSION WAR and NAR are pivotal in RH.Patients with increased NAR are more likely to experience extraesophageal symptoms.Age,hiatal hernia,and anxiety are significant independent risk factors for RH.展开更多
OBJECTIVE:To explore if Hewei Jiangni granule(和胃降逆颗粒,HWJNG)could regulate esophageal hypersensitivity via stromal interaction molecule 1(STIM1)/transient receptor potential vanilloid subfamily member 1(TRPV1)pat...OBJECTIVE:To explore if Hewei Jiangni granule(和胃降逆颗粒,HWJNG)could regulate esophageal hypersensitivity via stromal interaction molecule 1(STIM1)/transient receptor potential vanilloid subfamily member 1(TRPV1)pathway.METHODS:Qualitative analysis of HWJNG was analysis by high performance of liquid and gas chromatography.In vivo,animal model of non-erosive reflux disease(NERD)was established by fructose intake and restraint stress.HWJNG and Omeprazole were administered by gavage to the drug intervention group.Reflux and visceral hypersensitivity were analyzed by pathological changes,PH value test,mechanical paw withdrawal threshold,thermal withdrawal latency and mast cells(MCs)degranulation.In vitro,substance P(SP)-induced P815 cells and dorsal root ganglion(DRG)cells were cocultured.Expression in both mice and cells of STIM1,TRPV1,and esophageal visceral hypersensitivity-related gastrointestinal neurochemicals were validated by enzyme linked immunosorbent assays,quantitative realtime polymerase chain reaction(qRT-PCR)and Western blot.Moreover,overexpression and small interfering RNA against STIM1 were utilized to verify of the role of HWJNG in DRG cells.RESULTS:HWJNG significantly suppressed intercellular space widening,injury of mitochondrial,MCs degranulation,mechanical allodynia and heat neuropathic sensory and increased pH value of esophageal mucosa in NERD mice.HWJNG inhibited expression of visceral hypersensitivityrelated gastrointestinal neurochemicals in esophageal mucosa and activated P815 cells,and expression of the STIM1,TRPV1 and related neurotransmitters in DRG and DRG cells.STIM1 siRNA and HWJNG both reduced P815 cells adhesion to DRGs cells and Ca2+flow into the cytoplasmic space of DRG cells.Furthermore,HWJNG could reversed STIM1 overexpression induced upregulation of TRPV1.CONCLUSION:HWJNG suppressed intercellular space widening in NERD mice,stabilized MCs and restored neuronal hyperexcitability by regulating visceral hypersensitivity via STIM1/TRPV1 pathway.展开更多
BACKGROUND Visceral hypersensitivity is the core pathogenesis of irritable bowel syndrome(IBS)and is often accompanied by negative emotions such as anxiety or depression.Paraventricular hypothalamic nucleus(PVN)cortic...BACKGROUND Visceral hypersensitivity is the core pathogenesis of irritable bowel syndrome(IBS)and is often accompanied by negative emotions such as anxiety or depression.Paraventricular hypothalamic nucleus(PVN)corticotropin-releasing factor(CRF)is involved in the stress-related gastrointestinal dysfunction.Electroacupuncture(EA)has unique advantages for the treatment of visceral hypersensitivity and negative emotions in IBS patients.However,the underlying mechanisms remain unclear.AIM To investigate the pathological mechanisms visceral hypersensitivity and negative emotions in IBS,as well as the effect mechanism of EA.METHODS A model of diarrhoeal IBS(IBS-D)with negative emotions was prepared by chronic restraint combined with glacial acetic acid enema.The effect of EA was verified by abdominal withdrawal reflex and open-field test.PVN CRFcolonic mast cell(MC)/transient potential receptor vanilloid type 1(TRPV1)pathway was detected by immunofluorescence,Western blot,ELISA,and toluidine blue staining.Moreover,PVN CRFergic neurons were activated or inhibited by chemogenetical technique to observe the changes of effect indicator.RESULTS In the model group,IBS-D symptoms and negative emotions were successfully induced.Notably,the combination of Baihui(GV20)with Tianshu(ST25)and Dachangshu(BL25)acupoints showed the greatest efficacy in improving the negative emotions and visceral hypersensitivity in model mice.Furthermore,we found that EA inhibited overactivated PVN CRFergic neurons and the overexpression of serum CRF,colonic CRF,CRF-receptor 1(CRFR1),mast cell tryptase(MCT),protease-activated receptor 2 and TRPV1 in model mice.Moreover,we found that activating PVN CRFergic neurons induced negative emotions and visceral hypersensitivity in normal mice;however,inhibiting PVN CRFergic neurons alleviated negative emotions and intestinal symptoms in model mice and decreased the expression of colonic CRF-R1,MCT,and TRPV1.CONCLUSION This research highlights the key role of PVN CRF-MC CRF-R1 and the downstream MC/TRPV1 pathway in the pathological process of IBS-D and the mechanism of the effect of EA.展开更多
Dear Editor,The tuberculin skin test(TST)reagents have continuously improved,with the ESAT6-CFP10(EC)test having recently been introduced,but are seldom based on the direction of the delayed-type hypersensitivity(DTH)...Dear Editor,The tuberculin skin test(TST)reagents have continuously improved,with the ESAT6-CFP10(EC)test having recently been introduced,but are seldom based on the direction of the delayed-type hypersensitivity(DTH)mechanism.Previous studies only partially showed the infiltration and activation of immune cells and the production of cytokines of the skin induration[1,2],and lack the detailed measurements of cell proportions and gene expression in the DTH response.Therefore,in this study,we revealed the comprehensive characteristics of DTH by single-cell RNA sequencing(scRNA-seq)in the guinea pig tuberculosis(TB)model[Experimental Animal Welfare Ethics Committee,Beijing Tuberculosis and Thoracic Tumor Research Institute(2021-064)].展开更多
The pathophysiology of irritable bowel syndrome（IBS） is complex and not fully understood, so the aim of this study was to evaluate whether visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction,...The pathophysiology of irritable bowel syndrome（IBS） is complex and not fully understood, so the aim of this study was to evaluate whether visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction, and low-grade inflammation of the gut wall are associated with diarrhea-predominant IBS（D-IBS）. Sixty-two patients with D-IBS and 20 control subjects participated in the study. Using the ascending method of limits（AML） protocol, we demonstrated that D-IBS patients had significantly lower sensory thresholds compared with healthy controls（P〈0.001）. Using diverse methods, especially the ischemic sensitivity test, for the first time in China, we confirmed that D-IBS patients have somatic hypersensitivity. They had a significantly higher systolic blood pressure and heart rate after a cold stimulus, indicative of autonomic cardiovascular dysfunction. Compared with the control group, D-IBS patients had a significantly higher level of calprotectin（P〈0.001）. We also found significant correlations between visceral and somatic hypersensitivity, visceral hypersensitivity and autonomic cardiovascular dysfunction, and somatic hypersensitivity and autonomic cardiovascular dysfunction. Our findings may provide valuable suggestions for the treatment of D-IBS.展开更多
BACKGROUND Acute pancreatitis(AP)and recurring AP are serious health care problems causing excruciating pain and potentially lethal outcomes due to sepsis.The validated caerulein-(CAE)induced mouse model of acute/recu...BACKGROUND Acute pancreatitis(AP)and recurring AP are serious health care problems causing excruciating pain and potentially lethal outcomes due to sepsis.The validated caerulein-(CAE)induced mouse model of acute/recurring AP produces secondary persistent hypersensitivity and anxiety-like behavioral changes for study.AIM To determine efficacy of acetyl-L-carnitine(ALC)to reduce pain-related behaviors and brain microglial activation along the pain circuitry in CAE-pancreatitis.METHODS Pancreatitis was induced with 6 hly intraperitoneal(i.p.)injections of CAE(50μg/kg),3 d a week for 6 wk in male C57BL/6J mice.Starting in week 4,mice received either vehicle or ALC until experiment’s end.Mechanical hypersensitivity was assessed with von Frey filaments.Heat hypersensitivity was determined with the hotplate test.Anxiety-like behavior was tested in week 6 using elevated plus maze and open field tests.Microglial activation in brain was quantified histologically by immunostaining for ionized calcium-binding adaptor molecule 1(Iba1).RESULTS Mice with CAE-induced pancreatitis had significantly reduced mechanical withdrawal thresholds and heat response latencies,indicating ongoing pain.Treatment with ALC attenuated inflammation-induced hypersensitivity,but hypersensitivity due to abdominal wall injury caused by repeated intraperitoneal injections persisted.Animals with pancreatitis displayed spontaneous anxiety-like behavior in the elevated plus maze compared to controls.Treatment with ALC resulted in increased numbers of rearing activity events,but time spent in“safety”was not changed.After all the abdominal injections,pancreata were translucent if excised at experiment’s end and opaque if excised on the subsequent day,indicative of spontaneous healing.Post mortem histopathological analysis performed on pancreas sections stained with Sirius Red and Fast Green identified wide-spread fibrosis and acinar cell atrophy in sections from mice with CAE-induced pancreatitis that was not rescued by treatment with ALC.Microglial Iba1 immunostaining was significantly increased in hippocampus,thalamus(intralaminar nuclei),hypothalamus,and amygdala of mice with CAE-induced pancreatitis compared to naïve controls but unchanged in the primary somatosensory cortex compared to naïves.CONCLUSION CAE-induced pancreatitis caused increased pain-related behaviors,pancreatic fibrosis,and brain microglial changes.ALC alleviated CAE-induced mechanical and heat hypersensitivity but not abdominal wall injury-induced hypersensitivity caused by the repeated injections.展开更多
Functional, or non-ulcer, dyspepsia （FD） is one of the most common reasons for referral to gastroenterologists. It is associated with significant morbidity and impaired quality of life. Many authorities believe that...Functional, or non-ulcer, dyspepsia （FD） is one of the most common reasons for referral to gastroenterologists. It is associated with significant morbidity and impaired quality of life. Many authorities believe that functional dyspepsia and irritable bowel syndrome represent part of the spectrum of the same disease process. The pathophysiology of FD remains unclear but several theories have been proposed including visceral hypersensitivity, gastric motor dysfunction, Helicobacter pylori infection and psychosocial factors. In this review, we look at the evidence, to date, for the role of visceral hypersensitivity in the aetiology of FD.展开更多
BACKGROUND Visceral hypersensitivity is considered to play a vital role in the pathogenesis of irritable bowel syndrome(IBS). Neurotrophins have drawn much attention in IBS recently. Brain-derived neurotrophic factor(...BACKGROUND Visceral hypersensitivity is considered to play a vital role in the pathogenesis of irritable bowel syndrome(IBS). Neurotrophins have drawn much attention in IBS recently. Brain-derived neurotrophic factor(BDNF) was found to mediate visceral hypersensitivity via facilitating sensory nerve growth in pre-clinical studies. We hypothesized that BDNF might play a role in the pathogenesis of diarrhea-predominant IBS(IBS-D).AIM To investigate BDNF levels in IBS-D patients and its role in IBS-D pathophysiology.METHODS Thirty-one IBS-D patients meeting the Rome IV diagnostic criteria and 20 ageand sex-matched healthy controls were recruited. Clinical and psychological assessments were first conducted using standardized questionnaires. Visceral sensitivity to rectal distension was tested using a high-resolution manometry system. Colonoscopic examination was performed and four mucosal pinch biopsies were taken from the rectosigmoid junction. Mucosal BDNF expression and nerve fiber density were analyzed using immunohistochemistry. Mucosal BDNF mRNA levels were quantified by quantitative real-time polymerase chain reaction. Correlations between these parameters were examined.RESULTS The patients had a higher anxiety score [median(interquartile range), 6.0(2.0-10.0) vs 3.0(1.0-4.0), P = 0.003] and visceral sensitivity index score [54.0(44.0-61.0)vs 21.0(17.3-30.0), P < 0.001] than controls. The defecating sensation threshold[60.0(44.0-80.0) vs 80.0(61.0-100.0), P = 0.009], maximum tolerable threshold[103.0(90.0-128.0) vs 182.0(142.5-209.3), P < 0.001] and rectoanal inhibitory reflex threshold [30.0(20.0-30.0) vs 30.0(30.0-47.5), P = 0.032] were significantly lower in IBS-D patients. Intestinal mucosal BDNF protein [3.46 E-2(3.06 E-2-4.44 E-2) vs3.07 E-2(2.91 E-2-3.48 E-2), P = 0.031] and mRNA [1.57(1.31-2.61) vs 1.09(0.74-1.42), P = 0.001] expression and nerve fiber density [4.12 E-2(3.07 E-2-7.46 E-2) vs1.98 E-2(1.21 E-2-4.25 E-2), P = 0.002] were significantly elevated in the patients.Increased BDNF expression was positively correlated with abdominal pain and disease severity and negatively correlated with visceral sensitivity parameters.CONCLUSION Elevated mucosal BDNF may participate in the pathogenesis of IBS-D via facilitating mucosal nerve growth and increasing visceral sensitivity.展开更多
AIM:To investigate the roles of toll-like receptor 4(TLR4) and nuclear factor(NF)-κB on cystathionine βsynthetase(CBS) expression and visceral hypersensitivity in rats.METHODS:This study used 1-7-wk-old male Sprague...AIM:To investigate the roles of toll-like receptor 4(TLR4) and nuclear factor(NF)-κB on cystathionine βsynthetase(CBS) expression and visceral hypersensitivity in rats.METHODS:This study used 1-7-wk-old male SpragueDawley rats.Western blot analysis was employed to measure the expression of TLR4,NF-kB and the endogenous hydrogen sulfide-producing enzyme CBS in colon dorsal root ganglia(DRG) from control and "irritable bowel syndrome" rats induced by neonatal colonic inflammation(NCI).Colon-specific DRG neurons were labeled with Dil and acutely dissociated to measure excitability with patch-clamp techniques.Immunofluorescence was employed to determine the co-expression of TLR4,NF-kB and CBS in Dil-labeled DRG neurons.RESULTS:NCI significantly upregulated the expression of TLR4 in colon-related DRGs(0.34 ± 0.12 vs 0.72 ±0.02 for the control and NCI groups,respectively,P <0.05).Intrathecal administration of the TLR4-selective inhibitor CLI-095 significantly enhanced the colorectal distention threshold of NCI rats.CLI-095 treatment also markedly reversed the hyperexcitability of colonspecific DRG neurons and reduced the expression of CBS(1.7 ± 0.1 vs 1.1 ± 0.04,p < 0.05) and of the NF-kB subunit p65(0.8 ± 0.1 vs 0.5 ± 0.1,P< 0.05).Furthermore,the NF-KB-selective inhibitor pyrrolidine dithiocarbamate(PDTC) significantly reduced the upregulation of CBS(1.0 ± 0.1 vs 0.6 ± 0.1,P< 0.05)and attenuated visceral hypersensitivity in the NCI rats.In vitro,incubation of cultured DRG neurons with the TLR4 agonist lipopolysaccharide significantly enhanced the expression of p65(control vs 8 h:0.9 ± 0.1 vs1.3 ± 0.1;control vs 12 h:0.9 ± 0.1 vs 1.3 ± 0.1,P< 0.05;control vs 24 h:0.9 ± 0.1 vs 1.6 ± 0.1,P <0.01) and CBS(control vs 12 h:1.0 ± 0.1 vs 2.2 ±0.4;control vs 24 h:1.0 ± 0.1 vs 2.6 ± 0.1,P< 0.05),whereas the inhibition of p65 via pre-incubation with PDTC significantly reversed the upregulation of CBS expression(1.2 ± 0.1 vs 0.6 ± 0.0,P< 0.01).CONCLUSION:Our results suggest that the activation of TLR4 by NCI upregulates CBS expression,which is mediated by the NF-kB signaling pathway,thus contributing to visceral hypersensitivity.展开更多
AIM： To investigate the role of endogenous pain modulatory mechanisms in the central sensitization implicated by the visceral hypersensitivity demonstrated in patients with irritable bowel syndrome （IBS）. Dysfuncti...AIM： To investigate the role of endogenous pain modulatory mechanisms in the central sensitization implicated by the visceral hypersensitivity demonstrated in patients with irritable bowel syndrome （IBS）. Dysfunction of modulatory mechanisms would be expected to also result in changes of somatic sensory function. METHODS： Endogenous pain modulatory mechanisms were assessed using heterotopic stimulation and somatic and visceral sensory testing in IBS. Pain intensities （visual analogue scale, VAS 0-100） during suprathreshold rectal distension with a barostat, cold pressor stimulation of the foot and during both stimuli simultaneously （heterotopic stimulation） were recorded in 40 female patients with IBS and 20 female healthy controls. RESULTS： Rectal hypersensitivity （defined by 95% Cl of controls） was seen in 21 （53%）, somatic hypersensitivity in 22 （55%） and both rectal and somatic hypersensitivity in 14 of these IBS patients. Heterotopic stimulation decreased rectal pain intensity by 6 （-11 to -1） in controls, but increased rectal pain by 2 （-3 to ＋6） in all IBS patients （P 〈 0.05） and by 8 （-2 to ＋19） in IBS patients with somatic and visceral hypersensitivity （P 〈 0.02）. CONCLUSION： A majority of IBS patients had abnormal endogenous pain modulation and somatic hypersensitivity as evidence of central sensitization.展开更多
BACKGROUND Irritable bowel syndrome (IBS) is a common chronic non-organic disease of the digestive system. Berberine (BBR) has been used to treat patients with IBS, but the underlying therapeutic mechanism is little u...BACKGROUND Irritable bowel syndrome (IBS) is a common chronic non-organic disease of the digestive system. Berberine (BBR) has been used to treat patients with IBS, but the underlying therapeutic mechanism is little understood. We believe that BBR achieves its therapeutic effect on IBS by preventing stress intestinal inflammation and visceral hypersensitivity and reducing bowel motility. AIM To test the hypothesis that BBR achieves its therapeutic effect on IBS by preventing subclinical inflammation of the intestinal mucosa and reducing visceral hypersensitivity and intestinal motility. METHODS IBS was induced in rats via water avoidance stress (WAS). qRT-PCR and histological analyses were used to evaluate the levels of cytokines and mucosal inflammation, respectively. Modified ELISA and qRT-PCR were used to evaluate the nuclear factor kappa-B (NF-κB) signal transduction pathway. Colorectal distention test, gastrointestinal transit measurement, Western blot, and qRT-PCR were used to analyze visceral sensitivity, intestinal motility, the expression of Ckit (marker of Cajal mesenchymal cells), and the expression of brain derived neurotrophic factor (BDNF) and its receptor TrkB.RESULTS WAS led to mucosal inflammation, visceral hyperalgesia, and high intestinal motility. Oral administration of BBR inhibited the NF-κB signal transduction pathway, reduced the expression of pro-inflammatory cytokines [interleukin (IL)- 1β, IL-6, interferon-γ, and tumor necrosis factor-α], promoted the expression of anti-inflammatory cytokines (IL-10 and transforming growth factor-β), and improved the terminal ileum tissue inflammation. BBR inhibited the expression of BDNF, TrkB, and C-kit in IBS rats, leading to the reduction of intestinal motility and visceral hypersensitivity. The therapeutic effect of BBR at a high dose (100 mg/kg) was superior to than that of the low-dose (25 mg/kg) group. CONCLUSION BBR reduces intestinal mucosal inflammation by inhibiting the intestinal NF-κB signal pathway in the IBS rats. BBR reduces the expression of BDNF, its receptor TrkB, and C-kit. BBR also reduces intestinal motility and visceral sensitivity to achieve its therapeutic effect on IBS.展开更多
AIM To observe whether there are differences in the effects of electro-acupuncture(EA) and moxibustion(Mox) in rats with visceral hypersensitivity. METHODS EA at 1 m A and 3 m A and Mox at 43?℃ and 46?℃ were applied...AIM To observe whether there are differences in the effects of electro-acupuncture(EA) and moxibustion(Mox) in rats with visceral hypersensitivity. METHODS EA at 1 m A and 3 m A and Mox at 43?℃ and 46?℃ were applied to the Shangjuxu(ST37, bilateral) acupoints in model rats with visceral hypersensitivity. Responses of wide dynamic range neurons in dorsal horns of the spinal cord were observed through the extracellular recordings. Mast cells(MC) activity in the colons of rats were assessed, and 5-hydroxytryptamine(5-HT), 5-hydroxytryptamine 3 receptor(5-HT3R) and 5-HT4Rexpressions in the colons were measured.RESULTS Compared with normal control group, responses of wide dynamic range neurons in the dorsal horn of the spinal cord were increased in the EA at 1 m A and 3 m A groups(1 m A: 0.84 ± 0.74 vs 2.73 ± 0.65, P < 0.001; 3 m A: 1.91 ± 1.48 vs 6.44 ± 1.26, P < 0.001) and Mox at 43?℃ and 46?℃ groups(43?℃: 1.76 ± 0.81 vs 4.14 ± 1.83, P = 0.001; 46?℃: 5.19 ± 2.03 vs 7.91 ± 2.27, P = 0.01). MC degranulation rates and the expression of 5-HT, 5-HT3 R and 5-HT4 R in the colon of Mox 46?℃ group were decreased compared with model group(MC degranulation rates: 0.47 ± 0.56 vs 0.28 ± 0.78, P < 0.001; 5-HT: 1.42 ± 0.65 vs 7.38 ± 1.12, P < 0.001; 5-HT3R: 6.62 ± 0.77 vs 2.86 ± 0.88, P < 0.001; 5-HT4R: 4.62 ± 0.65 vs 2.22 ± 0.97, P < 0.001). CONCLUSION The analgesic effects of Mox at 46?℃ are greater than those of Mox at 43?℃, EA 1 m A and EA 3 m A.展开更多
AIM: To explore the role of nesfatin-1 on irritable bowel syndrome (IBS)-like visceral hypersensitivity. METHODS: The animal model of IBS-like visceral hypersensitivity was induced by intracolonic infusion of 0.5% ace...AIM: To explore the role of nesfatin-1 on irritable bowel syndrome (IBS)-like visceral hypersensitivity. METHODS: The animal model of IBS-like visceral hypersensitivity was induced by intracolonic infusion of 0.5% acetic acid (AA) in saline once daily from postnatal days 8-21. Experiments were performed when rats became adults. The visceral sensitivity of rats was evaluated by abdominal withdrawal reflex (AWR) and electromyographic (EMG) activity of the external oblique muscle to graded colorectal distension. The content of nesfatin-1 in serum was determined using enzyme-linked immunosorbent assay. After implantation of an intracerebroventricular (ICV) cannula and two electrodes into the external oblique muscle, model rats were randomly divided into four groups. Animals then received ICV injection of 8 μg of anti-nesfatin-1/ nucleobindin-2 (NUCB2), 50 μg of α-helical cortico-tropin releasing factor (CRF) 9-41 (non-selective CRF receptor antagonist), 50 μg of NBI-27914 (selective CRF1 receptor antagonist) or 5 μL of vehicle. After 1 h of ICV administration, visceral sensitivity of each group was measured again, and comparisons between groups were made. RESULTS: Rats treated with AA showed higher mean AWR scores and EMG activity at all distension pressures compared with controls (P < 0.05). On histopathologic examination, no evidence of inflammation or abnormalities in structure were noted in the colon of either control or AA-treated groups. Myeloperoxidase values were not significantly different between the two groups. The level of nesfatin-1 in serum was significantly higher in the AA-treated group than in the control group (5.34 ± 0.37 ng/mL vs 4.81 ± 0.42 ng/mL, P < 0.01). Compared with rats injected with vehicle, rats which received ICV anti-nesfatin-1/NUCB2, α-helical CRF9-41 or NBI-27914 showed decreased mean AWR scores and EMG activity at all distension pressures (P < 0.05). CONCLUSION: Nesfatin-1 may be associated with IBS-like visceral hypersensitivity, which may be implicated in brain CRF/CRF1 signaling pathways.展开更多
AIM: To assess the protective effect of berberine administration and the role of nitric oxide (NO) in visceral hypersensitivity. METHODS: Fifty male Sprague-Dawley rats were randomly assigned to five groups. An inflam...AIM: To assess the protective effect of berberine administration and the role of nitric oxide (NO) in visceral hypersensitivity. METHODS: Fifty male Sprague-Dawley rats were randomly assigned to five groups. An inflammatory bowel disease model was induced in rats by intracolonic instillation of 1 mL 4% acetic acid at 8 cm proximal to the anus for 30 s and restraint stress. After subsidence of inflammation on day 7 of the experiment, the rats were subjected to rectal distension, performed by a balloon (6-Fr, 2 mm external diameter, disposable silicon balloon-urethral catheter for pediatric use) which was rapidly inflated with increasing volumes of prewarmed (37 ℃) water (0.1, 0.2, 0.3, 0.4, 0.6, 0.8 and 1 mL) for 30 s at four-minute intervals, and then the abdominal withdrawal reflex (AWR) and the level of fecal output were measured, respectively. AWR scores either 0, 1, 2, 3 or 4 were obtained by blinded observers. Rats had been pretreated with berberine or aminoguanidine (NO synthetase inhibitor) or berberine + aminoguanidine before measurement. RESULTS: The rats in the placebo group showed a hypersensitive response to rectal distension (2.69 ± 0.08 vs 1.52 ± 0.08, P = 0.000) and defecated more frequently than those in the control group (5.0 ± 0.16 vs 0.44 ± 0.16, P = 0.000). Comparing the berberine with placebo group, the AWR scores were reduced for all distension volumes and were significant at 0.2-1 mL (1.90 ± 0.08 vs 2.69 ± 0.08, P = 0.000), while the numbers of hard pellets, soft pellets, formless stools, and total fecal output in the placebo group were significantly larger than in the berberine group (5.0 ± 0.16 vs 2.56 ± 0.16, P = 0.000). Administration of aminoguanidine or berberine + aminoguanidine before VH score measurement reversed the antinociceptive effect of berberine (2.52 ± 0.08 vs 1.90 ± 0.08, P = 0.000; 2.50 ± 0.08 vs 1.90 ± 0.08, P = 0.000). The numbers of hard pellets, soft pellets, formless stool, and total of fecal output in aminoguanidine group were significantly larger than the corresponding values in control group, berberine group, and berberine + aminoguanidine group (4.81 ± 0.16 vs 0.44 ± 0.16, P = 0.000; 4.81 ± 0.16 vs 2.56 ± 0.16, P = 0.000; 4.81 ± 0.16 vs 3.75 ± 0.16, P = 0.000). The berberine and berberine + aminoguanidine groups showed reduced defecation, but aminoguanidine alone did not reduce defecation (2.56 ± 0.16 vs 4.81 ± 0.16, P = 0.000; 3.75 ± 0.16 vs 4.81 ± 0.16, P = 0.000). CONCLUSION: Berberine had an antinociceptive effect on visceral hypersensitivity, and NO might play a role in this effect.展开更多
BACKGROUND Visceral hypersensitivity and psychological performance are the main pathophysiological mechanisms of irritable bowel syndrome(IBS).Previous studies have found that cholecystokinin(CCK)can enhance colon mov...BACKGROUND Visceral hypersensitivity and psychological performance are the main pathophysiological mechanisms of irritable bowel syndrome(IBS).Previous studies have found that cholecystokinin(CCK)can enhance colon movement and that serotonin transporter(SERT)is a transmembrane transport protein with high affinity for 5-hydroxytryptamine,which can rapidly reuptake 5-hydroxytryptamine and then regulate its action time and intensity.We speculate that SERT and CCK might play a role in the pathogenesis of diarrheapredominant IBS(IBS-D)by affecting visceral sensitivity and the brain-gut axis.AIM To determine SERT and CCK levels in IBS-D patients diagnosed using Rome IV criteria and to analyze their associations with abdominal pain,visceral hypersensitivity and psychological performance.METHODS This study collected data from 40 patients with IBS-D at the China-Japan Friendship Hospital from September 2017 to April 2018 and 18 healthy controls.The severity of abdominal pain,visceral sensitivity and psychological performance were evaluated in IBS-D patients and healthy controls,the levels of SERT and CCK in plasma and colonic mucosa were evaluated,and the correlations between them were analyzed.RESULTS There were significant differences in the initial sensation threshold(31.00±8.41 mL vs 52.22±8.09 mL,P<0.001),defecating sensation threshold(51.75±13.57 mL vs 89.44±8.73 mL,P<0.001)and maximum tolerable threshold(97.25±23.64 mL vs 171.11±20.83 mL,P<0.001)between the two groups.IBS-D patients had more severe anxiety(7.78±2.62 vs 2.89±1.02,P<0.001)and depressive(6.38±2.43 vs 2.06±0.73,P<0.001)symptoms than healthy controls.Significant differences were also found in mucosal CCK(2.29±0.30 vs 1.66±0.17,P<0.001)and SERT(1.90±0.51 vs 3.03±0.23,P<0.001)between the two groups.There was a significant positive correlation between pain scores and mucosal CCK(r=0.96,0.93,0.94,P<0.001).Significant negative correlations between anxiety(r=-0.98;P<0.001),depression(r=-0.99;P<0.001),pain evaluation(r=-0.96,-0.93,-0.95,P<0.001)and mucosal SERT were observed.CONCLUSION IBS-D patients had psychosomatic disorders and visceral hypersensitivity.SERT and CCK might be involved in the pathogenesis of IBS-D by regulating the braingut axis and affecting visceral sensitivity.This provides a new potential method for identifying a more specific and effective therapeutic target.展开更多
BACKGROUND Fecal metabolites are associated with gut visceral sensitivity,mucosal immune function and intestinal barrier function,all of which have critical roles in the pathogenesis of irritable bowel syndrome(IBS).H...BACKGROUND Fecal metabolites are associated with gut visceral sensitivity,mucosal immune function and intestinal barrier function,all of which have critical roles in the pathogenesis of irritable bowel syndrome(IBS).However,the metabolic profile and pathophysiology of IBS are still unclear.We hypothesized that altered profiles of fecal metabolites might be involved in the pathogenesis of IBS with predominant diarrhea(IBS-D).AIM To investigate the fecal metabolite composition and the role of metabolites in IBSD pathophysiology.METHODS Thirty IBS-D patients and 15 age-and sex-matched healthy controls(HCs)underwent clinical and psychological assessments,including the IBS Symptom Severity System(IBS-SSS),an Italian modified version of the Bowel Disease Questionnaire,the Bristol Stool Form Scale(BSFS),the Hospital Anxiety and Depression Scale,and the Visceral Sensitivity Index.Visceral sensitivity to rectal distension was tested using high-resolution manometry system by the same investigator.Fecal metabolites,including amino acids and organic acids,were measured by targeted metabolomics approaches.Correlation analyses between these parameters were performed.RESULTS The patients presented with increased stool water content,more psychological symptoms and increased visceral hypersensitivity compared with the controls.In fecal metabolites,His[IBS-D:0.0642(0.0388,0.1484),HC:0.2636(0.0780,0.3966),P=0.012],Ala[IBS-D:0.5095(0.2826,0.9183),HC:1.0118(0.6135,1.4335),P=0.041],Tyr[IBS-D:0.1024(0.0173,0.4527),HC:0.5665(0.2436,1.3447),P=0.018],Phe[IBS-D:0.1511(0.0775,0.3248),HC:0.3967(0.1388,0.7550),P=0.028],and Trp[IBS-D:0.0323(0.0001,0.0826),HC:0.0834(0.0170,0.1759),P=0.046]were decreased in IBS-D patients,but isohexanoate[IBS-D:0.0127(0.0060,0.0246),HC:0.0070(0.0023,0.0106),P=0.028]was significantly increased.Only Tyr was mildly correlated with BSFS scores in all subjects(r=-0.347,P=0.019).A possible potential biomarker panel was identified to correlate with IBS-SSS score(R2 Adjusted=0.693,P<0.001).In this regression model,the levels of Tyr,Val,hexanoate,fumarate,and pyruvate were significantly associated with the symptom severity of IBS-D.Furthermore,visceral sensation,including abdominal pain and visceral hypersensitivity,was correlated with isovalerate,valerate and isohexanoate.CONCLUSION Altered profiles of fecal metabolites may be one of the origins or exacerbating factors of symptoms in IBS-D via increasing visceral sensitivity.展开更多
Objective:To investigate the impact of the preinduced intestinal heat shock protein 70(HSP70)on the visceral hypersensitivity and abnormal intestinal motility in a post-infectious irritable bowel syndrome(PI-IBS) mous...Objective:To investigate the impact of the preinduced intestinal heat shock protein 70(HSP70)on the visceral hypersensitivity and abnormal intestinal motility in a post-infectious irritable bowel syndrome(PI-IBS) mouse model.Methods:Eighty-four female C57BL/6 mice were randomly assigned to four groups:control group(n=21) and induction+PI-IBS group(n=21),PI-IBS group(n=21) and induction group(n=21).The mice in PI-IBS group were infected in vivo with trichinella spiralis by oral administration.The visceral hypersensitivity and intestinal motility were evaluated respectively with abdominal withdrawal reflex and colon transportation test.The intestinal HSP70 protein and mRNA level was measured by Western blot and realtime PCR.Meanwhile,the intestinal proinflammatory cytokines IL-10 and TNF-α level was detected by ELISA.Results:Compared with their counterparts in PI-IBS group,the animals in the Induction+PI-IBS group show significantly increased intestinal level of HSP70 and obviously ameliorative clinical tigurcs.including abdominal withdrawal reflex score,intestine transportation time and Bristol scores(P<0.05).Meanwhile,the intestinal post-inflammatory cytokines remarkably changed,including increased IL-10 level and decreased TNF-αlevel(P<0.05).Conclusions:Intestinal IISP70 may play a potential protective role through improving the imbalance between the intestinal post-inflammatory and anti-inflammatory cytokines in PI-IBS.展开更多
基金Supported by Science and Technology Plan Project of Zhongshan City(2022B1126).
文摘[Objectives]To explore the mechanism of action of Tongxieyaofang ultrafine granular powder in treating visceral hypersensitivity in rats with diarrhea-predominant irritable bowel syndrome(IBS-D)based on enteric glial cells(EGCs).[Methods]Eighty-four healthy male Wistar rats of SPF grade were selected and randomly assigned to seven groups,each comprising 12 rats:a normal control group,a model control group,a traditional Tongxieyaofang granular powder group(4.060 g/kg),three Tongxieyaofang ultrafine granular powder groups at low,medium,and high doses(1.015,2.030,and 4.060 g/kg of raw drug,respectively),and a pinaverium bromide group(0.018 g/kg).With the exception of the normal control group,all other groups were subjected to an IBS-D visceral hypersensitivity sensitivity model in rats developed by the chronic water avoidance stress method.Three days post modeling,the rats received continuous oral gavage administration for 8 d.Following the treatment period,serum and colon tissue samples were collected from each group.The BDNF level in the serum was quantified using ELISA.Additionally,the protein expression levels of GFAP,BDNF,and TrkB in colon tissues were assessed via Western blot assay.[Results]Compared to the normal control group,the serum BDNF levels in the model control group were significantly elevated(P<0.01).In contrast,each treatment group exhibited a significant reduction in serum BDNF levels relative to the model control group(P<0.01).Furthermore,the protein expression levels of GFAP,BDNF,and TrkB in colon tissue were significantly higher in the model control group compared to the normal control group(P<0.05,P<0.01).Conversely,these protein expressions were significantly decreased in each treatment group compared to the model control group(P<0.05,P<0.01).[Conclusions]Tongxieyaofang ultrafine granular powder effectively alleviates visceral sensitivity in IBS-D rats and inhibits the activation of EGCs,speculating that its mechanism of action involves the suppression of abnormal EGC activation.
基金supported in part by grants from the Tianshan Innovation Team Fund Project of Xinjiang Uygur Autonomous Region(2023D14005)the General Project of the Natural Science Foundation of the Xinjiang Uygur Autonomous Region(2022D01A109).
文摘Drug hypersensitivity reactions(DHRs),which produce symptoms from skin rash to anaphylaxis,are immune-mediated adverse reactions caused by drug formulations.The diagnosis of DHRs is challenging due to the lack of standardization for many drugs,and both underdiagnosis and overdiagnosis hamper the follow-up treatment of patients.Therefore,improved methods for diagnosing patients with suspected DHRs are needed.In this review,we analyzed traditional methods used to diagnose DHRs as well as new diagnostic advances made during the last 2 years.None of the diagnostic methods is perfect,as each exhibits varying sensitivities to different types of DHRs.Overall,our analysis indicates that the accuracy of DHR diagnosis can be improved by obtaining a detailed clinical history,physical examination,in vivo and in vitro testing.
基金the National Natural Science Foundation of China(No.81373724,Transient Potential Vanilloid Receptor1 Participates In The Mechanism Of Acupuncture Alleviating Visceral Hypersensitivity)the Joint Innovation Funds of China Academy of Chinese Medical Sciences(No.ZJYB2021-06,Clinical observation of acupuncture in the treatment of chronic urticaria)。
文摘OBJECTIVE:this study to investigate the mechanism underlying the electroacupuncture(EA)alleviates colorectal hypersensitivity,a feature of irritable bowel syndrome(IBS).METHODS:The colorectal hypersensitivity model was established by treating mice with zymosan.Electrophysiological techniques,Western blotting and immunofluorescence staining were used to detect the changes of the sensitive state of the colorectum and the response in spinal ganglion and spinal cord after acupuncture intervention.RESULTS:colorectal distension studies revealed that repetitive applied electroacupuncture treatment on mice could significant alleviates colorectal intensity.Western blotting studies with nerve growth factor(NGF)in the colorectum,substance P(SP)in the spinal ganglion,protein kinase C gamma(PKCγ)in the spinal cord,and transient receptor potential vanilloid 1(TRPV1)showed that electroacupuncture suppressed zymosan-induced expression of TRPV1,NGF and SP in multiple tissues.Immunofluorescence labeling results showed that EA attenuated the expression of NGF in the colorectum,SP in the spinal ganglion,PKCγin the spinal cord,and TRPV1 in all three tissues in zymosan-treated mice.Moreover,the number of neurons double-positive for TRPV1/Isolectin B4(IB4)and TRPV1/Neurofilament(NF)200 was increased in the spinal ganglion.CONCLUSION:these results provide molecular-level evidence that EA alleviates zymosan-induced colorectal hypersensitivity by altering the expression of pain-associated proteins in the colorectum and spinal cord.EA has a potential to be therapeutic intervention option for IBS treatment.
基金Supported by the Foundation of the Second Affiliated Hospital of Xi’an Jiaotong University,No.YJ(ZD)202301.
文摘BACKGROUND Reflux hypersensitivity(RH)constitutes roughly 14%of patients with heartburn and 34%of those with refractory heartburn,yet it is inadequately comprehended.AIM To investigate the clinical characteristics and risk factors associated with RH.METHODS We conducted a retrospective analysis of 109 patients with RH and 384 healthy controls from three medical centers between January 2022 and December 2023.Comprehensive data encompassing symptoms,motility,impedance-pH monitoring,and psychological evaluations were collected.RESULTS RH patients encountered a greater frequency of weakly acidic reflux(WAR)events compared to acidic reflux or nonacidic reflux(NAR)events.Upright reflux time(1.22%)exceeds supine reflux time(0.54%)(P<0.05).Extraesophageal symptoms were more prevalent among younger patients and those with elevated NAR(P<0.05).The acidic reflux,WAR,NAR,and peristaltic contraction break length in male patients exceeded those in female patients(P<0.05).Age[odds ratio(OR)=5.633],hiatal hernia(OR=13.103),and anxiety(OR=17.342)constituted independent risk factors for RH.CONCLUSION WAR and NAR are pivotal in RH.Patients with increased NAR are more likely to experience extraesophageal symptoms.Age,hiatal hernia,and anxiety are significant independent risk factors for RH.
基金National Natural Science Foundation of China:Study on the Molecular Mechanism of the Regulation of Crypt Goblet Cell Pyroptosis and Exocytosis to Repair Ulcerative Colitis Mucus Barrier by the Method of Clearing and Opening the Xuanfu from the Perspective of"Xuanfu-Crypt"(No.82305143),and National Natural Science Foundation of China:Exploring the Molecular Mechanism of"Hewei Jiangni Fang"Intervention in Non-erosive Reflux Disease Esophageal Hypersensitivity from the Perspective of Mas-related Gene X2/Stromal Interaction Molecule 1/Cell Adhesion Molecule 1 Pathway Regulation of Mast Cell/Dorsal Root Ganglion Communication based on the"Xinkai-Kujiang"Method(No.82374401)。
文摘OBJECTIVE:To explore if Hewei Jiangni granule(和胃降逆颗粒,HWJNG)could regulate esophageal hypersensitivity via stromal interaction molecule 1(STIM1)/transient receptor potential vanilloid subfamily member 1(TRPV1)pathway.METHODS:Qualitative analysis of HWJNG was analysis by high performance of liquid and gas chromatography.In vivo,animal model of non-erosive reflux disease(NERD)was established by fructose intake and restraint stress.HWJNG and Omeprazole were administered by gavage to the drug intervention group.Reflux and visceral hypersensitivity were analyzed by pathological changes,PH value test,mechanical paw withdrawal threshold,thermal withdrawal latency and mast cells(MCs)degranulation.In vitro,substance P(SP)-induced P815 cells and dorsal root ganglion(DRG)cells were cocultured.Expression in both mice and cells of STIM1,TRPV1,and esophageal visceral hypersensitivity-related gastrointestinal neurochemicals were validated by enzyme linked immunosorbent assays,quantitative realtime polymerase chain reaction(qRT-PCR)and Western blot.Moreover,overexpression and small interfering RNA against STIM1 were utilized to verify of the role of HWJNG in DRG cells.RESULTS:HWJNG significantly suppressed intercellular space widening,injury of mitochondrial,MCs degranulation,mechanical allodynia and heat neuropathic sensory and increased pH value of esophageal mucosa in NERD mice.HWJNG inhibited expression of visceral hypersensitivityrelated gastrointestinal neurochemicals in esophageal mucosa and activated P815 cells,and expression of the STIM1,TRPV1 and related neurotransmitters in DRG and DRG cells.STIM1 siRNA and HWJNG both reduced P815 cells adhesion to DRGs cells and Ca2+flow into the cytoplasmic space of DRG cells.Furthermore,HWJNG could reversed STIM1 overexpression induced upregulation of TRPV1.CONCLUSION:HWJNG suppressed intercellular space widening in NERD mice,stabilized MCs and restored neuronal hyperexcitability by regulating visceral hypersensitivity via STIM1/TRPV1 pathway.
基金Supported by the Excellent Youth Project of Anhui Universities,No.2022AH030065National Natural Science Foundation of China,No.82474224 and No.82405244+3 种基金Anhui Provincial Natural Science Foundation,No.2408085MH223Open Projects of Anhui Province Key Laboratory of Meridian Viscera Correlationship,No.2024AHMVC04Research Project of Xin’an Medical and Chinese Medicine Modernization Research Institute,No.2023CXMMTCM016the Anhui Province Scientific Research Planning Project,No.2022AH050438.
文摘BACKGROUND Visceral hypersensitivity is the core pathogenesis of irritable bowel syndrome(IBS)and is often accompanied by negative emotions such as anxiety or depression.Paraventricular hypothalamic nucleus(PVN)corticotropin-releasing factor(CRF)is involved in the stress-related gastrointestinal dysfunction.Electroacupuncture(EA)has unique advantages for the treatment of visceral hypersensitivity and negative emotions in IBS patients.However,the underlying mechanisms remain unclear.AIM To investigate the pathological mechanisms visceral hypersensitivity and negative emotions in IBS,as well as the effect mechanism of EA.METHODS A model of diarrhoeal IBS(IBS-D)with negative emotions was prepared by chronic restraint combined with glacial acetic acid enema.The effect of EA was verified by abdominal withdrawal reflex and open-field test.PVN CRFcolonic mast cell(MC)/transient potential receptor vanilloid type 1(TRPV1)pathway was detected by immunofluorescence,Western blot,ELISA,and toluidine blue staining.Moreover,PVN CRFergic neurons were activated or inhibited by chemogenetical technique to observe the changes of effect indicator.RESULTS In the model group,IBS-D symptoms and negative emotions were successfully induced.Notably,the combination of Baihui(GV20)with Tianshu(ST25)and Dachangshu(BL25)acupoints showed the greatest efficacy in improving the negative emotions and visceral hypersensitivity in model mice.Furthermore,we found that EA inhibited overactivated PVN CRFergic neurons and the overexpression of serum CRF,colonic CRF,CRF-receptor 1(CRFR1),mast cell tryptase(MCT),protease-activated receptor 2 and TRPV1 in model mice.Moreover,we found that activating PVN CRFergic neurons induced negative emotions and visceral hypersensitivity in normal mice;however,inhibiting PVN CRFergic neurons alleviated negative emotions and intestinal symptoms in model mice and decreased the expression of colonic CRF-R1,MCT,and TRPV1.CONCLUSION This research highlights the key role of PVN CRF-MC CRF-R1 and the downstream MC/TRPV1 pathway in the pathological process of IBS-D and the mechanism of the effect of EA.
基金supported by the National Natural Science Foundation(81871691)the Beijing Municipal Natural Science Foundation(KZ202110025034).
文摘Dear Editor,The tuberculin skin test(TST)reagents have continuously improved,with the ESAT6-CFP10(EC)test having recently been introduced,but are seldom based on the direction of the delayed-type hypersensitivity(DTH)mechanism.Previous studies only partially showed the infiltration and activation of immune cells and the production of cytokines of the skin induration[1,2],and lack the detailed measurements of cell proportions and gene expression in the DTH response.Therefore,in this study,we revealed the comprehensive characteristics of DTH by single-cell RNA sequencing(scRNA-seq)in the guinea pig tuberculosis(TB)model[Experimental Animal Welfare Ethics Committee,Beijing Tuberculosis and Thoracic Tumor Research Institute(2021-064)].
基金Project supported by the National Science & Technology Pillar Program during the Twelfth Five-year Plan Period of China(No.2014BAI08B02)the National Science & Technology Major Projects(Major Drug Discovery)of China(No.2012ZX09103201-021)
文摘The pathophysiology of irritable bowel syndrome（IBS） is complex and not fully understood, so the aim of this study was to evaluate whether visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction, and low-grade inflammation of the gut wall are associated with diarrhea-predominant IBS（D-IBS）. Sixty-two patients with D-IBS and 20 control subjects participated in the study. Using the ascending method of limits（AML） protocol, we demonstrated that D-IBS patients had significantly lower sensory thresholds compared with healthy controls（P〈0.001）. Using diverse methods, especially the ischemic sensitivity test, for the first time in China, we confirmed that D-IBS patients have somatic hypersensitivity. They had a significantly higher systolic blood pressure and heart rate after a cold stimulus, indicative of autonomic cardiovascular dysfunction. Compared with the control group, D-IBS patients had a significantly higher level of calprotectin（P〈0.001）. We also found significant correlations between visceral and somatic hypersensitivity, visceral hypersensitivity and autonomic cardiovascular dysfunction, and somatic hypersensitivity and autonomic cardiovascular dysfunction. Our findings may provide valuable suggestions for the treatment of D-IBS.
基金United States Department of Veterans Affairs,VA Merit Grant,No.BX002695United States National Institute of Health,No.R01AG055359,No.R01GM126181 and No.R01NS39041-15.
文摘BACKGROUND Acute pancreatitis(AP)and recurring AP are serious health care problems causing excruciating pain and potentially lethal outcomes due to sepsis.The validated caerulein-(CAE)induced mouse model of acute/recurring AP produces secondary persistent hypersensitivity and anxiety-like behavioral changes for study.AIM To determine efficacy of acetyl-L-carnitine(ALC)to reduce pain-related behaviors and brain microglial activation along the pain circuitry in CAE-pancreatitis.METHODS Pancreatitis was induced with 6 hly intraperitoneal(i.p.)injections of CAE(50μg/kg),3 d a week for 6 wk in male C57BL/6J mice.Starting in week 4,mice received either vehicle or ALC until experiment’s end.Mechanical hypersensitivity was assessed with von Frey filaments.Heat hypersensitivity was determined with the hotplate test.Anxiety-like behavior was tested in week 6 using elevated plus maze and open field tests.Microglial activation in brain was quantified histologically by immunostaining for ionized calcium-binding adaptor molecule 1(Iba1).RESULTS Mice with CAE-induced pancreatitis had significantly reduced mechanical withdrawal thresholds and heat response latencies,indicating ongoing pain.Treatment with ALC attenuated inflammation-induced hypersensitivity,but hypersensitivity due to abdominal wall injury caused by repeated intraperitoneal injections persisted.Animals with pancreatitis displayed spontaneous anxiety-like behavior in the elevated plus maze compared to controls.Treatment with ALC resulted in increased numbers of rearing activity events,but time spent in“safety”was not changed.After all the abdominal injections,pancreata were translucent if excised at experiment’s end and opaque if excised on the subsequent day,indicative of spontaneous healing.Post mortem histopathological analysis performed on pancreas sections stained with Sirius Red and Fast Green identified wide-spread fibrosis and acinar cell atrophy in sections from mice with CAE-induced pancreatitis that was not rescued by treatment with ALC.Microglial Iba1 immunostaining was significantly increased in hippocampus,thalamus(intralaminar nuclei),hypothalamus,and amygdala of mice with CAE-induced pancreatitis compared to naïve controls but unchanged in the primary somatosensory cortex compared to naïves.CONCLUSION CAE-induced pancreatitis caused increased pain-related behaviors,pancreatic fibrosis,and brain microglial changes.ALC alleviated CAE-induced mechanical and heat hypersensitivity but not abdominal wall injury-induced hypersensitivity caused by the repeated injections.
文摘Functional, or non-ulcer, dyspepsia （FD） is one of the most common reasons for referral to gastroenterologists. It is associated with significant morbidity and impaired quality of life. Many authorities believe that functional dyspepsia and irritable bowel syndrome represent part of the spectrum of the same disease process. The pathophysiology of FD remains unclear but several theories have been proposed including visceral hypersensitivity, gastric motor dysfunction, Helicobacter pylori infection and psychosocial factors. In this review, we look at the evidence, to date, for the role of visceral hypersensitivity in the aetiology of FD.
基金Supported by the National Key Technology Support Program during "12th Five-Year Plan"Period of China,No.2014BAI08B00the Leapforward Development Program for Beijing Biopharmaceutical Industry(G20),No.Z171100001717008
文摘BACKGROUND Visceral hypersensitivity is considered to play a vital role in the pathogenesis of irritable bowel syndrome(IBS). Neurotrophins have drawn much attention in IBS recently. Brain-derived neurotrophic factor(BDNF) was found to mediate visceral hypersensitivity via facilitating sensory nerve growth in pre-clinical studies. We hypothesized that BDNF might play a role in the pathogenesis of diarrhea-predominant IBS(IBS-D).AIM To investigate BDNF levels in IBS-D patients and its role in IBS-D pathophysiology.METHODS Thirty-one IBS-D patients meeting the Rome IV diagnostic criteria and 20 ageand sex-matched healthy controls were recruited. Clinical and psychological assessments were first conducted using standardized questionnaires. Visceral sensitivity to rectal distension was tested using a high-resolution manometry system. Colonoscopic examination was performed and four mucosal pinch biopsies were taken from the rectosigmoid junction. Mucosal BDNF expression and nerve fiber density were analyzed using immunohistochemistry. Mucosal BDNF mRNA levels were quantified by quantitative real-time polymerase chain reaction. Correlations between these parameters were examined.RESULTS The patients had a higher anxiety score [median(interquartile range), 6.0(2.0-10.0) vs 3.0(1.0-4.0), P = 0.003] and visceral sensitivity index score [54.0(44.0-61.0)vs 21.0(17.3-30.0), P < 0.001] than controls. The defecating sensation threshold[60.0(44.0-80.0) vs 80.0(61.0-100.0), P = 0.009], maximum tolerable threshold[103.0(90.0-128.0) vs 182.0(142.5-209.3), P < 0.001] and rectoanal inhibitory reflex threshold [30.0(20.0-30.0) vs 30.0(30.0-47.5), P = 0.032] were significantly lower in IBS-D patients. Intestinal mucosal BDNF protein [3.46 E-2(3.06 E-2-4.44 E-2) vs3.07 E-2(2.91 E-2-3.48 E-2), P = 0.031] and mRNA [1.57(1.31-2.61) vs 1.09(0.74-1.42), P = 0.001] expression and nerve fiber density [4.12 E-2(3.07 E-2-7.46 E-2) vs1.98 E-2(1.21 E-2-4.25 E-2), P = 0.002] were significantly elevated in the patients.Increased BDNF expression was positively correlated with abdominal pain and disease severity and negatively correlated with visceral sensitivity parameters.CONCLUSION Elevated mucosal BDNF may participate in the pathogenesis of IBS-D via facilitating mucosal nerve growth and increasing visceral sensitivity.
基金Supported by National Natural Science Foundation of China,No.81230024,No.81471137(to GYX)and No.31400947(to HHZ)Priority Academic Program Development of Jiangsu Higher Education Institutions
文摘AIM:To investigate the roles of toll-like receptor 4(TLR4) and nuclear factor(NF)-κB on cystathionine βsynthetase(CBS) expression and visceral hypersensitivity in rats.METHODS:This study used 1-7-wk-old male SpragueDawley rats.Western blot analysis was employed to measure the expression of TLR4,NF-kB and the endogenous hydrogen sulfide-producing enzyme CBS in colon dorsal root ganglia(DRG) from control and "irritable bowel syndrome" rats induced by neonatal colonic inflammation(NCI).Colon-specific DRG neurons were labeled with Dil and acutely dissociated to measure excitability with patch-clamp techniques.Immunofluorescence was employed to determine the co-expression of TLR4,NF-kB and CBS in Dil-labeled DRG neurons.RESULTS:NCI significantly upregulated the expression of TLR4 in colon-related DRGs(0.34 ± 0.12 vs 0.72 ±0.02 for the control and NCI groups,respectively,P <0.05).Intrathecal administration of the TLR4-selective inhibitor CLI-095 significantly enhanced the colorectal distention threshold of NCI rats.CLI-095 treatment also markedly reversed the hyperexcitability of colonspecific DRG neurons and reduced the expression of CBS(1.7 ± 0.1 vs 1.1 ± 0.04,p < 0.05) and of the NF-kB subunit p65(0.8 ± 0.1 vs 0.5 ± 0.1,P< 0.05).Furthermore,the NF-KB-selective inhibitor pyrrolidine dithiocarbamate(PDTC) significantly reduced the upregulation of CBS(1.0 ± 0.1 vs 0.6 ± 0.1,P< 0.05)and attenuated visceral hypersensitivity in the NCI rats.In vitro,incubation of cultured DRG neurons with the TLR4 agonist lipopolysaccharide significantly enhanced the expression of p65(control vs 8 h:0.9 ± 0.1 vs1.3 ± 0.1;control vs 12 h:0.9 ± 0.1 vs 1.3 ± 0.1,P< 0.05;control vs 24 h:0.9 ± 0.1 vs 1.6 ± 0.1,P <0.01) and CBS(control vs 12 h:1.0 ± 0.1 vs 2.2 ±0.4;control vs 24 h:1.0 ± 0.1 vs 2.6 ± 0.1,P< 0.05),whereas the inhibition of p65 via pre-incubation with PDTC significantly reversed the upregulation of CBS expression(1.2 ± 0.1 vs 0.6 ± 0.0,P< 0.01).CONCLUSION:Our results suggest that the activation of TLR4 by NCI upregulates CBS expression,which is mediated by the NF-kB signaling pathway,thus contributing to visceral hypersensitivity.
基金the Brain-Gut Research Group, Berne, Switzerland
文摘AIM： To investigate the role of endogenous pain modulatory mechanisms in the central sensitization implicated by the visceral hypersensitivity demonstrated in patients with irritable bowel syndrome （IBS）. Dysfunction of modulatory mechanisms would be expected to also result in changes of somatic sensory function. METHODS： Endogenous pain modulatory mechanisms were assessed using heterotopic stimulation and somatic and visceral sensory testing in IBS. Pain intensities （visual analogue scale, VAS 0-100） during suprathreshold rectal distension with a barostat, cold pressor stimulation of the foot and during both stimuli simultaneously （heterotopic stimulation） were recorded in 40 female patients with IBS and 20 female healthy controls. RESULTS： Rectal hypersensitivity （defined by 95% Cl of controls） was seen in 21 （53%）, somatic hypersensitivity in 22 （55%） and both rectal and somatic hypersensitivity in 14 of these IBS patients. Heterotopic stimulation decreased rectal pain intensity by 6 （-11 to -1） in controls, but increased rectal pain by 2 （-3 to ＋6） in all IBS patients （P 〈 0.05） and by 8 （-2 to ＋19） in IBS patients with somatic and visceral hypersensitivity （P 〈 0.02）. CONCLUSION： A majority of IBS patients had abnormal endogenous pain modulation and somatic hypersensitivity as evidence of central sensitization.
基金the National Natural Science Foundation of China,No.81800489Shenzhen Health and Family Planning System Research Project,No.SZXJ2017030Technical Research and Development Project of Shenzhen,Nos.JCYJ20170307100538697 and JCYJ20170307100911479
文摘BACKGROUND Irritable bowel syndrome (IBS) is a common chronic non-organic disease of the digestive system. Berberine (BBR) has been used to treat patients with IBS, but the underlying therapeutic mechanism is little understood. We believe that BBR achieves its therapeutic effect on IBS by preventing stress intestinal inflammation and visceral hypersensitivity and reducing bowel motility. AIM To test the hypothesis that BBR achieves its therapeutic effect on IBS by preventing subclinical inflammation of the intestinal mucosa and reducing visceral hypersensitivity and intestinal motility. METHODS IBS was induced in rats via water avoidance stress (WAS). qRT-PCR and histological analyses were used to evaluate the levels of cytokines and mucosal inflammation, respectively. Modified ELISA and qRT-PCR were used to evaluate the nuclear factor kappa-B (NF-κB) signal transduction pathway. Colorectal distention test, gastrointestinal transit measurement, Western blot, and qRT-PCR were used to analyze visceral sensitivity, intestinal motility, the expression of Ckit (marker of Cajal mesenchymal cells), and the expression of brain derived neurotrophic factor (BDNF) and its receptor TrkB.RESULTS WAS led to mucosal inflammation, visceral hyperalgesia, and high intestinal motility. Oral administration of BBR inhibited the NF-κB signal transduction pathway, reduced the expression of pro-inflammatory cytokines [interleukin (IL)- 1β, IL-6, interferon-γ, and tumor necrosis factor-α], promoted the expression of anti-inflammatory cytokines (IL-10 and transforming growth factor-β), and improved the terminal ileum tissue inflammation. BBR inhibited the expression of BDNF, TrkB, and C-kit in IBS rats, leading to the reduction of intestinal motility and visceral hypersensitivity. The therapeutic effect of BBR at a high dose (100 mg/kg) was superior to than that of the low-dose (25 mg/kg) group. CONCLUSION BBR reduces intestinal mucosal inflammation by inhibiting the intestinal NF-κB signal pathway in the IBS rats. BBR reduces the expression of BDNF, its receptor TrkB, and C-kit. BBR also reduces intestinal motility and visceral sensitivity to achieve its therapeutic effect on IBS.
基金Supported by National Basic Research Program of China(973 Program)No.2009CB522900 and No.2015CB554501National Natural Science Foundation of China,No.30973784
文摘AIM To observe whether there are differences in the effects of electro-acupuncture(EA) and moxibustion(Mox) in rats with visceral hypersensitivity. METHODS EA at 1 m A and 3 m A and Mox at 43?℃ and 46?℃ were applied to the Shangjuxu(ST37, bilateral) acupoints in model rats with visceral hypersensitivity. Responses of wide dynamic range neurons in dorsal horns of the spinal cord were observed through the extracellular recordings. Mast cells(MC) activity in the colons of rats were assessed, and 5-hydroxytryptamine(5-HT), 5-hydroxytryptamine 3 receptor(5-HT3R) and 5-HT4Rexpressions in the colons were measured.RESULTS Compared with normal control group, responses of wide dynamic range neurons in the dorsal horn of the spinal cord were increased in the EA at 1 m A and 3 m A groups(1 m A: 0.84 ± 0.74 vs 2.73 ± 0.65, P < 0.001; 3 m A: 1.91 ± 1.48 vs 6.44 ± 1.26, P < 0.001) and Mox at 43?℃ and 46?℃ groups(43?℃: 1.76 ± 0.81 vs 4.14 ± 1.83, P = 0.001; 46?℃: 5.19 ± 2.03 vs 7.91 ± 2.27, P = 0.01). MC degranulation rates and the expression of 5-HT, 5-HT3 R and 5-HT4 R in the colon of Mox 46?℃ group were decreased compared with model group(MC degranulation rates: 0.47 ± 0.56 vs 0.28 ± 0.78, P < 0.001; 5-HT: 1.42 ± 0.65 vs 7.38 ± 1.12, P < 0.001; 5-HT3R: 6.62 ± 0.77 vs 2.86 ± 0.88, P < 0.001; 5-HT4R: 4.62 ± 0.65 vs 2.22 ± 0.97, P < 0.001). CONCLUSION The analgesic effects of Mox at 46?℃ are greater than those of Mox at 43?℃, EA 1 m A and EA 3 m A.
基金Supported by Natural Science Foundation of China,No.81070308/H0308
文摘AIM: To explore the role of nesfatin-1 on irritable bowel syndrome (IBS)-like visceral hypersensitivity. METHODS: The animal model of IBS-like visceral hypersensitivity was induced by intracolonic infusion of 0.5% acetic acid (AA) in saline once daily from postnatal days 8-21. Experiments were performed when rats became adults. The visceral sensitivity of rats was evaluated by abdominal withdrawal reflex (AWR) and electromyographic (EMG) activity of the external oblique muscle to graded colorectal distension. The content of nesfatin-1 in serum was determined using enzyme-linked immunosorbent assay. After implantation of an intracerebroventricular (ICV) cannula and two electrodes into the external oblique muscle, model rats were randomly divided into four groups. Animals then received ICV injection of 8 μg of anti-nesfatin-1/ nucleobindin-2 (NUCB2), 50 μg of α-helical cortico-tropin releasing factor (CRF) 9-41 (non-selective CRF receptor antagonist), 50 μg of NBI-27914 (selective CRF1 receptor antagonist) or 5 μL of vehicle. After 1 h of ICV administration, visceral sensitivity of each group was measured again, and comparisons between groups were made. RESULTS: Rats treated with AA showed higher mean AWR scores and EMG activity at all distension pressures compared with controls (P < 0.05). On histopathologic examination, no evidence of inflammation or abnormalities in structure were noted in the colon of either control or AA-treated groups. Myeloperoxidase values were not significantly different between the two groups. The level of nesfatin-1 in serum was significantly higher in the AA-treated group than in the control group (5.34 ± 0.37 ng/mL vs 4.81 ± 0.42 ng/mL, P < 0.01). Compared with rats injected with vehicle, rats which received ICV anti-nesfatin-1/NUCB2, α-helical CRF9-41 or NBI-27914 showed decreased mean AWR scores and EMG activity at all distension pressures (P < 0.05). CONCLUSION: Nesfatin-1 may be associated with IBS-like visceral hypersensitivity, which may be implicated in brain CRF/CRF1 signaling pathways.
文摘AIM: To assess the protective effect of berberine administration and the role of nitric oxide (NO) in visceral hypersensitivity. METHODS: Fifty male Sprague-Dawley rats were randomly assigned to five groups. An inflammatory bowel disease model was induced in rats by intracolonic instillation of 1 mL 4% acetic acid at 8 cm proximal to the anus for 30 s and restraint stress. After subsidence of inflammation on day 7 of the experiment, the rats were subjected to rectal distension, performed by a balloon (6-Fr, 2 mm external diameter, disposable silicon balloon-urethral catheter for pediatric use) which was rapidly inflated with increasing volumes of prewarmed (37 ℃) water (0.1, 0.2, 0.3, 0.4, 0.6, 0.8 and 1 mL) for 30 s at four-minute intervals, and then the abdominal withdrawal reflex (AWR) and the level of fecal output were measured, respectively. AWR scores either 0, 1, 2, 3 or 4 were obtained by blinded observers. Rats had been pretreated with berberine or aminoguanidine (NO synthetase inhibitor) or berberine + aminoguanidine before measurement. RESULTS: The rats in the placebo group showed a hypersensitive response to rectal distension (2.69 ± 0.08 vs 1.52 ± 0.08, P = 0.000) and defecated more frequently than those in the control group (5.0 ± 0.16 vs 0.44 ± 0.16, P = 0.000). Comparing the berberine with placebo group, the AWR scores were reduced for all distension volumes and were significant at 0.2-1 mL (1.90 ± 0.08 vs 2.69 ± 0.08, P = 0.000), while the numbers of hard pellets, soft pellets, formless stools, and total fecal output in the placebo group were significantly larger than in the berberine group (5.0 ± 0.16 vs 2.56 ± 0.16, P = 0.000). Administration of aminoguanidine or berberine + aminoguanidine before VH score measurement reversed the antinociceptive effect of berberine (2.52 ± 0.08 vs 1.90 ± 0.08, P = 0.000; 2.50 ± 0.08 vs 1.90 ± 0.08, P = 0.000). The numbers of hard pellets, soft pellets, formless stool, and total of fecal output in aminoguanidine group were significantly larger than the corresponding values in control group, berberine group, and berberine + aminoguanidine group (4.81 ± 0.16 vs 0.44 ± 0.16, P = 0.000; 4.81 ± 0.16 vs 2.56 ± 0.16, P = 0.000; 4.81 ± 0.16 vs 3.75 ± 0.16, P = 0.000). The berberine and berberine + aminoguanidine groups showed reduced defecation, but aminoguanidine alone did not reduce defecation (2.56 ± 0.16 vs 4.81 ± 0.16, P = 0.000; 3.75 ± 0.16 vs 4.81 ± 0.16, P = 0.000). CONCLUSION: Berberine had an antinociceptive effect on visceral hypersensitivity, and NO might play a role in this effect.
基金Supported by the National Key Technology Support Program during “12th Five-Year Plan”period of China,No.2014BAI08B00the Leapforward Development Program for Beijing Biopharmaceutical Industry(G20),No. Z171100001717008.
文摘BACKGROUND Visceral hypersensitivity and psychological performance are the main pathophysiological mechanisms of irritable bowel syndrome(IBS).Previous studies have found that cholecystokinin(CCK)can enhance colon movement and that serotonin transporter(SERT)is a transmembrane transport protein with high affinity for 5-hydroxytryptamine,which can rapidly reuptake 5-hydroxytryptamine and then regulate its action time and intensity.We speculate that SERT and CCK might play a role in the pathogenesis of diarrheapredominant IBS(IBS-D)by affecting visceral sensitivity and the brain-gut axis.AIM To determine SERT and CCK levels in IBS-D patients diagnosed using Rome IV criteria and to analyze their associations with abdominal pain,visceral hypersensitivity and psychological performance.METHODS This study collected data from 40 patients with IBS-D at the China-Japan Friendship Hospital from September 2017 to April 2018 and 18 healthy controls.The severity of abdominal pain,visceral sensitivity and psychological performance were evaluated in IBS-D patients and healthy controls,the levels of SERT and CCK in plasma and colonic mucosa were evaluated,and the correlations between them were analyzed.RESULTS There were significant differences in the initial sensation threshold(31.00±8.41 mL vs 52.22±8.09 mL,P<0.001),defecating sensation threshold(51.75±13.57 mL vs 89.44±8.73 mL,P<0.001)and maximum tolerable threshold(97.25±23.64 mL vs 171.11±20.83 mL,P<0.001)between the two groups.IBS-D patients had more severe anxiety(7.78±2.62 vs 2.89±1.02,P<0.001)and depressive(6.38±2.43 vs 2.06±0.73,P<0.001)symptoms than healthy controls.Significant differences were also found in mucosal CCK(2.29±0.30 vs 1.66±0.17,P<0.001)and SERT(1.90±0.51 vs 3.03±0.23,P<0.001)between the two groups.There was a significant positive correlation between pain scores and mucosal CCK(r=0.96,0.93,0.94,P<0.001).Significant negative correlations between anxiety(r=-0.98;P<0.001),depression(r=-0.99;P<0.001),pain evaluation(r=-0.96,-0.93,-0.95,P<0.001)and mucosal SERT were observed.CONCLUSION IBS-D patients had psychosomatic disorders and visceral hypersensitivity.SERT and CCK might be involved in the pathogenesis of IBS-D by regulating the braingut axis and affecting visceral sensitivity.This provides a new potential method for identifying a more specific and effective therapeutic target.
基金the National Key Technology Support Program for the “12th Five-Year Plan” of China,No.2014BAI08B00the Research Projects on Biomedical Transformation of China-Japan Friendship Hospital,No.PYBZ1815
文摘BACKGROUND Fecal metabolites are associated with gut visceral sensitivity,mucosal immune function and intestinal barrier function,all of which have critical roles in the pathogenesis of irritable bowel syndrome(IBS).However,the metabolic profile and pathophysiology of IBS are still unclear.We hypothesized that altered profiles of fecal metabolites might be involved in the pathogenesis of IBS with predominant diarrhea(IBS-D).AIM To investigate the fecal metabolite composition and the role of metabolites in IBSD pathophysiology.METHODS Thirty IBS-D patients and 15 age-and sex-matched healthy controls(HCs)underwent clinical and psychological assessments,including the IBS Symptom Severity System(IBS-SSS),an Italian modified version of the Bowel Disease Questionnaire,the Bristol Stool Form Scale(BSFS),the Hospital Anxiety and Depression Scale,and the Visceral Sensitivity Index.Visceral sensitivity to rectal distension was tested using high-resolution manometry system by the same investigator.Fecal metabolites,including amino acids and organic acids,were measured by targeted metabolomics approaches.Correlation analyses between these parameters were performed.RESULTS The patients presented with increased stool water content,more psychological symptoms and increased visceral hypersensitivity compared with the controls.In fecal metabolites,His[IBS-D:0.0642(0.0388,0.1484),HC:0.2636(0.0780,0.3966),P=0.012],Ala[IBS-D:0.5095(0.2826,0.9183),HC:1.0118(0.6135,1.4335),P=0.041],Tyr[IBS-D:0.1024(0.0173,0.4527),HC:0.5665(0.2436,1.3447),P=0.018],Phe[IBS-D:0.1511(0.0775,0.3248),HC:0.3967(0.1388,0.7550),P=0.028],and Trp[IBS-D:0.0323(0.0001,0.0826),HC:0.0834(0.0170,0.1759),P=0.046]were decreased in IBS-D patients,but isohexanoate[IBS-D:0.0127(0.0060,0.0246),HC:0.0070(0.0023,0.0106),P=0.028]was significantly increased.Only Tyr was mildly correlated with BSFS scores in all subjects(r=-0.347,P=0.019).A possible potential biomarker panel was identified to correlate with IBS-SSS score(R2 Adjusted=0.693,P<0.001).In this regression model,the levels of Tyr,Val,hexanoate,fumarate,and pyruvate were significantly associated with the symptom severity of IBS-D.Furthermore,visceral sensation,including abdominal pain and visceral hypersensitivity,was correlated with isovalerate,valerate and isohexanoate.CONCLUSION Altered profiles of fecal metabolites may be one of the origins or exacerbating factors of symptoms in IBS-D via increasing visceral sensitivity.
基金supported by Natural Science Foundation of China Grant(No.81160057):International Science and Technique Corporation Foundation of Hainan Province Grant(No.KJHZ2013-14)
文摘Objective:To investigate the impact of the preinduced intestinal heat shock protein 70(HSP70)on the visceral hypersensitivity and abnormal intestinal motility in a post-infectious irritable bowel syndrome(PI-IBS) mouse model.Methods:Eighty-four female C57BL/6 mice were randomly assigned to four groups:control group(n=21) and induction+PI-IBS group(n=21),PI-IBS group(n=21) and induction group(n=21).The mice in PI-IBS group were infected in vivo with trichinella spiralis by oral administration.The visceral hypersensitivity and intestinal motility were evaluated respectively with abdominal withdrawal reflex and colon transportation test.The intestinal HSP70 protein and mRNA level was measured by Western blot and realtime PCR.Meanwhile,the intestinal proinflammatory cytokines IL-10 and TNF-α level was detected by ELISA.Results:Compared with their counterparts in PI-IBS group,the animals in the Induction+PI-IBS group show significantly increased intestinal level of HSP70 and obviously ameliorative clinical tigurcs.including abdominal withdrawal reflex score,intestine transportation time and Bristol scores(P<0.05).Meanwhile,the intestinal post-inflammatory cytokines remarkably changed,including increased IL-10 level and decreased TNF-αlevel(P<0.05).Conclusions:Intestinal IISP70 may play a potential protective role through improving the imbalance between the intestinal post-inflammatory and anti-inflammatory cytokines in PI-IBS.
