AIM:To evaluate the utility of serum and urine metabolomic analysis in diagnosing and monitoring of inflammatory bowel diseases(IBD).METHODS:Serum and urine samples were collected from 24 patients with ulcerative coli...AIM:To evaluate the utility of serum and urine metabolomic analysis in diagnosing and monitoring of inflammatory bowel diseases(IBD).METHODS:Serum and urine samples were collected from 24 patients with ulcerative colitis(UC),19 patients with the Crohn’s disease(CD)and 17 healthy controls.The activity of UC was assessed with the Simple Clinical Colitis Activity Index,while the activity of CD was determined using the Harvey-Bradshaw Index.The analysis of serum and urine samples was performed using proton nuclear magnetic resonance(NMR)spectroscopy.All spectra were exported to Matlab for preprocessing which resulted in two data matrixes for serum and urine.Prior to the chemometric analysis,both data sets were unit variance scaled.The differences in metabolite fingerprints were assessed using partial least-squaresdiscriminant analysis(PLS-DA).Receiver operating characteristic curves and area under curves were used to evaluate the quality and prediction performance of the obtained PLS-DA models.Metabolites responsible for separation in models were tested using STATISTICA10 with the Mann-Whitney-Wilcoxon test and the Student’s t test(α=0.05).RESULTS:The comparison between the group of patients with active IBD and the group with IBD in remission provided good PLS-DA models(P value 0.002for serum and 0.003 for urine).The metabolites that allowed to distinguish these groups were:N-acetylated compounds and phenylalanine(up-regulated in serum),low-density lipoproteins and very low-density lipoproteins(decreased in serum)as well as glycine(increased in urine)and acetoacetate(decreased in urine).The significant differences in metabolomic profiles were also found between the group of patients with active IBD and healthy control subjects providing the PLS-DA models with a very good separation(P value<0.001 for serum and 0.003 for urine).The metabolites that were found to be the strongest biomarkers included in this case:leucine,isoleucine,3-hydroxybutyric acid,N-acetylated compounds,acetoacetate,glycine,phenylalanine and lactate(increased in serum),creatine,dimethyl sulfone,histidine,choline and its derivatives(decreased in serum),as well as citrate,hippurate,trigonelline,taurine,succinate and 2-hydroxyisobutyrate(decreased in urine).No clear separation in PLS-DA models was found between CD and UC patients based on the analysis of serum and urine samples,although one metabolite(formate)in univariate statistical analysis was significantly lower in serum of patients with active CD,and two metabolites(alanine and N-acetylated compounds)were significantly higher in serum of patients with CD when comparing jointly patients in the remission and active phase of the diseases.Contrary to the results obtained from the serum samples,the analysis of urine samples allowed to distinguish patients with IBD in remission from healthy control subjects.The metabolites of importance included in this case up-regulated acetoacetate and down-regulated citrate,hippurate,taurine,succinate,glycine,alanine and formate.CONCLUSION:NMR-based metabolomic fingerprinting of serum and urine has the potential to be a useful tool in distinguishing patients with active IBD from those in remission.展开更多
Compelling evidence indicates sex and gender differences in epidemiology,symptomatology,pathophysiology,and treatment outcome in irritable bowel syndrome(IBS).Based on the female predominance as well as the correlatio...Compelling evidence indicates sex and gender differences in epidemiology,symptomatology,pathophysiology,and treatment outcome in irritable bowel syndrome(IBS).Based on the female predominance as well as the correlation between IBS symptoms and hormonal status,several models have been proposed to examine the role of sex hormones in gastrointestinal(GI)function including differences in GI symptoms expression in distinct phases of the menstrual cycle,in pre-and post-menopausal women,during pregnancy,hormonal treatment or after oophorectomy.Sex hormones may influence peripheral and central regulatory mechanisms of the brain-gut axis involved in the pathophysiology of IBS contributing to the alterations in visceral sensitivity,motility,intestinal barrier function,and immune activation of intestinal mucosa.Sex differences in stress response of the hypothalamic-pituitary-adrenal axis and autonomic nervous system,neuroimmune interac-tions triggered by stress,as well as estrogen interactions with serotonin and corticotropin-releasing factor signaling systems are being increasingly recognized.A concept of"microgenderome"related to the potential role of sex hormone modulation of the gut microbiota is also emerging.Significant differences between IBS female and male patients regarding symptomatology and comorbidity with other chronic pain syndromes and psychiatric disorders,together with differences in efficacy of serotonergic medications in IBS patients confirm the necessity for more sex-tailored therapeutic approach in this disorder.展开更多
Parkinson's disease(PD) is characterized by alphasynucleinopathy that affects all levels of the braingut axis including the central, autonomic, and enteric nervous systems. Recently, it has been recognized that th...Parkinson's disease(PD) is characterized by alphasynucleinopathy that affects all levels of the braingut axis including the central, autonomic, and enteric nervous systems. Recently, it has been recognized that the brain-gut axis interactions are significantly modulated by the gut microbiota via immunological,neuroendocrine, and direct neural mechanisms. Dysregulation of the brain-gut-microbiota axis in PD may be associated with gastrointestinal manifestations frequently preceding motor symptoms, as well as with the pathogenesis of PD itself, supporting the hypothesis that the pathological process is spread from the gut to the brain. Excessive stimulation of the innate immune system resulting from gut dysbiosis and/or small intestinal bacterial overgrowth and increased intestinal permeability may induce systemic inflammation, while activation of enteric neurons and enteric glial cells may contribute to the initiation of alpha-synuclein misfolding.Additionally, the adaptive immune system may be disturbed by bacterial proteins cross-reacting with human antigens. A better understanding of the brain-gutmicrobiota axis interactions should bring a new insight in the pathophysiology of PD and permit an earlier diagnosis with a focus on peripheral biomarkers within the enteric nervous system. Novel therapeutic options aimed at modifying the gut microbiota composition and enhancing the intestinal epithelial barrier integrity in PD patients could influence the initial step of the following cascade of neurodegeneration in PD.展开更多
AIM To evaluate circulating IL9 in inflammatory bowel disease and disease-associated anemia/cachexia and assess its potential as a mucosal healing marker.METHODS Serum IL9 as well as other cytokines(IL1β, IL6, IL13, ...AIM To evaluate circulating IL9 in inflammatory bowel disease and disease-associated anemia/cachexia and assess its potential as a mucosal healing marker.METHODS Serum IL9 as well as other cytokines(IL1β, IL6, IL13, IFNγ, TNFα, and VEGF-A) were determined in 293 individuals: 97 patients with Crohn's disease(CD) and 74 with ulcerative colitis(UC) and in 122 apparently healthy controls. The clinical activity of CD and UC was expressed in terms of the Crohn's Disease Activity Index(CDAI) and the Mayo Scoring System(MDAI), respectively, and the severity of bowel inflammation in UC patients was assessed using Mayo endoscopic score. Cytokine concentrations were measured by a flow cytometry-based method using Luminex x MAP? technology. Highsensitive C-reactive protein concentrations(hs CRP) were determined in CD and UC patients using the enhanced immunoturbidimetric method.RESULTS Systemic IL9 was significantly lower in healthy individuals [9 pg/m L(95%CI: 8.2-10)] than in patients with inflammatory bowel disease(IBD): both inactive [14.3 pg/m L(11.9-19.9)] and active [27.6 pg/m L(24.5-32), P < 0.0001]. Cytokine concentrations were significantly higher in active CD [27.4 pg/m L(23.4-32.2)] and in active UC [32.7 pg/m L(27-38.9)] compared to inactive diseases [15.9 pg/m L(10.8-23.4) in CD and 19.4 pg/m L(13.9-27.1) in UC, P = 0.001]. IL9 correlated weakly with CDAI(ρ = 0.32, P = 0.003) and MDAI(ρ = 0.35, P = 0.002) and strongly with endoscopic inflammation in UC(ρ = 0.74, P < 0.0001). As a negative marker of mucosal healing(MH), IL9 had an accuracy superior to hs CRP and IL6 [97%(P < 0.0001), 67%(P = 0.071), and 55%(P = 0.525), respectively]. IL9 was significantly higher in cachectic IBD patients [30.25 pg/m L(24.4-37.5) vs 21.88 pg/m L(18-26.5), P = 0.026] and negatively correlated with hemoglobin concentrations(ρ =-0.27, P < 0.001). Multiple regression showed IL1β and IL13 to be the independent predictors of circulating IL9 in healthy individuals, IFNγ or IL6 in active and inactive UC, respectively, and IL13 and VEGF-A in both active and inactive CD.CONCLUSION The systemic IL9 level is higher in IBD and corresponds with endoscopic inflammation, suggesting its possible application as a negative marker of mucosal healing in UC.展开更多
AIM: To investigate the influence of repeated water avoidance stress (rWAS) on the visceromotor response (VMR) to colorectal distension (CRD) and the modulation of the response by a prebiotic diet in rats using a nove...AIM: To investigate the influence of repeated water avoidance stress (rWAS) on the visceromotor response (VMR) to colorectal distension (CRD) and the modulation of the response by a prebiotic diet in rats using a novel surgery-free method of solid-state manometry.METHODS: Male Wistar rats fed a standard diet with or without 4% enzyme-treated rice fiber (ERF) for 5 wk were subjected to rWAS (1 h daily x 10 d) or no stress. The VMR to graded phasic CRD was assessed by intraluminal colonic pressure recording on days 0 (base-line), 1 and 10 (45 min) and 11 (24 h) after rWAS and expressed as percentage change from baseline. Cecal content of short chain fatty acids and distal colonic histology were assessed on day 11. RESULTS: WAS on day 1 reduced the VMR to CRD at 40 and 60 mmHg similarly by 28.9% ± 6.6% in both diet groups. On day 10, rWAS-induced reduction of VMR occurred only at 40 mmHg in the standard diet group (36.2% ± 17.8%) while in the ERF group VMR was lowered at 20, 40 and 60 mmHg by 64.9% ± 20.9%, 49.3% ± 11.6% and 38.9% ± 7.3% respectively. The visceral analgesia was still observed on day 11 in ERF-but not in standard diet-fed rats. By contrast the non-stressed groups (standard or ERF diet) exhibited no changes in VMR to CRD. In standard diet-fed rats, rWAS induced mild colonic histological changes that were absent in ERF-fed rats exposed to stress compared to non-stressed rats. The reduction of cecal content of isobutyrate and total butyrate, but not butyrate alone, was correlated with lower visceral pain response. Additionally, ERF diet increased rWAS-induced defecation by 26% and 75% during the first 0-15 min and last 15-60 min, respectively, compared to standard diet, and reduced rats' body weight gain by 1.3 fold independently of their stress status. CONCLUSION: These data provide the first evidence of psychological stress-related visceral analgesia in rats that was enhanced by chronic intake of ERF prebiotic.展开更多
基金Supported by Wroclaw Medical University Research Program,Grant Number 15/Pbmn
文摘AIM:To evaluate the utility of serum and urine metabolomic analysis in diagnosing and monitoring of inflammatory bowel diseases(IBD).METHODS:Serum and urine samples were collected from 24 patients with ulcerative colitis(UC),19 patients with the Crohn’s disease(CD)and 17 healthy controls.The activity of UC was assessed with the Simple Clinical Colitis Activity Index,while the activity of CD was determined using the Harvey-Bradshaw Index.The analysis of serum and urine samples was performed using proton nuclear magnetic resonance(NMR)spectroscopy.All spectra were exported to Matlab for preprocessing which resulted in two data matrixes for serum and urine.Prior to the chemometric analysis,both data sets were unit variance scaled.The differences in metabolite fingerprints were assessed using partial least-squaresdiscriminant analysis(PLS-DA).Receiver operating characteristic curves and area under curves were used to evaluate the quality and prediction performance of the obtained PLS-DA models.Metabolites responsible for separation in models were tested using STATISTICA10 with the Mann-Whitney-Wilcoxon test and the Student’s t test(α=0.05).RESULTS:The comparison between the group of patients with active IBD and the group with IBD in remission provided good PLS-DA models(P value 0.002for serum and 0.003 for urine).The metabolites that allowed to distinguish these groups were:N-acetylated compounds and phenylalanine(up-regulated in serum),low-density lipoproteins and very low-density lipoproteins(decreased in serum)as well as glycine(increased in urine)and acetoacetate(decreased in urine).The significant differences in metabolomic profiles were also found between the group of patients with active IBD and healthy control subjects providing the PLS-DA models with a very good separation(P value<0.001 for serum and 0.003 for urine).The metabolites that were found to be the strongest biomarkers included in this case:leucine,isoleucine,3-hydroxybutyric acid,N-acetylated compounds,acetoacetate,glycine,phenylalanine and lactate(increased in serum),creatine,dimethyl sulfone,histidine,choline and its derivatives(decreased in serum),as well as citrate,hippurate,trigonelline,taurine,succinate and 2-hydroxyisobutyrate(decreased in urine).No clear separation in PLS-DA models was found between CD and UC patients based on the analysis of serum and urine samples,although one metabolite(formate)in univariate statistical analysis was significantly lower in serum of patients with active CD,and two metabolites(alanine and N-acetylated compounds)were significantly higher in serum of patients with CD when comparing jointly patients in the remission and active phase of the diseases.Contrary to the results obtained from the serum samples,the analysis of urine samples allowed to distinguish patients with IBD in remission from healthy control subjects.The metabolites of importance included in this case up-regulated acetoacetate and down-regulated citrate,hippurate,taurine,succinate,glycine,alanine and formate.CONCLUSION:NMR-based metabolomic fingerprinting of serum and urine has the potential to be a useful tool in distinguishing patients with active IBD from those in remission.
基金Supported by The Veterans Administration Research Career Scientist Award(to TachéY)National Institute of Health grants No.P50 DK-64539(to TachéY)No.K01-DK088937(to Larauche M)
文摘Compelling evidence indicates sex and gender differences in epidemiology,symptomatology,pathophysiology,and treatment outcome in irritable bowel syndrome(IBS).Based on the female predominance as well as the correlation between IBS symptoms and hormonal status,several models have been proposed to examine the role of sex hormones in gastrointestinal(GI)function including differences in GI symptoms expression in distinct phases of the menstrual cycle,in pre-and post-menopausal women,during pregnancy,hormonal treatment or after oophorectomy.Sex hormones may influence peripheral and central regulatory mechanisms of the brain-gut axis involved in the pathophysiology of IBS contributing to the alterations in visceral sensitivity,motility,intestinal barrier function,and immune activation of intestinal mucosa.Sex differences in stress response of the hypothalamic-pituitary-adrenal axis and autonomic nervous system,neuroimmune interac-tions triggered by stress,as well as estrogen interactions with serotonin and corticotropin-releasing factor signaling systems are being increasingly recognized.A concept of"microgenderome"related to the potential role of sex hormone modulation of the gut microbiota is also emerging.Significant differences between IBS female and male patients regarding symptomatology and comorbidity with other chronic pain syndromes and psychiatric disorders,together with differences in efficacy of serotonergic medications in IBS patients confirm the necessity for more sex-tailored therapeutic approach in this disorder.
文摘Parkinson's disease(PD) is characterized by alphasynucleinopathy that affects all levels of the braingut axis including the central, autonomic, and enteric nervous systems. Recently, it has been recognized that the brain-gut axis interactions are significantly modulated by the gut microbiota via immunological,neuroendocrine, and direct neural mechanisms. Dysregulation of the brain-gut-microbiota axis in PD may be associated with gastrointestinal manifestations frequently preceding motor symptoms, as well as with the pathogenesis of PD itself, supporting the hypothesis that the pathological process is spread from the gut to the brain. Excessive stimulation of the innate immune system resulting from gut dysbiosis and/or small intestinal bacterial overgrowth and increased intestinal permeability may induce systemic inflammation, while activation of enteric neurons and enteric glial cells may contribute to the initiation of alpha-synuclein misfolding.Additionally, the adaptive immune system may be disturbed by bacterial proteins cross-reacting with human antigens. A better understanding of the brain-gutmicrobiota axis interactions should bring a new insight in the pathophysiology of PD and permit an earlier diagnosis with a focus on peripheral biomarkers within the enteric nervous system. Novel therapeutic options aimed at modifying the gut microbiota composition and enhancing the intestinal epithelial barrier integrity in PD patients could influence the initial step of the following cascade of neurodegeneration in PD.
基金Supported by National Science Center,No.DEC-2011/01/D/NZ5/02835
文摘AIM To evaluate circulating IL9 in inflammatory bowel disease and disease-associated anemia/cachexia and assess its potential as a mucosal healing marker.METHODS Serum IL9 as well as other cytokines(IL1β, IL6, IL13, IFNγ, TNFα, and VEGF-A) were determined in 293 individuals: 97 patients with Crohn's disease(CD) and 74 with ulcerative colitis(UC) and in 122 apparently healthy controls. The clinical activity of CD and UC was expressed in terms of the Crohn's Disease Activity Index(CDAI) and the Mayo Scoring System(MDAI), respectively, and the severity of bowel inflammation in UC patients was assessed using Mayo endoscopic score. Cytokine concentrations were measured by a flow cytometry-based method using Luminex x MAP? technology. Highsensitive C-reactive protein concentrations(hs CRP) were determined in CD and UC patients using the enhanced immunoturbidimetric method.RESULTS Systemic IL9 was significantly lower in healthy individuals [9 pg/m L(95%CI: 8.2-10)] than in patients with inflammatory bowel disease(IBD): both inactive [14.3 pg/m L(11.9-19.9)] and active [27.6 pg/m L(24.5-32), P < 0.0001]. Cytokine concentrations were significantly higher in active CD [27.4 pg/m L(23.4-32.2)] and in active UC [32.7 pg/m L(27-38.9)] compared to inactive diseases [15.9 pg/m L(10.8-23.4) in CD and 19.4 pg/m L(13.9-27.1) in UC, P = 0.001]. IL9 correlated weakly with CDAI(ρ = 0.32, P = 0.003) and MDAI(ρ = 0.35, P = 0.002) and strongly with endoscopic inflammation in UC(ρ = 0.74, P < 0.0001). As a negative marker of mucosal healing(MH), IL9 had an accuracy superior to hs CRP and IL6 [97%(P < 0.0001), 67%(P = 0.071), and 55%(P = 0.525), respectively]. IL9 was significantly higher in cachectic IBD patients [30.25 pg/m L(24.4-37.5) vs 21.88 pg/m L(18-26.5), P = 0.026] and negatively correlated with hemoglobin concentrations(ρ =-0.27, P < 0.001). Multiple regression showed IL1β and IL13 to be the independent predictors of circulating IL9 in healthy individuals, IFNγ or IL6 in active and inactive UC, respectively, and IL13 and VEGF-A in both active and inactive CD.CONCLUSION The systemic IL9 level is higher in IBD and corresponds with endoscopic inflammation, suggesting its possible application as a negative marker of mucosal healing in UC.
基金Supported by Central Labs for Frontier Technology Kirin Holdings Co., Ltd Japanthe National Institute of Health grants,P50 DK-64539 (to Taché Y and Larauche M)+2 种基金Center Grant DK-41301 (Animal Core, to Yvette Taché)R01 DK-33061 (to Yvette Taché) Veterans Administration Research Career Scientist Award
文摘AIM: To investigate the influence of repeated water avoidance stress (rWAS) on the visceromotor response (VMR) to colorectal distension (CRD) and the modulation of the response by a prebiotic diet in rats using a novel surgery-free method of solid-state manometry.METHODS: Male Wistar rats fed a standard diet with or without 4% enzyme-treated rice fiber (ERF) for 5 wk were subjected to rWAS (1 h daily x 10 d) or no stress. The VMR to graded phasic CRD was assessed by intraluminal colonic pressure recording on days 0 (base-line), 1 and 10 (45 min) and 11 (24 h) after rWAS and expressed as percentage change from baseline. Cecal content of short chain fatty acids and distal colonic histology were assessed on day 11. RESULTS: WAS on day 1 reduced the VMR to CRD at 40 and 60 mmHg similarly by 28.9% ± 6.6% in both diet groups. On day 10, rWAS-induced reduction of VMR occurred only at 40 mmHg in the standard diet group (36.2% ± 17.8%) while in the ERF group VMR was lowered at 20, 40 and 60 mmHg by 64.9% ± 20.9%, 49.3% ± 11.6% and 38.9% ± 7.3% respectively. The visceral analgesia was still observed on day 11 in ERF-but not in standard diet-fed rats. By contrast the non-stressed groups (standard or ERF diet) exhibited no changes in VMR to CRD. In standard diet-fed rats, rWAS induced mild colonic histological changes that were absent in ERF-fed rats exposed to stress compared to non-stressed rats. The reduction of cecal content of isobutyrate and total butyrate, but not butyrate alone, was correlated with lower visceral pain response. Additionally, ERF diet increased rWAS-induced defecation by 26% and 75% during the first 0-15 min and last 15-60 min, respectively, compared to standard diet, and reduced rats' body weight gain by 1.3 fold independently of their stress status. CONCLUSION: These data provide the first evidence of psychological stress-related visceral analgesia in rats that was enhanced by chronic intake of ERF prebiotic.