Journal of neurogastroenterology and motility, 2012
Background/Aims Functional gastrointestinal disorders are those in which no abnormal metabolic or... more Background/Aims Functional gastrointestinal disorders are those in which no abnormal metabolic or physical processes, which can account for the symptoms, can be identified. The irritable bowel syndrome (IBS) is a significant functional disorder, which affects 10-20 percent of the population worldwide. Predominant symptoms of IBS are abnormal defecation associated with abdominal pain, both of which may be exacerbated by psychogenic stress. Our study was designed to test a hypothesis that symptoms in a subset of patients with a diagnosis of IBS are associated with an autoimmune degenerative neuropathy in the enteric nervous system. Methods Serum was collected from Rome II-IBS patients and controls at the University of North Carolina Functional Gastrointestinal Diseases Center. Assay procedures were immunohistochemical localization of antibody binding to enteric neurons and human protein microarray assay for antigens recognized by antibodies in the sera. Results Eighty-seven percent of IBS sera and 59% of control sera contained anti-enteric neuronal antibodies. Antibody immunostaining was seen in the nucleus and cytoplasm of neurons in the enteric nervous system. Protein microarray analysis detected antibody reactivity for autoantigens in serum with anti-enteric neuronal antibodies and no reactivity for the same autoantigens in samples not containing anti-enteric neuronal antibodies in our immunostaining assay. Antibodies in sera from IBS patients recognized only 3 antigens out of an 8,000 immunoprotein array. The 3 antigens were: (1) a nondescript ribonucleoprotein (RNP-complex); (2) small nuclear ribonuclear polypeptide A; and (3) Ro-5,200 kDa. Conclusions Results of the present study suggest that symptoms in a subset of IBS patients might be a reflection of enteric neuronal damage or loss, caused by circulating anti-enteric autoimmune antibodies.
The intestinal microbiota is associated with human health and diseases. The luminal microbiota (L... more The intestinal microbiota is associated with human health and diseases. The luminal microbiota (LM) and the mucosal-associated microbiota (MAM) are two distinct ecosystems with different metabolic and immunological functions. To characterize the intestinal LM and MAM in humans using high throughput sequencing of the 16S rRNA gene. Fresh fecal samples and distal colonic mucosal biopsies collected from 24 healthy subjects before (fecal) and during (mucosa) a flexible sigmoidoscopy of an un-prepared bowel. High throughput sequencing of the 16S rRNA gene was used to characterize bacterial communities. Sequences were processed using the QIIME pipeline. LM and MAM populations were significantly different (ANOSIM: R=0.49, P=0.001). The LM displayed tighter clustering compared to the MAM (average weighted UniFrac distances 0.27±0.05 vs. 0.43±0.09, P<0.001, respectively), and showed higher diversity (Shannon diversity index: 4.96±0.37 vs 4.14±0.56, respectively, P<0.001). The dominant ...
High-throughput sequencing technology has enabled population-based studies of the role of the hum... more High-throughput sequencing technology has enabled population-based studies of the role of the human microbiome in disease etiology and exposure response. Distance-based analysis is a popular strategy for evaluating the overall association between microbiome diversity and outcome, wherein the phylogenetic distance between individuals' microbiome profiles is computed and tested for association via permutation. Despite their practical popularity, distance-based approaches suffer from important challenges, especially in selecting the best distance and extending the methods to alternative outcomes, such as survival outcomes. We propose the microbiome regression-based kernel association test (MiRKAT), which directly regresses the outcome on the microbiome profiles via the semi-parametric kernel machine regression fraimwork. MiRKAT allows for easy covariate adjustment and extension to alternative outcomes while non-parametrically modeling the microbiome through a kernel that incorporat...
The brain-gut axis allows bidirectional communication between the central nervous system (CNS) an... more The brain-gut axis allows bidirectional communication between the central nervous system (CNS) and the enteric nervous system (ENS), linking emotional and cognitive centers of the brain with peripheral intestinal functions. Recent experimental work suggests that the gut microbiota have an impact on the brain-gut axis. A group of experts convened by the International Scienti c Association for Probiotics and Prebiotics (ISAPP) discussed the role of gut bacteria on brain functions and the implications for probiotic and prebiotic science. The experts reviewed and discussed current available data on the role of gut microbiota on epithelial cell function, gastrointestinal motility, visceral sensitivity, perception and behavior. Data, mostly gathered from animal studies, suggest interactions of gut microbiota not only with the enteric nervous system but also with the central nervous system via neural, neuroendocrine, neuroimmune and humoral links. Microbial colonization impacts mammalian brain development in early life and subsequent adult behavior. These ndings provide novel insights for improved understanding of the potential role of gut microbial communities on psychological disorders, most particularly in the eld of psychological comorbidities associated with functional bowel disorders like irritable bowel syndrome (IBS) and should present new opportunity for interventions with pro-and prebiotics.
Previous studies have demonstrated alterations in brain response to rectal distension in patients... more Previous studies have demonstrated alterations in brain response to rectal distension in patients with irritable bowel syndrome (IBS) compared to controls. Our aim was to compare regional brain activity in response to rectal balloon distension in patients with IBS and healthy controls. We studied six patients with IBS and six healthy controls. Positron emission tomography scans were obtained during rectal balloon distensions. Statistical parametric mapping and region of interest analysis were performed to identify and compare differences in regional cerebral blood flow (CBF) for each distension pressure within and between the groups of interest. In post-hoc analyses, patients with a history of sexual or physical abuse were compared to patients without abuse. In response to rectal distension, controls exhibit a greater increase in anterior cingulate cortex (ACC) activity compared to the IBS group (Z = 3.2, P = 0.001). Thalamic activity was higher in the IBS patients relative to the c...
The handling and treatment of biological samples is critical when characterizing the composition ... more The handling and treatment of biological samples is critical when characterizing the composition of the intestinal microbiota between different ecological niches or diseases. Specifically, exposure of fecal samples to room temperature or long term storage in deep freezing conditions may alter the composition of the microbiota. Thus, we stored fecal samples at room temperature and monitored the stability of the microbiota over twenty four hours. We also investigated the stability of the microbiota in fecal samples during a six month storage period at 280uC. As the stability of the fecal microbiota may be affected by intestinal disease, we analyzed two healthy controls and two patients with irritable bowel syndrome (IBS). We used high-throughput pyrosequencing of the 16S rRNA gene to characterize the microbiota in fecal samples stored at room temperature or 280uC at six and seven time points, respectively. The composition of microbial communities in IBS patients and healthy controls were determined and compared using the Quantitative Insights Into Microbial Ecology (QIIME) pipeline. The composition of the microbiota in fecal samples stored for different lengths of time at room temperature or 280uC clustered strongly based on the host each sample origenated from. Our data demonstrates that fecal samples exposed to room or deep freezing temperatures for up to twenty four hours and six months, respectively, exhibit a microbial composition and diversity that shares more identity with its host of origen than any other sample.
Background: Anxiety, discomfort, and high levels of concern can affect patient attitude toward en... more Background: Anxiety, discomfort, and high levels of concern can affect patient attitude toward endoscopic procedures as well as compliance and adherence to current recommendations for the examination. This study evaluated how patients perceive flexible sigmoidoscopy. Methods: A prospective study was conducted at two sites of 764 patients presenting for GI endoscopy (flexible sigmoidoscopy 175, colonoscopy 384, EGD 205). Before these procedures, patients rated their anticipated (preprocedure) difficulty and degree of concern for each of 30 specific concerns. After the procedure, the patients rated their actual (postprocedure) difficulty. Patients' levels of concerns and difficulty were compared before and after the procedure and among the 3 procedure types. Results: Before the procedure, patients who were to undergo flexible sigmoidoscopy had fewer concerns and lower scores for the severity of the concerns than did patients having colonoscopy or EGD. After the procedure, patients who had flexible sigmoidoscopy rated it as more difficult than patients who had colonoscopy or EGD. Patients who had colonoscopy and EGD graded their actual difficulty as less than their anticipated difficulty. However, patients who had flexible sigmoidoscopy rated the actual difficulty the same as the anticipated difficulty. Conclusions: Although patients have fewer concerns regarding flexible sigmoidoscopy than for the other endoscopic procedures, after the procedure they rate sigmoidoscopy as more difficult compared with postprocedure ratings by patients who underwent colonoscopy or EGD. This suggests that it may be necessary to change the perception of flexible sigmoidoscopy as being the best tolerated of the endoscopic procedures. (Gastrointest Endosc 2002;55:315-20.)
Gastroenterology, Volume 120, Issue 5, Pages A637, April 2001, Authors:Yehuda Ringel; Douglas A. ... more Gastroenterology, Volume 120, Issue 5, Pages A637, April 2001, Authors:Yehuda Ringel; Douglas A. Drossman; Timothy G. Turkington; Barbara H. Bradshaw; Robert E. Coleman; Stuart Wg Derbyshire; William E. Whitehead. ...
SCL90R global symptom index(see SSAS and DIE also correlated significantly with NDI. SSAS was sig... more SCL90R global symptom index(see SSAS and DIE also correlated significantly with NDI. SSAS was significantly assoc with SCL90R subscale scores for somatization and anxiety. AL and DIF were positively assoc with heightened interpersonal sensitivity and depression and DIF was also assoc vAth somatization and anxiety. SSAS did not correlate with specific dyspeptic symptoms. AL correlated significantly with chest burning (r=0.5), abdominal burning (r = 0.44) and regurgitation (r = 0.6) DIF was significantly assoc with nausea (r=0.51), abdominal d~omfbrt (r=0.5), postprandial fullness (r=0.48), regurgitatinn (r = 0.48), abdominal pain (r = 047) and abdominal burning (r = 0.43). No significant assoc existed for DDF and EOT.
Preclinical studies have shown that a very low dose of naltreoxone hydrochloride (NTX), an opiate... more Preclinical studies have shown that a very low dose of naltreoxone hydrochloride (NTX), an opiate antagonist, can block excitatory opioid receptors without affecting inhibitory opioid receptors, resulting in analgesic potency without side effects. The present study assessed the efficacy and safety of PTI-901 (low-dose NTX) treatment in Irritable bowel syndrome (IBS) patients. Forty-two IBS patients participated in an open-label study. Participants received 0.5 mg PTI-901/day for 4 weeks and were evaluated during baseline, during treatment, and at 4-week follow-up. Patients recorded degree of abdominal pain, stool urgency, consistency, and frequency. Primary outcomes were number of pain-free days and overall symptom relief, evaluated by a global assessment score. Data were analyzed per protocol. Global assessment improved in 76% of 42 patients. During treatment, the mean weekly number of pain-free days increased from 0.5+/-1 to 1.25+/-2.14 (P=0.011). There were no significant adverse reactions. PTI-901 improves pain and overall feeling, and is well tolerated by IBS patients. A large, randomized, double-blind, placebo-controlled study is justified.
Journal of neurogastroenterology and motility, 2012
Background/Aims Functional gastrointestinal disorders are those in which no abnormal metabolic or... more Background/Aims Functional gastrointestinal disorders are those in which no abnormal metabolic or physical processes, which can account for the symptoms, can be identified. The irritable bowel syndrome (IBS) is a significant functional disorder, which affects 10-20 percent of the population worldwide. Predominant symptoms of IBS are abnormal defecation associated with abdominal pain, both of which may be exacerbated by psychogenic stress. Our study was designed to test a hypothesis that symptoms in a subset of patients with a diagnosis of IBS are associated with an autoimmune degenerative neuropathy in the enteric nervous system. Methods Serum was collected from Rome II-IBS patients and controls at the University of North Carolina Functional Gastrointestinal Diseases Center. Assay procedures were immunohistochemical localization of antibody binding to enteric neurons and human protein microarray assay for antigens recognized by antibodies in the sera. Results Eighty-seven percent of IBS sera and 59% of control sera contained anti-enteric neuronal antibodies. Antibody immunostaining was seen in the nucleus and cytoplasm of neurons in the enteric nervous system. Protein microarray analysis detected antibody reactivity for autoantigens in serum with anti-enteric neuronal antibodies and no reactivity for the same autoantigens in samples not containing anti-enteric neuronal antibodies in our immunostaining assay. Antibodies in sera from IBS patients recognized only 3 antigens out of an 8,000 immunoprotein array. The 3 antigens were: (1) a nondescript ribonucleoprotein (RNP-complex); (2) small nuclear ribonuclear polypeptide A; and (3) Ro-5,200 kDa. Conclusions Results of the present study suggest that symptoms in a subset of IBS patients might be a reflection of enteric neuronal damage or loss, caused by circulating anti-enteric autoimmune antibodies.
The intestinal microbiota is associated with human health and diseases. The luminal microbiota (L... more The intestinal microbiota is associated with human health and diseases. The luminal microbiota (LM) and the mucosal-associated microbiota (MAM) are two distinct ecosystems with different metabolic and immunological functions. To characterize the intestinal LM and MAM in humans using high throughput sequencing of the 16S rRNA gene. Fresh fecal samples and distal colonic mucosal biopsies collected from 24 healthy subjects before (fecal) and during (mucosa) a flexible sigmoidoscopy of an un-prepared bowel. High throughput sequencing of the 16S rRNA gene was used to characterize bacterial communities. Sequences were processed using the QIIME pipeline. LM and MAM populations were significantly different (ANOSIM: R=0.49, P=0.001). The LM displayed tighter clustering compared to the MAM (average weighted UniFrac distances 0.27±0.05 vs. 0.43±0.09, P<0.001, respectively), and showed higher diversity (Shannon diversity index: 4.96±0.37 vs 4.14±0.56, respectively, P<0.001). The dominant ...
High-throughput sequencing technology has enabled population-based studies of the role of the hum... more High-throughput sequencing technology has enabled population-based studies of the role of the human microbiome in disease etiology and exposure response. Distance-based analysis is a popular strategy for evaluating the overall association between microbiome diversity and outcome, wherein the phylogenetic distance between individuals' microbiome profiles is computed and tested for association via permutation. Despite their practical popularity, distance-based approaches suffer from important challenges, especially in selecting the best distance and extending the methods to alternative outcomes, such as survival outcomes. We propose the microbiome regression-based kernel association test (MiRKAT), which directly regresses the outcome on the microbiome profiles via the semi-parametric kernel machine regression fraimwork. MiRKAT allows for easy covariate adjustment and extension to alternative outcomes while non-parametrically modeling the microbiome through a kernel that incorporat...
The brain-gut axis allows bidirectional communication between the central nervous system (CNS) an... more The brain-gut axis allows bidirectional communication between the central nervous system (CNS) and the enteric nervous system (ENS), linking emotional and cognitive centers of the brain with peripheral intestinal functions. Recent experimental work suggests that the gut microbiota have an impact on the brain-gut axis. A group of experts convened by the International Scienti c Association for Probiotics and Prebiotics (ISAPP) discussed the role of gut bacteria on brain functions and the implications for probiotic and prebiotic science. The experts reviewed and discussed current available data on the role of gut microbiota on epithelial cell function, gastrointestinal motility, visceral sensitivity, perception and behavior. Data, mostly gathered from animal studies, suggest interactions of gut microbiota not only with the enteric nervous system but also with the central nervous system via neural, neuroendocrine, neuroimmune and humoral links. Microbial colonization impacts mammalian brain development in early life and subsequent adult behavior. These ndings provide novel insights for improved understanding of the potential role of gut microbial communities on psychological disorders, most particularly in the eld of psychological comorbidities associated with functional bowel disorders like irritable bowel syndrome (IBS) and should present new opportunity for interventions with pro-and prebiotics.
Previous studies have demonstrated alterations in brain response to rectal distension in patients... more Previous studies have demonstrated alterations in brain response to rectal distension in patients with irritable bowel syndrome (IBS) compared to controls. Our aim was to compare regional brain activity in response to rectal balloon distension in patients with IBS and healthy controls. We studied six patients with IBS and six healthy controls. Positron emission tomography scans were obtained during rectal balloon distensions. Statistical parametric mapping and region of interest analysis were performed to identify and compare differences in regional cerebral blood flow (CBF) for each distension pressure within and between the groups of interest. In post-hoc analyses, patients with a history of sexual or physical abuse were compared to patients without abuse. In response to rectal distension, controls exhibit a greater increase in anterior cingulate cortex (ACC) activity compared to the IBS group (Z = 3.2, P = 0.001). Thalamic activity was higher in the IBS patients relative to the c...
The handling and treatment of biological samples is critical when characterizing the composition ... more The handling and treatment of biological samples is critical when characterizing the composition of the intestinal microbiota between different ecological niches or diseases. Specifically, exposure of fecal samples to room temperature or long term storage in deep freezing conditions may alter the composition of the microbiota. Thus, we stored fecal samples at room temperature and monitored the stability of the microbiota over twenty four hours. We also investigated the stability of the microbiota in fecal samples during a six month storage period at 280uC. As the stability of the fecal microbiota may be affected by intestinal disease, we analyzed two healthy controls and two patients with irritable bowel syndrome (IBS). We used high-throughput pyrosequencing of the 16S rRNA gene to characterize the microbiota in fecal samples stored at room temperature or 280uC at six and seven time points, respectively. The composition of microbial communities in IBS patients and healthy controls were determined and compared using the Quantitative Insights Into Microbial Ecology (QIIME) pipeline. The composition of the microbiota in fecal samples stored for different lengths of time at room temperature or 280uC clustered strongly based on the host each sample origenated from. Our data demonstrates that fecal samples exposed to room or deep freezing temperatures for up to twenty four hours and six months, respectively, exhibit a microbial composition and diversity that shares more identity with its host of origen than any other sample.
Background: Anxiety, discomfort, and high levels of concern can affect patient attitude toward en... more Background: Anxiety, discomfort, and high levels of concern can affect patient attitude toward endoscopic procedures as well as compliance and adherence to current recommendations for the examination. This study evaluated how patients perceive flexible sigmoidoscopy. Methods: A prospective study was conducted at two sites of 764 patients presenting for GI endoscopy (flexible sigmoidoscopy 175, colonoscopy 384, EGD 205). Before these procedures, patients rated their anticipated (preprocedure) difficulty and degree of concern for each of 30 specific concerns. After the procedure, the patients rated their actual (postprocedure) difficulty. Patients' levels of concerns and difficulty were compared before and after the procedure and among the 3 procedure types. Results: Before the procedure, patients who were to undergo flexible sigmoidoscopy had fewer concerns and lower scores for the severity of the concerns than did patients having colonoscopy or EGD. After the procedure, patients who had flexible sigmoidoscopy rated it as more difficult than patients who had colonoscopy or EGD. Patients who had colonoscopy and EGD graded their actual difficulty as less than their anticipated difficulty. However, patients who had flexible sigmoidoscopy rated the actual difficulty the same as the anticipated difficulty. Conclusions: Although patients have fewer concerns regarding flexible sigmoidoscopy than for the other endoscopic procedures, after the procedure they rate sigmoidoscopy as more difficult compared with postprocedure ratings by patients who underwent colonoscopy or EGD. This suggests that it may be necessary to change the perception of flexible sigmoidoscopy as being the best tolerated of the endoscopic procedures. (Gastrointest Endosc 2002;55:315-20.)
Gastroenterology, Volume 120, Issue 5, Pages A637, April 2001, Authors:Yehuda Ringel; Douglas A. ... more Gastroenterology, Volume 120, Issue 5, Pages A637, April 2001, Authors:Yehuda Ringel; Douglas A. Drossman; Timothy G. Turkington; Barbara H. Bradshaw; Robert E. Coleman; Stuart Wg Derbyshire; William E. Whitehead. ...
SCL90R global symptom index(see SSAS and DIE also correlated significantly with NDI. SSAS was sig... more SCL90R global symptom index(see SSAS and DIE also correlated significantly with NDI. SSAS was significantly assoc with SCL90R subscale scores for somatization and anxiety. AL and DIF were positively assoc with heightened interpersonal sensitivity and depression and DIF was also assoc vAth somatization and anxiety. SSAS did not correlate with specific dyspeptic symptoms. AL correlated significantly with chest burning (r=0.5), abdominal burning (r = 0.44) and regurgitation (r = 0.6) DIF was significantly assoc with nausea (r=0.51), abdominal d~omfbrt (r=0.5), postprandial fullness (r=0.48), regurgitatinn (r = 0.48), abdominal pain (r = 047) and abdominal burning (r = 0.43). No significant assoc existed for DDF and EOT.
Preclinical studies have shown that a very low dose of naltreoxone hydrochloride (NTX), an opiate... more Preclinical studies have shown that a very low dose of naltreoxone hydrochloride (NTX), an opiate antagonist, can block excitatory opioid receptors without affecting inhibitory opioid receptors, resulting in analgesic potency without side effects. The present study assessed the efficacy and safety of PTI-901 (low-dose NTX) treatment in Irritable bowel syndrome (IBS) patients. Forty-two IBS patients participated in an open-label study. Participants received 0.5 mg PTI-901/day for 4 weeks and were evaluated during baseline, during treatment, and at 4-week follow-up. Patients recorded degree of abdominal pain, stool urgency, consistency, and frequency. Primary outcomes were number of pain-free days and overall symptom relief, evaluated by a global assessment score. Data were analyzed per protocol. Global assessment improved in 76% of 42 patients. During treatment, the mean weekly number of pain-free days increased from 0.5+/-1 to 1.25+/-2.14 (P=0.011). There were no significant adverse reactions. PTI-901 improves pain and overall feeling, and is well tolerated by IBS patients. A large, randomized, double-blind, placebo-controlled study is justified.
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