Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Irritable Bowel Syndrome: HELP
Articles by Alan R. Zinsmeister
Based on 34 articles published since 2010
(Why 34 articles?)
||||

Between 2010 and 2020, A. R. Zinsmeister wrote the following 34 articles about Irritable Bowel Syndrome.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Article Randomised clinical trial: pregabalin vs placebo for irritable bowel syndrome. 2019

Saito, Yuri A / Almazar, Ann E / Tilkes, Katherine E / Choung, Rok Seon / Van Norstrand, Michael D / Schleck, Cathy D / Zinsmeister, Alan R / Talley, Nicholas J. ·Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. · Division of Gastroenterology, Mayo Clinic Health System, LaCrosse, Wisconsin. · Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota. · Faculty of Health and Medicine, University of Newcastle, New Lambton, North South Wales, Australia. ·Aliment Pharmacol Ther · Pubmed #30663077.

ABSTRACT: BACKGROUND: Pregabalin is a calcium channel α2δ ligand that modifies visceral hypersensitivity in IBS patients. Clinical data for pregabalin in IBS are lacking. AIM: To test the efficacy of pregabalin on gastrointestinal symptoms in IBS patients. METHODS: A double-blind, placebo-controlled trial was performed. Adults meeting IBS Rome III criteria with ≥3 pain attacks per month were randomised to pregabalin 225 mg vs placebo twice daily for 12 weeks. Questionnaires were completed weekly. The primary endpoint was average pain Bowel Symptom Scale (BSS) scores weeks 9-12. An intention-to-treat analysis of covariance evaluated treatment effects on quantitative endpoints, adjusting for age and gender. Adequate relief and change in pain score were assessed using a chi-squared test. RESULTS: Eighty-five patients were recruited and randomised. Sample characteristics include: mean age 39.4 (SD = 14.6); 73 (86%) female; 37 (44%) IBS-D, 29 (35%) IBS-M, 18 (21%) IBS-C. The pregabalin arm had lower average pain-BSS scores weeks 9-12 (25 vs 42, P = 0.008). Compared with placebo, the overall IBS BSS severity score was lower in the pregabalin arm (26 vs 42, P = 0.009). Differences were observed for the diarrhoea-BSS and bloating-BSS scores (P = 0.049 and 0.016, respectively). No differences between groups were seen for constipation-BSS scores. Adequate relief was not different between the two arms (46% vs 36%, P = 0.35). 63% pregabalin vs 45% placebo had a change in pain score ≥30 at week 12 from baseline (P = 0.10). Post-treatment IBS-QoL scores did not differ between groups. CONCLUSION: This trial suggests that pregabalin may be beneficial for IBS abdominal pain, bloating and diarrhoea.

2 Article Identification and validation of functional gastrointestinal disorder subtypes using latent class analysis: a population-based study. 2018

Zinsmeister, Alan R / Herrick, Linda M / Saito Loftus, Yuri A / Schleck, Cathy D / Talley, Nicholas J. ·a Division of Biomedical Statistics and Informatics , Mayo Clinic , Rochester , MN , USA. · b Division of Gastroenterology and Hepatology , Mayo Clinic , Rochester , MN , USA. · c Faculty of Health , Newcastle University , Callaghan , Australia. ·Scand J Gastroenterol · Pubmed #29103329.

ABSTRACT: OBJECTIVE: Attempts to categorize distinct functional gastrointestinal disorders based on reported symptoms continue but symptoms frequently overlap. The study objective was to use latent class analysis (LCA) which accommodates both continuous and discrete manifest variables to determine mutually exclusive subgroup assignments of a population-based sample using gastrointestinal symptom and patient data. MATERIALS AND METHODS: A validated bowel disease questionnaire and somatic symptom questionnaire were mailed to an age and gender stratified randomly selected community sample. Responses to the symptom questions were dichotomized as frequent vs. infrequent based on Rome IV criteria. A LCA model was developed using a calibration subset and the results applied to the validation subset. RESULTS: There were 3831 total respondents (48%) with 3425 having complete data. The LCA algorithm was run for each of 10 (random) splits of the dataset and 2-6 latent classes were specified. Using the values of Akaike's Information Criterion coefficient c to determine fit of the data, 4 latent classes yielded better values resulting in four subgroups: 'asymptomatic,' 'upper' abdominal symptoms, 'lower' abdominal symptoms, and 'mixed' (upper and lower abdomen). CONCLUSIONS: Latent class analysis identified 4 groups based on symptoms. This approach resulted in differentiation by anatomical region rather than the Rome IV classification of symptoms.

3 Article Colonic Transit and Bile Acid Synthesis or Excretion in Patients With Irritable Bowel Syndrome-Diarrhea Without Bile Acid Malabsorption. 2017

Peleman, Cédric / Camilleri, Michael / Busciglio, Irene / Burton, Duane / Donato, Leslie / Zinsmeister, Alan R. ·Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota. · Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota. Electronic address: camilleri.michael@mayo.edu. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. · Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota. ·Clin Gastroenterol Hepatol · Pubmed #27856362.

ABSTRACT: BACKGROUND AND AIMS: Bile acids (BAs) are passively absorbed to a different extent along the mammalian colon, so that levels are lower in the feces than in proximal colon. Our aim was to explore associations among total, primary, and secretory BA in stool and colonic transit in patients with irritable bowel syndrome-diarrhea (IBS-D) without overt BA malabsorption (BAM). METHODS: In a cross-sectional observational study of 116 patients with IBS-D recruited from local communities in Minnesota, we measured total and individual main fecal BA excretion, fecal fat and fecal weight over 48 hours, fasting serum levels of C4 (surrogate for BA synthesis), and overall colonic transit by scintigraphy (geometric center at 24 hours and 48 hours). Patients without overt BAM were assigned to groups based on total fecal BA level below 2337 μmol/48 hours (n = 86) or serum levels of C4 below 47.1 ng/mL (n = 91). We used Spearman correlations to test study hypotheses with correction for 14 correlations tested (P < .0036). Data from 30 healthy volunteers were used as control subjects. RESULTS: Patients with IBS-D who had increased or normal total BA excretion in stool or BA synthesis had higher stool proportions of primary BAs (especially chenodeoxycholate), compared with healthy control subjects. In patients with IBS-D without overt BAM (normal 48-hour total fecal BA or serum C4), there were significant positive correlations between total fecal BA, fecal primary and secretory BA, fecal weight, and increased geometric center at 24 and 48 hours (P < .0036). Normal and slightly increased levels of total fecal BA have greatest effects on colonic transit at 48 hours. CONCLUSIONS: In the absence of overt BAM, the total, primary, and secretory BAs in stool contribute to the acceleration of colonic transit and fecal weight in the diarrhea of patients with IBS-D.

4 Article The incidence rate and characteristics of clinically diagnosed defecatory disorders in the community. 2016

Noelting, J / Eaton, J E / Choung, R S / Zinsmeister, A R / Locke, G R / Bharucha, A E. ·Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA. · Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. · Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA. bharucha.adil@mayo.edu. ·Neurogastroenterol Motil · Pubmed #27254309.

ABSTRACT: BACKGROUND: Defecatory disorders (DD) are defined by clinical and objective features of impaired rectal evacuation. The epidemiology of DD in the population is unknown, partly because many constipated patients do not undergo anorectal tests. Our objectives were to estimate the incidence rate and clinical features of DD in the community. METHODS: We reviewed the medical records of all patients older than 16 years in Olmsted County, MN, who had constipation and underwent anorectal manometry from 1999 through 2008. Criteria for diagnosing DD were constipation for 6 months or longer and one of the following: (i) abnormal rectal balloon expulsion test; (ii) reduced or increased perineal descent; or (iii) two or more abnormal features with defecography or surface electromyography. KEY RESULTS: Of 11 112 constipated patients, 516 had undergone anorectal tests; 245 of these (209 women, 36 men) had a DD. The mean (±SD) age at diagnosis was 44 years (±18) among women and 49 years (±19) among men. The overall age- and sex-adjusted incidence rate per 100 000 person-years was 19.3 (95% CI: 16.8-21.8). The age-adjusted incidence per 100 000 person-years was greater (p < 0.0001) in women (31.8, 95% CI: 27.4-36.1) than in men (6.6, 95% CI: 4.4-8.9). Prior to the diagnosis of DD, nearly 30% of patients had irritable bowel syndrome (IBS), 48% had a psychiatric diagnosis, 18% had a history of abuse, and 21% reported urinary and/or fecal incontinence. CONCLUSIONS & INFERENCES: Among constipated patients, DD are fourfold more common in women than men and often associated with IBS and psychiatric diagnoses.

5 Article Irritable bowel syndrome and the perinatal period: lower birth weight increases the risk. 2016

Raslau, D / Herrick, L M / Locke, G R / Schleck, C D / Zinsmeister, A R / Almazar, A / Talley, N J / Saito, Y A. ·Department of Medicine, Mayo Clinic, Rochester, MN, USA. · Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. · College of Nursing, South Dakota State University, Brookings, SD, USA. · Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA. · University of Newcastle, Callaghan, NSW, Australia. · Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. saito.yuri@mayo.edu. ·Neurogastroenterol Motil · Pubmed #27193962.

ABSTRACT: BACKGROUND: Early life events have been found to be associated with irritable bowel syndrome (IBS) suggesting a role in development of functional disorders. The study aim was to identify potential perinatal risk factors for adult IBS. METHODS: Utilizing a population-based nested case-control design, cases who met modified Rome III criteria for IBS and age- and-gender matched controls were identified using responses from prior mailed surveys to a random sample of Olmsted County residents. Medical records of eligible respondents were reviewed for perinatal events of interest. The association of early life events with subsequent case status was assessed using conditional logistic regression. KEY RESULTS: Of 3 417 respondents, 513 were born in Olmsted County and 108 met criteria for IBS. Due to missing records, 89 pairs were included in the final analyses. Logistic regression revealed only birth weight as a predictor of IBS. Lower birth weight increased the odds for IBS (OR = 1.54 [95% CI = (1.12, 2.08), p = 0.008]). Median birth weight was 3.35 kg (range: 1.96-5.24) and 3.57 kg (range: 2.18-4.59) for cases and controls, respectively. Maternal age, delivery method, and antibiotic exposure were not associated with IBS status but this study was only powered to detect large odds ratios. CONCLUSIONS AND INFERENCES: Lower birth weight was observed as a risk factor for IBS. It is not clear if in utero developmental delays directly lead to IBS or if low birth weight is a prospective marker for subsequent early life problems leading to IBS.

6 Article Non-enteric infections, antibiotic use, and risk of development of functional gastrointestinal disorders. 2015

Paula, H / Grover, M / Halder, S L / Locke, G R / Schleck, C D / Zinsmeister, A R / Talley, N J. ·Medizinisch-Diagnostische Laboratorium West OG, Vienna, Austria. · Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. · Division of Gastroenterology, McMaster University, Hamilton, ON, Canada. · Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA. · Faculty of Health and Medicine, University of Newcastle, New Lambton, NSW, Australia. ·Neurogastroenterol Motil · Pubmed #26303310.

ABSTRACT: BACKGROUND: Gastrointestinal infections are risk factors for irritable bowel syndrome (IBS) and functional dyspepsia (FD). We investigated whether non-enteric infections and antibiotic exposure are also associated with the development of functional gastrointestinal disorders (FGIDs). METHODS: In a nested case-control study, random samples of Olmsted County, MN, were mailed valid self-report questionnaires from 1988 through 1994, and then follow-up questionnaires from 1995 through 2003. Survey responders who did not report any FGID symptoms at baseline, but then reported such symptoms in at least one subsequent survey, were classified as new-onset cases. Age-matched controls were individuals who did not have symptoms at either the initial or subsequent surveys. KEY RESULTS: The overall response rate was 78% to the initial survey and 52% to the follow-up survey. Based on the responses, 316 participants had a new onset of an FGID (43 IBS constipation, 95 IBS diarrhea, 25 IBS mixed, and 153 other FGIDs, including FD) and 250 did not (controls). Around 76% (241/316) of cases reported a non-enteric infection vs 66% (166/250) of the controls. The frequency of enteric infections was similar between the two groups. Of the new FGID cases, 83% had a non-enteric infection that was treated with antibiotic. In a logistic regression model, treatment with antibiotics for a non-gastrointestinal infection was associated with the development of an FGID (odds ratio = 1.90; 95% CI: 1.21-2.98; p = 0.005), after adjusting for age and sex. CONCLUSIONS & INFERENCES: Based on a case-control study, treatment of a non-gastrointestinal infection with antibiotics appears to be a risk factor for development of an FGID.

7 Article Effects of Birth Cohorts on the Irritable Bowel Syndrome Support Early-Life Risk Factors. 2015

Brummond, Neil R / Locke, G Richard / Choung, Rok Seon / Chang, Joseph Y / Schleck, Cathy D / Zinsmeister, Alan R / Talley, Nicholas J. ·Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA. ·Dig Dis Sci · Pubmed #25680871.

ABSTRACT: BACKGROUND: Irritable bowel syndrome (IBS) is common with prevalence reported between 10 and 20 %. IBS clusters in families but it is unknown whether this is explained by a common environment, genes, or both. If early-life factors are important, IBS might be expected to demonstrate a birth cohort phenomenon. AIM: To investigate whether there is a birth cohort phenomenon for subjects with IBS. METHODS: Validated questionnaires were sent to a random sample of Olmsted County, Minnesota, residents who recorded gastrointestinal symptoms; IBS diagnosis was based on the modified Rome criteria. Birth cohorts were chosen a priori based on historical national trends in birth weights using 10-year increments. Logistic regression was used to develop odds ratios to assess the association of IBS with calendar period, birth cohort, age, gender, and somatic symptom score. RESULTS: A total of 4,893 surveys were completed with an overall survey response rate of 58 %. The survey responders were between 25 and 94 years of age and 53 % were female. The overall prevalence of IBS was 16.2 % (95 % CI 15.3-17.4). The univariate association of IBS with birth cohort was significant (p < 0.001) as was the association adjusted for age and gender. The prevalence of IBS was highest for the birth cohort 1963-1972 with an odds ratio of 2.6 (95 % CI 0.97-7.0, p = 0.058). CONCLUSIONS: Population-based data support a possible birth cohort phenomenon in IBS. If correct, early-life risk factors likely play a key role in the development of IBS.

8 Article Effect of colesevelam on faecal bile acids and bowel functions in diarrhoea-predominant irritable bowel syndrome. 2015

Camilleri, M / Acosta, A / Busciglio, I / Boldingh, A / Dyer, R B / Zinsmeister, A R / Lueke, A / Gray, A / Donato, L J. ·Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. ·Aliment Pharmacol Ther · Pubmed #25594801.

ABSTRACT: BACKGROUND: About one-third of patients with IBS-diarrhoea (irritable bowel syndrome-D) have evidence of increased bile acid synthesis or excretion. AIMS: To assess effects of the bile acid sequestrant, colesevelam, on faecal excretion of BAs, hepatic BA synthesis and diarrhoea in IBS-D; to appraise whether individual or random stool samples accurately reflect 48-h total faecal bile acid excretion and proportions of the main bile acids excreted and to study the faecal fat excretion in response to colesevelam. METHODS: A single-centre, unblinded, single-dose trial of effects of colesevelam, 1875 mg [3 tablets (625 mg tablets)] orally, twice daily, for 10 days on total 48-h faecal bile acid excretion and fasting serum C4 (7α-hydroxy-4-cholesten-3-one; surrogate of hepatic bile acid synthesis). Stool diaries documented bowel functions for 8 days prior and 8 days during colesevelam treatment. Stool 48-h samples and fasting serum were collected for faecal fat, faecal bile acid and serum C4. RESULTS: Colesevelam was associated with significantly increased faecal total bile acid excretion and deoxycholic acid excretion, increased serum C4 and more solid stool consistency. There was a significant inverse correlation between number of bowel movements per week and the total bile acid sequestered into stool during the last 48 h of treatment. Random stool samples did not accurately reflect 48-h total or individual faecal bile acid excretion. Sequestration of bile acids by colesevelam did not increase faecal fat. CONCLUSIONS: Colesevelam increases delivery of bile acids to stool while improving stool consistency, and increases hepatic bile acid synthesis, avoiding steatorrhoea in patients with IBS-D. Overall effects are consistent with luminal bile acid sequestration by colesevelam.

9 Article Family history of mental illness or alcohol abuse and the irritable bowel syndrome. 2015

Knight, James R / Locke, G Richard / Zinsmeister, Alan R / Schleck, Cathy D / Talley, Nicholas J. ·Division of Hospital Medicine, Department of Internal Medicine and Pediatrics, The Ohio State University Medical Center, Columbus, OH, USA. · Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. · Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA. · Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA; Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW, Australia. Electronic address: nicholas.talley@newcastle.edu.au. ·J Psychosom Res · Pubmed #25582802.

ABSTRACT: OBJECTIVE: We have observed that many patients with IBS drink very little alcohol and postulated that this may reflect membership in families affected by alcoholism and mental illness. We aimed to evaluate whether a family history of substance or alcohol abuse, or psychiatric illness, is associated with IBS. METHODS: A valid GI questionnaire was mailed to a randomly selected population-based cohort to identify IBS and healthy controls. The electronic medical record was reviewed to record the subjects' self-reported personal and family health histories. RESULTS: A total of 2300 subjects responded (response rate 55%; IBS 13%, n=287); 230 subjects with IBS and 318 controls were eligible. Family history of alcohol/substance abuse was reported by 33% of cases and 25% of controls (OR=1.4, 95% CI=1.0-2.1, p=0.06). Family history of psychiatric illness was reported by 37% of cases and 22% of controls (OR=2.0, 95% CI=1.3-2.9, p<0.001). In the absence of a personal history of alcohol use, a family history of alcohol/substance abuse was predictive of IBS status (OR adjusted for age and gender=1.5, 95% CI=1.0-2.3, p=0.05). In the absence of a personal history of alcohol use, reporting both a family history of alcohol/substance abuse and anxiety/depression/mental illness was clearly predictive of IBS status (OR=2.5, 95% CI=1.4-4.5; p<0.005). Substance abuse as a child was associated with an increased risk of IBS (OR=2.3, 95% CI=1.1-4.8; p<0.03). CONCLUSION: IBS is independently associated with a family history of psychiatric illness and may be linked to a family history of alcohol/substance abuse.

10 Article Validating biomarkers of treatable mechanisms in irritable bowel syndrome. 2014

Camilleri, M / Shin, A / Busciglio, I / Carlson, P / Acosta, A / Bharucha, A E / Burton, D / Lamsam, J / Lueke, A / Donato, L J / Zinsmeister, A R. ·Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic College of Medicine, Rochester, MN, USA. ·Neurogastroenterol Motil · Pubmed #25244349.

ABSTRACT: BACKGROUND: A valid biomarker is 'an indicator of normal biologic or pathogenic processes, or pharmacological responses to a therapeutic intervention'. There is no validated biomarker for irritable bowel syndrome (IBS). The aim of the study was to assess ability of three quantitative traits to identify treatable processes to discriminate between IBS-diarrhea (IBS-D) patients, IBS-constipation (IBS-C) patients and healthy volunteers (HV). METHODS: In 30 HV, 30 IBS-C patients and 64 IBS-D patients, we characterized bowel symptoms and quantitated pathophysiological mechanisms: bile acid (BA) synthesis (serum C4 and FGF19), fecal BA and fat, colonic transit (CT), and intestinal permeability (IP). We used multiple logistic regression and receiver-operating characteristic (ROCAUC ) to appraise three factors (fecal BA, CT, and IP) individually and in combination to identify discriminant targets for treatment in IBS. KEY RESULTS: There were significant associations between the three subgroups and symptoms reflecting bowel function and the quantitative traits. There were significant associations between fecal BA and CT at 48 h (r = 0.43; p < 0.001) and between fecal BA and IP (r = 0.23; p = 0.015). Individually, fecal BA and CT48 (but not IP) were significant independent predictors for distinguishing HV from IBS. In combination, they discriminated HV from IBS-D patients (ROCAUC 0.70), HV from IBS-C patients (ROCAUC 0.73), and IBS-C patients from IBS-D patients (ROCAUC 0.86). Colonic transit and fecal BA excretion together discriminate between healthy volunteers and IBS-C patients or IBS-D patients, or between the IBS subgroups with 75-90% specificity at 60% sensitivity. CONCLUSIONS & INFERENCES: Colonic transit and fecal BA individually and together constitute useful biomarkers to identify treatable mechanisms in IBS and to differentiate subgroups of IBS.

11 Article Effect of increased bile acid synthesis or fecal excretion in irritable bowel syndrome-diarrhea. 2014

Camilleri, Michael / Busciglio, Irene / Acosta, Andres / Shin, Andrea / Carlson, Paula / Burton, Duane / Ryks, Michael / Rhoten, Deborah / Lamsam, Jesse / Lueke, Alan / Donato, Leslie J / Zinsmeister, Alan R. ·Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic College of Medicine, Rochester, Minnesota, USA. · Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. · Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. ·Am J Gastroenterol · Pubmed #25070056.

ABSTRACT: OBJECTIVES: Approximately 25% of patients with irritable bowel syndrome-diarrhea (IBS-D) have increased total fecal bile acids (BA) and serum C4 (surrogate for BA synthesis). BA synthesis-related genes (KLB and FGFR4) are associated with colonic transit (CT) in IBS-D. Our aims were: (i) to compare phenotype and pathophysiology in IBS-D patients with increased or normal fecal excretion or synthesis of BA; and (ii) to explore association of variations in two candidate bile-acid synthesis genes (KLB and FGFR4) in these two subgroups of IBS-D. METHODS: A total of 64 IBS-D patients underwent on one occasion: fasting serum C4 and FGF19, total fecal fat and BA excretion, CT, intestinal and colonic permeability, and candidate genotyping (rs17618244 (KLB), rs351855 (FGFR4)). Colonic sensation and tone were measured in 47 of the IBS-D patients. IBS-D subgroups were identified by fecal BA >2,337 mM per 48 h or by serum C4 >47.1 ng/ml. RESULTS: IBS-D patients with fecal BA >2,337 mM per 48 h (19/54) had significantly greater body mass index, fecal fat, percent chenodeoxycholic acid (CDCA) in feces, and intestinal permeability, and borderline increased CT (P=0.13). Those IBS-D patients with serum C4 >47.1 ng/ml (13/54) had increased total fecal BA excretion and borderline increased colonic permeability. Variants in genes involved in feedback regulation of BA synthesis (KLB, P=0.06 and FGFR4, P=0.09) were potentially associated with the subgroup with elevated serum C4. CONCLUSIONS: IBS-D with increased BA excretion or synthesis is associated with significant pathophysiological changes relative to patients with normal BA profile. BA diarrhea is identified more effectively with total fecal BA than with serum C4.

12 Article Genetic variation in GPBAR1 predisposes to quantitative changes in colonic transit and bile acid excretion. 2014

Camilleri, Michael / Shin, Andrea / Busciglio, Irene / Carlson, Paula / Acosta, Andres / Bharucha, Adil E / Burton, Duane / Lamsam, Jesse / Lueke, Alan / Donato, Leslie J / Zinsmeister, Alan R. ·Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic College of Medicine, Rochester, Minnesota; camilleri.michael@mayo.edu. · Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic College of Medicine, Rochester, Minnesota; · Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota; and. · Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota. ·Am J Physiol Gastrointest Liver Physiol · Pubmed #25012842.

ABSTRACT: The pathobiology of irritable bowel syndrome (IBS) is multifaceted. We aimed to identify candidate genes predisposing to quantitative traits in IBS. In 30 healthy volunteers, 30 IBS-constipation, and 64 IBS-diarrhea patients, we measured bowel symptoms, bile acid (BA) synthesis (serum 7α-hydroxy-4-cholesten-3-one and FGF19), fecal BA and fat, colonic transit (CT by scintigraphy), and intestinal permeability (IP by 2-sugar excretion). We assessed associations of candidate genes controlling BA metabolism (KLB rs17618244 and FGFR4 rs351855), BA receptor (GPBAR1 rs11554825), serotonin (5-HT) reuptake (SLC6A4 through rs4795541 which encodes for the 44-bp insert in 5HTTLPR), or immune activation (TNFSF15 rs4263839) with three primary quantitative traits of interest: colonic transit, BA synthesis, and fecal BA excretion. There were significant associations between fecal BA and CT at 48 h (r = 0.43; P < 0.001) and IP (r = 0.23; P = 0.015). GPBAR1 genotype was associated with CT48 (P = 0.003) and total fecal BA [P = 0.030, false detection rate (FDR) P = 0.033]. Faster CT48 observed with both CC and TT GPBAR1 genotypes was due to significant interaction with G allele of KLB, which increases BA synthesis and excretion. Other univariate associations (P < 0.05, without FDR correction) observed between GPBAR1 and symptom phenotype and gas sensation ratings support the role of GPBAR1 receptor. Associations between SLC6A4 and stool consistency, ease of passage, postprandial colonic tone, and total fecal BA excretion provide data in support of future hypothesis-testing studies. Genetic control of GPBAR1 receptor predisposing to pathobiological mechanisms in IBS provides evidence from humans in support of the importance of GPBAR1 to colonic motor and secretory functions demonstrated in animal studies.

13 Article Irritable bowel syndrome-diarrhea: characterization of genotype by exome sequencing, and phenotypes of bile acid synthesis and colonic transit. 2014

Camilleri, Michael / Klee, Eric W / Shin, Andrea / Carlson, Paula / Li, Ying / Grover, Madhusudan / Zinsmeister, Alan R. ·Mayo Clinic, Charlton 8-110, 200 First St. S.W., Rochester, MN 55905. camilleri.michael@mayo.edu. ·Am J Physiol Gastrointest Liver Physiol · Pubmed #24200957.

ABSTRACT: The study objectives were: to mine the complete exome to identify putative rare single nucleotide variants (SNVs) associated with irritable bowel syndrome (IBS)-diarrhea (IBS-D) phenotype, to assess genes that regulate bile acids in IBS-D, and to explore univariate associations of SNVs with symptom phenotype and quantitative traits in an independent IBS cohort. Using principal components analysis, we identified two groups of IBS-D (n = 16) with increased fecal bile acids: rapid colonic transit or high bile acids synthesis. DNA was sequenced in depth, analyzing SNVs in bile acid genes (ASBT, FXR, OSTα/β, FGF19, FGFR4, KLB, SHP, CYP7A1, LRH-1, and FABP6). Exome findings were compared with those of 50 similar ethnicity controls. We assessed univariate associations of each SNV with quantitative traits and a principal components analysis and associations between SNVs in KLB and FGFR4 and symptom phenotype in 405 IBS, 228 controls and colonic transit in 70 IBS-D, 71 IBS-constipation. Mining the complete exome did not reveal significant associations with IBS-D over controls. There were 54 SNVs in 10 of 11 bile acid-regulating genes, with no SNVs in FGF19; 15 nonsynonymous SNVs were identified in similar proportions of IBS-D and controls. Variations in KLB (rs1015450, downstream) and FGFR4 [rs434434 (intronic), rs1966265, and rs351855 (nonsynonymous)] were associated with colonic transit (rs1966265; P = 0.043), fecal bile acids (rs1015450; P = 0.064), and principal components analysis groups (all 3 FGFR4 SNVs; P < 0.05). In the 633-person cohort, FGFR4 rs434434 was associated with symptom phenotype (P = 0.027) and rs1966265 with 24-h colonic transit (P = 0.066). Thus exome sequencing identified additional variants in KLB and FGFR4 associated with bile acids or colonic transit in IBS-D.

14 Article Pilot trial: pregabalin on colonic sensorimotor functions in irritable bowel syndrome. 2014

Iturrino, Johanna / Camilleri, Michael / Busciglio, Irene / Burton, Duane / Zinsmeister, Alan R. ·Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), College of Medicine, Mayo Clinic, Rochester, MN, United States; Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, MN, United States. · Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), College of Medicine, Mayo Clinic, Rochester, MN, United States; Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, MN, United States. Electronic address: camilleri.michael@mayo.edu. · Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, College of Medicine, Mayo Clinic, Rochester, MN, United States. ·Dig Liver Dis · Pubmed #24095618.

ABSTRACT: BACKGROUND: In prior studies, pregabalin reduced rectal or colonic pain in patients with irritable bowel syndrome and healthy adults, suggesting reduction of afferent function. AIM: To assess effects of pregabalin on colonic compliance, sensory and motor functions in patients with constipation-predominant irritable bowel syndrome. METHODS: In a pilot, double-blind, placebo-controlled, parallel-group study, we tested oral pregabalin, 200mg, in 18 patients with constipation-predominant irritable bowel syndrome. With a barostatically controlled polyethylene balloon in the left colon, we assessed sensation thresholds and colonic compliance using ascending method of limits, sensation ratings over 4 levels of distension, fasting and postprandial colonic tone and phasic motility. Analysis of covariance (adjusted for the corresponding pre-drug response) was used to compare placebo and pregabalin. After 45% participants completed studies, we conducted an interim analysis to assess the conditional power to detect pre-specified treatment effects given the observed variation and treatment group differences based on the planned sample size for the trial. RESULTS: Pregabalin did not significantly affect colonic compliance, sensation thresholds, sensation ratings, fasting or postprandial tone or motility index. The study was stopped for futility to detect an effect on visceral pain with the planned design and sample size. CONCLUSION: Pregabalin, 200mg, might not reduce distension-related colonic pain in constipation-predominant irritable bowel syndrome patients.

15 Article Bowel functions, fecal unconjugated primary and secondary bile acids, and colonic transit in patients with irritable bowel syndrome. 2013

Shin, Andrea / Camilleri, Michael / Vijayvargiya, Priya / Busciglio, Irene / Burton, Duane / Ryks, Michael / Rhoten, Deborah / Lueke, Alan / Saenger, Amy / Girtman, Adam / Zinsmeister, Alan R. ·Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), College of Medicine, Mayo Clinic, Rochester, Minnesota. ·Clin Gastroenterol Hepatol · Pubmed #23639599.

ABSTRACT: BACKGROUND & AIMS: There is an unclear relationship among bowel symptoms, excretion of unconjugated fecal bile acid (UBA), and colonic transit in irritable bowel syndrome (IBS). We measured total and main individual UBA in fecal samples of patients with IBS and assessed relationships among stool frequency or consistency, fecal UBA (total and individual), and colonic transit. METHODS: In this study 30 healthy volunteers (controls), 31 subjects with IBS with diarrhea (IBS-D), and 30 with IBS with constipation (IBS-C) were placed on 4-day diets containing 100 g fat; we measured stool characteristics, total fecal UBA and fat levels, and overall colonic transit. We assessed univariate associations of total and individual levels of fecal UBA with phenotype (controls, IBS-D, IBS-C) by using the Kruskal-Wallis test; associations between end points were assessed by using Spearman correlations. With response surface regression models, we assessed relationships between stool, colonic transit, and fecal total and secretory UBA. RESULTS: There was a significant association between total fecal UBA and phenotype (P = .029); the association was greater for IBS-D than IBS-C, compared with controls. Fecal levels of primary UBAs (cholic and chenodeoxycholic acids) were higher in subjects with IBS-D, compared with controls (both P < .01). Levels of fecal secretory UBAs (chenodeoxycholic acid, P = .019; deoxycholic acid, P = .025) were lower in subjects with IBS-C compared with controls, whereas levels of the nonsecretory UBA, lithocholic acid, were higher (P = .020). There were significant univariate associations between stool number and form and total fecal UBA (including percentages of lithocholic acid, chenodeoxycholic acid and cholic acid), fecal fat, and colonic transit at 24 and 48 hours after eating. In the regression models, the relative contribution of colonic transit was consistently greater and largely independent of the contribution of bile acids. CONCLUSIONS: Measurements of individual UBAs identify changes associated with stool characteristics in patients with IBS; these effects are independent of the effects of colonic transit.

16 Article A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. 2013

Vazquez-Roque, Maria I / Camilleri, Michael / Smyrk, Thomas / Murray, Joseph A / Marietta, Eric / O'Neill, Jessica / Carlson, Paula / Lamsam, Jesse / Janzow, Denise / Eckert, Deborah / Burton, Duane / Zinsmeister, Alan R. ·Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, MN 55905, USA. ·Gastroenterology · Pubmed #23357715.

ABSTRACT: BACKGROUND & AIMS: Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) could benefit from a gluten-free diet (GFD). METHODS: We performed a randomized controlled 4-week trial of a gluten-containing diet (GCD) or GFD in 45 patients with IBS-D; genotype analysis was performed for HLA-DQ2 and HLA-DQ8. Twenty-two patients were placed on the GCD (11 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive) and 23 patients were placed on the GFD (12 HLA-DQ2/8 negative and 11 HLA-DQ2/8 positive). We measured bowel function daily, small-bowel (SB) and colonic transit, mucosal permeability (by lactulose and mannitol excretion), and cytokine production by peripheral blood mononuclear cells after exposure to gluten and rice. We collected rectosigmoid biopsy specimens from 28 patients, analyzed levels of messenger RNAs encoding tight junction proteins, and performed H&E staining and immunohistochemical analyses. Analysis of covariance models was used to compare data from the GCD and GFD groups. RESULTS: Subjects on the GCD had more bowel movements per day (P = .04); the GCD had a greater effect on bowel movements per day of HLA-DQ2/8-positive than HLA-DQ2/8-negative patients (P = .019). The GCD was associated with higher SB permeability (based on 0-2 h levels of mannitol and the lactulose:mannitol ratio); SB permeability was greater in HLA-DQ2/8-positive than HLA-DQ2/8-negative patients (P = .018). No significant differences in colonic permeability were observed. Patients on the GCD had a small decrease in expression of zonula occludens 1 in SB mucosa and significant decreases in expression of zonula occludens 1, claudin-1, and occludin in rectosigmoid mucosa; the effects of the GCD on expression were significantly greater in HLA-DQ2/8-positive patients. The GCD vs the GFD had no significant effects on transit or histology. Peripheral blood mononuclear cells produced higher levels of interleukin-10, granulocyte colony-stimulating factor, and transforming growth factor-α in response to gluten than rice (unrelated to HLA genotype). CONCLUSIONS: Gluten alters bowel barrier functions in patients with IBS-D, particularly in HLA-DQ2/8-positive patients. These findings reveal a reversible mechanism for the disorder. Clinical trials.govNCT01094041.

17 Article Cannabinoid receptor 1 gene and irritable bowel syndrome: phenotype and quantitative traits. 2013

Camilleri, Michael / Kolar, Gururaj J / Vazquez-Roque, Maria I / Carlson, Paula / Burton, Duane D / Zinsmeister, Alan R. ·Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, MN 55905, USA. camilleri.michael@mayo.edu ·Am J Physiol Gastrointest Liver Physiol · Pubmed #23306084.

ABSTRACT: Genetic variations in metabolism of endocannabinoids and in CNR1 (gene for cannabinoid 1 receptor) are associated with symptom phenotype, colonic transit, and left colon motility in irritable bowel syndrome (IBS). Our aim was to evaluate associations between two variations in CNR1 genotype (rs806378 and [AAT]n triplets) with symptom phenotype, small bowel and colonic transit, and rectal sensations in 455 patients with IBS and 228 healthy controls. Small bowel and colonic transit were measured by scintigraphy, rectal sensation by isobaric distensions. Associations with genotype were assessed by χ(2) test (symptom phenotype) and ANCOVA (quantitative traits) based on a dominant genetic model. Significant association of CNR1 rs806378 (but not CNR1 [AAT]n) genotype and symptom phenotype was observed (χ(2) P = 0.028). There was significant association of CNR1 rs806378 (P = 0.014; CC vs. CT/TT) with colonic transit in IBS-diarrhea (IBS-D) group; the TT group had the fastest colonic transit at 24 and 48 h. There was significant overall association of CNR1 rs806378 with sensation rating of gas (P = 0.025), but not pain; the strongest associations for gas ratings were in IBS-D (P = 0.002) and IBS-alternating (P = 0.025) subgroups. For CNR1 (AAT)n, gene-by-phenotype interactions were observed for colonic transit at 24 (P = 0.06) and 48 h (P = 0.002) and gas (P = 0.046, highest for IBS-D, P = 0.034), but not pain sensation; the strongest association with transit was in controls, not in IBS. These data support the hypothesis that cannabinoid receptors may play a role in control of colonic transit and sensation in humans and deserve further study as potential mediators or therapeutic targets in lower functional gastrointestinal disorders.

18 Article Association of HLA-DQ gene with bowel transit, barrier function, and inflammation in irritable bowel syndrome with diarrhea. 2012

Vazquez-Roque, Maria I / Camilleri, Michael / Smyrk, Thomas / Murray, Joseph A / O'Neill, Jessica / Carlson, Paula / Lamsam, Jesse / Eckert, Deborah / Janzow, Denise / Burton, Duane / Ryks, Michael / Rhoten, Deborah / Zinsmeister, Alan R. ·Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, Charlton 8-110, 200 First St. SW, Rochester, MN 55905, USA. ·Am J Physiol Gastrointest Liver Physiol · Pubmed #23042942.

ABSTRACT: Patients with irritable bowel syndrome (IBS) with diarrhea (IBS-D) carrying human leukocyte antigen (HLA)-DQ2/8 genotypes benefit from gluten withdrawal. Our objective was to compare gastrointestinal barrier function, mucosal inflammation, and transit in nonceliac IBS-D patients and assess association with HLA-DQ2/8 status. In 45 IBS-D patients who were naive to prior exclusion of dietary gluten, we measured small bowel (SB) and colonic mucosal permeability by cumulative urinary lactulose and mannitol excretion (0-2 h for SB and 8-24 h for colon), inflammation on duodenal and rectosigmoid mucosal biopsies (obtained in 28 of 45 patients), tight junction (TJ) protein mRNA and protein expression in SB and rectosigmoid mucosa, and gastrointestinal and colonic transit by validated scintigraphy. SB mucosal biopsies were stained with hematoxylin-eosin to assess villi and intraepithelial lymphocytes, and immunohistochemistry was used to assess CD3, CD8, tryptase, and zonula occludens 1 (ZO-1); colonic biopsy intraepithelial lymphocytes were quantitated. Associations of HLA-DQ were assessed using Wilcoxon's rank-sum test. Relative to healthy control data, we observed a significant increase in SB permeability (P < 0.001), a borderline increase in colonic permeability (P = 0.10), and a decrease in TJ mRNA expression in rectosigmoid mucosa in IBS-D. In HLA-DQ2/8-positive patients, ZO-1 protein expression in the rectosigmoid mucosa was reduced compared with that in HLA-DQ2/8-negative patients and colonic transit was slower than in HLA-DQ2/8-negative patients. No other associations with HLA genotype were identified. There is abnormal barrier function (increased SB permeability and reduced mRNA expression of TJ proteins) in IBS-D relative to health that may be, in part, related to immunogenotype, given reduced ZO-1 protein expression in rectosigmoid mucosa in HLA-DQ2/8-positive relative to HLA-DQ2/8-negative patients.

19 Article Increased bile acid biosynthesis is associated with irritable bowel syndrome with diarrhea. 2012

Wong, Banny S / Camilleri, Michael / Carlson, Paula / McKinzie, Sanna / Busciglio, Irene / Bondar, Olga / Dyer, Roy B / Lamsam, Jesse / Zinsmeister, Alan R. ·Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Department of Internal Medicine, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. ·Clin Gastroenterol Hepatol · Pubmed #22610000.

ABSTRACT: BACKGROUND & AIMS: Variations in genes that regulate bile acid (BA) synthesis are associated with colonic transit in patients with irritable bowel syndrome (IBS). We investigated features of BA synthesis and excretion and genetic features of patients with different types of IBS. METHODS: In 26 healthy volunteers, 26 patients with IBS and constipation (IBS-C), and 26 with IBS and diarrhea (IBS-D), we measured serum levels of 7α-hydroxy-4-cholesten-3-one (C4; a surrogate for BA synthesis) and fibroblast growth factor (FGF) 19 (an ileal hormone that downregulates BA synthesis). For stool samples, we measured concentration of BA, weight, and amount of fat when participants were given high-fat diets. Spearman correlations were used to explore relationships among factors. We analyzed 1 polymorphism in Klotho-β (KLB) and 3 in fibroblast growth factor receptor-4 (FGFR4) for all members of each group using analysis of covariance. RESULTS: The concentration of BA in stool was associated with group (for a comparison of 3 groups; P = .057); it was higher in patients with IBS-D than IBS-C (P = .017). The serum level of C4 was higher in patients with IBS-D than IBS-C (P = .02) or healthy volunteers (P = .01); 38% of patients with IBS-D had increased serum levels of C4, compared with healthy volunteers. Serum level of C4 correlated with stool concentration of BA (rs = 0.606; P < .001), serum FGF19 (rs = -0.324; P = .007), and stool weight (rs = 0.366; P = .003). Stool concentration of BA correlated with weight (rs = 0.737; P < .001) and level of fat (rs = 0.528; P < .001). Body mass index correlated with serum level of C4 (rs = 0.423, P < .001) and stool concentration of BA (rs = 0.507, P < .001), and was higher in patients with IBS-D compared with other groups (overall P = .036). FGFR4 rs1966265 was associated with stool level of BA (P = .032). CONCLUSIONS: Patients with IBS-D have greater body mass index and synthesize and excrete higher levels of BA than individuals with IBS-C or healthy volunteers. Serum levels of C4 might be used to identify patients with IBS-D who have BA malabsorption; studies are needed to determine if some patients have a genetic predisposition to this disorder.

20 Article Effect of a glucagon-like peptide 1 analog, ROSE-010, on GI motor functions in female patients with constipation-predominant irritable bowel syndrome. 2012

Camilleri, Michael / Vazquez-Roque, Maria / Iturrino, Johanna / Boldingh, Amy / Burton, Duane / McKinzie, Sanna / Wong, Banny S / Rao, Archana S / Kenny, Enda / Månsson, Maria / Zinsmeister, Alan R. ·Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA. camilleri.michael@mayo.edu ·Am J Physiol Gastrointest Liver Physiol · Pubmed #22517769.

ABSTRACT: The glucagon-like peptide 1 (GLP-1) analog ROSE-010 reduced pain during acute exacerbations of irritable bowel syndrome (IBS). Our objective was to assess effects of ROSE-010 on several gastrointestinal (GI) motor and bowel functions in constipation-predominant IBS (IBS-C). In a single-center, randomized, parallel-group, double-blind, placebo-controlled, dose-response study, we evaluated safety, pharmacodynamics, and pharmacokinetics in female patients with IBS-C. ROSE-010 (30, 100, or 300 μg sc) or matching placebo was administered once daily for 3 consecutive days and on 1 day 2-10 days later. We measured GI and colonic transit by validated scintigraphy and gastric volumes by single-photon emission computed tomography. The primary end points were half time of gastric emptying of solids, colonic transit geometric center at 24 h, and gastric accommodation volume. Analysis included intent-to-treat principle, analysis of covariance (with body mass index as covariate), and Dunnett-Hsu test for multiple comparisons. Exposure to ROSE-010 was approximately dose-proportional across the dose range tested. Demographic data in four treatment groups of female IBS-C patients (total 46) were not different. Gastric emptying was significantly retarded by 100 and 300 μg of ROSE-010. There were no significant effects of ROSE-010 on gastric volumes, small bowel or colonic transit at 24 h, or bowel functions. The 30- and 100-μg doses accelerated colonic transit at 48 h. Adverse effects were nausea (P < 0.001 vs. placebo) and vomiting (P = 0.008 vs. placebo). Laboratory safety results were not clinically significant. In IBS-C, ROSE-010 delayed gastric emptying of solids but did not retard colonic transit or alter gastric accommodation; the accelerated colonic transit at 48 h with 30 and 100 μg of ROSE-010 suggests potential for relief of constipation in IBS-C.

21 Article Randomized pharmacodynamic and pharmacogenetic trial of dronabinol effects on colon transit in irritable bowel syndrome-diarrhea. 2012

Wong, B S / Camilleri, M / Eckert, D / Carlson, P / Ryks, M / Burton, D / Zinsmeister, A R. ·Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota, USA. ·Neurogastroenterol Motil · Pubmed #22288893.

ABSTRACT: BACKGROUND: Genetic variation in endocannabinoid metabolism is associated with colonic transit in irritable bowel syndrome (IBS) with diarrhea (IBS-D). The nonselective cannabinoid (CB) receptor agonist, dronabinol (DRO), reduced fasting colonic motility in nonconstipated IBS. FAAH and CNR1 variants influenced DRO's effects on colonic motility. Our aims were: (i) to compare dose-related effects of DRO to placebo (PLA) on gut transit in IBS-D, and (ii) to examine influence of genetic variations in CB mechanisms on DRO’s transit effects. METHODS: Thirty-six IBS-D volunteers were randomized (double-blind, concealed allocation) to twice per day PLA (n = 13), DRO 2.5 mg (n = 10), or DRO 5 mg (n = 13) for 2 days. We assessed gastric, small bowel, and colonic transit by validated radioscintigraphy and genotyped the single nucleotide polymorphisms CNR1 rs806378 and FAAH rs324420. Data analysis utilized a dominant genetic model. KEY RESULTS: Overall treatment effects of DRO on gastric, small bowel, or colonic transit were not detected. CNR1 rs806378 CT/TT was associated with a modest delay in colonic transit at 24 h compared with CC (P = 0.13 for differential treatment effects on postminus pretreatment changes in colonic transit by genotype). No significant interaction of treatment with FAAH rs324420 was detected. CONCLUSIONS & INFERENCES: Overall, DRO 2.5 or 5 mg twice per day for 2 days had no effect on gut transit in IBS-D. There appears to be a treatment-by-genotype effect, whereby DRO preferentially delays colonic transit in those with the CNR1 rs806378 CT/TT genotypes. Further study of CB pharmacogenetics may help identify a subset of IBS-D patients most likely to benefit from CB agonist therapy.

22 Article Pharmacogenetics of the effects of colesevelam on colonic transit in irritable bowel syndrome with diarrhea. 2012

Wong, Banny S / Camilleri, Michael / Carlson, Paula J / Odunsi-Shiyanbade, Suwebatu / McKinzie, Sanna / Busciglio, Irene / Burton, Duane / Zinsmeister, Alan R. ·Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Charlton 8-110, 200 First Street S.W., Rochester, MN 55905, USA. ·Dig Dis Sci · Pubmed #22271411.

ABSTRACT: BACKGROUND: Protein products of klothoβ (KLB) and fibroblast growth factor receptor 4 (FGFR4) impact fibroblast growth factor 19-mediated feedback inhibition of hepatic bile acid (BA) synthesis. Variants of KLB and FGFR4 influence colonic transit (CT) in diarrhea-predominant irritable bowel syndrome (IBS-D). AIM: The purpose of this study was to test the hypothesis that colesevelam's slowing effects on CT in IBS-D patients is influenced by genetic variants in KLB and FGFR4. METHODS: We examined pharmacogenetic effects of KLB and FGFR4 coding variants (SNPs) on scintigraphic CT response to the BA sequestrant, colesevelam 1.875 g b.i.d. versus placebo (PLA) for 14 days in 24 female IBS-D patients. RESULTS: FGFR4 rs351855 and KLB rs497501 were associated with differential colesevelam effects on ascending colon (AC) half-emptying time (t(1/2), P = 0.046 and P = 0.085 respectively) and on overall CT at 24 h (geometric center, GC24: P = 0.073 and P = 0.042, respectively), with slower transit for rs351855 GA/AA (but not for GG) and rs497501 CA/AA (but not CC) genotypes. CONCLUSION: FGFR4 rs351855 and KLB rs4975017 SNPs may identify a subset of IBS-D patients with beneficial response to colesevelam.

23 Article Association of bile acid receptor TGR5 variation and transit in health and lower functional gastrointestinal disorders. 2011

Camilleri, M / Vazquez-Roque, M I / Carlson, P / Burton, D / Wong, B S / Zinsmeister, A R. ·Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. camilleri.michael@mayo.edu ·Neurogastroenterol Motil · Pubmed #21883702.

ABSTRACT: BACKGROUND: The membrane bound bile acid (BA) receptor, TGR5, is located on myenteric, cholinergic and nitrergic neurons in colon and proximal small intestine. Our aim was to assess the association of genetic variation in TGR5 and small bowel transit (SBT) and colonic transit. METHODS: In 230 healthy controls and 414 patients with lower functional GI disorders [FGID: irritable bowel syndrome (IBS)-alternators (Alt) 84, IBS-constipation (IBS-C) 157, IBS-diarrhea (IBS-D) 173], we tested the association between TGR5 SNP rs11554825 (minor allele frequency 41%) with symptom phenotype (total cohort) and intermediate phenotype (SBT or colonic transit by radioscintigraphy) which was available in 213 people in this cohort. The association with symptom phenotype was assessed using logistic regression, while the association with colonic filling at 6 h (CF6), and colonic transit [geometric center (GC) at 24 h] was assessed using ancova, in each instance assuming a dominant genetic model. KEY RESULTS: There was no significant association with symptom phenotype. We observed a potential association of SNP rs11554825 with overall transit: CF6 (P = 0.061) and GC24 (P = 0.083). The association of the SNP with CF6 in the IBS-D subgroup (P = 0.017) indicated the TC/CC subgroup had an average 50% faster SBT compared with the TT subgroup. In IBS-D patients, GC24 was not significantly associated with rs11554825 (TC/CC vs TT). CONCLUSIONS & INFERENCES: Variation in TGR5 may contribute to altered SBT and colonic transit in lower FGID. Further studies are required to characterize the potential role of BA receptor, TGR5, in the mechanism and treatment of bowel dysfunction in lower FGID.

24 Article Urine sugars for in vivo gut permeability: validation and comparisons in irritable bowel syndrome-diarrhea and controls. 2011

Rao, Archana S / Camilleri, Michael / Eckert, Deborah J / Busciglio, Irene / Burton, Duane D / Ryks, Michael / Wong, Banny S / Lamsam, Jesse / Singh, Ravinder / Zinsmeister, Alan R. ·Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Biomedical Statistics and Informatics, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA. ·Am J Physiol Gastrointest Liver Physiol · Pubmed #21836056.

ABSTRACT: Mucosal barrier dysfunction contributes to gastrointestinal diseases. Our aims were to validate urine sugar excretion as an in vivo test of small bowel (SB) and colonic permeability and to compare permeability in patients with irritable bowel syndrome-diarrhea (IBS-D) to positive and negative controls. Oral lactulose (L) and mannitol (M) were administered with (99m)Tc-oral solution, (111)In-oral delayed-release capsule, or directly into the ascending colon (only in healthy controls). We compared L and M excretion in urine collections at specific times in 12 patients with IBS-D, 12 healthy controls, and 10 patients with inactive or treated ulcerative or microscopic colitis (UC/MC). Sugars were measured by high-performance liquid chromatography-tandem mass spectrometry. Primary endpoints were cumulative 0-2-h, 2-8-h, and 8-24-h urinary sugars. Radioisotopes in the colon at 2 h and 8 h were measured by scintigraphy. Kruskal-Wallis and Wilcoxon tests were used to assess the overall and pairwise associations, respectively, between group and urinary sugars. The liquid in the colon at 2 h and 8 h was as follows: health, 62 ± 9% and 89 ± 3%; IBS-D, 56 ± 11% and 90 ± 3%; and UC/MC, 35 ± 8% and 78 ± 6%, respectively. Liquid formulation was associated with higher M excretion compared with capsule formulation at 0-2 h (health P = 0.049; IBS-D P < 0.001) but not during 8-24 h. UC/MC was associated with increased urine L and M excretion compared with health (but not to IBS-D) at 8-24 h, not at 0-2 h. There were significant differences between IBS-D and health in urine M excretion at 0-2 h and 2-8 h and L excretion at 8-24 h. Urine sugars at 0-2 h and 8-24 h reflect SB and colonic permeability, respectively. IBS-D is associated with increased SB and colonic mucosal permeability.

25 Article Pharmacogenetic trial of a cannabinoid agonist shows reduced fasting colonic motility in patients with nonconstipated irritable bowel syndrome. 2011

Wong, Banny S / Camilleri, Michael / Busciglio, Irene / Carlson, Paula / Szarka, Lawrence A / Burton, Duane / Zinsmeister, Alan R. ·Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. ·Gastroenterology · Pubmed #21803011.

ABSTRACT: BACKGROUND & AIMS: Cannabinoid receptors are located on cholinergic neurons. Genetic variants that affect endocannabinoid metabolism are associated with colonic transit in patients with irritable bowel syndrome (IBS) with diarrhea. We compared the effects of dronabinol, a nonselective agonist of the cannabinoid receptor, with those of placebo on colonic motility and sensation in patients with IBS, and examined the effects of IBS subtype and specific genetic variants in cannabinoid mechanisms. METHODS: Seventy-five individuals with IBS (35 with IBS with constipation, 35 with IBS with diarrhea, and with 5 IBS alternating) were randomly assigned to groups that were given 1 dose of placebo or 2.5 mg or 5.0 mg dronabinol. We assessed left colonic compliance, motility index (MI), tone, and sensation during fasting and after a meal. We analyzed the single nucleotide polymorphisms CNR1 rs806378, fatty acid amide hydrolase (FAAH) rs324420, and MGLL rs4881. RESULTS: In all patients, dronabinol decreased fasting proximal left colonic MI compared with placebo (overall P = .05; for 5 mg dronabinol, P = .046), decreased fasting distal left colonic MI (overall P = .08; for 5 mg, P = .13), and increased colonic compliance (P = .058). The effects of dronabinol were greatest in patients with IBS with diarrhea or IBS alternating (proximal colonic MI, overall P = .022; compliance, overall P = .03). Dronabinol did not alter sensation or tone. CNR1 rs806378 (CC vs CT/TT) appeared to affect fasting proximal MI in all patients with IBS (P = .075). Dronabinol affected fasting distal MI in patients, regardless of FAAH rs324420 variant (CA/AA vs CC) (P = .046); the greatest effects were observed among IBS with constipation patients with the FAAH CC variant (P = .045). Dronabinol affected fasting proximal MI in patients with IBS with diarrhea or alternating with the variant FAAH CA/AA (P = .013). CONCLUSIONS: In patients with IBS with diarrhea or alternating, dronabinol reduces fasting colonic motility; FAAH and CNR1 variants could influence the effects of this drug on colonic motility.

Next