Kathleen Shari Chua

Development and Validation of a Biomarker for Diarrhea-Predominant Irritable Bowel Syndrome in Human Subjects

Diarrhea-predominant irritable bowel syndrome (IBS) is diagnosed through clinical criteria after excluding “organic” conditions, and can be precipitated by acute gastroenteritis. Cytolethal distending toxin B (CdtB) is produced by bacteria that cause acute gastroenteritis, and a post-infectious animal model demonstrates that host antibodies to CdtB cross-react with vinculin in the host gut, producing an IBS-like phenotype. Therefore, we assessed circulating anti-CdtB and anti-vinculin antibodies as biomarkers for D-IBS in human subjects. Subjects with D-IBS based on Rome criteria (n=2375) were recruited from a large-scale multicenter clinical trial for D-IBS (TARGET 3). Subjects with inflammatory bowel disease (IBD) (n=142), subjects with celiac disease (n=121), and healthy controls (n=43) were obtained for comparison. Subjects with IBD and celiac disease were recruited based on the presence of intestinal complaints and histologic confirmation of chronic inflammatory changes in the colon or small intestine. Subjects with celiac disease were also required to have an elevated tTG and biopsy. All subjects were aged between 18 and 65 years. Plasma levels of anti-CdtB and anti-vinculin antibodies were determined by ELISA, and compared between groups. Anti-CdtB titers were significantly higher in D-IBS subjects compared to IBD, healthy controls and celiac disease (P<0.001). Anti-vinculin titers were also significantly higher in IBS (P<0.001) compared to the other groups. The area-under-the-receiver operating curves (AUCs) were 0.81 and 0.62 for diagnosis of D-IBS against IBD for anti-CdtB and anti-vinculin, respectively. Both tests were less specific in differentiating IBS from celiac disease. Optimization demonstrated that for anti-CdtB (optical density≥2.80) the specificity, sensitivity and likelihood ratio were 91.6%, 43.7 and 5.2, respectively, and for anti-vinculin (OD≥1.68) were 83.8%, 32.6 and 2.0, respectively. These results confirm that anti-CdtB and anti-vinculin antibodies are elevated in D-IBS compared to non-IBS subjects. These biomarkers may be especially helpful in distinguishing D-IBS from IBD in the workup of chronic diarrhea.

Methane and Hydrogen Positivity on Breath Test Is Associated With Greater Body Mass Index and Body Fat

CONTEXT Colonization of the gastrointestinal tract with methanogenic archaea (methanogens) significantly affects host metabolism and weight gain in animal models, and breath methane is associated with a greater body mass index (BMI) among obese human subjects. OBJECTIVE The objective of the study was to characterize the relationship between methane and hydrogen on breath test (as a surrogate for colonization with the hydrogen requiring methanogen, Methanobrevibacter smithii), body weight, and percent body fat in a general population cohort. DESIGN AND SUBJECTS This was a prospective study (n = 792) of consecutive subjects presenting for breath testing. SETTING The study was conducted at a tertiary care center. OUTCOME MEASUREMENTS BMI and percent body fat were measured. RESULTS Subjects were classified into 4 groups based on breath testing: normal (N) (methane <3 ppm and hydrogen <20 ppm at or before 90 minutes); hydrogen positive only (H+) [methane <3 ppm and hydrogen ≥20 ppm); methane positive only (M+) (methane ≥3 ppm and hydrogen <20 ppm), or methane and hydrogen positive (M+/H+) (methane ≥3 ppm and hydrogen ≥20 ppm]. There were significant differences in age but not in gender across the groups. After controlling for age as a confounding variable, M+/H+ subjects had significantly higher BMI than other groups (N: 24.1 ± 5.2 kg/m(2); H+: 24.2 ± 4.5 kg/m(2); M+: 24.0 ± 3.75 kg/m(2); M+/H+: 26.5 ± 7.1 kg/m(2), P < .02) and also had significantly higher percent body fat (N: 28.3 ± 10.0%; H+: 27.5 ± 9.0%; M+: 28.0 ± 8.9%; M+/H+; 34.1 ± 10.9%, P < .001). CONCLUSIONS The presence of both methane and hydrogen on breath testing is associated with increased BMI and percent body fat in humans. We hypothesize that this is due to colonization with the hydrogen-requiring M smithii, which affects nutrient availability for the host and may contribute to weight gain.

Systematic review of diagnostic criteria for IBS demonstrates poor validity and utilization of Rome III

Background  In the absence of a clear biomarker for irritable bowel syndrome (IBS), clinical criteria are used. In this study, we conduct a systematic review to examine the validation and utilization of IBS criteria.

Pre-cebo: an unrecognized issue in the interpretation of adequate relief during irritable bowel syndrome drug trials.

Objectives: In drug trials involving subjects with irritable bowel syndrome (IBS), the placebo effect seems to be very important. However, events even before starting the study may also impact patient expectations. In this study, we utilized consent language from prior studies of diarrhea predominant IBS (D-IBS) drug trials to determine whether the knowledge imparted during this process affects the response to different therapies. Methods: Consecutive IBS subjects who met the Rome III criteria for IBS were enrolled. Patients were presented with a mock trial and randomized to 1 of 3 questionnaires with consent using similar language from consent forms of 3 drugs used in D-IBS: desipramine, alosetron, and rifaximin. Demographics, IBS symptoms using visual analog scale, and percent improvement needed for patients to report adequate relief of IBS from theoretically taking their assigned drug was asked. Data were expressed as mean±SE. Results: Subjects who were anticipating rifaximin had the highest expectation of improvement to determine adequate relief of 87.3±10.9% compared with 73.4±18.0% for desipramine (P<0.01) and 76.8±20% for alosetron (P=0.049). There was no major difference in expectation of response from any medication to satisfy adequate relief on the basis of a belief that IBS is psychologic or organic in origin. In addition, sex and previous use of a drug did not influence the expectation of adequate relief. Conclusions: Benefits of drugs in D-IBS drug trials have the potential to be influenced by preconceived notions derived from familiarity of drug class and the consent process even before the study begins which we refer to as the “pre-cebo” effect. The higher pre-cebo effect for rifaximin may be an obstacle to successful treatment effect during drug trials compared with drugs such as desipramine. The pre-cebo effect may need to be taken into account when formulating consent forms for IBS study.

Methane-producing human subjects have higher serum glucose levels during oral glucose challenge than non-methane producers: a pilot study of the effects of enteric methanogens on glycemic regulation

Abstract Background: Recent studies support that intestinal microbes contribute to human disease, and enteric methanogens have been specifically linked to altered gut metabolism and weight gain. In this study, we tested

Metabolic effects of eradicating breath methane using antibiotics in prediabetic subjects with obesity

Methanogens colonizing the human gut produce methane and influence host metabolism. This study examined metabolic parameters in methane‐producing subjects before and after antibiotic treatment.

Intestinal methane production is associated with decreased weight loss following bariatric surgery

To determine whether methane and hydrogen on breath test affects weight loss after bariatric surgery, 156 subjects (pre-surgery BMI ≥33) were recruited ≥4 months after surgery. Pre- and post-surgery weights and BMIs were recorded. Post-surgery methane and hydrogen levels were determined. % total weight loss and % change in BMI were prorated to six months after surgery. M+/H+ subjects (N=13) exhibited lower prorated % change in BMI vs. all other subjects (N=144) (p=0.13), and significantly lower prorated % total weight loss (p=0.036). These findings may suggest that subjects with positive breath methane and hydrogen lose less weight following bariatric surgery.

Tu1418 Physiologic Esophageal Length in Adults Is Associated With Gender and Presence of Hiatal Hernia but Not With Age

(15.6%) had at least one functional esophageal symptom (FES). FES were commoner among female than male (338/1924 [17.6%] vs. 186/1427 [13%]; p 5) than those without (36/521 [6.9%] vs 74/2809 [2.6%], p<0.000). Conclusions: 16% people in rural Bangladesh had at least one functional esophageal symptom, heartburn being the most common; other symptoms like globus, functional chest pain and dysphagia were uncommon. Female gender, marriage, Muslims religion and low income were the risk factors for EFS on univariate analysis. Psychological distress as evidenced by high GHQ-28 score was higher among subjects with EFS.

Examination of the effects of breath hydrogen and methane levels on the EC/IR II

ABSTRACT Fifty patients undergoing hydrogen and methane breath testing at Cedars-Sinai GI Motility Lab were recruited, and consented to having their breath tested for alcohol using the EC/IR II (Intoximeters, Inc., St. Louis). The subjects gave multiple breath samples for alcohol analysis during this controlled study. All subjects had hydrogen in their breath ranging from 1 to 176 parts per million (ppm). Methane was also present in some patients’ breath samples (0–107 ppm). In all cases, except for one subject that admitted to heavy drinking the night before, breath alcohol results were 0.000 g/210 L. Based on these findings, breath hydrogen and methane do not have any impact on breath alcohol results with the EC/IR II.

311 Large Scale Validation of a Biomarker for Diarrhea-Predominant Irritable Bowel Syndrome

of these patients had fasting FGF19 measured. Alanine transaminase (ALT) and appearance of fatty liver on imaging (ultrasound, CT or MR) were retrospectively added to the database. Where multiple investigations had been performed, the test nearest to the date of the SeHCAT test was recorded. Patients with known chronic liver disease or alcohol abuse were excluded from the final analysis. Results: Of 578 SeHCAT values on the database, 303 (52%) were positive with a value 31IU/L (36% v 21%, p 31IU/L (21% v 7%, p 31IU/L (43% v 22%, p 31IU/L (23% v 7%, p 40 IU/L (40% vs 12%, p<0.05), OR 5.13 (95%CI 1.28-20.61, p<0.05). Conclusions: Primary bile acid diarrhea is associated with NAFLD and may share a common pathology in low FGF19. Both conditions may be presentations of the metabolic syndrome associated with low FGF19.