Declining Rates of Referral for Irritable Bowel Syndrome Without Constipation at a Tertiary Care Center.

BACKGROUND: Irritable bowel syndrome (IBS) is a common chronic disorder of the gastrointestinal tract. Several treatments have been developed, including rifaximin for the treatment of IBS without constipation (non-IBS-C), but no studies have evaluated the effect of these therapies on patient referral rates to tertiary care gastroenterology clinics. AIM: To assess referral patterns for IBS patients at a tertiary motility clinic over a 10-year period. METHODS: Data from consecutive patients referred to the clinic during 2006-2016 were analyzed. Trends in the proportion of referrals and prior rifaximin use in IBS-C versus non-IBS-C groups were compared. RESULTS: A total of 814 adult patients were referred to a single physician panel for IBS-related symptoms. Of these, 776 were included in the study [528 females (68%), average age 45.7 ± 15.9 years), comprising 431 IBS-C (55.5%) and 345 non-IBS-C (44.5%) patients. The proportion of non-IBS-C referrals declined significantly from 53.0% in 2006 to 27.3% in 2016 (Chi-square, p < 0.0001, Cochran-Armitage trend test p = 0.0001), and the proportion of IBS-C referrals increased significantly from 46.9% in 2006 to 72.7% in 2016 (Chi-square, p < 0.0001, Cochran-Armitage trend test p = 0.0004). Non-IBS-C referrals with prior rifaximin use significantly increased from 22.7% in 2006 to 66.7% in 2016 (Cochran-Armitage trend test, p = 0.008). CONCLUSIONS: The results indicate a significantly declining tertiary care referral rate for non-IBS-C over the past decade. While not directly linked, there has been an increase in rifaximin use in the same population during the same time interval.

Assessment of Anti-vinculin and Anti-cytolethal Distending Toxin B Antibodies in Subtypes of Irritable Bowel Syndrome.

BACKGROUND: Antibodies to cytolethal distending toxin B (CdtB) and vinculin are novel biomarkers that rule-in and differentiate irritable bowel syndrome with diarrhea (IBS-D) from other causes of diarrhea and healthy controls. AIM: To determine whether these antibodies can also diagnose and differentiate other IBS subtypes. METHODS: Subjects with IBS-D based on Rome III criteria (n = 2375) were recruited from a large-scale multicenter clinical trial (TARGET 3). Healthy subjects without gastrointestinal (GI) diseases or symptoms (n = 43) and subjects with mixed IBS (IBS-M) (n = 25) or IBS with constipation (IBS-C) (n = 30) were recruited from two major medical centers. Plasma levels of anti-CdtB and anti-vinculin antibodies in all subjects were determined by enzyme-linked immunosorbent assay. Optical densities of ≥1.68 and ≥2.80 were considered positive for anti-vinculin and anti-CdtB, respectively. Plasma levels of anti-CdtB and anti-vinculin antibodies were highest in IBS-D and lowest in IBS-C and healthy controls (P < 0.001). Levels in IBS-C subjects were not statistically different from controls (P > 0.1). Positivity for anti-CdtB or anti-vinculin resulted in a statistically significant negative gradient from IBS-D (58.1%) to IBS-M (44.0%), IBS-C (26.7%), and controls (16.3%) (P < 0.001). CONCLUSIONS: Anti-CdtB and anti-vinculin titers and positivity rates differ in IBS subtypes, with higher antibody levels and positivity rates in IBS-D and IBS-M, and lower levels in IBS-C subjects that are similar to those in healthy controls. These antibodies appear useful in the diagnosis of IBS-M and IBS-D, but not IBS-C. Furthermore, these findings suggest that IBS-C is pathophysiologically distinct from subtypes with diarrheal components (i.e., IBS-M and IBS-D).

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.

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

OBJECTIVE: 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. METHODS: Eleven prediabetic methane-positive subjects (9F, 2M) with obesity (BMI 35.17 ± 7.71 kg/m(2) ) aged 47 ± 9 years were recruited. Subjects underwent breath testing, symptom questionnaire, oral glucose tolerance test (OGTT), lipid profile, and stool Methanobrevibacter smithii levels, gastric transit, and energy utilization analyses. After a 10-day antibiotic therapy (neomycin 500 mg bid/rifaximin 550 mg tid), all testing was repeated. RESULTS: Baseline stool M. smithii levels correlated with breath methane (R = 0.7, P = 0.05). Eight subjects (73%) eradicated breath methane and showed reduced stool M. smithii (P = 0.16). After therapy, methane-eradicated subjects showed significant improvements in low-density lipoprotein (LDL) (P = 0.028), total cholesterol (P = 0.01), and insulin levels on OGTT (P = 0.05 at 120 minutes), lower blood glucose levels on OGTT (P = 0.054 at 90 minutes), significant reductions in bloating (P = 0.018) and straining (P = 0.059), and a trend toward lower stool dry weight. No changes were detected in gastric emptying time or energy harvest. CONCLUSIONS: Breath methane eradication and M. smithii reduction are associated with significant improvements in total cholesterol, LDL, and insulin levels and with lower glucose levels in prediabetic subjects with obesity. The underlying mechanisms require further elucidation.

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.

Healthy control subjects are poorly defined in case-control studies of irritable bowel syndrome.

BACKGROUND: Case-control studies are vital for understanding the pathophysiology of gastrointestinal disease. While the definition of disease is clear, the definition of healthy control is not. This is particularly relevant for functional bowel diseases such as irritable bowel syndrome (IBS). In this study, a systematic review formed the basis for a prospective study evaluating the effectiveness of commonly used techniques for defining healthy controls in IBS. METHODS: A systematic review of the literature was conducted to identify case-control studies involving functional gastrointestinal disorders. "Lack of Rome criteria", self-description as "healthy" and the bowel disease questionnaire (BDQ) were common methods for identifying healthy controls. These 3 methods were then applied to a cohort of 53 non-patient subjects to determine their validity compared to objective outcome measures (7-day stool diary). RESULTS: "Lack of Rome criteria" and "healthy" self-description were the most common methods for identifying healthy control subjects, but many studies failed to describe the methods used. In the prospective study, more subjects were identified as non-healthy using the BDQ than using either lack of Rome criteria (P=0.01) or "healthy" self-description (P=0.026). Furthermore, stool diaries identified several subjects with abnormal stool form and/or frequency which were not identified using lack of Rome criteria or the "healthy" question. Comparisons revealed no agreement (κ) between the different methods for defining healthy controls. CONCLUSIONS: The definitions of healthy controls in studies of functional bowel diseases such as IBS are inconsistent. Since functional symptoms are common, a strict definition of "normal" is needed in this area of research.

Autoimmunity Links Vinculin to the Pathophysiology of Chronic Functional Bowel Changes Following Campylobacter jejuni Infection in a Rat Model.

BACKGROUND: Acute gastroenteritis can precipitate irritable bowel syndrome (IBS) in humans. Cytolethal distending toxin is common to all pathogens causing gastroenteritis. Its active subunit, CdtB, is associated with post-infectious bowel changes in a rat model of Campylobacter jejuni infection, including small intestinal bacterial overgrowth (SIBO). AIM: To evaluate the role of host antibodies to CdtB in contributing to post-infectious functional sequelae in this rat model. METHODS: Ileal tissues from non-IBS human subjects, C. jejuni-infected and control rats were immunostained with antibodies to CdtB, c-Kit, S-100, PGP 9.5 and vinculin. Cytosolic and membrane proteins from mouse enteric neuronal cell lysates were immunoprecipitated with anti-CdtB and analyzed by mass spectrometry. ELISAs were performed on rat cardiac serum using CdtB or vinculin as antigens. RESULTS: Anti-CdtB antibodies bound to a cytosolic protein in interstitial cells of Cajal (ICC) and myenteric ganglia in C. jejuni-infected and naïve rats and human subjects. Mass spectrometry identified vinculin, confirmed by co-localization and ELISAs. Anti-CdtB antibodies were higher in C. jejuni-infected rats (1.27 ± 0.15) than controls (1.76 ± 0.12) (P < 0.05), and rats that developed SIBO (2.01 ± 0.18) vs. rats that did not (1.44 ± 0.11) (P = 0.019). Vinculin expression levels were reduced in C. jejuni-infected rats (0.058 ± 0.053) versus controls (0.087 ± 0.023) (P = 0.0001), with greater reductions in rats with two C. jejuni infections (P = 0.0001) and rats that developed SIBO (P = 0.001). CONCLUSIONS: Host anti-CdtB antibodies cross-react with vinculin in ICC and myenteric ganglia, required for normal gut motility. Circulating antibody levels and loss of vinculin expression correlate with number of C. jejuni exposures and SIBO, suggesting that effects on vinculin are important in the effects of C. jejuni infection on the host gut.

Antibiotic treatment of constipation-predominant irritable bowel syndrome.

BACKGROUND: The antibiotic rifaximin is used to treat non-constipated irritable bowel syndrome (IBS). Methane production is associated with constipation and its severity in constipation-predominant IBS (C-IBS). A previous retrospective study suggested that rifaximin and neomycin was superior to neomycin alone in improving symptoms in methane-positive subjects. AIMS: To determine the effectiveness of neomycin alone or with rifaximin in improving symptoms in methane-positive C-IBS subjects. METHODS: A double-blind, randomized, placebo-controlled trial was performed from 2010 to 2013 at three tertiary care centers. Subjects aged 18-65 with C-IBS (Rome II criteria) and breath methane (>3 ppm) meeting the inclusion and exclusion criteria were recruited. Subjects completed a baseline symptom questionnaire rating the severity of abdominal and bowel symptoms on a visual analog scale and were randomized to receive neomycin and placebo or neomycin and rifaximin for 14 days. Symptom severity was assessed by weekly questionnaire for 2 weeks of therapy and 4 additional weeks of follow-up. RESULTS: Thirty-one subjects (16 neomycin and placebo, 15 neomycin and rifaximin) were included in the intention-to-treat analysis. Constipation severity was significantly lower in the neomycin and rifaximin group (28.6 ± 30.8) compared to neomycin alone (61.2 ± 24.1) (P = 0.0042), with greater improvement in constipation (P = 0.007), straining (P = 0.017) and bloating (P = 0.020), but not abdominal pain. In the neomycin and rifaximin group, subjects with methane <3 ppm after treatment reported significantly lower constipation severity (30.5 ± 21.8) than subjects with persistent methane (67.2 ± 32.1) (P = 0.020). CONCLUSIONS: Rifaximin plus neomycin is superior to neomycin alone in improving multiple C-IBS symptoms. This effect is predicted by a reduction in breath methane.

"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.

An estimation of the worldwide economic and health burden of visual impairment.

This study aims to provide a rigorous estimate of the worldwide costs of visual impairment (VI), and the associated health burden. The study used a prevalence-based model. Prevalence rates for mild VI (visual acuity (VA) worse than 6/12 but not worse than 6/18), moderate VI (VA worse than 6/18 but not worse than 6/60) and blindness (VA worse than 6/60) were applied to population forecasts for each World Health Organisation (WHO) subregion. The limited available country cost data were extrapolated between subregions using economic and population health indicators. Age and gender subgroup population numbers were derived from United Nations' data. Costs and the health burden of VI were estimated for each world subregion using published disease prevalence rates, health care expenditures and other economic data. The study includes direct health care costs, indirect costs and the health burden of VI. The total cost of VI globally was estimated at $3 trillion in 2010, of which $2.3 trillion was direct health costs. This burden is projected to increase by approximately 20% by 2020. VI is associated with a considerable disease burden. Unless steps are taken to reduce prevalence through prevention and treatment, this burden will increase alongside global population growth.

Effects of rifaximin treatment and retreatment in nonconstipated IBS subjects.

UNLABELLED: Recent evidence suggests a role for gut bacteria and antibiotics in the pathophysiology and treatment of irritable bowel syndrome (IBS), respectively. While the benefits of the antibiotic rifaximin have demonstrated efficacy and durable improvement in symptoms over 3 months, the long-term need for retreatment using this approach is mostly unknown. In this retrospective study, subjects with nonconstipated IBS who were retreated with rifaximin were examined. METHODS: Charts of patients who were seen at a tertiary care medical center between 2007 and 2011 were reviewed. After exclusion criteria were applied, subjects who had received rifaximin and were seen for retreatment were fully reviewed. During review, demographic information, duration of response, and success of treatment and retreatment were evaluated. RESULTS: A total of 522 charts were reviewed. Of these 522 charts, 71 subjects were nonconstipated IBS subjects who had received at least one retreatment. Of these, 48 had a second, 22 had a third, 7 had a fourth, and 4 had a fifth treatment. More than 75% of subjects who initially responded to rifaximin also responded to any further retreatment, with no significant reduction in benefit for successive retreatments. Furthermore, there was no change in the duration of benefit (median time between treatments) for successive retreatments. CONCLUSIONS: Retreatment with rifaximin for subjects with nonconstipated IBS in a real-world clinical practice was successful up to five times without decrease in duration or effect.