Dietary and Microbial Oxazoles Induce Intestinal Inflammation by Modulating Aryl Hydrocarbon Receptor Responses.

Genome-wide association studies have identified risk loci associated with the development of inflammatory bowel disease, while epidemiological studies have emphasized that pathogenesis likely involves host interactions with environmental elements whose source and structure need to be defined. Here, we identify a class of compounds derived from dietary, microbial, and industrial sources that are characterized by the presence of a five-membered oxazole ring and induce CD1d-dependent intestinal inflammation. We observe that minimal oxazole structures modulate natural killer T cell-dependent inflammation by regulating lipid antigen presentation by CD1d on intestinal epithelial cells (IECs). CD1d-restricted production of interleukin 10 by IECs is limited through activity of the aryl hydrocarbon receptor (AhR) pathway in response to oxazole induction of tryptophan metabolites. As such, the depletion of the AhR in the intestinal epithelium abrogates oxazole-induced inflammation. In summary, we identify environmentally derived oxazoles as triggers of CD1d-dependent intestinal inflammatory responses that occur via activation of the AhR in the intestinal epithelium.

Risk of Ectopic Pregnancy in Women With Inflammatory Bowel Disease: A 22-Year Nationwide Cohort Study.

BACKGROUND & AIMS: Few data are available on adverse events of pregnancy in women with inflammatory bowel diseases (IBD), such as ectopic pregnancy. We assessed the risk of ectopic pregnancy in pregnancies of women in Denmark with IBD compared with those without IBD over a 22-year period. We also examined the disease-specific risks of ectopic pregnancies in pregnancies of women with ulcerative colitis (UC) or Crohn's disease (CD) who underwent IBD-related surgical procedures. METHODS: We performed a retrospective study of all women of child-bearing age (ages, 15-50 y) registered in the Danish National Patient Registry with at least 1 pregnancy during the period from January 1994 through December 31, 2015. We collected data on all women with an ectopic pregnancy, hydatidiform mole, miscarriages (spontaneous and other abortions, including abnormal pregnancy products, missed abortion, and pregnancy without a fetus), induced abortions, and births in women with and without IBD. Our study population included 7548 pregnancies in women with UC, 6731 pregnancies in women with CD, and 1,832,732 pregnancies in women without IBD. We controlled for multiple covariates, including pelvic and abdominal surgery. RESULTS: Women with CD had a greater risk of ectopic pregnancy, per pregnancy, than women without IBD (odds ratio [OR], 1.23; 95% confidence interval [CI], 1.01-1.49), whereas women with UC did not (OR, 0.98; 95% CI, 0.80-1.20). In pregnancies of women with CD and UC who underwent IBD-related surgery before pregnancy, there was a nonsignificant increase in risk of ectopic pregnancy compared with pregnancies in women with IBD who did not have surgery (OR, 1.49; 95% CI, 0.91-2.44 for CD, and OR, 1.17; 95% CI, 0.54-2.52 for UC). CONCLUSIONS: We found a statistically significant increased risk of ectopic pregnancy in pregnancies of women with CD compared with pregnancies of women without IBD. Surgery for IBD before pregnancy increased the risk of ectopic pregnancy, although this increase was not statistically significant.

High Dietary Intake of Specific Fatty Acids Increases Risk of Flares in Patients With Ulcerative Colitis in Remission During Treatment With Aminosalicylates.

BACKGROUND & AIMS: Dietary factors may have a significant role in relapse of disease among patients with ulcerative colitis (UC). However, the relationship between diet and UC is inadequately understood. We analyzed data from the diet's role in exacerbations of mesalamine maintenance study to determine whether dietary factors affect the risk of disease flares in patients with UC. METHODS: We performed a prospective, multicenter, observational study of 412 patients, from 25 sites, with UC in remission during monotherapy with an aminosalicylate. Patients completed a validated food frequency questionnaire at enrollment and were followed for 12 months. We analyzed the relationship between diet and disease remission or flare for groups of macronutrients and micronutrients, and food groups previously associated with an increased risk of flare. RESULTS: Forty-five patients (11%) had a UC relapse within 1 year of study enrollment. When analyzed in tertiles, increasing intake of multiple fatty acids was associated with increasing odds of relapse. In multivariable logistic regression analysis, only myristic acid (odds ratio, 3.01; 95% confidence interval, 1.17-7.74) maintained this dose-response relationship. Other foods previously implicated in flares of UC, such as processed meat, alcohol, and foods high in sulfur, were not associated with an increased risk of flare. CONCLUSIONS: In a prospective study of more than 400 patients with UC undergoing treatment with aminosalicylates, we associated high dietary intake of specific fatty acids, including myristic acid (commonly found in palm oil, coconut oil, and dairy fats) with an increased risk of flare. These findings can help design interventional studies to evaluate dietary factors in UC.

Sexual Dysfunction in Female Patients with Inflammatory Bowel Disease: An Overview.

Sexual dysfunction is common among females with inflammatory bowel disease and may result in issues involving intimacy, sexual activity, and satisfaction, as well both the formation and preservation of personal relationships. Risk factors for sexual dysfunction include select surgical interventions, medications, mental illnesses, and IBD-related intestinal and extraintestinal comorbidities. In addition, certain demographic factors such as age, disease type and activity may influence the severity of sexual dysfunction. Evaluation of sexual dysfunction may include the use of validated sexual functioning questionnaires, a brief mental health assessment, initial inquiry into vulvovaginal or perineal symptoms, and a gynecologic and GI-focused physical exam. An interdisciplinary care team involving IBD specialists, obstetrician-gynecologists, pelvic floor physical therapists, and primary care physicians may be best suited to provide optimal care and treatment recommendations for patients with sexual dysfunction. Options for management often include pelvic floor physical therapy, biofeedback, and mental health support. Further research is necessary to delineate the impact of IBD activity on sexual dysfunction, to determine if health outcome differences exist depending on surgical approaches utilized during J-pouch operations, and finally to evaluate the care and perceptions of patients with IBD who identify as sexual and gender minorities.

An association between dietary arachidonic acid, measured in adipose tissue, and ulcerative colitis.

BACKGROUND & AIMS: Dietary arachidonic acid, an n-6 polyunsaturated fatty acid (n-6 PUFA), might be involved in the etiology of ulcerative colitis (UC). We performed a prospective cohort study to determine whether high levels of arachidonic acid in adipose tissue samples (which reflects dietary intake) are associated with UC. METHODS: We analyzed data collected from 57,053 men and women in the EPIC-Denmark Prospective Cohort Study from 1993 to 1997. Adipose tissue biopsy samples were collected from gluteal regions at the beginning of the study, the cohort was monitored over subsequent years, and participants who developed UC were identified. A subcohort of 2510 randomly selected participants were used as controls. Concentrations of arachidonic acid were measured in adipose tissue samples. In the analysis, arachidonic acid levels were divided into quartiles; relative risks (RR) were calculated and adjusted for smoking, use of aspirin and nonsteroidal anti-inflammatory drugs, and levels of n-3 PUFAs. RESULTS: A total of 34 subjects (56% men) developed incident UC at a median age of 58.8 years (range, 50.0-69.0 years). Those in the highest quartile for arachidonic acid concentrations in adipose tissue had an RR for UC of 4.16 (95% confidence interval [CI]: 1.56-11.04); a trend per 0.1% increase in arachidonic acid of 1.77 in RR was observed (95% CI: 1.38-2.27). The fraction attributed the highest levels of arachidonic acid was 40.3%. CONCLUSIONS: Individuals with the highest relative concentrations of arachidonic acid in adipose tissue have a significantly greater risk of developing UC. Dietary modifications might therefore prevent UC or reduce disease symptoms.

Diet Therapy for Inflammatory Bowel Diseases: A Call to the Dining Table.

There is vigorous interest among patients, caregivers, clinicians, and scientists to identify useful dietary interventions for inflammatory bowel diseases (IBD). Through the Cochrane Collaboration, we recently performed a systematic review and meta-analysis of dietary interventions for the induction or maintenance of remission in Crohn's disease (CD) and ulcerative colitis (UC) to assess the latest state of research. The current quality of evidence was formally graded to be low or very low for various methodological reasons, such as small sample sizes, heterogeneity among studies, and incomplete reporting. There are nonetheless emerging observational studies that progressively advance our knowledge and provide hope for a role of diet among traditional therapies to improve inflammation and symptoms. Further investments and concerted efforts in research are needed to significantly move the needle in identifying effective dietary therapies for IBD.

The Risk of Elective Abortion in Women With Crohn's Disease and Ulcerative Colitis: A Nationwide Cohort Study.

BACKGROUD: Women with inflammatory bowel disease (IBD) might have an increased tendency to choose an elective abortion due to a fear that their fetus could be harmed by use of medications, disease flares during pregnancy, or for genetic reasons. We examined the risk of elective abortions in women with ulcerative colitis (UC) and Crohn's disease (CD) compared with women without IBD. METHODS: This nationwide cohort study, based on Danish health registries, comprises all registered pregnancies from 1996 through 2015. The 2 exposed groups constituted pregnancies of women with UC or CD, and the unexposed group constituted all pregnancies of women without IBD. Our outcome was elective abortion by maternal request up until the end of the 12th completed week of gestation. We used logistic regression models and calculated the odds ratio (OR) for an elective abortion, controlling for confounders. RESULTS: The overall prevalence rates of elective abortions in women with UC and CD and without IBD were 12.4% (898 elective abortions/7250 pregnancies), 14.9% (978 elective abortions/6559 pregnancies), and 16.9% (285,251 elective abortions/1,691,857 pregnancies), respectively. In women with UC and CD, the adjusted ORs for an elective abortion (95% confidence interval) were 0.80 (0.74-0.86) and 0.96 (0.89-1.04), respectively. CONCLUSIONS: Pregnant women with IBD are not more likely to choose an elective abortion compared with women without IBD. These results are reassuring as they suggest that women with IBD are not so worried about a negative impact of their disease, disease activity, or medications that they would choose to terminate a pregnancy.

Sexual Dysfunction in Men With Inflammatory Bowel Disease: A New IBD-Specific Scale.

Background: Men with inflammatory bowel disease (IBD) may have increased sexual dysfunction. To measure the prevalence of sexual dysfunction in our male patients, we aimed to develop a new IBD-specific Male Sexual Dysfunction Scale (the IBD-MSDS). Methods: We used a cross-sectional survey and enrolled male patients (N = 175) ≥18 years old who attended IBD clinics at 2 Boston hospitals. We collected information on sexual functioning via a 15-item scale. General male sexual functioning was measured using the International Index of Erectile Dysfunction (IIEF); the Patient Health Questionnaire (PHQ-9) measured depressive symptoms. Medical history and sociodemographic information were extracted from medical record review. Exploratory factor analyses (EFA) assessed unidimensionality, factor structure, reliability, and criterion and construct validity of the 15-item scale. We used regression models to identify clinical factors associated with sexual dysfunction. Results: EFA suggested retaining 10-items generating a unidimensional scale with strong internal consistency reliability, α = 0.90. Criterion validity assessed using Spearman's coefficient showing that the IBD-MSDS was significantly correlated with all the subscales of the IIEF. The IBD-MSDS was significantly correlated (construct validity) with the PHQ-9 (P < 0.001) and the composite score for active IBD cases (P < 0.05). Male sexual dysfunction in IBD was significantly associated with the presence of an ileoanal pouch anastomosis (P = 0.047), depression (P < 0.001), and increased disease activity (P = 0.021). Conclusions: We have developed and validated an IBD-specific scale to assess the psychosexual impact of IBD. This new survey tool may help physicians screen for and identify factors contributing to impaired sexual functioning in their male patients.

Development of a Sexual Dysfunction Scale for Women With Inflammatory Bowel Disease.

Background: Women with inflammatory bowel disease (IBD) may have decreased sexual function. To understand how common this condition is in our female patients, we developed a new IBD-specific Female Sexual Dysfunction Scale (the IBD-FSDS). Methods: We performed a prospective cross-sectional study of 454 female IBD patients ≥18 years of age attending 1 of 3 IBD clinics in the United States or Denmark. We gathered information on sexual function via a de novo 23-item scale. General sexual functioning was measured with the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale-Revised (FSDS-R). Depressive symptoms were measured with the Patient Health Questionnaire-9 (PHQ-9). Medical history and sociodemographic data were collected via chart review. Exploratory factor analyses (EFAs) of the English language version of IBD-FSDS assessed unidimensionality, factor structure, reliability, criterion validity, and construct validity. Results: EFAs suggested retaining 15-items creating a unidimensional scale with strong internal consistency reliability (α = 0.93). Validity of the English language IBD-FSDS was measured using Spearman's coefficient, demonstrating significant criterion validity with the FSDS-R (P < 0.05) and the FSFI (P < 0.05) and significant construct validity with the composite for cases of active IBD (P < 0.05) and PHQ-9 (P < 0.05). Sexual dysfunction in women with IBD was significantly associated with depression (P = 0.042), active IBD (P = 0.002), and no history of surgery (P = 0.044). Conclusions: We have developed and validated an IBD-specific scale to assess the psychosexual impact of IBD in women. This novel screening questionnaire may help health care providers recognize factors contributing to impaired sexual function in their female patients.

The Transition of the Gastrointestinal Patient from Pediatric to Adult Care.

Transition is the long process of developing independent self-management skills whereas transfer is the actual move from pediatric to adult-centered provider. Structured anticipated transition works best with timelines of tasks to master and discussion of the stylistic differences between pediatric and adult practices. Disease-specific issues need to be addressed, such as earlier timelines for diet-based therapies, parental support for critical illnesses, and differences in therapeutic strategies.

Dietary Iron and Heme Iron Consumption, Genetic Susceptibility, and Risk of Crohn's Disease and Ulcerative Colitis.

BACKGROUND: Dietary iron and heme, likely through their effect on gut commensal bacteria and colonic barrier function, have been shown to modulate colonic inflammation in animal models of colitis. Nonetheless, the link between dietary total and heme iron and risk of Crohn's disease (CD) and ulcerative colitis (UC) has not been previously explored. METHODS: We conducted a prospective cohort study of 165,331 U.S. women enrolled in the Nurses' Health Study and Nurses' Health Study II. Dietary information was collected using a validated food frequency questionnaire at baseline (1984) and updated every 2 to 4 years. Self-reported CD and UC diagnoses were confirmed through medical records review. We used Cox proportional hazard models to calculate hazard ratios and 95% confidence intervals while adjusting for potential confounders. In a case-control study nested within these cohorts, we evaluated the interaction between single-nucleotide polymorphisms associated with genome-wide susceptibility to CD and UC and dietary total and heme iron intake on risk of CD and UC using logistic regression modeling. RESULTS: Through 2011, over 3,038,049 person-years of follow-up, we documented 261 incident cases of CD and 321 incident cases of UC. Dietary heme iron was nonsignificantly associated with increased risk of UC (Ptrend = 0.12). This association seemed to be modified by the UC susceptibility locus, rs1801274, a coding variant in the FcγRIIA gene (Pinteraction = 7.00E-05). In contrast, there was no association between dietary heme iron and risk of CD (Ptrend = 0.67). We also did not observe an association between total dietary intake of iron and risk of CD or UC (All Ptrend > 0.35). CONCLUSION: In 2 large prospective cohort studies, dietary total and heme iron were not associated with risk of CD or UC. Our suggestive finding that the association between dietary heme iron intake and risk of UC may be modified by a coding variant in FcγRIIA gene warrants additional investigation.

Association of urinary phenolic compounds, inflammatory bowel disease and chronic diarrheal symptoms: Evidence from the National Health and Nutrition Examination Survey.

Endocrine disruptors such as phenolic compounds and parabens may be involved in chronic non-infective disease. While products incorporating these compounds are extensively utilized in consumer and personal products, little is known about their effect on bowel health. Inflammatory bowel disease (IBD) - consisting of the diseases ulcerative colitis and Crohn's disease - and irritable bowel syndrome are common chronic non-infectious diarrheal diseases. Despite limited knowledge on the etiology of IBD, these diseases have increased prevalence in industrialized countries and cause significant impairment to quality of life. In the present study we examine relationships between urinary environmental phenolic compounds, chronic diarrhea and inflammatory bowel disease. Data was obtained from the 2005-2010 US National Health and Nutrition Examination Survey (NHANES) including demographics, lifestyle factors, self-reported health conditions, inflammatory markers and urinary phenolic chemical concentrations. Only participants with complete environmental phenols & parabens component were included in our analysis. Chronic diarrheal symptoms were determined by using the 2009-2010 NHANES questionnaire which included questions pertaining to bowel health. We utilized chronic bowel leakage symptoms as a surrogate marker for chronic diarrhea. The presence of IBD was also analyzed from 2009 to 2010 NHANES data, as a sub-analysis for arthropathy directly querying the presence or absence of IBD. Among the subset of 5218 American adults aged 20-80 years in the NHANES study period who completed environmental phenols & parabens component, 25.5% reported chronic diarrheal symptoms. Abnormal markers of inflammation were present in 2200 (42.2%) of respondents. For IBD, 19 individuals with arthropathy confirmed a diagnosis of ulcerative colitis, and 1 person confirmed a Crohn's diagnosis. After adjustment for demographics, inflammatory and subsample weighing; lower paraben levels were associated with chronic bowel leakage (diarrheal) symptoms. Higher 4-tert-octylphenol levels was significantly associated with ulcerative colitis. Further study of underlying mechanisms should be considered.

Transition of the patient with IBD from pediatric to adult care-an assessment of current evidence.

Inflammatory bowel disease is a chronic disease of remitting and relapsing nature that is increasingly diagnosed in childhood or adolescence. The importance of the transition from pediatric to adult health care is increasingly recognized, yet the preparation of patient and family before transfer and early subsequent care in the adult health care environment can be variable and challenging. Pediatric providers need to start early and prepare patients in a stepwise fashion. However, patients may not have mastered all the steps before transfer or may regress to earlier behaviors during stress. Thus, adult providers will need to understand how to maintain and finish the transition process. This is an updated literature review of the transition process in inflammatory bowel disease, which focuses on the practical ways that both pediatric and adult health care providers can optimize care.

Dietary arachidonic and oleic acid intake in ulcerative colitis etiology: a prospective cohort study using 7-day food diaries.

INTRODUCTION: Dietary fatty acids may be involved in the etiology of ulcerative colitis (UC). Arachidonic acid (AA), an n-6 polyunsaturated fatty acid, is a precursor of the proinflammatory cytokines prostaglandin E2 and leukotriene B4, and its metabolism is competitively inhibited by oleic acid (OA). This study aimed to prospectively investigate whether AA is positively and OA is negatively associated with incident UC development, using data from 7-day food diaries. METHODS: A total of 25 639 men and women, aged between 40 and 79 years, from Norfolk, UK, were recruited into the prospective European Prospective Investigation into Cancer (EPIC)-Norfolk cohort between 1993 and 1997. At baseline, participants completed 7-day food diaries, checked by nutritionists using a database containing 11 000 foods and 55 000 portion sizes. The cohort was monitored until June 2004 to identify participants who developed UC. Each patient was matched for age and sex with four controls, and conditional logistic regression was used to calculate adjusted odds ratios for AA and OA intakes, and UC association. RESULTS: Of the participants, 26 (58% men) developed incident UC (53% left sided) after a median follow-up time of 3.8 years (0.5-8.3 years). The highest AA tertile was positively associated with an odds ratio of 6.09 [95% confidence interval (CI) 1.05-35.23], with a trend across tertiles [odds ratio (OR) 2.43, 95% CI 1.06-5.61, P=0.04]. The highest tertile of OA intake was inversely associated with a 0.03 OR for UC (95% CI 0.002-0.56) and an inverse trend (OR 0.30, 95% CI 0.10-0.90, P=0.03). CONCLUSION: Dietary AA was positively and OA was inversely associated with UC development, with large effect sizes in a dose-dependent manner. This supports roles for measuring these nutrients in future etiological studies and modifying intake in future interventional studies in patients with established disease.