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The prevalence of several autoimmune diseases, including thyroid dysfunction, has been reported to be increased in patients with endometriosis. Upregulated thyroid stimulation hormone (TSH) receptors in ectopic endometrium and elevated serum titers of TSH receptor antibodies (TRAb) IgG in endometriosis patients indicates an overlap in pathophysiology. However, cross-reactivity with other antibodies must be excluded. The objective of this study was to compare the expression of autoantibodies in women with endometriosis and two control groups to evaluate the potential of TRAb IgG as a diagnostic marker for endometriosis.This cross-sectional study was carried out in 172 women with surgically confirmed endometriosis and two control groups consisting of 50 healthy blood donors and 114 women from Malmö Offspring Study consisting of people from the general population. Serum levels of thyroid hormones, TSH and TRAb autoantibodies, AXIN1, and autoantibodies against follicle stimulating hormone (FSH), human chorionic gonadotropin (hCG), luteinizing hormone (LH), and their receptors, were analyzed. The patients answered a questionnaire and estimated their gastrointestinal symptoms using the Visual Analogue Scale for Irritable Bowel Syndrome.Of the endometriosis patients, 29.1 % had TRAb IgG above the present detection limit of ≥ 1.0 IE/L compared to 2.6 % of the controls from MOS (p 0.001) and 94.5 % had levels of TRAb over the previous detection limit ≥ 0.3 IE/L compared to 7.9 % of the controls (p 0.001). Titers of both TRAb IgG and IgM were increased in patients compared to controls from MOS and blood donors, respectively (p 0.001). There was no increase of autoantibodies against FSH, FSH receptor (FSHR), hCG, LH, LH receptor (LHR) or TSH compared to the blood donor controls. TRAb titers did not correlate with age, disease duration, AXIN1, TSH, thyroid hormones or gastrointestinal symptoms.TRAb IgG and IgM are slightly elevated in patients with endometriosis with no cross-reactivity with other autoantibodies. The results indicate that TRAb is truly elevated and thereby has the potential to be used to support the diagnosing of endometriosis.

The gut microbiota has been associated with many diseases, including endometriosis. However, very few studies have been conducted on this topic in human. This study aimed to investigate the association between endometriosis and gut microbiota. Women with endometriosis (N=66) were identified at the Department of Gynaecology and each patient was matched with three controls (N=198) from the general population. All participants answered questionnaires about socioeconomic data, medical history, and gastrointestinal symptoms and passed stool samples. Gut bacteria were analyzed using 16S ribosomal RNA sequencing, and in total, 58 bacteria were observed at genus level in both patients with endometriosis and controls. Comparisons of the microbiota between patients and controls and within the endometriosis cohort were performed. Both alpha and beta diversities were higher in controls than in patients. With the false discovery rate q

Several patients with irritable bowel syndrome (IBS) do not seek medical attention for their symptoms. When patients with IBS seek help, the majority of them are handled at primary healthcare centers, whereas research studies are performed at tertiary healthcare centers. The present study aimed to summarize findings from4,000 participants of the general population included in the Malmö Offspring Study (inclusion rate 46.7%). The participants were clinically examined, their blood and fecal samples collected, and their questionnaires completed. The participants were divided into subjects with or without self‑reported IBS and those having functional gastrointestinal (GI) symptoms in the past 2 weeks. The presence of IBS and GI symptoms in the participants were associated with each other. Zonulin levels did not differ between participants with or without GI diseases and were not associated with the degree of GI symptoms. The parameters low body weight at birth and small for gestational age were associated with the degree of the symptoms' influence on daily life. IBS and GI symptoms were positively associated with

As cardio metabolic disease manifestations tend to cluster in families there is a need to better understand the underlying mechanisms in order to further develop preventive strategies. In fact, genetic markers used in genetic risk scores, important as they are, will not be able alone to explain these family clusters. Therefore, the search goes on for the so called missing heritability to better explain these associations. Shared lifestyle and social conditions in families, but also early life influences may be of importance. Gene-environmental interactions should be explored. In recent years interest has grown for the role of diet-microbiota associations, as microbiota patterns may be shared by family members. In the Malmö Offspring Study that started in 2013, we have so far been able to examine about 4700 subjects (18–71 years) representing children and grandchildren of index subjects from the first generation, examined in the Malmö Diet Cancer Study during 1991 to 1996. This will provide rich data and opportunities to analyse family traits of chronic disease across three generations. We will provide extensive genotyping and phenotyping including cardiovascular and respiratory function, as well as markers of glucose metabolism. In addition, also cognitive function will be assessed. A 4-day online dietary recall will be conducted and gut as well as oral microbiota analysed. The ambition is to provide one of the first large-scale European family studies with individual data across three generations, which could deepen our knowledge about the role of family traits for chronic disease and its underlying mechanisms. Electronic supplementary material The online version of this article (10.1007/s10654-020-00695-4) contains supplementary material, which is available to authorized users.

BACKGROUND Recently, a technique has been developed to use magnetic resonance enterography (MRE) for the evaluation of small bowel motility. The hypothesis was that assessment of the motility index (MI) should reflect differences in motility between clinical conditions. AIM To aim of the present observational, cross-sectional study was to evaluate the use of the MI in daily clinical practice. METHODS All consecutive patients aged 18-70 years who were referred for MRE at the Department of Radiology during a 2-year period were asked to participate. Healthy volunteers were included as controls. MRE was prepared and conducted in accordance with clinical routines. On the day of examination, all the participants had to complete the visual analog scale for irritable bowel syndrome (IBS) and IBS-symptom severity scale. Maps of MI were calculated from dynamic MR images. ANOVA was used to evaluate differences in MI between groups, classified as healthy, Crohn’s disease, ulcerative colitis, IBS, other assorted disorders and dysmotility. Logistic and linear regression were applied to the MI values. All medical records were scrutinized for medical history. RESULTS In all, 224 examinations were included (inclusion prevalence 76.3%), with 22 controls and 202 patients. There was a significant difference in the MI of the jejunum (P = 0.021) and terminal ileum (P = 0.007) between the different groups. The MI was inversely associated with the mural thickness of the terminal ileum in men (P < 0.001) and women (P = 0.063) after adjustments, and tended to be lower in men than in women (P = 0.056). Subjectively observed reduction of motility on MRI was accomplished by reduced MI of terminal ileum in men (P < 0.001) and women (P = 0.030). In women, diarrhea was inversely associated with the MI of the jejunum (P = 0.029), and constipation was positively associated with the MI of the terminal ileum (P = 0.039). CONCLUSION Although MIs differ across diseases, a lower MI of the terminal ileum is mainly associated with male sex and an increased mural thickness. Symptoms are weakly associated with the MI.

International audience; Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.

Background Gastrointestinal (GI) symptoms are common in patients with ulcerative colitis (UC), even when the disease is in remission, possibly due to abnormalities in GI motility. Small bowel motility can be assessed globally and in specific intestinal regions during magnetic resonance enterography (MRE) using a displacement mapping technique. Purpose To investigate whether small bowel motility in MRE differs between patients with UC and controls, and if altered motility correlates with GI symptoms. Material and Methods In 2016–2018, patients who were admitted for MRE, regardless of clinical indication, were consecutively invited to the study. Healthy volunteers were recruited. The participants completed a questionnaire regarding GI symptoms and relevant clinical data were reviewed in the medical records. The dynamic imaging series obtained during MRE were sent for motility mapping and a motility index (MI) was calculated in jejunum, ileum and terminal ileum in all participants. Results In total, 224 patients and healthy volunteers were enrolled in the study. Fifteen were diagnosed with UC and 22 were considered healthy controls. In UC, the prevalence of GI symptoms was higher than in controls ( P Conclusion Jejunal motility is decreased in UC compared with healthy controls, but there is no relationship between small bowel motility and GI symptoms in UC.

Background and Aim: Altered gut microbiota have been suggested as part of an etiology of irritable bowel syndrome (IBS), but studies have shown contrasting results. Our aim was to examine gut microbiota composition in a large population-based cohort, with respect to presence and severity of bowel symptoms. Methods: The study cohort consisted of 1988 participants of the Malmo Offspring Study (mean age 40 years, 53% women). From a questionnaire, 19% reported having bowel symptoms the last 2 weeks and 15% reported having IBS. Bowel symptoms were assessed by a validated set of questions with visual analog scales. Gut microbiota was assessed by 16S rRNA gene sequencing (300 bp*2 in V1–V3 region) from fecal samples. The association between abundance of bacteria at genus level and bowel symptoms was calculated by logistic regression or general linear model, adjusted for false discovery rate (q

Telocytes (TCs) are recently described interstitial cells, present in almost all human organs. Among many other functions, TCs regulate gastrointestinal motility together with the interstitial cells of Cajal (ICCs). TCs and ICCs have close localization in the human myenteric plexus; however, the exact spatial relationship cannot be clearly examined by previously applied double immunofluorescence/confocal microscopy. Data on TCs and submucosal ganglia and their relationship to intestinal nerves are scarce. The aim of the study was to analyse the spatial relationship among these components in the normal human ileum and colon with double CD34/CD117 and CD34/S100 immunohistochemistry and high‐resolution light microscopy. TCs were found to almost completely encompass both myenteric and submucosal ganglia in ileum and colon. An incomplete monolayer of ICCs was localized between the TCs and the longitudinal muscle cells in ileum, whereas only scattered ICCs were present on both surfaces of the colonic myenteric ganglia. TC‐telopodes were observed within colonic myenteric ganglia. TCs, but no ICCs, were present within and around the interganglionic nerve fascicles, submucosal nerves and mesenterial nerves, but were only observed along small nerves intramuscularly. These anatomic differences probably reflect the various roles of TCs and ICCs in the bowel function.

Endometriosis and Irritable Bowel Syndrome (IBS) are common conditions among young women of reproductive age. The etiologies to the diseases are uncertain, but multifactorial pathophysiology has been proposed for each of them. Many studies have examined the two conditions separately, but the literature on the associations between endometriosis and IBS is sparse. However, there is an increasing amount of research on how endometriosis patients are likely to also have a diagnosis of IBS. Furthermore, endometriosis shares several features with IBS, such as low-grade inflammation and visceral hypersensitivity. This systematic review summarized published original articles in English that have compared associations between endometriosis and IBS. The inclusion criteria for articles in the review were: i) endometriosis was diagnosed by surgical methods, ii) gastrointestinal symptoms were examined in a structured manner and iii) IBS was diagnosed by Rome criteria. From the initial 254 publications identified on PubMed, Web of Science and EMBASE, 13 fulfilled the criteria and could finally be included in the summary. The findings from the review showed that women diagnosed with endometriosis seem to have a twofold or threefold risk to also fulfill the criteria for IBS. The summary risk estimate of the four studies included in the meta-analysis was 2.39 (95 % confidence interval: 1.83-3.11). In women initially diagnosed with IBS, some studies reported a threefold risk of having an endometriosis diagnosis. Despite the strong associations reported between the two conditions, this review also revealed a gap in adjusting for factors that may have affected the expression of gastrointestinal symptoms, e.g., phases of the menstrual cycle, medication and psychological aspects, which may have interpretation of the reviewed articles' results. The conclusion of this review is that there is a coexistence of gastrointestinal symptoms fulfilling the Rome criteria in patients with endometriosis, but it is uncertain whether there is a true comorbidity between endometriosis and IBS, or whether the gastrointestinal symptomatology in endometriosis depends on medication. Additionally, the adequacy of the Rome criteria to differentiate IBS from the shared symptomatology of other diseases with visceral hypersensitivity must be further evaluated.

Background Risk prediction is an essential part of preventative medicine and in recent years genomic information has become an interesting factor in risk models. Polygenic risk scores (PRS) combine the effect of many genetic variations into a single score which has been shown to have predictive value for many diseases. This study aimed to investigate the association between PRS for endometriosis and the clinical presentation of the disease. Methods Women with endometriosis (N = 172) were identified at the Department of Gynecology. All participants answered questionnaires regarding sociodemographic factors, lifestyle habits and medical history, registered bowel symptoms on the Visual Analog Scale for Irritable Bowel Syndrome and passed blood samples. DNA was extracted and samples were genotyped, and a PRS was calculated based on previous genome-wide association studies of endometriosis. Inflammatory proteins and TSH receptor antibodies (TRAb) in serum were analyzed. Results Inverse associations were identified between PRS and spread of endometriosis, involvement of the gastrointestinal tract and hormone treatment. However, significance was lost when calculated as p for trend and the specificity and sensitivity were low. There were no correlations between PRS and TRAb or inflammatory proteins. Conclusion The findings indicate that specific PRS should be developed to predict clinical presentations in patient with endometriosis.

This is the peer reviewed version of the following article: Stepien et.al (2021). Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma. International Journal of Cancer, which has been published in final form at https://doi.org/10.1002/ijc.33885. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited. Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (ORdoubling = 2.30, 95% confidence intervals [CI]: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.

Background Gastrointestinal (GI) symptoms similar to irritable bowel syndrome (IBS) are often present in women with endometriosis and microscopic colitis (MC). The objective of this study was to estimate GI symptoms in IBS, endometriosis, and MC, to compare the clinical expression of the diseases. Methods Women with IBS, endometriosis, and MC were identified by diagnosis codes at a tertiary center. The patients had to complete the visual analog scale for IBS to estimate specific GI symptoms. Women fulfilling Rome III criteria for IBS were diagnosed as IBS (n = 109) and divided into subgroups depending on predominating symptoms. Women diagnosed with endometriosis (n = 158) and MC (n = 88) were evaluated whether they also fulfilled the Rome III criteria for IBS. Results Women with IBS experienced aggravated abdominal pain, diarrhea, bloating and flatulence, nausea and vomiting, the urgency to defecate, the sensation of incomplete evacuation and intestinal symptom's influence on daily life, and impaired psychological wellbeing, compared to women with endometriosis. When patients with endometriosis also fulfilled the criteria for IBS, all symptoms in the 2 cohorts, except intestinal symptom's influence on daily life, were equal. Women with IBS or diarrhea-predominated IBS experienced aggravated abdominal pain, bloating and flatulence, intestinal symptom's influence on daily life, and impaired psychological well-being compared to MC, but at equal levels as MC with IBS-like symptoms. Conclusions Women with IBS generally experience aggravated GI symptoms and impaired psychological well-being compared to endometriosis and MC. Patients with endometriosis or MC, in combination with IBS, express similar symptoms as patients with sole IBS.

Objectives Gastrointestinal symptoms are common in endometriosis, but the mechanisms behind these symptoms are yet poorly understood. Associations between endometriosis and irritable bowel syndrome (IBS), celiac disease, and various autoimmune diseases have been reported. These diseases express characteristic autoantibodies. The aim of the current study was to investigate autoantibodies against gonadotropin-releasing hormone 1 (GnRH1) and luteinizing hormone (LH) and their receptors, tenascin-C, matrix metalloproteinase-9, deamidated gliadin peptide, and tissue transglutaminase in a cohort of women with endometriosis, compared to controls and women with IBS or enteric dysmotility. Study design One hundred seventy-two women with laparoscopy-verified endometriosis completed questionnaires regarding socio-demographics, lifestyle habits, medical history, and gastrointestinal symptoms, and sera were analyzed with ELISA for the abovementioned antibodies. Healthy female blood donors (N = 100) served as controls, and women with IBS or enteric dysmotility (N = 29) were used for comparison. Results A non-significantly higher prevalence of IgM antibodies directed at tenascin-C (7.6% vs. 2.0%; p = 0.06) was the only observed difference in autoantibody levels in endometriosis compared to controls. Antibody presence was not associated with any clinical parameters. Patients with IBS or enteric dysmotility expressed higher levels of IgM antibodies against GnRH1 compared to both patients with endometriosis (p = 0.004) and healthy controls (p = 0.002), and higher levels of tenascin-C antibodies compared to healthy controls (17.2% vs. 2.0%; p = 0.006). Conclusions Women with endometriosis do not express higher prevalence of autoantibodies found to be characteristic in other patient groups with gastrointestinal symptoms.

Objectives: Endometriosis has been associated with a wide range of factors. The disease share immunological features with autoimmune diseases, and the prevalence of both hypo- and hyperthyroidism has been reported to be increased. However, the associations have to be confirmed and the mechanisms explored. The aim of this observational study was to investigate socioeconomic factors, lifestyle habits, and somatic and mental comorbidities in endometriosis compared to the general population. Study design: In all, 172 women with endometriosis completed a study questionnaire and were interviewed regarding socioeconomic factors, lifestyle habits, psychological well-being, and medical history. Bowel symptoms were measured by the Visual Analogue Scale for Irritable Bowel Syndrome (VAS-IBS). Serum was analyzed for IgG levels of TSH receptor antibodies (TRAb) and anti-thyroid peroxidase (TPO) antibodies. Women from the general population served as controls. Differences were calculated by logistic regression, adjusted for confounders. Results: Alcohol intake, leisure time physical activity, body mass index and asthma were inversely, whereas IBS was positively associated with endometriosis. Hypothyroidism and anti-TPO antibodies did not associate, but elevated TRAb antibody titers were associated with endometriosis (odds ratio (OR): 539.26; 95% confidence interval (CI): 114.29–2544.32 for highest versus lowest tertile; p for trend < 0.001). Impaired psychological well-being (p for trend = 0.003) and current intake of antidepressant medication (OR: 3.54; 95% CI: 1.22–10.28; p = 0.020) associated with endometriosis, and impaired psychological well-being correlated with all gastrointestinal symptoms measured (all p < 0.001). Conclusions: Lifestyle habits and asthma are inversely associated, and IBS and impaired psychological well-being are positively associated with endometriosis. TRAb titers are associated with endometriosis, supporting a link between endometriosis, autoimmunity and thyroid pathophysiology, although overt thyroid diseases do not associate. (Less)

ObjectiveThe present population-based study aimed to examine the association of chronic stress and sleeping difficulties with self-reported irritable bowel syndrome (IBS), gastrointestinal (GI) symptoms past 2 weeks, and psychological well-being.ResultsThe Malmö Offspring Study included subjects from the general population to complete a questionnaire regarding sociodemographic factors, lifestyle factors, and medical health. Experience of chronic stress during the past or past 5 years was reported. Sleeping patterns included sleeping quality, sleeping hours per day, sleeping onset difficulties, and wake-up frequency. The severity of GI symptoms was measured with the visual analog scale for IBS. Associations of stress and sleeping habits with IBS and GI symptoms were calculated by logistic regression and generalized linear model, adjusted for sociodemographic and lifestyle factors. After exclusion of organic GI disorders or missing values, 2648 participants remained. Participants with self-reported IBS (n = 316) and GI symptoms (n = 459) were often women and smokers. After full adjustment, chronic stress past year was associated with GI symptoms (OR: 1.347; 95% CI 1.030–1.762), whereas stress past 5 years (OR: 1.415; 95% CI 1.058–1.892) and sleeping onset difficulties ≥ 3 times weekly (OR: 2.153: 95% CI 1.228–3.774) were associated with IBS. Stress, poor sleeping quality, sleeping onset difficulties, and IBS/GI symptoms were all associated with poor psychological well-being (p

The studies of early life factors and development of functional bowel diseases show inconsistent results. We therefore examined associations between certain early life factors and functional bowel symptoms in adulthood. Population-based cross-sectional study. Weight and height were measured and questionnaires were completed at the time point of enrollment in MOS. 1013 participants in the Malmö Offspring Study (MOS) without organic bowel disease with data available from the Swedish Medical Birth Registry. Associations were calculated between gestational age, birth weight, small-for-gestational-age and Apgar score from the Birth Registry, and symptoms according to the visual analog scale for irritable bowel syndrome (VAS-IBS) (abdominal pain, diarrhea, constipation, bloating and flatulence, vomiting and nausea, and symptoms’ influence on daily life) or self-reported IBS using logistic regression. In all, 253 (25.0%) participants reported bowel symptoms during the past 2 weeks and 179 (17.7%) self-reported IBS; conditions which were strongly associated (p < 0.001). Female sex and chronic stress were two independent factors more common among participants with bowel symptoms compared with asymptomatic participants (p < 0.001). Early life factors were not associated with presence of overall bowel symptoms (p = 0.080), any specific bowel symptoms or self-reported IBS. Lower birth weight (p = 0.038) and being born small for gestational age (p = 0.043) were associated with severe influence of intestinal symptoms on daily life in adulthood. Lower birth weight and small for gestational age are not associated with the presence of overall bowel symptoms but with more pronounced influence of such symptoms on daily adult life.Key pointsLower gestational age tended to be associated with functional bowel symptoms in adulthood.Lower birth weight and being small for gestational age are associated with increased negative influences of symptoms on daily life in adulthood.Patients born preterm or with low birth weights may be at increased risk to develop functional bowel symptoms later in life. Lower gestational age tended to be associated with functional bowel symptoms in adulthood. Lower birth weight and being small for gestational age are associated with increased negative influences of symptoms on daily life in adulthood. Patients born preterm or with low birth weights may be at increased risk to develop functional bowel symptoms later in life.

Pro-inflammatory diets are associated with risk of developing colorectal cancer (CRC), however inconsistencies exist in subsite- and sex-specific associations. The relationship between CRC and combined lifestyle-related factors that contribute towards a low-grade inflammatory profile has not yet been explored. We examined the association between the dietary inflammatory potential and an inflammatory profile and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. This cohort included 476,160 participants followed-up of 14 years and 5,991 incident CRC cases (3,897 colon and 2,094 rectal tumours). Dietary inflammatory potential was estimated using an Inflammatory Score of the Diet (ISD). An Inflammatory Profile Score (IPS) was constructed, incorporating the ISD, physical activity level and abdominal obesity. The associations between the ISD and CRC and IPS and CRC were assessed using multivariable regression models. More pro- inflammatory diets were related to a higher CRC risk, particularly for colon cancer; Hazar Ratio (HR) for highest versus lowest ISD quartile was 1.15 (95% confidence interval (CI) 1.04-1.27) for CRC, 1.24 (95% CI 1.09-1.41) for colon cancer and 0.99 (95% CI 0.83-1.17) for rectal cancer. Associations were more pronounced in men and not significant in women. The IPS was associated with CRC risk, particularly colon cancer among men; HRs for the highest versus lowest IPS were 1.62 (95% CI 1.31- 2.01) for colon cancer overall and 2.11 (95% CI 1.50-2.97) for colon cancer in men. This study shows that more pro-inflammatory diets and a more inflammatory profile are associated with higher risk of CRC, principally colon cancer and in men. This article is protected by copyright. All rights reserved.

Alterations in gut endocrine cells and hormone levels have been measured in patients with irritable bowel syndrome (IBS). The hypothesis of the present study was that hormone levels would change after 4 weeks of a starch- and sucrose-reduced diet (SSRD) intervention corresponding to decreased carbohydrate intake and symptoms. Among 105 IBS patients from primary and tertiary healthcare, 80 were randomized to SSRD, while 25 followed their ordinary diet. Food diaries, Rome IV, and IBS-symptom severity score (IBS-SSS) questionnaires were completed, and blood samples were collected at baseline and after the intervention. Serum C-peptide, gastric inhibitory peptide, glucagon, glucagon-like peptide-1, insulin, leptin, luteinizing hormone, polypeptide YY, and glucose were measured, along with the prevalence of autoantibodies against gonadotropin-releasing hormone; its precursor, progonadoliberin-2, and receptor; and tenascin C. Carbohydrate intake was lower in the intervention group than in controls at week 4 (median: 88 [66-128] g vs 182 [89-224] g; P < .001). The change in carbohydrate intake, adjusted for weight, was associated with a decrease in C-peptide (β: 14.43; 95% confidence interval [CI]: 4.12-24.75) and insulin (β: 0.18; 95% CI: 0.04-0.32) levels. Glucose levels remained unchanged. The IBS-SSS scores were lower in the intervention group but not in controls (P < .001), without any association with changes in hormone concentrations. There was no difference in autoantibody prevalence between patients and healthy controls. In conclusion, the hypothesis that reduced carbohydrate intake corresponded to altered hormonal levels in IBS was accepted; however, there was no relationship between hormonal concentrations and symptoms.

Sociodemographic factors and lifestyle habits affect body weight and body composition. A new syndrome, called normal-weight obesity (NWO), is found in individuals with normal weight and excess body fat in contrast to lean and overweight individuals. The aim of the present study was to explore the associations between sociodemographic factors and smoking and alcohol habits and lower versus higher BMI (≥25 kg/m2) and to examine whether categorization into lean, NWO, and overweight leads to further information about sociodemographic and lifestyle associations, compared with the common categorization defined by BMI. A cohort of 17,724 participants (9,936 females, 56.1%) from the EpiHealth study, with a median age of 61 (53–67) years, was examined. The participants answered a questionnaire about lifestyle, and weight and fat percentage were measured. Associations between sociodemographic factors and lifestyle habits and lower versus higher BMI, and lean versus NWO or lean and NWO versus overweight were calculated by binary logistic regression. Male sex, age, sick leave/disability, married/cohabitating, divorced/widowed, former smoking, and a high alcohol consumption were associated with higher BMI, whereas higher education and frequent alcohol consumption were inversely associated (all p<0.001). The associations were similar to associations with lean versus overweight and NWO versus overweight, except for age in the latter case. Associations with lean versus NWO differed from those of lower versus higher BMI, with an association with retirement, an inverse association with male sex (OR, 0.664; 95% confidence interval, 0.591–0.746), and no associations with marital status, smoking, and alcohol consumption frequency. Associations with age and occupation were sex dependent, in contrast to other variables examined. Thus, sociodemographic and lifestyle habits showed similar associations with lower versus higher BMI as with lean and NWO versus overweight, whereas lean versus NWO showed different directions of associations regarding sex, marital status, occupation, smoking, and frequency of alcohol consumption.

Background Quantified terminal ileal motility during magnetic resonance enterography (MRE) has been suggested to be used as a biomarker of Crohn's disease (CD). The aim of the present study was to evaluate this method in clinical practice. Methods Healthy volunteers and all consecutive patients referred to MRE during a 2-year period were asked to participate and complete the Irritable Bowel Syndrome-Symptom Severity Scale (IBS-SSS) to assess gastrointestinal symptoms. Medical records were scrutinized, and motility indices (MIs) were calculated from MR images. Key results Twenty-two healthy controls and 134 examinations with CD were included (inclusion rate: 76.3%). Patients with CD had increased mural thickness of the terminal ileum, increased fecal calprotectin, and more symptoms than controls. Patients with active CD had increased mural thickness of ileum and terminal ileum, higher MR activity indices, and signs of inflammation in laboratory analyses, but similar symptoms, compared with inactive disease. After exclusion of sole colon disease (n = 13), MI inversely correlated with mural thickness in terminal ileum, and MI was lower in active disease versus controls in ileum (P = .019) and terminal ileum (P = .005), and versus inactive disease in terminal ileum (P = .044). The area under the curve of MI in terminal ileum was 0.736 for active CD against healthy controls (P = .002) and 0.682 for active against inactive CD (P = .001). MIs were similar in controls and inactive CD. Conclusions and interferences MI reflects inflammatory activity in the intestine. Alterations in MI did not explain symptomatology in inactive CD, without measurable inflammatory parameters in morphology or laboratory analyses.

Objectives: Functional gastrointestinal (GI) symptoms, such as IBS (irritable bowel syndrome), have been suggested to be associated with autonomic neuropathy. We therefore examined associations between hemodynamic indices of autonomic control, functional GI symptoms and stress in a population-based cohort.Methods and materials: The study included 2094 participants of the Malmo Offspring Study (mean age 40.6 ± 13.8 years, 53.9% women). 509 (24.3%) reported having GI symptoms the last 2 weeks, without having organic GI disease, and 347 subjects (16.6%) reported IBS. Office and ambulatory 24-h systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate were measured. Associations between hemodynamic parameters and abdominal pain, diarrhea, constipation, bloating and flatulence, vomiting and nausea and psychological well-being according to the visual analog scale for IBS (VAS-IBS), and stress, were performed by Spearman’s correlation test and linear regression models.Results: Subjects who reported GI symptoms had lower office supine and standing DBP and lower 24 h SBP and DBP compared with those without GI symptoms. Regarding specific symptoms, diarrhea was correlated with 24-h measurements of SBP (rs = 0.197), DBP (rs = 0.173) and heart rate (rs = 0.134). Subjects with the most severe diarrhea had higher 24-h SBP (125.2 vs. 119.0 mmHg; p = .038), DBP (74.0 vs. 69.0 mmHg; p = .033) and heart rate (74.5 vs 71.1 beats/minute; p = .048), after adjustments for confounders, compared to the other. There were no associations between other GI symptoms, IBS, stress and hemodynamic alterations.Conclusion: Functional diarrhea was associated with hemodynamic indices of sympathetic activation, supporting a possible role of the autonomic nervous system in diarrhea. (Less)

Background High levels of blood glucose are thought to be associated with colorectal cancer (CRC) and hyperinsulinemia, an interstage in the development of CRC. The purpose of this study was to examine associations between incident CRC and blood glucose; plasma insulin; and the homeostasis model assessment for insulin resistance (HOMA2-IR), respectively, and to determine whether these associations were dependent on sex and cancer site. Methods The Malmö Diet and Cancer cardiovascular cohort comprises 6103 individuals. During 81,781 person-years of follow-up, 145 cases of CRC were identified. The hazard ratio of measured blood glucose and plasma insulin and calculated HOMA2-IR were estimated with Cox proportional hazard regression. Results An association was found between high levels of blood glucose and risk of CRC (HR: 1.72 for the highest compared with the lowest quartile; 95% CI: 1.05, 2.84; ptrend = 0.044), and colon cancer (HR: 1.70 for the highest compared with the lowest quartile; 95% CI: 0.87, 3.33; ptrend = 0.032). In men, an association was found between blood glucose and CRC (HR: 2.80 for the highest compared with the lowest quartile; 95% CI: 1.37, 5.70; ptrend = 0.001), and colon cancer (HR: 4.48 for the highest compared with the lowest quartile; 95% CI: 1.27, 15.84; ptrend = 0.007), but this was not found in women. No associations between plasma insulin, or HOMA2-IR, and CRC, were found. Conclusion High levels of blood glucose in men are associated with risk of colon cancer. The findings contribute to facilitating to identify those most in need of prevention and screening.

Patients with irritable bowel syndrome (IBS) exhibit low-grade inflammation and increased gut permeability. Dietary sugar has been shown to contribute to low-grade inflammation and increased gut permeability, and to correlate with gastrointestinal (GI) symptoms. The aim of the present study was to examine the effect of a starch- and sucrose-reduced diet (SSRD) on gastrointestinal (GI) and extra-intestinal symptoms in IBS. One hundred and five IBS patients (82 women, 46.06 &plusmn, 13.11 years), with irritable bowel syndrome-symptom severity scale (IBS-SSS) &gt, 175, were randomized to SSRD for 4 weeks or continued ordinary eating habits. The visual analog scale for irritable bowel syndrome (VAS-IBS), IBS-SSS, and 4-day food diaries were collected at baseline and after 2 and 4 weeks. After the intervention, one-third of the patients did not fulfill the criteria for IBS/functional gastrointestinal disorder. Half of the participants changed from moderate/severe disease to no/mild disease according to IBS-SSS. Comparisons between the groups showed decreased weight and sweet cravings, and parallel decreases in total IBS-SSS and extra-intestinal IBS-SSS scores, in the intervention group compared to controls (p &lt, 0.001 for all). When calculating separate extra-intestinal symptoms, belching (p = 0.001), muscle/joint pain (p = 0.029), urinary urgency (p = 0.017), and tiredness (p = 0.011) were decreased after introduction of SSRD compared to controls. In conclusion, SSRD improves both GI and extra-intestinal symptoms in IBS.

Accepted manuscript version, licensed CC BY-NC-ND 4.0. Background & Aims - To date, evidence on the association between physical activity and risk of hepatobiliary cancers has been inconclusive. We examined this association in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC). Methods - We identified 275 hepatocellular carcinoma (HCC) cases, 93 intrahepatic bile duct cancers (IHBCs), and 164 non-gallbladder extrahepatic bile duct cancers (NGBCs) among 467,336 EPIC participants (median follow-up 14.9 years). We estimated cause-specific hazard ratios (HRs) for total physical activity and vigorous physical activity and performed mediation analysis and secondary analyses to assess robustness to confounding (e.g. due to hepatitis virus infection). Results - In the EPIC cohort, the multivariable-adjusted HR of HCC was 0.55 (95% CI 0.38–0.80) comparing active and inactive individuals. Regarding vigorous physical activity, for those reporting >2 hours/week compared to those with no vigorous activity, the HR for HCC was 0.50 (95% CI 0.33–0.76). Estimates were similar in sensitivity analyses for confounding. Total and vigorous physical activity were unrelated to IHBC and NGBC. In mediation analysis, waist circumference explained about 40% and body mass index 30% of the overall association of total physical activity and HCC. Conclusions - These findings suggest an inverse association between physical activity and risk of HCC, which is potentially mediated by obesity. Lay summary - In a pan-European study of 467,336 men and women, we found that physical activity is associated with a reduced risk of developing liver cancers over the next decade. This risk was independent of other liver cancer risk factors, and did not vary by age, gender, smoking status, body weight, and alcohol consumption.

Background/aim The role of the microbiome has been widely discussed in the etiology of appendicitis. The primary aim was to evaluate the microbiome in the normal appendix and in appendicitis specifically divided into the three clinically and histopathologically defined grades of inflammation. Secondary aims were to examine whether there were any microbiome differences between proximal and distal appendices, and relate the microbiome with histopathological findings. Methods A prospective pilot study was conducted of children undergoing appendectomy for appendicitis. The diagnosis was based on histopathological analysis. Children with incidental appendectomy were used as controls. The proximal and distal mucosa from the appendices were analyzed with 16S rRNA gene sequencing. Results A total of 22 children, 3 controls and 19 appendicitis patients; 11 phlegmonous, 4 gangrenous, and 4 perforated appendices, were prospectively included. The amount of Fusobacterium increased and Bacteroides decreased in phlegmonous and perforated appendicitis compared to controls, but statistical significance was not reached, and this pattern was not seen in gangrenous appendicitis. No relation could be seen between different bacteria and the grade of inflammation, and there was a wide variation of abundances at phylum, genus, and species level within every specific group of patients. Further, no significant differences could be detected when comparing the microbiome in proximal and distal mucosa, which may be because the study was underpowered. A trend with more abundance of Fusobacteria in the distal mucosa was seen in appendicitis patients with obstruction (25 and 13 %, respectively, p = 0.06). Conclusion The pattern of microbiome differed not only between groups, but also within groups. However, no statistically significant differences could be found in the microbiome between groups or clinical conditions. No correlation between a specific bacteria and grade of inflammation was found. In the vast majority of cases of appendicitis, changes in microbiome do not seem to be the primary event. Since there seem to be differences in microbiome patterns depending on the sample site, the exact localization of biopsy sampling must be described in future studies.

Few studies have examined how lifestyle factors affect functional gastrointestinal disorders. The aim of this study was to see if leisure time physical inactivity, dietary habits or body mass index (BMI) were associated with increased risk of functional abdominal pain, functional bloating, functional constipation or functional diarrhea.This study was based on a questionnaire as part of the Swedish EpiHealth study. The cohort included 16,840 subjects between 45 and 75 years of age. Subjects with organic gastrointestinal diseases were excluded. Gastrointestinal symptoms were defined as functional abdominal pain, functional bloating, functional constipation and functional diarrhea. A meal (breakfast, lunch and dinner) was considered irregular if not taken every day. The impact of leisure time physical activity, dietary habits and BMI on functional symptoms were examined by logistic regression, adjusted for age, gender, socio-economy, smoking and alcohol habits.Higher the degree of physical activity, lower the risk for all kind of gastrointestinal complaints (p ≤ 0.001). Intakes of lunch more seldom or never versus every day were associated with diarrhea (OR: 1.592; 95% CI: 1.046-2.422). Irregular breakfast habits tended to associate with bloating (OR: 1.366; 95% CI 0.995-1.874). BMI was not significantly associated with gastrointestinal complaints, but BMI ≥25 kg/m(2) tended to reduce risk of constipation compared with BMI25 kg/m(2).Physical inactivity during leisure time shows independent associations with all functional gastrointestinal symptoms, whereas irregular dietary habits mainly associates with functional diarrhea. Higher degree of physical activity is associated with corresponding risk reductions of symptoms.

The diagnosis of pediatric appendicitis is still a challenge, resulting in perforation and negative appendectomies. The aim of this study was to evaluate novel biomarkers in urine and to use the most promising biomarkers in conjunction with the Pediatric Appendicitis Score (PAS), to see whether this could improve the accuracy of diagnosing appendicitis. A prospective study of children with suspected appendicitis was conducted with assessment of PAS, routine blood tests, and measurements of four novel urinary biomarkers: leucine-rich α-2-glycoprotein (LRG), calprotectin, interleukin 6 (IL-6), and substance P. The biomarkers were blindly determined with commercial ELISAs. Urine creatinine was used to adjust for dehydration. The diagnosis of appendicitis was based on histopathological analysis. Forty-four children with suspected appendicitis were included, of which twenty-two (50 %) had confirmed appendicitis. LRG in urine was elevated in children with appendicitis compared to children without (p

Our hypothesis was that carbohydrate, fat, and protein contents of meals affect satiety, glucose homeostasis, and hormone secretion. The objectives of this crossover trial were to examine satiety, glycemic-insulinemic response, and plasma peptide levels in response to 2 different recommended diabetes diets with equivalent energy content. One traditional reference breakfast and one test breakfast, with lower carbohydrate and higher fat and protein content, were randomly administered to healthy volunteers (8 men, 12 women). Blood samples were collected, and satiety was scored on a visual analog scale before and 3 hours after meals. Plasma glucose was measured, and levels of C-peptide, ghrelin, glucagon, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide (GIP), insulin, plasminogen activator inhibitor-1, and adipokines were analyzed by Luminex. Greater satiety, visual analog scale, and total and delta area under the curve (P < .001), and lower glucose postprandial peak (max) and change from baseline (dmax; P < .001) were observed after test meal compared with reference meal. Postprandial increments of C-peptide, insulin, and GIP were suppressed after test meal compared with reference meal (total delta area under the curve [P = .03, .006, and .004], delta area under the curve [P = .006, .003, and .02], max [P = .01, .007, and .002], and dmax [P = .004, .008, and .007], respectively). Concentrations of other peptides were similar between meals. A lower carbohydrate and higher fat and protein content provides greater satiety and attenuation of C-peptide, glucose, insulin, and GIP responses compared with the reference breakfast but does not affect adipokines, ghrelin, glucagon, glucagon-like peptide-1, and plasminogen activator inhibitor-1.

Background Clinical observations have suggested repeated gonadotropin-releasing hormone (GnRH) exposure to cause intestinal dysfunction and loss of enteric neurons. This has been further studied and confirmed in a rat in vivo model involving iterated GnRH treatments. Mechanisms behind are enigmatic since no GnRH receptors are found to be expressed in enteric neurons neither in man nor rat. Both species, however, harbor substantial subpopulations of luteinizing hormone (LH) receptor-immunoreactive myenteric neurons which suggests that intestinal GnRH-induced neuropathy may be mediated by LH release. Aims To reveal if exposures of GnRH or LH to rat myenteric neurons in vitro cause neuronal loss. Methods Primary cultured adult rat myenteric neurons were exposed to single or repeated treatments of the GnRH analog buserelin or the LH analog lutrotropin alpha, and neuronal survival was determined by cell counting. Possible presence of GnRH- or LH receptor -immunoreactive neurons was determined by immunocytochemistry. Results Exposure to the LH, but not the GnRH, analog caused significantly reduced neuronal survival. LH, but not GnRH, receptors were found to be expressed on cultured myenteric neurons. Conclusion Myenteric neurons express LH receptors in vitro and LH exposure causes reduced neuronal survival. This suggests that GnRH-induced enteric neuropathy in vivo is mediated by way of LH release and activation of enteric neuronal LH receptors.

The World Cancer Research Fund International has concluded strong evidence for that high intake of dairy products and foods containing dietary fiber and low intake of processed meat are associated with decreased risk of colorectal cancer (CRC). As food items are consumed together, it is important to study dietary patterns. The aim of the present study was to examine the association between an a priori constructed dietary index and incident CRC and between intake of processed meat, fiber, and dairy products and CRC. In the Malmo Diet and Cancer study cohort, 923 cases of CRC were identified, during 502 136 person-years of follow-up. A Colorectal Diet Quality Index (CDQI) was constructed regarding intakes of processed meat, fiber, and dairy products in relation to CRC. Higher index indicated a higher dietary quality. Higher CDQI was associated with lower risk of CRC [hazard ratios (HR): 0.57 for highest compared with lowest quintile; 95% confidence interval (CI): 0.43, 0.75; P

BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10-8) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10-6). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10-10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS. ispartof: GASTROENTEROLOGY vol:155 issue:1 pages:168-179 ispartof: location:United States status: published

The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. European Research Council (ERC-2009-AdG 232997); Health Research Fund (FIS): PI13/00061 to Granada; PI13/01162 to EPICMurcia, Regional Governments of Andalucı´a, Asturias, Basque Country, Murcia and Navarra, AGAUR - Generalitat de Catalunya (exp. 2014 SGR 726), The Health Research Funds RD12/0036/0018, cofunded by European Regional Development Fund (ERDF) ‘‘A way to build Europe (Spain);RZ-R was supported by the ‘‘Miguel Servet’’ program (CP15/00100) from the Institute of Health Carlos III and European Social Fund (ESF). (...), Zamora-Ros, R., Cayssials, V., Jenab, M., Rothwell, J.A., Fedirko, V., Aleksandrova, K., Tjønneland, A., Kyrø, C., Overvad, K., Boutron-Ruault, M.-C., Carbonnel, F., Mahamat-Saleh, Y., Kaaks, R., Kühn, T., Boeing, H., Trichopoulou, A., Valanou, E., Vasilopoulou, E., Masala, G., Pala, V., Panico, S., Tumino, R., Ricceri, F., Weiderpass, E., Lukic, M., Sandanger, T.M., Lasheras, C., Agudo, A., Sánchez, M.-J., Amiano, P., Navarro, C., Ardanaz, E., Sonestedt, E., Ohlsson, B., Nilsson, L.M., Rutegård, M., Bueno-de-Mesquita, B., Peeters, P.H., Khaw, K.-T., Wareham, N.J., Bradbury, K., Freisling, H., Romieu, I., Cross, A.J., Vineis, P., Scalbert, A.

Background Chronic inflammation plays a critical role in the pathogenesis of the two major types of gastric cancer. Several foods, nutrients, and non-nutrient food components seem to be involved in the regulation of chronic inflammation. Objective To assess the association between the inflammatory potential of the diet and the risk of gastric carcinoma, overall and for the two major subsites: cardia cancers and non-cardia cancers. Design A total 476160 subjects (30% males, 70% females) from the European Investigation into Cancer and Nutrition (EPIC) study were followed for 14 years, during which 913 incident cases of gastric carcinoma were identified, including 236 located in the cardia, 341 in the distal part of the stomach (non-cardia), and 336 with overlapping or unknown tumor site. The dietary inflammatory potential was assessed by means of an inflammatory score of the diet (ISD), calculated using 28 dietary components and their corresponding inflammatory scores. The association between the ISD and gastric cancer risk was estimated by hazard ratios (HR) and 95%-confidence intervals (CI) calculated by multivariate Cox regression models adjusted for confounders. Results The inflammatory potential of diet was associated with an increased risk of gastric cancer. The HR (95% CI) for each increase in one standard deviation of the ISD were 1.25 (1.12, 1.39) for all gastric cancers, 1.30 (1.06, 1.59) for cardia cancers, and 1.07 (0.89, 1.28) for non-cardia cancers. The corresponding values for the highest compared to the lowest quartiles of the ISD were 1.66 (1.26, 2.20), 1.94 (1.14, 3.30), and 1.07 (0.70, 1.70) respectively. Conclusions Our results suggest that low-grade chronic inflammation induced by the diet may be associated with gastric cancer risk. This pattern seems to be more consistent for gastric carcinomas located in the cardia than for those located in the distal stomach.

Food may induce inflammation and favor development of metabolic diseases, which have been associated with increased inflammation and potential risk of cognitive impairment. It is customary to know whether food or disease promote inflammation. Our hypothesis was that Okinawan-based Nordic (O-BN) diet leads to decreased circulating concentrations of inflammatory and neural biomarkers. The objectives of this study were to examine the effects of the O-BN diet on inflammatory and neural responses. First, 2 different breakfasts; one standard and another O-BN-based, were given in random order to 19 healthy volunteers. Second, a 12-week O-BN-dietary intervention was performed in type 2 diabetes mellitus (T2DM), where the participants were followed for another 16-weeks, with registration of anthropometry and metabolic parameters. Non-diabetic subjects served as controls at baseline. Plasma was analyzed for cytokines by a 10-plex Luminex assay and neurofilament light (NfL) by an ultrasensitive Single molecule assay. Cytokine levels decreased after a single breakfast intake, independent of diet composition. Cytokine levels were higher in T2DM than in controls. Anthropometric and metabolic parameters were improved by the dietary intervention. In parallel, cytokine levels were lowered, although only significantly for IL-18 (P = .001), with a tendency of significance for IL-12p70 (P = .07). Levels of IL-18 correlated with glucose, HbA1c and lipids, but not with body mass index, insulin or blood pressure. NfL levels increased during the intervention (P = .049). O-BN-based diet does not affect postprandial cytokine levels in health, whereas it renders decreased circulating IL-18 levels along with metabolic biomarkers in T2DM, with no beneficial effect on NfL.

ObjectiveIBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase–isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase–isomaltase (SI) gene variants for their potential relevance in IBS.DesignWe sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population.ResultsCSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case–control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (pConclusionsSI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.

The Okinawan-based Nordic (O-BN) diet improves anthropometry and metabolism in type 2 diabetes mellitus (T2DM) patients. The aim of this study was to study mechanisms behind improvements by examining Enterobacteriaceae abundance, microbial diversity, and concentrations of short-chain fatty acids (SCFAs). A secondary aim was exploring if metformin treatment affects microbiota or SCFAs. Thirty T2DM patients received the O-BN diet for 12 weeks. Faecal and blood samples were collected at baseline, 12 and 28 weeks. Although patients experienced weight loss and improved metabolic parameters, there were no significant changes in Enterobacteriaceae abundance or microbial diversity. Patients on metformin displayed higher Enterobacteriaceae abundance throughout the study (p = .008, p = .038, and p = .001, respectively). Isovaleric acid was decreased after 12 weeks (p = .018). Butyric acid was decreased at follow-up (p = .007). Improved anthropometry and metabolism in T2DM after introduction of the O-BN diet is not associated with changes in Enterobacteriaceae abundance, microbial diversity or SCFA concentrations.

Studies on fibre intake and incident colorectal cancer (CRC) indicate inverse associations. Differences by tumour stage have not been examined. We examined associations between fibre intake and its sources, and incidental CRC. Separate analyses were carried out on the basis of sex, tumour location and the Tumour, Node, Metastasis (TNM) classification. The Malmö Diet and Cancer Study is a population-based cohort study, including individuals aged 45–74 years. Dietary data were collected through a modified diet history method. The TNM classification was obtained from pathology/clinical records and re-evaluated. Among 27 931 individuals (60 % women), we found 728 incident CRC cases during 428 924 person-years of follow-up. Fibre intake was inversely associated with CRC risk (Ptrend=0·026). Concerning colon cancer, we observed borderline interaction between fibre intake and sex (P=0·052) and significant protective association restricted to women (Ptrend=0·013). Intake of fruits and berries was inversely associated with colon cancer in women (Ptrend=0·022). We also observed significant interactions between intakes of fibre (P=0·048) and vegetables (P=0·039) and sex on rectal cancer, but no significant associations were seen between intake of fibre, or its sources, in either of the sexes. Except for inverse associations between intake of fibre-rich cereal products and N0- and M0-tumours, we did not observe significant associations with different TNM stages. Our findings suggest different associations between fibre intake and CRC depending on sex, tumour site and fibre source. High fibre intake, especially from fruits and berries, may, above all, prevent tumour development in the colon in women. No clear differences by TNM classification were detected.

Background Altered microbial composition of the intestine, commonly referred to as dysbiosis, has been associated with several autoimmune diseases including primary Sjögren’s syndrome (pSS). The aims of the current study were to study the intestinal microbial balance in pSS and to identify clinical features associated with dysbiosis. Methods Forty-two consecutive pSS patients and 35 age-matched and sex-matched control subjects were included in the study in an open clinic setting. Stool samples were analyzed for intestinal dysbiosis using a validated 16S rRNA-based microbiota test (GA-map™ Dysbiosis Test; Genetic Analysis, Oslo, Norway). Dysbiosis and severe dysbiosis were defined in accordance with the manufacturer’s instructions. Patients were evaluated with regard to disease activity (European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI) and Clinical ESSDAI (ClinESSDAI)). In addition, patients were examined for laboratory and serological features of pSS as well as fecal calprotectin levels. Furthermore, patients were investigated regarding patient-reported outcomes for pSS (EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI)) and irritable bowel syndrome (IBS)-like symptoms according to the Rome III criteria. Results Severe dysbiosis was more prevalent in pSS patients in comparison to controls (21 vs 3%; p = 0.018). Subjects with pSS and severe dysbiosis had higher disease activity as evaluated by the ESSDAI total score (13 vs 5; p = 0.049) and the ClinESSDAI total score (12 vs 5; p = 0.049), lower levels of complement component 4 (0.11 vs 0.17 g/L; p = 0.004), as well as higher levels of fecal calprotectin (110 vs 33 μg/g; p = 0.001) compared to the other pSS patients. In contrast, severe dysbiosis among pSS patients was not associated with disease duration, IBS-like symptoms, or the ESSPRI total score. Conclusions Severe intestinal dysbiosis is a prevalent finding in pSS and is associated both with clinical and laboratory markers of systemic disease activity as well as gastrointestinal inflammation. Further studies are warranted to elucidate a potential causative link between dysbiosis and pSS.

Objectives: The pathophysiology behind functional gastrointestinal disease (FGID) has not been defined, but an intestinal accumulation of fermentable short-chain carbohydrates (FODMAPs) is thought to be involved. A restricted coffee intake is recommended. The aim was to investigate if symptoms of FGID were associated with intake of certain foods (including FODMAPs), as well as beverages (including coffee and tea). Method and materials: Data were used from participants, age range 45–75 years, who had answered the EpiHealth questionnaire about their background factors, health status and intake of food and beverages. After exclusion of organic bowel diseases, 16,840 participants remained. The impact of food and beverages on functional abdominal pain, functional bloating, functional constipation and functional diarrhea were examined by adjusted binary logistic regression. Results: Wholemeal bread (Swedish cracker) (OR: 1.361; 95% CI: 1.001–1.851) and white bread (low fiber content) (OR: 1.527; 95% CI: 1.075–2.169) were associated with constipation, whereas soft wholemeal bread (high fiber content) was associated with diarrhea (OR: 1.601; 95% CI: 1.040–2.463). Cheese was associated with bloating (OR: 1.460; 95% CI: 1.004–2.123). A high tea intake was associated with abdominal pain (p for trend =.003), bloating (p for trend =.039) and diarrhea (p for trend

Functional gastrointestinal disorders (FGIDs) are common disorders in the population. Lifestyle habits have been suspected to influence the presence and degree of symptoms, and many studies have examined the role of food components and physical activity on the disease development. The role of smoking and alcohol intake on FGID has been less thoroughly examined. This systematic literature review, of a large amount of studies from different countries around the world with different design and application of FGID criteria, shows that smoking seems to be associated with a significant 50% increased risk of FD for current compared with never smokers. The associations between smoking and other FGIDs are weak, if present at all. A moderate alcohol intake is not associated with FGIDs. On the other hand, a high alcohol intake may lead to development and aggravation of FGID symptoms, especially functional dyspepsia.

All Author: Veronika Fedirko, Hao Quang Tran, Andrew T. Gewirtz, Magdalena Stepien, Antonia Trichopoulou, Krasimira Aleksandrova, Anja Olsen, Anne Tjønneland, Kim Overvad, Franck Carbonnel, Marie-Christine Boutron-Ruault, Gianluca Severi, Tilman Kühn, Rudolf Kaaks, Heiner Boeing, Christina Bamia, Pagona Lagiou, Sara Grioni, Salvatore Panico, Domenico Palli, Rosario Tumino, Alessio Naccarati, Petra H. Peeters, H. B. Bueno-de-Mesquita, Elisabete Weiderpass, José María Huerta Castaño, Aurelio Barricarte, María-José Sánchez, Miren Dorronsoro, J. Ramón Quirós, Antonio Agudo, Klas Sjöberg, Bodil Ohlsson, Oskar Hemmingsson, Mårten Werner, Kathryn E. Bradbury, Kay-Tee Khaw, Nick Wareham, Konstantinos K. Tsilidis, Dagfinn Aune, Augustin Scalbert, Isabelle Romieu, Elio Riboli and Mazda Jenab., Background: Leakage of bacterial products across the gut barrier may play a role in liver diseases which often precede the development of liver cancer. However, human studies, particularly from prospective settings, are lacking. Methods: We used a case-control study design nested within a large prospective cohort to assess the association between circulating levels of anti-lipopolysaccharide (LPS) and anti-flagellin immunoglobulin A (IgA) and G (IgG) (reflecting long-term exposures to LPS and flagellin, respectively) and risk of hepatocellular carcinoma. A total of 139 men and women diagnosed with hepatocellular carcinoma between 1992 and 2010 were matched to 139 control subjects. Multivariable rate ratios (RRs), including adjustment for potential confounders, hepatitis B/C positivity, and degree of liver dysfunction, were calculated with conditional logistic regression. Results: Antibody response to LPS and flagellin was associated with a statistically significant increase in the risk of hepatocellular carcinoma (highest vs. lowest quartile: RR = 11.76, 95% confidence interval = 1.70–81.40; Ptrend = 0.021). This finding did not vary substantially by time from enrollment to diagnosis, and did not change after adjustment for chronic infection with hepatitis B and C viruses. Conclusions: These novel findings, based on exposures up to several years prior to diagnosis, support a role for gut-derived bacterial products in hepatocellular carcinoma development. Further study into the role of gut barrier failure and exposure to bacterial products in liver diseases is warranted., This work was supported by the French National Cancer Institute (L’Institut National du Cancer; INCA) (grant number 2009-139; Principal Investigator: M. Jenab). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); the Sicilian Government, AIRE ONLUS Ragusa, AVIS Ragusa, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), and Statistics Netherlands (the Netherlands); Nordic Centre of Excellence programme on Food, Nutrition and Health. (Norway); Health Research Fund (FIS), PI13/00061 to Granada), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, Regional Government of Asturias (Asturias, Spain), and ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council, and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 to EPIC-Oxford) and Medical Research Council (1000143 to EPIC-Norfolk) (United Kingdom); and a Girdlers’ New Zealand Health Research Council Fellowship (to Dr. K.E. Bradbury). The funding sources had no influence on the design of the study; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the paper for publication.

This work was supported by the French National Cancer Institute (L'Institut National du Cancer; INCA; grant number 2009-139; PI: M Jenab) and the Health Research Board of Ireland (award number HRA_PHS/2013/397; PI: DJ Hughes). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Nordic Centre of Excellence programme on Food, Nutrition and Health. (Norway); Health Research Fund (FIS), PI13/00061 to Granada), Regional Governments of Andalucia, Asturias, Basque Country, Murcia (No. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk and MR/M012190/1 to EPIC- Oxford) (UK); Medical Research Council (1000143 to EPIC- Norfolk) (UK). For information on how to submit an application for gaining access to EPIC data and/or bio-specimens, please follow the instructions at http://epic.iarc.fr/access/index.php, Stepien, M., Hughes, D.J., Hybsier, S., Bamia, C., Tjønneland, A., Overvad, K., Affret, A., His, M., Boutron-Ruault, M.-C., Katzke, V., Kühn, T., Aleksandrova, K., Trichopoulou, A., Lagiou, P., Orfanos, P., Palli, D., Sieri, S., Tumino, R., Ricceri, F., Panico, S., Bueno-De-Mesquita, H.B., Peeters, P.H., Weiderpass, E., Lasheras, C., Bonet Bonet, C., Molina-Portillo, E., Dorronsoro, M., Huerta, J.M., Barricarte, A., Ohlsson, B., Sjöberg, K., Werner, M., Shungin, D., Wareham, N., Khaw, K.-T., Travis, R.C., Freisling, H., Cross, A.J., Schomburg, L., Jenab, M.

BACKGROUND & AIMS: SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of Nav1.5. METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without (controls). Mutant forms of SCN5A were expressed in HEK-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study (GWAS) was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. RESULTS: Missense mutations were found in SCN5A in 13/584 patients (2.2%, probands). Diarrhea-predominant IBS (IBS-D) was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (IBS-C, 31%) than IBS-D (10%, P

Primary Sjogren’s syndrome (pSS) is an autoimmune disease affecting the exocrine glands, resulting in diminished glandular secretion and mucosal dryness. In addition, various non-exocrine organs, i...

OBJECTIVES: The pathophysiology behind gastrointestinal dysmotility in diabetes mellitus is unknown. Both esophageal dysmotility and gastroparesis have been shown to be associated with retinopathy, suggesting that microangiopathy is important in the common etiology. The aim of the present study was to examine whether patients with diabetes exhibit microangiopathy in the colon, and if present, to correlate microangiopathy with the clinical picture. METHODS: Consecutive patients subjected to colon surgery were identified in the southernmost districts of Skåne between January 2011 and May 2013. Medical records were scrutinized, and patients with a history of diabetes were noted. Gender, age, type of diabetes, treatment, complications, and other concomitant diseases were registered. Histopathologic re-evaluation of surgical biopsies with morphometric analyses of submucosal vessels in the colon was performed. Morphometric examination and clinical data were compared with non-diabetic patients. RESULTS: Of 1135 identified patients during the time period studied, 95 patients with diabetes were recognized and included. Fifty-three non-diabetic, randomly chosen patients served as controls. The mean age was 71.8 ± 10.2 and 71.4 ± 9.5 years in diabetic and non-diabetic patients, respectively. Microangiopathy was found in 68.4% of diabetic patients and in 7.5% of non-diabetic patients (p < 0.001). The wall-to-lumen ratio was 0.31 (0.23-0.46) in patients with diabetes compared with 0.16 (0.12-0.21) in non-diabetic patients (p < 0.001). No clinical association with microangiopathy could be verified. CONCLUSION: Microangiopathy in the colon is more common in diabetic than in non-diabetic patients. The clinical significance of microangopathy has yet to be clarified.

Although endometriosis is considered an inflammatory disease, no reliable diagnostic biomarkers exist for use in clinical practice. The aim was to investigate the inflammatory profile in endometriosis using an exploratory approach of inflammation-related proteins. Patients with laparoscopy-verified endometriosis (N = 172), women with microscopic colitis (N = 50), healthy controls (N = 31), and age-matched controls from the general population (N = 100) were enrolled and questionnaires regarding socioeconomic factors, lifestyle habits, and medical history were completed. Sera from patients and healthy controls were analyzed for 92 inflammatory biomarkers using Proximity Extension Assay technology (PEA). Plasma AXIN1 levels were analyzed in patients with endometriosis and controls from the general population by ELISA. General linear model adjusted for age, Mann&ndash, Whitney U-test, and principal component analysis (PCA) were used for statistical calculations. Serum levels of AXIN1 and ST1A1 were increased in endometriosis compared with MC (p &lt, 0.001) and healthy controls (p = 0.001), whereas CXCL9 levels were decreased. Plasma levels of AXIN1 were elevated in endometriosis compared with age-matched controls from the general population (30.0 (17.0&ndash, 38.0) pg/mL vs. 19.5 (15.0&ndash, 28.0) pg/mL, p &lt, 0.001). PCA analysis identified four clusters of proteins, where one cluster differed between endometriosis and controls, with strong correlations for AXIN1 and ST1A1. Plasma/serum AXIN1 is an interesting biomarker to be further evaluated in endometriosis.

BACKGROUND AND AIMS. Microscopic colitis (MC), predominantly affecting women, is associated with thyroid disorders, although purely defined of which type, or compared with controls. Its association with subclinical thyroid disorders, and related increased risk of cardiovascular diseases, has never been examined. The aim was to examine the prevalence of autoantibodies and subclinical and clinical thyroid dysfunction in female patients with MC compared with controls. METHODS. Women younger than 73 years old with biopsy-verified MC from the Department of Gastroenterology in Skåne, during 2002-2010, were invited. Out of 240 identified, 133 were finally included. A questionnaire about medical history was completed and blood samples were collected. Serum was analyzed for free thyroxin and triiodothyronine, thyroid-stimulating hormone and anti-thyroid peroxidase (anti-TPO) antibodies. A population-based group of 737 women served as controls. RESULT. The prevalence of thyroid disorders in patients was higher compared to controls [odds ratio (OR) = 2.98, 95% confidence interval (CI) = 1.78-4.99], but the prevalence of subclinical disorders was not different (OR = 1.18, 95% CI = 0.48-2.85). Anti-TPO antibodies were present in 10.6% of MC patients and 18.6% of controls. Twenty-five MC patients had hypothyroidism: 15 with Hashimoto's hypothyroidism, 6 with completed treatment of thyrotoxicosis and 4 with completed surgery after nontoxic goiter. CONCLUSION. Thyroid disorders, autoimmune hypothyroidism being most frequent, are more prevalent in patients with MC than in controls, whereas the prevalence of subclinical thyroid disorders in MC patients does not differ significantly from controls.

Background Many patients with microscopic colitis (MC) also suffer from symptoms of irritable bowel syndrome (IBS), but the only treatment given is corticosteroids for the diarrhoea. The aim of this study was to examine how social factors, life style factors and drug treatment affect symptoms and well-being in patients suffering from MC. Methods Women, over the age of 73 years, with biopsy-verified MC, at any Departments of Gastroenterology, Skane, between 2002 and 2010 were invited. The questionnaires Gastrointestinal Symptom Rating Scale (GSRS) and Psychological General Well-being Index (PGWB) were sent by mail, along with questions about social and life style factors, and medical history. Results Of 240 invited, 158 patients (66%) were included (median age 63 years, range 27–73 years). Only 26% had never smoked. Smoking and concomitant IBS were associated with both impaired gastrointestinal symptoms (OR = 3.96, 95% CI = 1.47–10.66 and OR = 4.40, 95% CI = 2.09–9.26, respectively) and impaired psychological well-being (OR = 2.77, 95% CI = 1.04–7.34 and OR = 3.82, 95% CI = 1.83–7.99, respectively). Treatment with proton pump inhibitors (PPI) was associated with increased gastrointestinal symptoms (OR = 3.44, 95% CI = 1.45–8.16). Age, social factors, and corticosteroids had no effect on symptoms or well-being. Smoking was the only risk factor associated with IBS (OR = 2.68, 95% CI = 1.115–6.26). Conclusion Smoking and IBS are associated with impaired gastrointestinal symptoms and psychological well-being in MC patients. PPI is associated with impaired gastrointestinal symptoms.