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Objectives. Postural orthostatic tachycardia syndrome (POTS) is characterized by cardiovascular autonomic dysfunction of unknown etiology with high a prevalence of gastrointestinal symptoms. The aim of the present study was to examine sociodemographic, lifestyle, and nutritional factors as well as inflammatory markers in patients with POTS. Materials and Methods. Forty-three patients with POTS and 61 healthy controls completed questionnaires about sociodemographic factors, lifestyle habits, and gastrointestinal symptoms. Blood samples were analyzed for serum levels of cobalamins, folic acid, iron, total iron-binding capacity (TIBC), ferritin, sodium, potassium, magnesium, phosphorus, albumin, high-sensitive C-reactive protein (CRP), and 25-hydroxyvitamin D (25-OH vitamin D). Results. POTS patients were predominantly women with a lower education level and were more often working part-time, on sick leave, and living alone compared with healthy controls. They reported lower alcohol intake and physical activity levels than controls. The nutrient intake was in general similar in both groups, but POTS patients had a higher intake of different drinks and reported more gastrointestinal symptoms than controls. POTS was associated with higher CRP levels (β: 1.370; 95% CI: 0.004–2.737; p = 0.049 ), lower albumin levels (β: -1.443; 95% CI: -2.648–(-0.238); p = 0.019 ), and higher sodium levels (β: 1.392; 95% CI: 0.559–2.225; p = 0.001 ). Abdominal pain ( p = 0.004 ) and intestinal symptoms’ influence on daily life ( p = 0.025 ) were negatively associated with albumin levels. Abdominal pain ( p = 0.011 ), vomiting and nausea ( p = 0.003 ), and intestinal symptoms’ influence on daily life ( p = 0.026 ) were associated with higher sodium levels. Serum levels representing iron and vitamin metabolism were equal between groups. Conclusions. POTS is associated with poorer sociodemographic status, but malnutrition cannot explain POTS or related gastrointestinal symptoms. Higher CRP and lower albumin levels suggest low-grade inflammation as one possible etiological factor.

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.

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We previously identified osteopontin (OPN) as a promising marker for the early detection of hepatocellular carcinoma (HCC). In this study, we investigated the association between prediagnostic circulating OPN levels and HCC incidence in a large population-based cohort. A nested case–control study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. During a mean follow-up of 4.8 years, 100 HCC cases were identified. Each case was matched to two controls and OPN levels were measured in baseline plasma samples. Viral hepatitis, liver function, and α-fetoprotein (AFP) tests were also conducted. Conditional logistic regression models were used to calculate multivariable odds ratio (OR) and 95% confidence intervals (95% CI) for OPN levels in relation to HCC. Receiver operating characteristics curves were constructed to determine the discriminatory accuracy of OPN alone or in combination with other liver biomarkers in the prediction of HCC. OPN levels were positively associated with HCC risk (per 10% increment, ORmultivariable = 1.30; 95% CI, 1.14–1.48). The association was stronger among cases diagnosed within 2 years of follow-up. Adding liver function tests to OPN improved the discriminatory performance for subjects who developed HCC (AUC = 0.86). For cases diagnosed within 2 years, the combination of OPN and AFP was best able to predict HCC risk (AUC = 0.88). The best predictive model for HCC in this low-risk population is OPN in combination with liver function tests. Within 2 years of diagnosis, the combination of OPN and AFP best predicted HCC development, suggesting that measuring OPN and AFP could identify high-risk groups independently of a liver disease diagnosis. Cancer Prev Res; 9(9); 758–65. ©2016 AACR.

Plasma levels of OPN (ng/ml) in HCC Cases and matched Controls.

Multivariable adjusted odds ratio (continuous line) and 95% CI (dotted line) are shown for the continuous levels of OPN values associated to HCC. Reference value was set at 47.15 ng/ml (the optimal cut-off point) for all subjects. For better visibility, the levels were truncated at 1 and 99 percentile of distribution.

A randomized clinical trial with a starch- and sucrose-reduced diet (SSRD) in irritable bowel syndrome (IBS) patients has shown clear improvement of participants' symptoms. The present study aimed to explore the effects of the SSRD on the gut microbiota and circulating micro-RNA in relation to nutrient intake and gastrointestinal symptoms.IBS patients were randomized to a 4-week SSRD intervention (n = 80) or control group (n = 25); habitual diet). At baseline and 4 weeks, blood and fecal samples, 4 day-dietary records, and symptom questionnaires were collected, that is, Rome IV questionnaires, IBS-symptom severity score (IBS-SSS) and visual analog scale for IBS (VAS-IBS). Micro-RNA was analyzed in blood and microbiota in faeces by 16S rRNA from regions V1-V2.The alpha diversity was unaffected, whereas beta diversity was decreased (p 0.001) along with increased abundance of Proteobacteria (p = 0.0036) and decreased abundance of Bacteroidetes phyla (p 0.001) in the intervention group at 4 weeks. Few changes were noted in the controls. The shift in beta diversity and phyla abundance correlated with decreased intakes of carbohydrates, disaccharides, and starch and increased fat and protein intakes. Proteobacteria abundance also correlated positively (RThe SSRD induced a shift in beta diversity along with several bacteria at different levels, associated with changes in nutrient intakes and reduced gastrointestinal symptoms. No corresponding changes were observed in the control group. Neither the nutrient intake nor the microbiota changes affected micro-RNA expression. The study was registered at ClinicalTrials.gov data base (NCT03306381).

Poor food habits with insufficient intake of micronutrients have been described in irritable bowel syndrome (IBS), which could be of importance for development of gastrointestinal and extraintestinal symptoms. The study aims were to examine intake and plasma/serum levels of micronutrients in IBS and whether these factors were associated with symptoms and restrictions and to study the effects of a starch- and sucrose-reduced diet (SSRD).One hundred five patients with IBS or functional gastrointestinal disorder (FGID) according to Rome IV criteria were included to SSRD/controls for 4 weeks. Patients completed a study questionnaire about lifestyle habits, medical health, IBS-symptom severity score (IBS-SSS), visual analog scale for IBS (VAS-IBS), and diary books before and after study start. Plasma/serum levels of micronutrients were analyzed at baseline.Intake of micronutrients at baseline was lower than recommended according to national guidelines. Gastrointestinal symptoms were inversely associated with intake and plasma levels of iron. Extraintestinal symptoms and fatigue inversely associated with intake of vitamin B6, phosphorus, magnesium, and iodine, as was plasma levels of iron, and positively associated with plasma iron-binding capacity. Fatigue was also inversely associated with calcium, iron, and zinc intakes. Plasma ferritin was lower in participants on restrictions. SSRD increased the intake of several vitamins, selenium, and fat, whereas sodium intake was decreased, with markedly reduced symptoms.Irritable bowel syndrome patients had low intake of micronutrients at baseline, which associated inversely with total IBS-SSS, extraintestinal IBS-SSS, and fatigue. SSRD increased the intake of several micronutrients, which correlated weakly with symptom improvement.

Advanced glycation endproducts (AGEs) may contribute to liver carcinogenesis because of their proinflammatory and prooxidative properties. Diet is a major source of AGEs, but there is sparse human evidence on the role of AGEs intake in liver cancer etiology. We examined the association between dietary AGEs and the risk of hepatobiliary cancers in the European Prospective Investigation into Cancer and Nutrition prospective cohort (n = 450 111). Dietary intake of three AGEs, Nε‐[carboxymethyl]lysine (CML), Nε‐[1‐carboxyethyl]lysine (CEL) and Nδ‐[5‐hydro‐5‐methyl‐4‐imidazolon‐2‐yl]‐ornithine (MG‐H1), was estimated using country‐specific dietary questionnaires linked to an AGEs database. Cause‐specific hazard ratios (HR) and their 95% confidence intervals (CI) for associations between dietary AGEs and risk of hepatocellular carcinoma (HCC), gallbladder and biliary tract cancers were estimated using multivariable Cox proportional hazard regression. After a median follow‐up time of 14.9 years, 255 cases of HCC, 100 cases of gallbladder cancer and 173 biliary tract cancers were ascertained. Higher intakes of dietary AGEs were inversely associated with the risk of HCC (per 1 SD increment, HR‐CML = 0.87, 95% CI: 0.76‐0.99, HR‐CEL = 0.84, 95% CI: 0.74‐0.96 and HR‐MH‐G1 = 0.84, 95% CI: 0.74‐0.97). In contrast, positive associations were observed with risk of gallbladder cancer (per 1 SD, HR‐CML = 1.28, 95% CI: 1.05‐1.56, HR‐CEL = 1.17; 95% CI: 0.96‐1.40, HR‐MH‐G1 = 1.27, 95% CI: 1.06‐1.54). No associations were observed for cancers of the intra and extrahepatic bile ducts. Our findings suggest that higher intakes of dietary AGEs are inversely associated with the risk of HCC and positively associated with the risk of gallbladder cancer., What's new? Advanced glycation endproducts (AGEs) are proteins or lipids with sugars added to them, and they can form in foods during cooking. They have pro‐inflammatory and pro‐oxidative properties in the body. These authors investigated whether dietary consumption of AGEs affect risk of liver cancer, using the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants filled out food questionnaires to determine AGE consumption. Higher intakes of AGEs were associated with reduced risk of hepatocellular carcinoma (HCC) and increased risk of gallbladder cancer. However, it's still not entirely clear how much AGEs in the diet contribute to circulating AGE levels.

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

World journal of gastroenterology 28(29), 3994 - 4006 (2022). doi:10.3748/wjg.v28.i29.3994, BACKGROUNDThe enteric nervous system (ENS) is situated along the entire gastrointestinal tract and is divided into myenteric and submucosal plexuses in the small and large intestines. The ENS consists of neurons, glial cells, and nerves assembled into ganglia, surrounded by telocytes, interstitial cells of Cajal, and connective tissue. Owing to the complex spatial organization of several interconnections with nerve fascicles, the ENS is difficult to examine in conventional histological sections of 3-5 μm.AIMTo examine human ileum full-thickness biopsies using X-ray phase-contrast nanotomography without prior staining to visualize the ENS.METHODSSix patients were diagnosed with gastrointestinal dysmotility and neuropathy based on routine clinical and histopathological examinations. As controls, full-thickness biopsies were collected from healthy resection ileal regions after hemicolectomy for right colon malignancy. From the paraffin blocks, 4-µm thick sections were prepared and stained with hematoxylin and eosin for localization of the myenteric ganglia under a light microscope. A 1-mm punch biopsy (up to 1 cm in length) centered on the myenteric plexus was taken and placed into a Kapton® tube for mounting in the subsequent investigation. X-ray phase-contrast tomography was performed using two custom-designed laboratory setups with micrometer resolution for overview scanning. Subsequently, selected regions of interest were scanned at a synchrotron-based end-station, and high-resolution slices were reported. In total, more than 6000 virtual slices were analyzed from nine samples.RESULTSIn the overview scans, the general architecture and quality of the samples were studied, and the myenteric plexus was localized. High-resolution scans revealed details, including the ganglia, interganglional nerve fascicles, and surrounding tissue. The ganglia were irregular in shape and contained neurons and glial cells. Spindle-shaped cells with very thin cellular projections could be observed on the surface of the ganglia, which appeared to build a network. In the patients, there were no alterations in the general architecture of the myenteric ganglia. Nevertheless, several pathological changes were observed, including vacuolar degeneration, autophagic activity, the appearance of sequestosomes, chromatolysis, and apoptosis. Furthermore, possible expulsion of pyknotic neurons and defects in the covering cellular network could be observed in serial slices. These changes partly corresponded to previous light microscopy findings.CONCLUSIONThe analysis of serial virtual slices could provide new information that cannot be obtained by classical light microscopy. The advantages, disadvantages, and future possibilities of this method are also discussed., Published by WJG Press, Beijing

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: Enteric neuropathy is described in most patients with gastrointestinal dysmotility and may be found together with reduced intraepidermal nerve fiber density (IENFD). The aim of this pilot study was to assess whether three-dimensional (3d) imaging of skin biopsies could be used to examine various tissue components in patients with gastrointestinal dysmotility. Material and methods: Four dysmotility patients of different etiology and two healthy volunteers were included. From each subject, two 3-mm punch skin biopsies were stained with antibodies against protein gene product 9.5 or evaluated as a whole with two X-ray phase-contrast computed tomography (CT) setups, a laboratory µCT setup and a dedicated synchrotron radiation nanoCT end-station. Results: Two patients had reduced IENFD, and two normal IENFD, compared with controls. µCT and X-ray phase-contrast holographic nanotomography scanned whole tissue specimens, with optional high-resolution scans revealing delicate structures, without differentiation of various fibers and cells. Irregular architecture of dermal fibers was observed in the patient with Ehlers-Danlos syndrome and the patient with idiopathic dysmotility showed an abundance of mesenchymal ground substance. Conclusions: 3d phase-contrast tomographic imaging may be useful to illustrate traits of connective tissue dysfunction in various organs and to demonstrate whether disorganized dermal fibers could explain organ dysfunction. (Less)

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

Objectives: Crohn's disease and ulcerative colitis are associated with an increased risk to develop anemia, cutaneous diseases, liver diseases, malignancy, osteoporosis, rheumatic diseases, thromboembolism and uveitis. The association between these diseases and microscopic colitis (MC) is not known. The aim of the present systematic review was to examine associations between MC and diseases observed in association with Crohn's disease and ulcerative colitis.Material and methods: According to the review protocol, original articles which described the prevalence of abovementioned diseases in relation to MC, were searched for in PubMed, Embase and Web of Science.Results: After exclusion of duplicates, 928 articles remained. Based on relevancy of their title, abstract or type of article, 16 articles were ordered in full text and after assessment, nine articles could be included in the review. A second research strategy with individual diseases rendered further two articles. Seven articles covered malignancy/neoplasia, where four showed no association with malignancy and three a reduced association compared with controls. Four articles covering rheumatic diseases showed an association between these diseases and MC. One study showed an association between MC and osteoporosis, whereas one did not. One study showed an association between MC and cutaneous diseases, whereas anemia, eye diseases and thromboembolism showed no associations.Conclusions: Due to short follow-up time in small studies, with selection bias due to exclusion of former or prevalent malignancy in an older population, no conclusions can be drawn concerning the true association between MC and malignancy. Rheumatic diseases seem to be associated with MC.

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.

Neuropathy should be considered as a possible etiological factor in patients with severe gastrointestinal symptoms, without signs of disease on routine investigations. Examinations of the autonomic and peripheral nervous systems may be helpful to select the patients who should be investigated with full‐thickness intestinal biopsy, and to give appropriate care.

Irritable bowel syndrome (IBS) is characterized by gastrointestinal symptoms. Overweight and increased risk of metabolic syndromes/diabetes are observed in IBS, conditions associated with plasminogen activator inhibitor-1 (PAI-1) and visfatin. The aim of this study was to measure blood levels of AXIN1, cholecystokinin (CCK), enkephalin, ghrelin, neuropeptide Y (NPY), PAI-1, and visfatin before and after a 4-week intervention with a starch- and sucrose-reduced diet (SSRD). A total of 105 IBS patients were randomized to either SSRD (

The pathogenesis of appendicitis is not understood completely and establishing a correct diagnosis can be clinically challenging. Previous investigations have shown an association between a T helper cell (Th)2-mediated inflammatory response, for example immunoglobulin E (IgE)-mediated allergy, and a decreased risk of complicated appendicitis. The present study aimed to evaluate differences in serum concentrations of IgE and Th2-associated interleukins (IL) in children with uncomplicated and complicated appendicitis.A prospective study including children15 years with appendicitis. Blood samples were collected preoperatively at the time of clinical assessment at the Pediatric Emergency Department and analyzed for concentrations of serum total IgE and IL-4, IL-9, and IL-13. Associations with complicated appendicitis were evaluated through logistic regression adjusting for age, appendicolith, and symptom duration.138 children with confirmed appendicitis were included. The median age was 10 (IQR 8-12) years, 87 (63%) were boys and 58 (42%) had complicated appendicitis. Children with complicated appendicitis had significantly higher concentrations of IL-9 and IL-13 compared to children with uncomplicated appendicitis. In the univariate logistic regression, high concentrations of IL-13 were associated with an increased risk of complicated appendicitis [OR 1.02 (95% CI 1.01-1.04)High levels of IL-13 seem to be associated with an increased risk of complicated appendicitis. This is incongruent with the hypothesis of an Th1/Th17-driven inflammation in this type of appendicitis.

The prevalence of functional gastrointestinal (FGI) symptoms and irritable bowel syndrome (IBS) is high in the society, but the etiology is mainly unknown. This population-based, cross-sectional study aimed to examine the associations between self-reported IBS or gastrointestinal (GI) symptoms within the past 2 weeks and concomitant diseases, drug consumption and family history of diseases. Participants from the Malm�� Offspring Study (MOS) answered a questionnaire about lifestyle habits, medical history and GI symptoms. Associations between self-reported IBS or GI symptoms and other diseases, drugs, and family history of diseases were calculated by logistic regression, adjusted for false discovery rate (FDR; q Of 2648 included patients, 316 had IBS and 459 had GI symptoms. There was an association between IBS and asthma (OR: 1.66; 95% confidence interval [CI]: 1.19���2.32; q = 0.018), and between IBS and using of prescription (OR: 1.44; 95% CI: 1.10���1.89; q = 0.028) and nonprescription drugs (OR: 1.92; 95% CI: 1.43���2.59; q q q q = 0.009), and myocardial infarction (OR: 1.48; 95% CI: 1.09���2.99; q = 0.043) were associated with GI symptoms. Abdominal pain was the specific symptom with strongest associations. IBS and GI symptoms were mainly associated with GI diseases in the family and drug consumption. To take a family and drug history is pertinent to all clinical history taking, irrespective of the symptomatology.

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.

Background Alcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed because of measurement error in self-reported assessments. Biomarkers of habitual alcohol intake may provide novel insight into the relationship between alcohol and cancer risk. Methods Untargeted metabolomics was used to identify metabolites correlated with self-reported habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n = 454). Statistically significant correlations were tested in independent datasets of controls from case-control studies nested within EPIC (n = 280) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n = 438) study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations of alcohol-associated metabolites and self-reported alcohol intake with risk of pancreatic cancer, hepatocellular carcinoma (HCC), liver cancer, and liver disease mortality in the contributing studies. Results Two metabolites displayed a dose-response association with self-reported alcohol intake: 2-hydroxy-3-methylbutyric acid and an unidentified compound. A 1-SD (log2) increase in levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR = 2.54, 95% CI = 1.51 to 4.27) and pancreatic cancer (OR = 1.43, 95% CI = 1.03 to 1.99) in EPIC and liver cancer (OR = 2.00, 95% CI = 1.44 to 2.77) and liver disease mortality (OR = 2.16, 95% CI = 1.63 to 2.86) in ATBC. Conversely, a 1-SD (log2) increase in questionnaire-derived alcohol intake was not associated with HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with liver disease mortality (OR = 2.19, 95% CI = 1.60 to 2.98) in ATBC. Conclusions 2-hydroxy-3-methylbutyric acid is a candidate biomarker of habitual alcohol intake that may advance the study of alcohol and cancer risk in population-based studies.

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.

Background: The influence of daily life exposure on the gastrointestinal tract is not fully understood. This study aimed to examine associations between functional gastrointestinal symptoms and sociodemographic status and lifestyle habits in the general population.Methods: The Malmö Offspring Study (MOS) included 2,648 participants from the general population who had answered a questionnaire about sociodemographic status, lifestyle habits, medical health, and self-reported irritable bowel syndrome (IBS). The visual analog scale for IBS (VAS-IBS) was completed to assess gastrointestinal symptoms the past 2 weeks. Subjects with organic gastrointestinal diseases were excluded. Presence of self-reported IBS and gastrointestinal symptoms the past 2 weeks were used as dependent variables to study the associations with age, sex, body mass index, education, occupation, marital status, smoking, snuff using, alcohol drinking frequency, alcohol amount per drinking occasion, physical activity at work, and physical activity during leisure time, using logistic regression and generalized linear model.Results: Self-reported IBS was associated with gastrointestinal symptoms the past 2 weeks (p < 0.001). There was an association between IBS and female sex (p < 0.001), former smoking (p < 0.001), present smoking (p < 0.001), and an inverse association with drinking 3–4 standard glasses per occasion (p = 0.038). Gastrointestinal symptoms were associated with age 50–59 years (p = 0.009), ≥60 years (p = 0.004), female sex (p < 0.001), studying (p = 0.036), unemployment (p = 0.009), former smoking (p = 0.001), and present smoking (p = 0.012). In men, IBS was associated with middle-age and both IBS and gastrointestinal symptoms were associated with unemployment (p < 0.001 and p = 0.001, respectively). In women, IBS was associated with present smoking (p = 0.022), and gastrointestinal symptoms were associated with former smoking and inversely associated with higher age (p = 0.006) and intermediate physical activity at work (p = 0.008). No associations were found with BMI, education, marital status, or snuff using.Conclusion: Self-reported IBS in the general population shows strongest association with female sex and smoking, whereas gastrointestinal symptoms also are associated with unemployment and inversely associated with higher age. In men, both IBS and gastrointestinal symptoms are associated with unemployment. In women, both IBS and gastrointestinal symptoms are associated with smoking, whereas symptoms are inversely associated with higher age and intermediate physical activity.

Increased amounts of starch and sugar have been added to the diet in the Western world during the last decades. Undigested carbohydrates lead to bacterial fermentation and gas production with diffusion of water, causing abdominal bloating, pain and diarrhea. Therefore, dietary advice is the first line of treatment of irritable bowel syndrome (IBS), a disease characterized by abdominal pain and altered bowel habits without any organic findings. Recently, a diet with a reduction of starch and sucrose led to a marked effect on gastrointestinal (GI) symptoms. The mechanism is unknown, but three possible mechanisms are presented in the present review. First, functional variants of the enzyme sucrase-isomaltase (SI) have been described in IBS. A subgroup of patients with IBS may thus suffer from partial SI deficiency with reduced digestion of starch and sucrose. Second, fructose absorption is less efficient than glucose absorption, which may lead to a physiological fructose malabsorption when ingesting high amounts of sucrose. A third mechanism is that high-sugar diets causing hyperglycemia, hyperinsulinemia and weight gain have led to painful neuropathy in animal models; whereas, improved metabolic control in humans has led to improvement of neuropathy. Starch- and sucrose-reduced diets lead to decreased levels of C-peptide, insulin, gastric inhibitory peptide, leptin and weight reduction. These metabolic changes may reduce the excitability of the hypersensitive nervous system often found in IBS and, thereby, lead to the reduced symptoms found after the diet. In conclusion, further studies are needed to investigate the pathophysiology behind development of symptoms after starch and sucrose intake, and the mechanisms behind symptom relief after reduced intake.

PURPOSE: Peripheral autonomic neuropathy, including enteric neuropathy, may be subtle and unrecognized for several years. Diagnosis of enteric neuropathy demands complicated examinations such as full-thickness bowel biopsy. We hypothesized that knowledge about simultaneous occurrence of different types of neuropathy would lead to faster recognition and diagnosis of autonomic/enteric neuropathy. The aim of the present systematic review was to increase the awareness of disease groups causing autonomic and enteric neuropathy along with sensorimotor neuropathy.METHODS: A systematic search strategy was used in PubMed, Embase and Web of Science. First, 4978 articles were identified. Review of titles/abstracts rendered exclusion of animal studies, articles not written in English or full-length, case reports, conference abstracts and duplicates until 357 articles remained. The full-length evaluation resulted in 35 studies (27 non-systematic reviews) which described objectively verified peripheral autonomic, enteric and sensorimotor neuropathy within the same disease.RESULTS: Diabetes is the most common disease in society rendering generalized peripheral neuropathy. Accumulation of tissue deposits in amyloidosis, Lewy body disorders and sarcoidosis lead to widespread peripheral neuropathy. Several autoimmune disorders such as systemic sclerosis and primary Sjogren's syndrome present themselves with neuropathy. Paraneoplastic neuropathy may appear prior to symptoms from the malignancy. Both the infection per se, as well as the autoimmune response to the infection, i.e., Guillain-Barre syndrome, may lead to widespread peripheral neuropathy. Hereditary disorders with disturbed metabolism lead to intermittent attacks of neuropathy.CONCLUSIONS: The major causes of generalized peripheral neuropathy are diabetes, diseases with tissue deposits, autoimmunity, infections, malignancy and metabolic diseases. (Less)

Purpose Infections from the oral microbiome may lead to exacerbations of chronic obstructive pulmonary disease (COPD). We investigated whether advanced dental cleaning could reduce exacerbation frequency. Secondary outcomes were disease-specific health status, lung function, and whether the bacterial load and composition of plaque microbiome at baseline were associated with a difference in outcomes. Patients and Methods One-hundred-one primary and secondary care patients with COPD were randomized to intervention with advanced dental cleaning or to dental examination only, repeated after six months. At baseline and at 12 months, data of exacerbations, lung function, COPD Assessment Test (CAT) score, and periodontal status were collected from questionnaires, record review, and periodontal examination. Student’s t-test and Mann–Whitney-U (MWU) test compared changes in outcomes. The primary outcome variable was also assessed using multivariable linear regression with adjustment for potential confounders. Microbiome analyses of plaque samples taken at baseline were performed using Wilcoxon signed ranks tests for calculation of alpha diversity, per mutational multivariate analysis of variance for beta diversity, and receiver operating characteristic curves for prediction of outcomes based on machine learning models. Results In the MWU test, the annual exacerbation frequency was significantly reduced in patients previously experiencing frequent exacerbations (p = 0.020) and in those with repeated advanced dental cleaning (p = 0.039) compared with the non-treated control group, but not in the total population including both patients with a single and repeated visits (p = 0.207). The result was confirmed in multivariable linear regression, where the risk of new exacerbations was significantly lower in patients both in the intention to treat analysis (regression coefficient 0.36 (95% CI 0.25–0.52), p < 0.0001) and in the population with repeated dental cleaning (0.16 (0.10–0.27), p < 0.0001). The composition of microbiome at baseline was moderately predictive of an increased risk of worsened health status at 12 months (AUC = 0.723). Conclusion Advanced dental cleaning is associated with a reduced frequency of COPD exacerbations. Regular periodontal examination and dental cleaning may be of clinical importance to prevent COPD exacerbations.

For a whole century, citrate has been used as an in vitro anticoagulant via chelation of calcium. Later, also EDTA was introduced as an anticoagulant. An often overlooked fact is that zinc is bound to citrate and EDTA with affinities much greater than that for calcium, imposing problems in biomedical research. In vivo, proteins of the S100 family are released from leukocytes and known to bind calcium. Some of them, e.g., calprotectin, also chelate zinc. Thus, at an inflamed site, the ratio between Ca2+ and Zn2+ is changed. This mechanism is of importance for the modulation of the activation of a fascinating family of post-translationally acting calcium-dependent thiol enzymes, the transglutaminases, which are inhibited by zinc. This presentation illustrates the complexity of in vitro studies with zinc. Moreover, it exemplifies the role of Zn2+ in pathophysiological situations such as celiac disease and neurodegeneration., Highlights • Citrate, EDTA and DTT bind zinc as well as calcium. • At inflammation, calprotectin binds Zn2+, which leads to low concentrations of the ion. • Zn2+ inhibits the activation of transglutaminases and peptidylarginine deiminases.

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

This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. For EPIC-Oxford, it is: Cancer Research UK C8221/A29017 and C8221/A19170, and Medical Research Council MR/M012190/1. RZ-R was supported by the “Miguel Servet” program (CP15/00100) from the Institute of Health Carlos III (Cofunded by the European Social Fund (ESF) - ESF investing in your future). This work was supported in part by the French National Cancer Institute (L’Institut National du Cancer; INCA; grant numbers 2009-139 and 2014-1-RT-02-CIRC-1; PI: M. Jenab). For pancreatic cancer in EPIC the work was supported by internal IARC funds., Background: Alcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed due to measurement error in self-reported assessments. The identification of biomarkers of habitual alcohol intake may enhance evidence on the role of alcohol in cancer onset. Methods: Untargeted metabolomics was used to identify metabolites correlated with habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n=454). Significant correlations were replicated in independent datasets of controls from casecontrol studies nested within EPIC (n=281) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n=438) study. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals for associations of alcohol-associated metabolites and selfreported alcohol intake with risk of pancreatic cancer, hepatocellular carcinoma (HCC), liver cancer, and liver disease mortality in the contributing studies. Results: Two metabolites displayed a dose-response association with alcohol intake: 2-hydroxy-3- methylbutyric acid and an unidentified compound (m/z(+):231.0839). A 1-SD increase in log2- transformed levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR=2.14; 1.39-3.31) and pancreatic cancer (OR=1.65; 1.17-2.32) in EPIC and liver cancer (OR=2.00; 1.44-2.77) and liver disease mortality (OR=2.16; 1.63-2.86) in ATBC. Conversely, a 1-SD increase in log2- transformed questionnaire-derived alcohol intake was not associated with HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with liver disease mortality (OR=2.19; 1.60-2.98) in ATBC. Conclusions: 2-Hydroxy-3-methylbutyric acid is a candidate biomarker of habitual alcohol intake that may advance the study of alcohol and cancer risk in population-based studies., Intramural Research Program of the National Cancer Institute at the National Institutes of Health, Cancer Research UK C8221/A29017 and C8221/A19170, Medical Research Council MR/M012190/1, “Miguel Servet” program (CP15/00100) from the Institute of Health Carlos III (Cofunded by the European Social Fund (ESF) - ESF investing in your future), French National Cancer Institute 2009-139 and 2014-1-RT-02-CIRC-1, IARC funds

There is increasing evidence suggesting a role of intestinal dysfunction in a number of autoimmune diseases. Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease with a documented increased level of intestinal inflammation, whereas multiple sclerosis (MS) is an organ-specific autoimmune disease known to exhibit increased intestinal permeability. In this study we determine to what extent intestinal inflammation, analysed by a faecal calprotectin ELISA, is accompanied by altered intestinal wall permeability, as measured by a lactulose and mannitol intestinal absorption assay. Intestinal permeability was increased in both pSS and MS patients, while faecal calprotectin was elevated in pSS but normal in MS. Our findings suggest different mechanisms mediating a leaky gut in these two diseases: in pSS there is autoimmune attack directly on the intestinal wall; in MS, with autoimmunity being limited to the CNS, it may be due to a disturbed CNS regulation of enteric nerve function., Highlights • Intestinal permeability analysed by sugar absorption is increased in primary Sjögren’s syndrome and multiple sclerosis. • Intestinal wall inflammation as determined by faecal calprotectin is observed in pSS but not in MS. • Leaky gut may be due to autoimmune targeting of the intestinal wall in pSS and to disturbed intestinal innervation in MS.

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.

The cytoplasmic protein AXIN1 is involved in the Wnt signalling pathway and its expression is increased in patients with endometriosis compared with healthy controls. The aim of the present cross-sectional study was to further assess the levels of AXIN1 and other inflammatory biomarkers in patients with endometriosis. Patients with laparoscopy-verified endometriosis were recruited (n=172) and completed a questionnaire regarding socioeconomic factors, lifestyle habits and medical history. Plasma AXIN1 and high-sensitivity C-reactive protein (hs-CRP) levels were analysed by ELISA. The levels of calprotectin were determined in the faeces, and the haemoglobin concentration and number of erythrocytes, leukocytes and platelets were determined in the blood in a subgroup of 64 patients during clinical routine procedures. F-calprotectin expression was detected in 18 women (28.1%), who had more severe constipation and more frequently experienced incomplete evacuation when defecating, and 5 women (7.8%) exhibited elevated levels. P-AXIN1 levels were higher in patients who received hormonal treatment, and correlated inversely with faecal-calprotectin levels (P=0.003), B-haemoglobin levels (P=0.030) and the numbers of B-erythrocytes (P=0.033) and B-platelets (P=0.017), but were not correlated with hs-CRP levels (P=0.818). Higher levels of AXIN1 were associated with the duration of the gastrointestinal symptoms and with diarrhoea, constipation, vomiting and nausea and the intestinal symptoms' effect on quality of life, and tended to be associated with the duration of endometriosis. Hs-CRP expression was not associated with the clinical characteristics or symptoms of endometriosis, but higher levels were associated with obesity (P=0.002) and hormonal treatment (P=0.011). In conclusion, P-AXIN1 expression was negatively correlated with certain inflammatory biomarkers and was positively associated with gastrointestinal symptoms. P-AXIN1 levels were increased in patients who received hormonal treatment, highlighting the importance of obtaining native samples for future studies regarding its role in the development and presentation of endometriosis. However, hs-CRP and other studied biomarkers seemed to be of no value for the assessment and diagnosis of endometriosis.

The cover image is based on the Case Report Autonomic and peripheral neuropathy with reduced intraepidermal nerve fiber density can be observed in patients with gastrointestinal dysmotility by Bodil Ohlsson, Béla Veress, LARS B DAHLIN et al., https://doi.org/10.1002/ccr3.2575. [Image: see text]

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.

Background & Aims There is an unclear association between intake of fish and long-chain n-3 polyunsaturated fatty acids (n-3 LC-PUFAs) and colorectal cancer (CRC). We examined the association between fish consumption, dietary and circulating levels of n-3 LC-PUFAs, and ratio of n-6:n-3 LC-PUFA with CRC using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods Dietary intake of fish (total, fatty/oily, lean/white) and n-3 LC-PUFA were estimated by food frequency questionnaires given to 521,324 participants in the EPIC study; among these, 6291 individuals developed CRC (median follow up, 14.9 years). Levels of phospholipid LC-PUFA were measured by gas chromatography in plasma samples from a sub-group of 461 CRC cases and 461 matched individuals without CRC (controls). Multivariable Cox proportional hazards and conditional logistic regression models were used to calculate hazard ratios (HRs) and odds ratios (ORs), respectively, with 95% CIs. Results Total intake of fish (HR for quintile 5 vs 1, 0.88; 95% CI, 0.80–0.96; Ptrend = .005), fatty fish (HR for quintile 5 vs 1, 0.90; 95% CI, 0.82–0.98; Ptrend = .009), and lean fish (HR for quintile 5 vs 1, 0.91; 95% CI, 0.83–1.00; Ptrend = .016) were inversely associated with CRC incidence. Intake of total n-3 LC-PUFA (HR for quintile 5 vs 1, 0.86; 95% CI, 0.78–0.95; Ptrend = .010) was also associated with reduced risk of CRC, whereas dietary ratio of n-6:n-3 LC-PUFA was associated with increased risk of CRC (HR for quintile 5 vs 1, 1.31; 95% CI, 1.18–1.45; Ptrend < .001). Plasma levels of phospholipid n-3 LC-PUFA was not associated with overall CRC risk, but an inverse trend was observed for proximal compared with distal colon cancer (Pheterogeneity = .026). Conclusions In an analysis of dietary patterns of participants in the EPIC study, we found regular consumption of fish, at recommended levels, to be associated with a lower risk of CRC, possibly through exposure to n-3 LC-PUFA. Levels of n-3 LC-PUFA in plasma were not associated with CRC risk, but there may be differences in risk at different regions of the colon.

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.