I urval från Stockholms universitets publikationsdatabas

• Comorbidity of atopic diseases and gastro-oesophageal reflux evidence of a shared cause

  2022. Bronwyn K. Brew (et al.). Clinical and Experimental Allergy

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  Introduction: Gastro-oesophageal reflux disease (GERD) is the most common non-allergic comorbidity in adults with asthma; however, comorbidity with other atopic diseases such as eczema and hay fever is unclear. The objective was to assess the comorbidity of GERD with asthma and atopic diseases and to investigate possible mechanisms, including genetic and/or affective factors.

  Methods: A co-twin control study harnessing 46 583 adult twins. Questionnaires on health status were linked to national patient and prescribed drug register data. Analyses tested associations of comorbidity between multiple definitions of atopic diseases (self-report and register-based) with GERD. Comparisons were made between unpaired, monozygotic (MZ) and dizygotic (DZ) twins to assess genetic liability. Affective traits (depression, anxiety and neuroticism) were added to models as possible explanatory factors.

  Results: The risk of GERD in those with asthma was OR (odds ratio) 1.52 (95% CI 1.38, 1.68), hay fever OR 1.22 (95%CI 1.12, 1.34) and eczema OR 1.23 (95%CI 1.10, 1.38). Adjusting for affective traits completely attenuated the comorbidity associations for hay fever and eczema with GERD, and partly for asthma with GERD. Co-twin control associations attenuated suggesting a shared cause for both GERD and atopic diseases. For example, all twins adjOR 1.32 (95%CI 1.00, 1.74), 0.97 (95% CI 0.76–1.23) and 1.11 (95%CI 0.85–1.45) for self-report asthma, hay fever and eczema with GERD respectively.

  Conclusions: GERD is a common comorbidity in adults with asthma, hay fever and/or eczema. We found evidence for shared mechanisms suggesting common underlying causes that may involve affective traits requiring further investigation.

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• Evaluating the construct validity and internal consistency of the Sickness Questionnaire in a Swedish sample of adults with longstanding pain

  2022. Jenny Åström (et al.). Scandinavian Journal of Pain 22 (1), 88-96

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  Objectives: Low-grade inflammation is a possible contributing factor in the development and persistence of chronic primary pain syndromes. Related to inflammatory activity is sickness behavior, a set of behavioral responses including increased pain sensitivity, fatigue, malaise, fever, loss of appetite, as well as depressive behavior and anhedonia. To capture these behavioral responses and their relation to longstanding pain, psychometrically sound self-report questionnaires are needed. The Sickness Questionnaire (SicknessQ) was developed to assess self-reported sickness behavior based on studies on acute immune activation while maintaining relevance for persistent conditions. The aim of the current study was to evaluate aspects of the validity and reliability of the SicknessQ in a Swedish sample of persons with longstanding pain.

  Methods: Aspects of construct validity were evaluated by means of performing a confirmatory factor analysis (CFA) (testing structural validity) and by relevant hypothesis testing i.e., that ratings of sickness behavior in combination with other related factors (e.g., depression and anxiety) would be significantly related to ratings of avoidance. Reliability was evaluated by means of analyzing the internal consistency of items.

  Results: Following the CFA, a non-significant Chi-Square test (chi(2) [32, N=190] = 42.95, p=0.094) indicated perfect model fit. Also, the relative fit indices supported adequate model fit (CFI = 0.978; TLI = 0.969; RMSEA = 0.0430). Sickness behavior (p<0.0001), depression (p<0.05) and pain duration (p<0.05) significantly contributed to the regression model, explaining 45% of the total variance in avoidance. Internal consistency was adequate, as indicated by a Cronbach's alpha value of 0.82 for the entire questionnaire.

  Conclusions: Results indicate that the SicknessQ has adequate structural validity as well as adequate internal consistency, and is significantly associated with avoidance. The SicknessQ appears to have utility as a self-report questionnaire to assess symptoms of sickness behavior for adults with longstanding pain.

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• An Increasing Incidence of Upper Gastrointestinal Disorders Over 23 Years

  2021. Anna Andreasson (et al.). American Journal of Gastroenterology 116 (1), 210-213

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  INTRODUCTION: We hypothesized that the prevalence of functional dyspepsia and gastroesophageal reflux disease in the community may be increasing.

  METHODS: Randomly selected adults were surveyed on 4 occasions: 1988 (n = 1,151, 21–79 years, response rate [rr] = 90%), 1989 (n = 1,097, 22–80 years, rr = 87%), 1995 (n = 1,139, 20–85 years, rr = 76%), and 2011 (n = 1,175, 20–93 years, rr = 63%).

  RESULTS: In functional dyspepsia, the odds of postprandial distress syndrome tripled over 23 years' follow-up (odds ratio [OR]: 3.55; 95% confidence interval [CI]: 2.60–4.84, mixed-effect regression analysis), whereas a small decrease in epigastric pain syndrome was observed (OR: 0.65, 95% CI: 0.42–1.00). The odds of reporting gastroesophageal reflux disease doubled (OR: 2.02; 95% CI: 1.50–2.73).

  DISCUSSION: The underlying mechanisms behind the increase in postprandial distress syndrome and gastroesophageal reflux disease remain to be determined.

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• Clusters of community-dwelling individuals empirically derived from stool diaries correspond with clinically meaningful outcomes

  2021. Michael P. Jones (et al.). European Journal of Gastroenterology and Hepathology 33 (1S), e740-e745

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  Background Functional gastrointestinal disorders (FGIDs) are diagnosed according to expert consensus criteria based on recall of symptoms over periods of 3 months or longer. Whether the expert opinion concords with underlying disease process and whether individual recall is accurate are both in doubt. This study aimed to identify naturally occurring clusters of individuals with respect to symptom pattern, evaluate their significance, compare cluster profiles with expert opinion and evaluate their temporal stability.

  Methods  As part of a random population study of FGID-related symptoms, we first explored the use of prospective stool and symptom diaries combined with empirical grouping of individuals into clusters using nonhierarchical cluster analysis.

  Results The analysis identified two clusters of individuals, one of which was characterized by elevated scores on all domains of symptoms (26% of the sample) and one that was low to average on all domains (74% of the sample). Cluster membership was found to be stable over a long interval. Clusters were found to differ on most domains of quality-of-life (d = 0.46–0.74), self-rated health (d = −0.42) and depression (d = −0.42) but not anxiety. Prevalence of clinically diagnosed irritable bowel syndrome (IBS) was higher in the more impacted cluster (33%) compared with the healthy cluster (13%; P < 0.0001).

  Conclusion A naturalistic classification of individuals challenges consensus criteria in showing that some IBS individuals have a symptom experience not unlike health. The proposed approach has demonstrated temporal stability over time, unlike consensus criteria. A naturalistic disease classification system may have practical advantages over consensus criteria when supported by a decision-analytic system.

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• Duodenal eosinophilia and the link to anxiety

  2021. Jukka Ronkainen (et al.). Neurogastroenterology and Motility 33 (10)

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  Introduction: The concept of gut-to-brain communication via microbial or inflammatory pathways is gaining increased attention but genuine pathology directly linking gut perturbation to anxiety is lacking. We hypothesized that duodenal eosinophilia, as known to occur in functional dyspepsia (FD), may be an underlying cause of anxiety and may help explain the striking association between FD and anxiety.

  Methods: Randomly selected subjects from the national population register of Sweden completed the validated Abdominal Symptom Questionnaire; 1000 completed esophagogastroduodenoscopy and the Hospital Anxiety and Depression Scale questionnaire. Duodenal biopsies were obtained from 1(st) (D1) and 2(nd) portion (D2). Eligible subjects who underwent endoscopy (n = 887) were invited to participate in a 10-year follow-up study with the same questionnaires. Among endoscopy normal subjects, FD was identified by Rome criteria, and controls were symptom free. Duodenal eosinophilia was based on pre-defined cut-offs. Finding are reported as odds ratios (ORs) with 95% confidence interval and p-value.

  Results: The study population comprised 89 cases with FD and 124 healthy controls (mean age 62 years, SD 12, 34% male). Clinical anxiety at follow-up was elevated in those with D1 eosinophilia at baseline considering either new-onset anxiety (OR = 4.5, 95% CI 0.8, 23.8; p = 0.08) or follow-up anxiety adjusting for baseline anxiety (OR = 4.51 (95% CI 1.03, 19.81; p = 0.046).

  Conclusion: Duodenal eosinophilia may potentially be a mechanism linked to anxiety independent of FD.

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• Ileocolonic Histopathological and Microbial Alterations in the Irritable Bowel Syndrome

  2021. Nicholas J. Talley (et al.). Clinical and Translational Gastroenterology 12 (1)

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  INTRODUCTION: Histopathological alterations in the ileum and colon in irritable bowel syndrome (IBS) are controversial, and normal values are poorly established. We hypothesized that changes in mucosal immune cells characterize IBS and key changes in immune composition are associated with the mucosa-associated microbiota (MaM).

  METHODS: A nested case-control study (48 IBS and 106 controls included) from 745 colonoscopy participants in a random population sample. Intraepithelial lymphocytes (IELs)/100 enterocytes and eosinophils/5 nonoverlapping high-power fields counted; mast cells identified by immunocytochemistry (CD117)/5 high-power fields. Paneth cells quantified per 5 crypts. 16S rRNA gene amplicon sequencing performed on available sigmoid MaM, n = 55 and fecal microbiota, n = 20. Microbiota profiles compared between samples with high and low IEL counts.

  RESULTS: IBS had increased IELs in the terminal ileum (relative risk ratio = 1.70, 95% confidence interval 1.08–2.76, P = 0.022 adjusted for age, sex, and smoking). Cecal IELs were increased in IBS—diarrhea (relative risk ratio = 2.03, 95% confidence interval 1.13–3.63, P = 0.017). No difference was observed in alpha diversity of MaM or fecal microbiota based on IEL count. There was no difference in beta diversity of the MaM according to IEL count in the terminal ileal (TI) (P = 0.079). High TI IEL counts associated with a significant expansion of the genus Blautia (P = 0.024) and unclassified Clostridiales (P = 0.036) in colon MaM.

  DISCUSSION: A modest but significant increase in IELs was observed in IBS vs. controls in a population-based setting. Subtle TI and cecal inflammation may play a pathogenic role in IBS but needs confirmation. Modest but discernible differences in the colonic MaM were seen according to TI IEL count but not IBS status.

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• Large-scale association analyses identify host factors influencing human gut microbiome composition

  2021. Alexander Kurilshikov (et al.). Nature Genetics 53 (2), 156-165

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  To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10⁻⁸) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10⁻²⁰), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10⁻¹⁰ < P < 5 × 10⁻⁸) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.

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• Measuring the impact of gastrointestinal inconvenience and symptoms on perceived health in the general population - validation of the Short Health Scale for gastrointestinal symptoms (SHS-GI)

  2021. Susanna Walter (et al.). Scandinavian Journal of Gastroenterology 56 (12), 1406-1463

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  Objectives Gastrointestinal (GI) symptoms are intimately related to our wellbeing. The Short Health Scale for GI symptoms (SHS-GI) is a simple questionnaire to measure the impact of GI inconvenience and symptoms on quality of life. The aim was to validate the SHS-GI in a general population sample and to compare it with SHS-data across different patient groups.

  Method A subsample of 170 participants from a population-based colonoscopy study completed the Rome II questionnaire, GI diaries, psychological questionnaire (hospital anxiety and depression scale) and SHS-GI at follow-up investigation. Psychometric properties of SHS-GI as an overall score were determined by performing a confirmatory factor analysis (CFA). Spearman correlation between SHS total score and symptoms was calculated in the general population sample. SHS-GI data was compared with SHS data from patients with inflammatory bowel disease (IBD) and fecal incontinence (FI).

  Results As expected, the general population rated their impact of GI inconvenience on quality of life as better than the patient populations in terms of all aspects of the SHS-GI. The CFA showed a good model fit meeting all fit criteria in the general population. Cronbach's alpha for the total scale was 0.80 in the general population sample and ranged from 0.72 in the FI sample to 0.88 and 0.89 in the IBD samples.

  Conclusions SHS-GI demonstrated appropriate psychometric properties in a sample of the normal population. We suggest that SHS-GI is a valid simple questionnaire suitable for measuring the impact of GI symptoms and inconvenience on quality of life in both general and patient populations.

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• Neutrophils, eosinophils, and intraepithelial lymphocytes in the squamous esophagus in subjects with and without gastroesophageal reflux symptoms

  2021. Mudar Zand Irani (et al.). Human Pathology 115, 112-122

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  Whilst intraepithelial lymphocytes (IELs) are considered normal within the distal esophageal mucosa, they have an increasingly recognised role in the pathogenesis of reflux esophagitis, and IEL quantification establishes the diagnosis of lymphocytic esophagitis. Knowledge regarding the upper limit of a normal IEL count in health is lacking. We studied 117 non-healthcare seeking adult volunteers from a random community sample (the Kalixanda study) with esophageal biopsies 2 cm above the gastroesophageal junction. Subjects were divided into four groups based on the presence or absence of gastro-esophageal reflux symptoms and/or esophagitis on endoscopy. Asymptomatic subjects with no endoscopic esophagitis were selected as controls, and the cell counts in this group were used to define the upper limit of normal of IELs, eosinophils and neutrophils. The entire sample was used to identify independent predictors of increased cellular counts by logistic regression analysis. None of the healthy controls had an IEL count of more than three per five high power fields (HPF), and therefore this was considered as the upper limit of normal; no controls had eosinophils or neutrophils in esophageal biopsies. Independent predictors of an elevated IEL count were spongiosis on histology (OR 11.17, 95% CI 3.32–37.58, P < 0.01) and current smoking (OR 4.84, 95% CI 1.13–2.71, P = 0.03). A receiver operating characteristics analysis concluded that a threshold of 3 IELs/5HPFs performs best in predicting reflux symptoms when a normal esophageal mucosa is visualized on endoscopy (sensitivity = 100.0%, specificity = 35.2%). The healthy esophageal mucosa does not contain more than three IELs per five HPF in the distal esophagus.

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• Objective and Subjective Sleep in Rheumatoid Arthritis and Severe Seasonal Allergy

  2021. Sandra Tamm (et al.). Nature and Science of Sleep 13, 775-789

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  Introduction: Disturbed sleep in inflammatory disorders such as allergy and rheumatoid arthritis (RA) is common and may be directly or indirectly related to disease processes, but has not been well characterized in these patient groups, especially not with objective methods.

  Aim: The present study aimed to characterize objective and subjective sleep in patients with allergy or RA using sleep diaries, one-channel EEG and actigraphy. It also aimed to investigate if sleep measures were associated with central immune activation, assessed using translocator protein (TSPO) positron emission tomography, as well as cytokine markers of peripheral inflammation and disease-specific symptoms or general symptoms of sickness.

  Methods: In total, 18 patients with seasonal pollen allergy, 18 patients with RA and 26 healthy controls were included in the study. Allergy patients and matched controls were assessed twice, in and out of pollen season, and RA patients and controls were assessed once. Sleep was recorded for approximately 1 week at each occasion.

  Results: Patients with allergy had increased levels of slow-wave sleep during pollen season. In contrast, patients with RA had less SWS compared to healthy controls, while no differences were observed in sleep duration or subjective sleep quality. Across groups, neither proinflammatory cytokines, grey matter TSPO levels nor general sickness symptoms were associated with objective or subjective measures of sleep. Rhinitis, but not conjunctivitis, was correlated to worse subjective sleep and more slow wave sleep in allergy. Functional status, but not disease activity, predicted lower subjective sleep in RA.

  Conclusion: This study tentatively indicates that both patients with allergy and RA display sleep alterations but does not support inflammation as an independent predictor of the sleep disturbance across these patient groups.

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• Poor sleep quality is associated with worse self-rated health in long sleep duration but not short sleep duration

  2021. Anna Andreasson (et al.). Sleep Medicine 88, 262-266

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  Unhealthy sleep duration, either short or long, is associated with worse health and central subjective dimensions of sleep and health such as fatigue. It has been argued that the link between sleep duration and health may depend on the quality of the slept hours, and on its functional impact (ie, fatigue). The present study therefore assessed whether the relationship between last night's sleep duration and general self-rated health (SRH) differs as a function of sleep quality, and secondly, whether current fatigue and sleep quality are factors linking sleep duration and SRH. The present cross-sectional dataset involved 1304 individuals (57% female, M age = 28.8, range 18-79). Participants completed surveys for general SRH, previous night's sleep duration and sleep quality, and current fatigue. Results showed the expected inverted U-shaped (ie, quadratic) relation between last night's sleep duration and SRH and a linear relation between last night's sleep quality and SRH. However, long sleep duration was only associated with poorer SRH in individuals who also reported poor sleep quality. Further, the quadratic relationship between sleep duration and SRH was partially mediated by fatigue and sleep quality. The results of this multi-study analysis suggest that SRH is particularly poor in those who slept both long and with poor quality the night before, while good sleep quality may protect those with a long sleep duration from poor SRH. Thus, last night's long sleep does not seem to be associated with poor subjective health unless it is coupled with poor sleep quality. Furthermore, fatigue and sleep quality are potential pathways linking short and long sleep duration with SRH. Different dimensions of sleep interact in their association with health, and future research will benefit from an integrative approach. 

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• Role of smoking in functional dyspepsia and irritable bowel syndrome

  2021. Nicholas J. Talley (et al.). Alimentary Pharmacology and Therapeutics 54 (1), 32-42

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  Background: It is uncertain if functional dyspepsia (FD) or irritable bowel syndrome (IBS) are linked to smoking, and smoking cessation is not part of the routine advice provided to these patients.

  Aim: To assess if smoking is an independent risk factor for FD and IBS.

  Methods: Three population-based endoscopy studies in Sweden with 2560 community individuals in total (mean age 51.5 years, 46% male). IBS (14.9%), FD (33.5%), and associated symptoms were assessed using the validated abdominal symptom questionnaire, and smoking (17.9%) was obtained from standardised questions during a clinic visit. The effect of smoking on symptom status was analysed in an individual person data meta-analysis using mixed effect logistic regression, adjusted for snuffing, age and sex.

  Results: Individuals smoking cigarettes reported significantly higher odds of postprandial distress syndrome (FD-PDS) (OR 10-19 cig/day = 1.42, 95% CI 1.04-1.98 P = 0.027, OR ≥20 cig/day = 2.16, 95% CI 1.38-3.38, P = 0.001) but not epigastric pain. Individuals smoking 20 or more cigarettes per day reported significantly higher odds of IBS-diarrhoea (OR = 2.40, 95% CI 1.12-5.16, P = 0.025), diarrhoea (OR = 2.01, 95%CI 1.28-3.16, P = 0.003), urgency (OR = 2.21, 95%CI 1.41-3.47, P = 0.001) and flatus (OR = 1.77, 95%CI 1.14-2.76, P = 0.012) than non-smokers. Smoking was not associated with IBS-constipation or IBS-mixed.

  Conclusion: Smoking is an important environmental risk factor for postprandial distress syndrome, the most common FD subgroup, with over a twofold increased odds of PDS in heavy smokers. The role of smoking in IBS-diarrhoea, but not constipation, is also likely important.

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• Ability of Noninvasive Scoring Systems to Identify Individuals in the Population at Risk for Severe Liver Disease

  2020. Hannes Hagström (et al.). Gastroenterology 158 (1), 200-214

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  BACKGROUND & AIMS: Noninvasive scoring systems are used to identify persons with advanced liver fibrosis. We investigated the ability of scoring systems to identify individuals in the general population at risk for future liver-related events. METHODS: We collected data from the Swedish Apolipoprotein Mortality Risk cohort on persons 35 to 79 years old who had blood samples collected from 1985 through 1996. We collected APRI (n = 127,302), BARD (n = 75,303), FIB-4 (n = 126,941), Forns (n = 122,419), and the nonalcoholic fatty liver disease (NAFLD) fibrosis scores (NFS, n = 13,160). We ascertained incident cases of cirrhosis or complications by linking Swedish health data registers. Cox regression was used to estimate hazard ratios (HRs) for severe liver disease at 5, 10, and a maximum follow-up time of 27 years. The predictive ability of the scores was evaluated using area under the receiver operating characteristic (AUROC) curve and C-statistics analyses. Our specific aims were to investigate the predictive capabilities of scoring systems for fatal and nonfatal liver disease, determine which scoring system has the highest level of accuracy, and investigate the predictive abilities of the scoring systems in persons with a higher probability of NAFLD at baseline. RESULTS: A similar proportion of individuals evaluated by each scoring system developed cirrhosis or complications thereof (1.0%-1.4%). The incidence of any outcome was increased in intermediate- and high-risk groups compared with low-risk groups, with HRs at 10 years in the high-risk group ranging from 1.67 for the BARD score to 45.9 for the APRI score. The predictive abilities of all scoring systems decreased with time and were higher in men. All scoring systems were more accurate in persons with risk factors for NAFLD at baseline, with AUROCs reaching 0.83. CONCLUSIONS: Higher scores from noninvasive scoring systems to evaluate fibrosis are associated with an increased risk of cirrhosis in a general population, but their predictive ability is modest. Performance was better when patients were followed for shorter time periods and in persons with a higher risk of NAFLD, with AUROC values reaching 0.83. New scoring systems are needed to evaluate risk of fibrosis in the general population and in primary care.

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• Compositional and functional differences of the mucosal microbiota along the intestine of healthy individuals

  2020. Stefania Vaga (et al.). Scientific Reports 10 (1)

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  Gut mucosal microbes evolved closest to the host, developing specialized local communities. There is, however, insufficient knowledge of these communities as most studies have employed sequencing technologies to investigate faecal microbiota only. This work used shotgun metagenomics of mucosal biopsies to explore the microbial communities' compositions of terminal ileum and large intestine in 5 healthy individuals. Functional annotations and genome-scale metabolic modelling of selected species were then employed to identify local functional enrichments. While faecal metagenomics provided a good approximation of the average gut mucosal microbiome composition, mucosal biopsies allowed detecting the subtle variations of local microbial communities. Given their significant enrichment in the mucosal microbiota, we highlight the roles of Bacteroides species and describe the antimicrobial resistance biogeography along the intestine. We also detail which species, at which locations, are involved with the tryptophan/indole pathway, whose malfunctioning has been linked to pathologies including inflammatory bowel disease. Our study thus provides invaluable resources for investigating mechanisms connecting gut microbiota and host pathophysiology.

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• High-Definition Chromoendoscopy Superior to High-Definition White-Light Endoscopy in Surveillance of Inflammatory Bowel Diseases in a Randomized Trial

  2020. Bjarki Alexandersson (et al.). Clinical Gastroenterology and Hepatology 18 (9), 2101-2107

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  BACKGROUND & AIMS: There is debate over the optimal method for colonoscopic surveillance of patients with inflammatory bowel diseases. Guidelines recommend chromoendoscopy, but the value of chromoendoscopy in high-definition colonoscopy has not been proven. Furthermore, the value of random biopsies is controversial. METHODS: We performed a prospective study of 305 patients with ulcerative colitis or Crohn's colitis referred for surveillance colonoscopy at a university hospital in Sweden, from March 2011 through April 2016. Patients randomly assigned to a group that received high-definition chromoendoscopy with indigo carmine (HD-CE; n=152), collection of 32 random biopsies, and targeted biopsies or polypectomies or to a group that received high-definition white light endoscopy (HD-WLE; n=153), collection of 32 random biopsies, and targeted biopsies or polypectomies. The primary endpoint was number of patients with dysplastic lesions. RESULTS: Dysplastic lesions were detected in 17 patients with HD-CE and 7 patients with HD-WLE (P=.032). Dysplasias in random biopsies (n=9760) were detected in 9 patients: 6 (3.9%) in the HD-CE group and 3 (2.0%) in the HD-WLE group (P=.72). Of the 9 patients with dysplasia, 3 patients (33%) had primary sclerosing cholangitis-only 18% of patients (54/305) included in the study had primary sclerosing cholangitis. The number of dysplastic lesions per 10 min of withdrawal time was 0.066 with HD-CE and 0.027 with HD-WLE (P=.056). CONCLUSIONS: In a randomized trial, we found HD-CE with collection of random biopsies to be superior to HD-WLE with random biopsies for detection of dysplasia per colonoscopy. These results support the use of chromoendoscopy for surveillance of patients with inflammatory bowel diseases. ClinicalTrials.gov no: NCT01505842.

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• Inflammatory cytokines in patients with common mental disorders treated with cognitive behavior therapy

  2020. Fredrik Santoft (et al.). Brain, Behavior, & Immunity - Health 3

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  Peripheral inflammation has been found associated with psychiatric disorders. However, results are inconclusive as to its role in common mental disorders (CMDs), i.e., depression, anxiety, insomnia and stress-related disorders. Further, some research suggests that cognitive behavior therapy (CBT) could reduce inflammatory markers in CMDs. In the present study, we measured pro-inflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin-6 [IL-6] and IL-8) pre- and post-treatment in two clinical trials (N ​= ​367) investigating CBT for patients with CMDs in primary care. We hypothesized that higher levels of these cytokines would be associated with more severe psychiatric symptoms (i.e., symptoms of depression, stress and anxiety). We also hypothesized that level of cytokines would decrease after CBT and that the reduced levels would correlate with a reduction in symptoms. Results showed that in men, higher levels of TNF-α were associated with more severe psychiatric symptoms. Further, age moderated the association between TNF-α, as well as IL-6, and stress, and exploratory stratified analyses revealed significant associations in subgroups. No other significant associations between cytokines and psychiatric symptoms were found. None of the cytokines were reduced following CBT, and the marked improvements in psychiatric symptoms after treatment were not associated with changes in cytokines. In conclusion, although inflammation might be of relevance in subgroups, it seems to be of limited importance for clinical improvements across mild to moderate CMDs.

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• No distinct microbiome signature of irritable bowel syndrome found in a Swedish random population

  2020. Luisa W. Hugerth (et al.). Gut 69 (6), 1076-1084

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  Objective The ethiopathogenesis of irritable bowel syndrome (IBS) is unknown. While a link to the gut microbiome is postulated, the heterogeneity of the healthy gut makes it difficult to draw definitive conclusions. We aimed to describe the faecal and mucosa-associated microbiome (MAM) and health correlates on a community cohort of healthy and IBS individuals with no colonoscopic findings.

  Design The PopCol study recruited a random sample of 3556 adults; 745 underwent colonoscopy. IBS was defined by Rome IV criteria and organic disease excluded. 16S rRNA gene sequencing was conducted on sigmoid biopsy samples from 376 representative individuals (63 IBS cases) and faecal samples from 185 individuals (32 IBS cases).

  Results While sigmoid MAM was dominated by Lachnospiraceae, faeces presented a higher relative abundance of Ruminococcaceae. Microbial richness in MAM was linearly correlated to that in faeces from the same individual (R-2=0.255, p<3E-11) as was diversity (R-2=0.06, p=0.0022). MAM diversity decreased with increasing body mass index (BMI; Pearson's r=-0.1, p=0.08) and poorer self-rated health (r=-0.15, p=0.007), but no other health correlates. Faecal microbiome diversity was correlated to stool consistency (r=-0.16, p=0.043). Several taxonomic groups were correlated to age, BMI, depression and self-reported health, including Coprococcus catus associated with lower levels of depression (r=-0.003, p=0.00017). The degree of heterogeneity observed between IBS patients is higher than that observed between healthy individuals.

  Conclusions No distinct microbial signature was observed in IBS. Individuals presenting with low self-rated health or high BMI have lower gut microbiome richness.

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• Patients with ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain report similar level of sickness behavior as individuals injected with bacterial endotoxin at peak inflammation

  2020. Martin A. Jonsjö (et al.). Brain, Behavior, & Immunity - Health 2

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  Background: Chronic sickness behavior is implicated in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) and chronic pain but the level of subjective sickness behavior in these conditions has not been investigated or compared to other clinical and non-clinical samples, or to the level in experimental inflammation. Furthermore, the relationship between sickness behavior and self-rated health and functioning is not known in patients with ME/CFS and chronic pain. The aim of the present study was to investigate how sickness behavior in patients with chronic conditions differs from that in individuals with experimental acute sickness, primary care patients, the general population and healthy subjects. In addition, we wanted to explore how sickness behavior is related to self-rated health and health-related functioning.

  Methods: Sickness behavior was quantified using the sickness questionnaire (SicknessQ). Self-ratings were collected at one time-point in 6 different samples. Levels of sickness behavior in patients with ME/CFS (n ​= ​38) and patients with chronic pain (n ​= ​190) were compared to healthy subjects with lipopolysaccharide(LPS)-induced inflammation (n ​= ​29), primary care patients (n ​= ​163), individuals from the general population (n ​= ​155) and healthy subjects (n ​= ​48), using linear regression. Correlations and moderated regression analyses were used to investigate associations between sickness behavior and self-rated health and health-related functioning in ME/CFS, chronic pain and the general population.

  Results: LPS-injected individuals (M ​= ​16.3), patients with ME/CFS (M ​= ​16.1), chronic pain (M ​= ​16.1) and primary care patients (M ​= ​10.7) reported significantly higher SicknessQ scores than individuals from the general population (M ​= ​5.4) and healthy subjects (M ​= ​3.6) all p’s ​< ​0.001). In turn, LPS-injected individuals, patients with ME/CFS and chronic pain reported significantly higher SicknessQ scores than primary care patients (p’s ​< ​0.01). Higher levels of sickness behavior were associated with poorer self-rated health and health-related functioning (p’s ​< ​0.01), but less so in patients with ME/CFS and chronic pain than in individuals from the general population.

  Conclusions: Patients with ME/CFS and chronic pain report similar high levels of sickness behavior; higher than primary care patients, and comparable to levels in experimental inflammation. Further study of sickness behavior in ME/CFS and chronic pain populations is warranted as immune-to-brain interactions and sickness behavior may be of importance for functioning as well as in core pathophysiological processes in subsets of patients.

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• Presence of Fermentable Oligo-, Di-, Monosaccharides, and Polyols (FODMAPs) in commonly eaten foods

  2020. Therese Liljebo, Stine Störsrud, Anna Andreasson. BMC Nutrition 6 (1)

  Artikel

  Background: FODMAPs (Fermentable Oligo-, Di-, Monosaccharides And Polyols) are known for their health benefits but their fermentation may trigger gastrointestinal symptoms and a low-FODMAP diet is a commonly used intervention for functional gastrointestinal disorders. The use of direct measures of FODMAP is labor intensive and expensive and to facilitate the assessment of FODMAP intake in research and clinical work, a nutritional content database with good quality estimates on FODMAP values is needed. Further, the average intake of FODMAP in a general population would be a useful reference and knowledge of the most commonly eaten foods containing FODMAPs would facilitate clinical work utilizing FODMAP diet interventions.

  Methods: A nutritional content database was extended with published FODMAP content data. The database was used to calculate FODMAP intake from four-day food diaries from 117 individuals from the general population in Sweden and the most common food items containing FODMAPs were identified.

  Results: FODMAP content for 1060 food items was added to the database resulting in 1805 listed FODMAP values. Mean intake of total FODMAP in the diaries was 19 g (fructose: 15.2 g; fructan: 3.5 g; lactose: 14.1 g; galacto-oligosaccharides (GOS) 0.43 g and polyols 1.3 g per day). Overall the most common eaten food items containing FODMAPs were rye and wheat based foods.

  Conclusion: Intake of FODMAPs as calculated using the extended database were in line with previous studies supporting its use of the database in both research and clinical interventions. The lists of the most commonly eaten FODMAP food items are provided and may be used to facilitate FODMAP diet interventions.

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• Properties of the Sickness Questionnaire in an Australian sample with chronic medically unexplained symptoms

  2020. Anna Andreasson (et al.). Brain, Behavior, & Immunity - Health 3

  Artikel

  Sickness behavior including malaise, fatigue and increased pain sensitivity is thought to be adaptive and facilitate recovery from disease. However, it may also reduce functioning and health if symptoms persists, which is why validated instruments for its assessment are needed. We evaluated the English translation of the Sickness Questionnaire (SicknessQ) in an Australian population of 156 participants with high level of persistent musculoskeletal pain and/or gastrointestinal symptoms without an organic explanation. The SicknessQ total score had an adequate model fit and no other models were found to fit data better. The SicknessQ correlated most strongly with fatigue, stress, anxiety and depression, which explained 62% of the variance in SicknessQ, but not with physical functioning. The mean score (8.9; 95 %CI: 8.0–9.8) was in between those previously reported in a general population sample and in primary care patients. In conclusion, the evaluation of the English version of the SicknessQ in an Australian sample with significant, chronic unexplained medical symptoms supports the use of the English version of the total SicknessQ score as an overall measure of sickness behavior.

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• Repeated FIB-4 measurements can help identify individuals at risk of severe liver disease

  2020. Hannes Hagström (et al.). Journal of Hepatology 73 (5), 1023-1029

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  Background & Aims: It is unclear whether the identification of individuals at risk of cirrhosis using non-invasive tests can be improved by repeated measurements. Herein, we tested whether repeated measurements of fibrosis-4 index (FIB-4) could improve the identification of individuals at risk of severe liver disease.

  Methods: Data were derived from the population-based Swedish AMORIS cohort with baseline examinations from 1985-1996. FIB4 was calculated at 2 time points within 5 years. Thereafter, we associated changes in FIB-4 with outcomes. Incident severe liver disease data was ascertained through linkage to Swedish national registers until 2011. Hazard ratios (HRs) and CIs for outcomes were calculated using Cox regression.

  Results: Of 126,942 individuals with available FIB-4 data, 40,729 (32.1%) underwent a second test within 5 years (mean interval 2.4 years). During 613,376 person-years of follow-up, 581 severe liver disease events were documented (0.95/1,000 person-years). An increase of 1 unit in FIB-4 was associated with an elevated risk of severe liver disease (adjusted hazard ratio [aHR] 1.81; 95% CI 1.67-1.96). Transitioning from a low-or intermediate-to a high-risk group was associated with an increased risk of severe liver disease compared with those consistently in the low-risk group (aHR 7.99 and 8.64, respectively). A particularly increased risk of severe liver disease was found in individuals defined as high risk at both tests (aHR 17.04; 95% CI 11.67-24.88). However, almost half of all events occurred in those consistently in the low-risk group.

  Conclusions: Repeated testing of FIB-4 within 5 years improves the identification of individuals at an increased risk of severe liver disease in the general population. However, the sensitivity is comparatively low and improved tests are needed for screening in a general population or primary care setting.

  Lay summary: The fibrosis-4 scoring system is often used to estimate the risk of advanced fibrosis in liver diseases. Herein, we found that changes in this score over time are associated with the risk of future severe liver disease in a population-based cohort. However, even if the prediction is improved by repeated testing, the overall ability of the score to predict future events is relatively low.

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• The gut microbiota and mental health in adults

  2020. Ellionore Jarbrink-Sehgal, Anna Andreasson. Current Opinion in Neurobiology 62, 102-114

  Artikel

  A growing body of evidence point toward the bidirectional gut microbiota-brain axis playing a role in mental health. Most of this research is conducted on animals why we in this review summarize and comment upon recent studies evaluating the gut microbiome in mental health in humans. Further support for the relevance of the bidirectional gut microbiota-brain communication in mood disorders has been presented, such as the effect of probiotics on brain connectivity and mental health outcomes and pregnancy related stress on gut microbiota in the newborn child. However, the heterogeneity between studies precludes conclusions regarding differences in microbiota composition in mental disease and health and many of the studies are limited by a cross-sectional design, small sample sizes and multiple comparisons. Thus, welldesigned longitudinal studies with larger sample size, accounting for confounders are needed.

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• Discriminant and convergent validity of the GSRS-IBS symptom severity measure for irritable bowel syndrome

  2020. Brjánn Ljótsson (et al.). United European Gastroenterology journal 8 (3), 284-292

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  Background The Gastrointestinal Symptom Rating Scale-Irritable Bowel Syndrome (GSRS-IBS) is a 13-item measure of IBS symptom severity. The scale has been used in several studies, but its psychometric properties have been insufficiently investigated and population-based data are not available. Objective The objective of this article is to establish the factor structure and discriminant and convergent validity of the GSRS-IBS. Methods The study was based on a Swedish population sample (the Popcol study), of which 1158 randomly selected participants provided data on the GSRS-IBS. We used confirmatory factor analysis (CFA) and compared total and subscales scores in different groups, including IBS diagnostic status, treatment-seeking behavior, and predominant bowel habits. The GSRS-IBS scores were also correlated with quality of life indexes. Results The sample included 164 participants with a confirmed Rome III IBS diagnosis and 994 participants without the disease. The CFA confirmed the subscales with one exception, in which the incomplete bowel-emptying item belonged to the constipation subscale rather than the diarrhea subscale. The GSRS-IBS total score and subscales were associated with diagnostic status, treatment-seeking behavior, and quality of life dimensions. The relevant subscales scores also differed between the diarrhea- and constipation-predominant subtypes of IBS. Conclusion The GSRS-IBS total score and subscales have high discriminant and convergent validity. The CFA confirmed the overall validity of the subscales but suggest that a sense of incomplete emptying belongs to the constipation rather than the diarrhea symptom cluster. We conclude that the GSRS-IBS is an excellent measure of IBS symptom severity in the general population.

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• Effects of Psychology and Extragastrointestinal Symptoms on Health Care Use by Subjects With and Without Irritable Bowel Syndrome

  2020. David T. McNaughton (et al.). Clinical Gastroenterology and Hepatology 18 (4), 847-852

  Artikel

  Background & Aims

  There is controversy about whether psychological factors (anxiety and depression) increase health care seeking by patients with irritable bowel syndrome (IBS). We investigated whether psychological factors increase health care seeking by patients with IBS and the effects of extragastrointestinal (extra-GI) symptoms.

  Methods

  We performed a population-based prospective study of health care use over a 12-year period in Sweden. From 2002 through 2006, 1244 subjects were selected randomly for an examination by a gastroenterologist and to complete questionnaires, including the Rome II modular questionnaire. Psychological factors were measured with the valid Hospital Anxiety and Depression scale and extra-GI symptoms were measured with a symptom checklist. Responses from 1159 subjects (57% female; mean age, 48.65 y) were matched with health records in 2016 (164 were classified as having IBS based on Rome II criteria).

  Results

  The overall association between depression or anxiety and health care use varied in subjects with and without IBS at baseline. The presence of extra-GI symptoms strengthened the relationship between anxiety and depression and prospective psychiatric visits for subjects with IBS and without IBS (incidence rate ratio, 1.14-1.26). Extra-GI symptoms did not alter the association of anxiety or depression with use of GI or extra-GI health care.

  Conclusions

  In a population-based study in Sweden, we found that individuals with high baseline anxiety or depression were more likely to seek psychiatric health care, but not GI or extra-GI health care, in the presence of extra-GI symptoms at baseline. Patients with IBS might benefit from more thorough assessments that examine extra-GI and psychological symptoms, to reduce health care utilization.

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• Fatigue and sleepiness responses to experimental inflammation and exploratory analysis of the effect of baseline inflammation in healthy humans

  2020. Julie Lasselin (et al.). Brain, behavior, and immunity 83, 309-314

  Artikel

  Inflammation is believed to be a central mechanism in the pathophysiology of fatigue. While it is likely that dynamic of the fatigue response after an immune challenge relates to the corresponding cytokine release, this lacks evidence. Although both fatigue and sleepiness are strong signals to rest, they constitute distinct symptoms which are not necessarily associated, and sleepiness in relation to inflammation has been rarely investigated. Here, we have assessed the effect of an experimental immune challenge (administration of lipopolysaccharide, LPS) on the development of both fatigue and sleepiness, and the associations between increases in cytokine concentrations, fatigue and sleepiness, in healthy volunteers. In addition, because chronic-low grade inflammation may represent a risk factor for fatigue, we tested whether higher baseline levels of inflammation result in a more pronounced development of cytokine-induced fatigue and sleepiness. Data from four experimental studies was combined, giving a total of 120 subjects (LPS N = 79, 18 (23%) women; Placebo N = 69, 12 (17%) women). Administration of LPS resulted in a stronger increase in fatigue and sleepiness compared to the placebo condition, and the development of both fatigue and sleepiness closely paralleled the cytokine responses. Individuals with stronger increases in cytokine concentrations after LPS administration also suffered more from fatigue and sleepiness (N = 75), independent of gender. However, there was no support for the hypothesis that higher baseline inflammatory markers moderated the responses in fatigue or sleepiness after an inflammatory challenge. The results demonstrate a tight connection between the acute inflammatory response and development of both fatigue and sleepiness, and motivates further investigation of the involvement of inflammation in the pathophysiology of central fatigue.

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• The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) - associations with symptoms

  2020. Martin A. Jonsjö (et al.). Psychoneuroendocrinology 113

  Artikel

  Background: Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often present with a range of flu-like symptoms resembling sickness behavior as well as widespread pain and concentration deficits. The aim of this study was to explore the association between inflammatory markers previously shown to be related to fatigue severity in ME/CFS and common ME/CFS symptoms post-exertional fatigue, impaired cognitive processing, musculoskeletal pain and recurrent flu-like symptoms, and the moderating effect of sex on these associations. Methods: 53 adult patients diagnosed with ME/CFS at a specialist clinic were included in the study. Fasting blood plasma was analyzed using the Olink Proseek Multiplex Inflammation panel (beta-NGF, CCL11, CXCL1, CXCL10, IL-6, IL-7, IL-8, IL-10, IL-18, TGF-alpha, TGF-beta-1 and SCF) and BioRad Human Cytokine Type 1 assay (TNF-alpha). Participants rated the average severity of symptoms (0-10) based on the 2011 International Consensus Criteria of ME/CFS during a structured clinical interview. Associations between inflammatory markers and symptom severity were analyzed using bivariate correlations and moderated regression analyses bootstrapped with 5000 repetitions. Results and conclusions: Only beta-NGF was associated with the fatigue severity measure. However, higher levels of CCL11, CXCL10, IL-7, TNF-alpha and TGF-beta-1 were significantly associated with higher levels of impaired cognitive processing and musculoskeletal pain, and sex was a significant moderator for CXCL10, IL-7 and TGF-beta-1. Future studies should investigate the relationship between inflammatory markers and key symptoms in ME/CFS in a longitudinal design in order to explore if and for whom low-grade inflammation may contribute to illness development.

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