Publications by authors named "Lars Agreus"

105 Publications

[Significant over- and misuse of PPIs].

Lakartidningen 2021 07 1;118. Epub 2021 Jul 1.

adjungerad professor, institutionen för medicin Huddinge, Karolinska institutet; PF mag- och tarmsjukdomar, Karolinska universitetssjukhuset, Stockholm.

PPIs (Proton-pump inhibitors) offers the best treatment for acid related diseases. The predominant indications for PPI prescription are: GERD eradication of H. pylori-infection in combination with antibiotics H. pylori-negative peptic ulcer  healing of and prophylaxis against NSAID/COXIB--induced gastroduodenal lesions  acid hypersecretory states such as Zollinger-Ellisons syndrome. The market for PPIs continues to expand in most countries. A significant over- and misuse of PPIs prevails in hospital care as well as in general practice. The predominant reasons for and mechanisms behind the over- and misuse of PPIs are well recognised. The most important consequences of this overprescription of PPIs are increasing medical costs and risk for long-term adverse side effects. Continued education and dedicated information are key factors to guide physicians, medical personnel and patients to adopt to generally accepted principles for and balanced use of PPIs.
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July 2021

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

Hum Pathol 2021 Sep 25;115:112-122. Epub 2021 Jun 25.

University of Newcastle, Newcastle, Australia; NHMRC Centre of Research Excellence in Digestive Health.

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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http://dx.doi.org/10.1016/j.humpath.2021.06.004DOI Listing
September 2021

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

Eur J Gastroenterol Hepatol 2021 Jun 17. Epub 2021 Jun 17.

Psychology Department, Macquarie University, North Ryde, NSW, Australia Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, Australia Department of Gastroenterology and Hepatology, Princess Alexandra Hospital Gastrointestinal Genetics Lab, CIC BioGUNE - BRTA, Bizkaia, Spain Division of Family Medicine and Primary Care, Karolinska Institutet Stress Research Institute, Stockholm University, Stockholm, Sweden.

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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http://dx.doi.org/10.1097/MEG.0000000000002236DOI Listing
June 2021

Editorial: tobacco use in functional dyspepsia-another smoking gun? Authors' reply.

Aliment Pharmacol Ther 2021 07;54(1):79

Department of Psychology, Macquarie University, North Ryde, NSW, Australia.

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http://dx.doi.org/10.1111/apt.16401DOI Listing
July 2021

Role of smoking in functional dyspepsia and irritable bowel syndrome: three random population-based studies.

Aliment Pharmacol Ther 2021 07 13;54(1):32-42. Epub 2021 May 13.

Department of Psychology, Macquarie University, North Ryde, NSW, Australia.

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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http://dx.doi.org/10.1111/apt.16372DOI Listing
July 2021

Duodenal eosinophilia and the link to anxiety: A population-based endoscopic study.

Neurogastroenterol Motil 2021 Mar 9:e14109. Epub 2021 Mar 9.

Priority Research Centre for Digestive Health and Neurogastroenterology, Faculty of Health and Medicine, University of Newcastle, Newcastle, Australia.

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 (D1) and 2 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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http://dx.doi.org/10.1111/nmo.14109DOI Listing
March 2021

Ileocolonic Histopathological and Microbial Alterations in the Irritable Bowel Syndrome: A Nested Community Case-Control Study.

Clin Transl Gastroenterol 2020 12 22;12(1):e00296. Epub 2020 Dec 22.

Department of Psychology, Macquarie University, North Ryde, Australia.

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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http://dx.doi.org/10.14309/ctg.0000000000000296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345925PMC
December 2020

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

Nat Genet 2021 02 18;53(2):156-165. Epub 2021 Jan 18.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

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) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 < P < 5 × 10) 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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http://dx.doi.org/10.1038/s41588-020-00763-1DOI Listing
February 2021

An Increasing Incidence of Upper Gastrointestinal Disorders Over 23 Years: A Prospective Population-Based Study in Sweden.

Am J Gastroenterol 2021 01;116(1):210-213

Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.

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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http://dx.doi.org/10.14309/ajg.0000000000000972DOI Listing
January 2021

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

Sci Rep 2020 09 11;10(1):14977. Epub 2020 Sep 11.

Centre for Host-Microbiome Interactions, Dental Institute, King's College London, London, UK.

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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http://dx.doi.org/10.1038/s41598-020-71939-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486370PMC
September 2020

Gastric Microbiota in a Low-Helicobacter pylori Prevalence General Population and Their Associations With Gastric Lesions.

Clin Transl Gastroenterol 2020 07;11(7):e00191

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Introduction: Non-Helicobacter pylori microbiota might account for some cases with unexplained chronic gastritis that may in a minority eventually progress to gastric cancer through the Correa cascade. We characterized gastric microbiota by describing the normal stomach, compared it with early precancerous lesions and other disease states, and assessed whether H. pylori status affects bacterial diversity.

Methods: In a population-based study of those with and without gastrointestinal symptoms, cytology brush samples were collected during endoscopy from 316 individuals. Mucosal status was classified as normal mucosa (171), nonatrophic H. pylori gastritis (33), atrophic gastritis (12), or antral chemical gastritis (61). The 16S rRNA gene sequencing and analysis were performed to characterize the microbiota.

Results: Microbiota in atrophic gastritis and nonatrophic H. pylori gastritis stomachs were dysbiotic and differed from those in the normal stomach (P = 0.001). The normal stomach had the highest microbial diversity, followed by antral chemical gastritis. The atrophic gastritis and chronic H. pylori gastritis groups had the lowest diversity, a difference that was statistically significant (P = 0.01). Besides H. pylori, non-H. pylori bacteria accounted for group differences. Microbial network analysis showed that the normal group network was most highly connected, whereas the H. pylori gastritis group had the lowest connection. We found an increasing positive co-occurrence of oral bacteria in the stomach because samples deviated from the normal network, some of which were pathogens. The H. pylori-negative group had the highest microbial diversity (Shannon index) compared with the H. pylori-positive group (P = 0.001).

Discussion: In this low-H. pylori prevalence general population, the gastric mucosal microbiota of the normal stomach differed significantly from those with nonatrophic or atrophic gastritis. There was an increasing abundance of pathogenic bacteria from the normal state to early precancerous states.
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http://dx.doi.org/10.14309/ctg.0000000000000191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431247PMC
July 2020

Discriminant and convergent validity of the GSRS-IBS symptom severity measure for irritable bowel syndrome: A population study.

United European Gastroenterol J 2020 04 14;8(3):284-292. Epub 2020 Jan 14.

Department of Psychology, Macquarie University, North Ryde, NSW, Australia.

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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http://dx.doi.org/10.1177/2050640619900577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184654PMC
April 2020

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

Gut 2020 06 10;69(6):1076-1084. Epub 2019 Oct 10.

Center for Translational Microbiome Research, CTMR, Department of Microbiology, Tumour and Cell Biology (MTC), Karolinska Institutet, Science for Life Laboratory, Solna, Sweden

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 (R²=0.255, p<3E-11) as was diversity (R²=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 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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http://dx.doi.org/10.1136/gutjnl-2019-318717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282555PMC
June 2020

Peptic ulcer disease.

BMJ 2019 Oct 2;367:l5495. Epub 2019 Oct 2.

Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

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http://dx.doi.org/10.1136/bmj.l5495DOI Listing
October 2019

Z-line alterations and gastroesophageal reflux: an endoscopic population-based prospective cohort study.

Scand J Gastroenterol 2019 Sep 27;54(9):1065-1069. Epub 2019 Aug 27.

Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet , Stockholm , Sweden.

Barrett's esophagus is a premalignant condition in the distal esophagus associated with esophageal adenocarcinoma. Since gastroesophageal reflux is known to be of etiological importance in both Barrett's esophagus and esophageal adenocarcinoma, we aimed to study which endoscopic alterations at the Z-line can be attributed to a previous history of reflux symptoms. From 1988, a population cohort in Sweden has been prospectively studied regarding gastrointestinal symptoms, using a validated questionnaire. In 2012, the population was invited to undergo a gastroscopy and participate in the present study. In order to determine which endoscopic alterations that can be attributed to a previous history of gastroesophageal reflux, three different endoscopic definitions of columnar-lined esophagus (CLE) were used: (1) ZAP I, An irregular Z-line with a suspicion of tongue-like protrusions; (2) ZAP II/III, Distinct, obvious tongues of metaplastic columnar epithelium; (3) CLE ≥1 cm, The Prague C/M-classification with a minimum length of 1 cm. A total of 165 community subjects were included in the study. Of these, 40 had CLE  1 cm, 99 had ZAP I, and 26 had ZAP II/III. ZAP II/III was associated with an over threefold risk of previous GER symptoms (OR: 3.60, CI: 1.49-8.70). No association was found between gastroesophageal reflux and ZAP I (OR: 2.06, CI: 0.85-5.00), or CLE ≥1 cm (OR: 1.64, CI: 0.77-3.49). In a general community, the only endoscopic alteration to the Z-line definitely linked to longstanding GER symptoms was the presence of obvious tongues of metaplastic columnar epithelium (ZAP II/III).
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http://dx.doi.org/10.1080/00365521.2019.1656775DOI Listing
September 2019

Isolates from Colonic Spirochetosis in Humans Show High Genomic Divergence and Potential Pathogenic Features but Are Not Detected Using Standard Primers for the Human Microbiota.

J Bacteriol 2019 11 4;201(21). Epub 2019 Oct 4.

Center for Translational Microbiome Research, Department of Microbiology, Cell and Tumor Biology, Karolinska Institutet, Stockholm, Sweden

Colonic spirochetosis, diagnosed based on the striking appearance in histological sections, still has an obscure clinical relevance, and only a few bacterial isolates from this condition have been characterized to date. In a randomized, population-based study in Stockholm, Sweden, 745 healthy individuals underwent colonoscopy with biopsy sampling. Of these individuals, 17 (2.3%) had colonic spirochetosis, which was associated with eosinophilic infiltration and a 3-fold-increased risk for irritable bowel syndrome (IBS). We aimed to culture the bacteria and perform whole-genome sequencing of the isolates from this unique representative population sample. From 14 out of 17 individuals with spirochetosis we successfully isolated, cultured, and performed whole-genome sequencing of in total 17 isolates, including the type strain, 513A. Also, 16S analysis of the mucosa-associated microbiota was performed in the cases and nonspirochetosis controls. We found one isolate to be of the species ; all remaining isolates were of the species Besides displaying extensive genetic heterogeneity, the isolates harbored several mucin-degrading enzymes and other virulence-associated genes that could confer a pathogenic potential in the human colon. We also showed that 16S amplicon sequencing using standard primers for human microbiota studies failed to detect due to primer incompatibility. This is the first report of whole-genome analysis of clinical isolates from individuals with colonic spirochetosis. This characterization provides new opportunities in understanding the physiology and potentials of these bacteria that densely colonize the gut in the individuals infected. The observation that standard 16S amplicon primers fail to detect colonic spirochetosis may have major implications for studies searching for associations between members of the microbiota and clinical conditions such as irritable bowel syndrome (IBS) and should be taken into consideration in project design and interpretation of gastrointestinal tract microbiota in population-based and clinical settings.
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http://dx.doi.org/10.1128/JB.00272-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779451PMC
November 2019

Editorial: the overlap between dyspepsia and gastro-oesophageal reflux-is duodenal eosinophilia the missing link? Authors' reply.

Aliment Pharmacol Ther 2019 08;50(4):455-456

Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.

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http://dx.doi.org/10.1111/apt.15406DOI Listing
August 2019

The Gut Microbiota in Collagenous Colitis Shares Characteristics With Inflammatory Bowel Disease-Associated Dysbiosis.

Clin Transl Gastroenterol 2019 07;10(7):e00065

Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.

Introduction: In inflammatory bowel disease (IBD), an aberrant immune response to gut microbiota is important, but the role of the microbiota in collagenous colitis (CC) is largely unknown. We aimed to characterize the microbiota of patients with CC compared with that of healthy control and patients with IBD.

Methods: Fecal samples were collected from patients with CC (n = 29), age- and sex-matched healthy controls (n = 29), patients with Crohn's disease (n = 32), and patients with ulcerative colitis (n = 32). Sequence data were obtained by 454 sequencing of 16S rRNA gene amplicons, and the obtained sequences were subsequently taxonomically classified.

Results: Analysis of similarity statistics showed a segregation between patients with CC and healthy controls with increasing taxonomic resolution, becoming significant comparing operational taxonomic unit data (P = 0.006). CC had a lower abundance of 10 different taxa. Taxa-specific analyses revealed a consistent lower abundance of several operational taxonomic units belonging to the Ruminococcaceae family in patients with CC, q < 0.05 after false discovery rate correction. Loss of these taxa was seen in patients with CC with active disease and/or corticosteroid treatment only and resembled the findings in patients with IBD.

Discussion: CC is associated with a specific fecal microbiome seen primarily in patients with active disease or ongoing corticosteroid treatment, whereas the microbiome of CC patients in remission resembled that of healthy controls. Notably, the shift in key taxa, including the Ruminococcaceae family, was also observed in IBD. There may be common mechanisms in the pathogenesis of CC and IBD.
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http://dx.doi.org/10.14309/ctg.0000000000000065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708665PMC
July 2019

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

Clin Gastroenterol Hepatol 2020 04 16;18(4):847-854.e1. Epub 2019 Jul 16.

Department of Psychology, Macquarie University, Sydney, NSW, Australia. Electronic address:

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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http://dx.doi.org/10.1016/j.cgh.2019.07.019DOI Listing
April 2020

Response to Tursi.

Am J Gastroenterol 2019 08;114(8):1350-1351

Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

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http://dx.doi.org/10.14309/ajg.0000000000000319DOI Listing
August 2019

Response to Zidar et al.

Am J Gastroenterol 2019 08;114(8):1348-1349

Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

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http://dx.doi.org/10.14309/ajg.0000000000000323DOI Listing
August 2019

Duodenal eosinophilia is associated with functional dyspepsia and new onset gastro-oesophageal reflux disease.

Aliment Pharmacol Ther 2019 07 20;50(1):24-32. Epub 2019 May 20.

Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.

Background: It is unexplained why functional dyspepsia and gastro-oesophageal reflux disease (GERD) overlap more often than expected by chance. Post-prandial distress syndrome has been linked to impaired gastric fundic accommodation which may induce increased transient lower oesophageal sphincter relaxations and consequent GERD. Duodenal eosinophilia has been linked to functional dyspepsia and post-prandial distress syndrome.

Aim: To identify if there is an association between duodenal eosinophilia in functional dyspepsia and symptoms of GERD and whether post-prandial distress syndrome or epigastric pain syndrome are associated with new onset GERD.

Methods: Participants (n = 1000) were randomly selected from the national Swedish population register and surveyed by questionnaires and oesophagogastroduodenoscopy in 1999-2001. All eligible subjects (n = 887) were invited to a follow-up study in 2010 (response rate 79%). In a case-control study of 213 subjects (functional dyspepsia vs healthy controls), histology from the duodenum was evaluated at baseline and the possible association of eosinophilia to new onset GERD symptoms was analysed.

Results: Functional dyspepsia (OR 7.6; 95% CI 2.93-19.4, P < 0.001) and post-prandial distress syndrome at baseline (OR 9.0, 95% CI 3.36-24.0, P < 0.001) were associated with an increased risk of GERD at follow-up. Eosinophilia in the second part of duodenum only was independently associated with an increased risk of GERD amongst those with functional dyspepsia (OR 4.2; 95% CI 1.2-4.77, P = 0.024) and post-prandial distress syndrome at baseline (OR 6.0; 95% CI 1.50-23.6, P = 0.011), respectively.

Conclusions: Duodenal eosinophilia is associated with increased risk of GERD at 10-year follow-up in those with functional dyspepsia and post-prandial distress syndrome at baseline. Duodenal eosinophilia may explain the link between GERD and functional dyspepsia, suggesting subsets of functional dyspepsia and GERD may be part of the same disease spectrum.
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http://dx.doi.org/10.1111/apt.15308DOI Listing
July 2019

A nationwide cohort study of the incidence of microscopic colitis in Sweden.

Aliment Pharmacol Ther 2019 06 15;49(11):1395-1400. Epub 2019 Apr 15.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Epidemiological studies of microscopic colitis have shown varying but increasing incidence rates.

Aim: To assess the incidence of microscopic colitis in Sweden.

Methods: Nationwide cohort study performed in 1995-2015 based on biopsy reports. Age-specific and age-standardised incidence rates were calculated.

Results: We identified 13 844 patients with an incident diagnosis of microscopic colitis. Lymphocytic colitis (n = 9238) constituted 67% and collagenous colitis (n = 4606) 33% of microscopic colitis. The mean age at time of diagnosis of microscopic colitis was 60.2 years (58.6 for lymphocytic colitis, 63.3 for collagenous colitis). The lifetime risk of developing microscopic colitis was 0.87% in women (95% confidence interval, CI: 0.85-0.88) and 0.35% in men (95% CI: 0.34-0.36). From 2006, the overall incidence of microscopic colitis was approximately 10.5 cases per 100 000 person-years (95% CI: 9.8-11.3) with higher rates in women (72% of cases, incidence rate ratio = 2.4 (95% CI: 2.3-2.5) and the elderly with increasing rates up to 75-79 years. From 2006-2015, there was a significant increase of 1% per year (P = 0.02) in the overall microscopic colitis incidence rate in women; the estimated annual percent change was similar, although not statistically significant, in men (P = 0.15).

Conclusions: In Sweden, the incidence of microscopic colitis is still increasing in women, although the rate appears to be stabilising. The incidence is particularly high in women and the elderly up to age 75-79 years. Finally, across a lifetime, 1 in 115 females and 1 in 286 males are expected to be diagnosed with microscopic colitis and thus posing a considerable disease burden.
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http://dx.doi.org/10.1111/apt.15246DOI Listing
June 2019

Diverticulosis, Symptoms and Colonic Inflammation: A Population-Based Colonoscopy Study.

Am J Gastroenterol 2019 03;114(3):500-510

Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

Introduction: Low-grade chronic inflammation has been suggested to play a role in uncomplicated asymptomatic and symptomatic diverticular disease. However, population-based studies are lacking. We investigated whether community participants with diverticulosis, with or without symptoms, would have colonic inflammation on histology and serology.

Methods: In a nested case-control study of 254 participants from the population-based colonoscopy (PopCol) study, colonic histological inflammatory markers and serological C-reactive protein levels were analyzed in cases with diverticulosis and controls without diverticulosis. Statistical methods included logistic and linear regression models.

Results: Background variables including age (P = 0.92), sex (P = 1.00), body mass index (P = 0.71), smoking (P = 0.34), and recent antibiotic exposure (P = 0.68) were similar between cases and controls. Cases reported more abdominal pain (P = 0.04) and diarrhea symptoms (mushy and high-frequency stools) than controls (P = 0.01 and P = 0.03, respectively) but were otherwise similar. The median C-reactive protein levels were similar among cases and controls [1.05 mg/L (0.3, 2.7) vs 0.8 (0.4, 2.2), P = 0.53]. There was a trend of increased numbers of cecal lymphoid aggregates in cases vs controls (P = 0.07), but no other associations between diverticulosis and inflammatory markers on histology were found. Similarly, no serological or mucosal inflammation was associated with symptomatic cases of diarrhea or abdominal pain vs asymptomatic controls.

Conclusions: In a general community sample, both asymptomatic and symptomatic diverticulosis are not associated with colonic mucosal inflammation. Other explanations for symptomatic colonic diverticulosis need to be identified.
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http://dx.doi.org/10.14309/ajg.0000000000000113DOI Listing
March 2019

Differential clustering of fecal and mucosa-associated microbiota in 'healthy' individuals.

J Dig Dis 2018 Dec;19(12):745-752

Department of Microbiology, Tumor and Cell Biology & Science for Life Laboratory, Karolinska Institute, Solna, Sweden.

Objective: Fecal samples are often used to characterize gut microbiota. However, whether or not fecal microbiota differs from mucosa-associated microbiota remains largely unknown. This may be specifically relevant in conditions that are characterized by complex mucosal microbe-host interactions, such as Crohn's disease. We aimed to determine the degree of agreement between fecal and mucosal microbiota profiles in 'healthy' individuals, using two commonly used collection procedures.

Methods: The gut microbiota composition of fecal samples (sent at ambient temperature before storage at -70°C) and of colonic biopsies (obtained at endoscopy and immediately stored at -70°C) was determined by sequencing the 16S rRNA gene. Altogether 31 randomly selected 'healthy' individuals from the population-based colonoscopy (Popcol) study were included.

Results: The fecal samples were characterized by a reduced degree of richness (P < 0.0001) and diversity (P = 0.016), and also differences in several phyla, including a lower relative abundance of Proteobacteria (P < 0.0001) and Verrucomicrobia (P = 0.008) than in biopsies. Only three of 30 individuals had a similar fecal and mucosal microbiota profile, based on weighted UniFrac analysis. A difference in Crohn's disease dysbiosis-associated bacteria was observed, including a lower relative abundance of Faecalibacterium (P = 0.004) and a higher relative abundance of Ruminococcus (P = 0.001) in feces than in biopsies.

Conclusions: The observed differences between fecal samples, transported at ambient temperature, and the colonic mucosa-associated microbiota have implications for the interpretation of the previous literature, and may be specifically relevant to studies on Crohn's disease.
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http://dx.doi.org/10.1111/1751-2980.12688DOI Listing
December 2018

Gastrointestinal recall questionnaires compare poorly with prospective patient diaries for gastrointestinal symptoms: data from population and primary health centre samples.

Eur J Gastroenterol Hepatol 2019 02;31(2):163-169

Division for Family Medicine and Primary Care, Karolinska Institutet.

Background: Clinical understanding of gastrointestinal symptoms is commonly based on patient reports of symptom experience. For diagnosis and treatment choices to be appropriate, symptom reports need to be accurate. We examined the agreement between questionnaire recall and prospective diary enumeration of symptoms relevant to the irritable bowel syndrome.

Patients And Methods: Data are reported from a randomly selected general population sample (n=238) and also a primary healthcare centre (PHC) sample (n=503, 10 PHCs). All the patients completed the questionnaires, which included Rome III-qualifying irritable bowel syndrome items and a stool and symptom diary over either 7 or 14 days. Agreement between retrospective questionnaire reports and prospective diaries was evaluated.

Results: Concordance between questionnaires and diaries was highest for the simple construct of the occurrence of abdominal pain, although after adjusting for possible chance, agreement was only moderate in the general population sample. More complex constructs, such as pain relieved by defecation, yielded poorer concordance. In general, concordance was stronger among PHC respondents than in the general population sample.

Conclusion: Concordance between questionnaires and diaries was generally poor and related to the complexity of the symptom construct and the type of respondent. The information used to classify individuals based on patient self-report may be unreliable, and therefore, more effort is needed to develop data collection instruments.
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http://dx.doi.org/10.1097/MEG.0000000000001296DOI Listing
February 2019

Acute upper gastrointestinal bleeding.

BMJ 2018 Oct 25;363:k4023. Epub 2018 Oct 25.

Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

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http://dx.doi.org/10.1136/bmj.k4023DOI Listing
October 2018

Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome.

Gastroenterology 2018 07 5;155(1):168-179. Epub 2018 Apr 5.

G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California.

Background & Aims: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants.

Methods: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations.

Results: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 × 10) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0×10). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 × 10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia.

Conclusions: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.
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http://dx.doi.org/10.1053/j.gastro.2018.03.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035117PMC
July 2018

Identifying clinically relevant sliding hiatal hernias: a population-based endoscopy study.

Scand J Gastroenterol 2018 06 4;53(6):657-660. Epub 2018 Apr 4.

c Division of Family Medicine and Primary Care , Karolinska Institutet , Huddinge , Sweden.

Objectives: The clinical relevance of small to moderate sliding hiatal hernias is controversial. The aims of the present study were to (1) investigate which symptoms are associated with sliding hiatal hernias and (2) define the length of a sliding hiatal hernia at which gastrointestinal symptoms occur.

Methods: A study population representative of the general Swedish population answered a questionnaire regarding gastrointestinal symptoms and was investigated with an upper endoscopy. The length of any sliding hiatal hernia was measured.

Results: Only reflux-related symptoms were associated with length of the hiatal hernia (acid regurgitation OR 1.46, CI 1.19-1.79, heartburn OR 1.27, CI 1.05-1.54), and the association did not become significant until an axial hiatal hernia length of 2 cm.

Conclusions: Only reflux symptoms could be attributed to sliding hiatal hernias. Hiatal hernias less than 2 cm should be considered clinically insignificant.
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http://dx.doi.org/10.1080/00365521.2018.1458896DOI Listing
June 2018

ABC om - IBS – irritabel tarm.

Lakartidningen 2018 03 7;115. Epub 2018 Mar 7.

Avd för Invärtesmedicin & Klinisk Nutrition, Institutionen för Medicin, Sahlgrenska Akademin - Göteborgs Universitet Göteborg, Sweden Avd för Invärtesmedicin & Klinisk Nutrition, Institutionen för Medicin, Sahlgrenska Akademin - Göteborgs Universitet Göteborg, Sweden.

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March 2018
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