Diverticulosis is not associated with altered gut microbiota nor is it predictive of future diverticulitis: a population-based colonoscopy study.

BACKGROUND: The etiopathogenesis of diverticular disease is unknown. OBJECTIVE: To compare the fecal and mucosa-associated microbiota between participants with and without diverticulosis and participants who later developed diverticulitis versus those that did not from a population-based study. METHODS: The PopCol study, conducted in Stockholm, Sweden, invited a random sample of 3556 adults to participate, of which 745 underwent colonoscopy. Overall, 130 participants (17.5%) had diverticulosis. 16S rRNA gene sequencing was conducted on available sigmoid biopsy samples from 529 and fecal samples from 251 individuals. We identified individuals who subsequently developed acute diverticulitis up to 13 years after sample collection. In a case-control design matching for gender, age (+/-5 years), smoking and antibiotic exposure, we compared taxonomic composition, richness and diversity of the microbiota between participants with or without diverticulosis, and between participants who later developed acute diverticulitis versus those who did not. RESULTS: No differences in microbiota richness or diversity were observed between participants with or without diverticulosis, nor for those who developed diverticulitis compared with those who did not. No bacterial taxa were significantly different between participants with diverticulosis compared with those without diverticulosis. Individuals who later developed acute diverticulitis (2.8%) had a higher abundance of genus Comamonas than those who did not (p = .027). CONCLUSIONS: In a population-based cohort study the only significant difference was that those who later develop diverticulitis had more abundance of genus Comamonas. The significance of Comamonas is unclear, suggesting a limited role for the gut microbiota in the etiopathogenesis of diverticular disease.

Chronic fatigue syndromes: real illnesses that people can recover from.

The 'Oslo Chronic Fatigue Consortium' consists of researchers and clinicians who question the current narrative that chronic fatigue syndromes, including post-covid conditions, are incurable diseases. Instead, we propose an alternative view, based on research, which offers more hope to patients. Whilst we regard the symptoms of these conditions as real, we propose that they are more likely to reflect the brain's response to a range of biological, psychological, and social factors, rather than a specific disease process. Possible causes include persistent activation of the neurobiological stress response, accompanied by associated changes in immunological, hormonal, cognitive and behavioural domains. We further propose that the symptoms are more likely to persist if they are perceived as threatening, and all activities that are perceived to worsen them are avoided. We also question the idea that the best way to cope with the illness is by prolonged rest, social isolation, and sensory deprivation.Instead, we propose that recovery is often possible if patients are helped to adopt a less threatening understanding of their symptoms and are supported in a gradual return to normal activities. Finally, we call for a much more open and constructive dialogue about these conditions. This dialogue should include a wider range of views, including those of patients who have recovered from them.

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

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.

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

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.

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

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).

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.

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

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 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.

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

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. FIB-4 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.

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

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.

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

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.

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

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.

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.

OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10-10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). CONCLUSION: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

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.

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 Brachyspira aalborgi 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 Brachyspira pilosicoli; all remaining isolates were of the species Brachyspira aalborgi 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 Brachyspira due to primer incompatibility.IMPORTANCE 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.

Predictive Capacity for Mortality and Severe Liver Disease of the Relative Fat Mass Algorithm.

In the latest decades, obesity has become a major global health problem. Obesity has traditionally been defined as a body mass index (BMI) of equal to or more than 30 kg/m2. It is now well known that persons with obesity to a high degree develop nonalcoholic fatty liver disease and are at risk for developing cirrhosis.1 However, BMI has been criticized for being an imperfect measurement of body fat composition.2 Recently, a new algorithm was developed to better estimate the percentage of body fat.3 The relative fat mass (RFM) was based on height, waist circumference (WC), and sex. The RFM was found to be superior to BMI and other estimators in estimating body fat percentage, using dual-energy X-ray absorptiometry as the gold standard. RFM had also a stronger association with diabetes status than BMI. However, because the analyzed data came from a cross-sectional source, it is unclear if the RFM is superior to BMI or other measures of body composition in predicting incident clinically significant outcomes, including mortality. In addition, RFM was not compared with WC or waist-hip-ratio (WHR), which are commonly used clinically and in epidemiologic studies.

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

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

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

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.

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

Background and study aims: 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. Patients and methods: 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. Results: 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). Conclusions: 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).

Risk Behaviors Associated with Alcohol Consumption Predict Future Severe Liver Disease.

BACKGROUND: Excess consumption of alcohol can lead to cirrhosis, but it is unclear whether the type of alcohol and pattern of consumption affects this risk. AIMS: We aimed to investigate whether type and pattern of alcohol consumption early in life could predict development of severe liver disease. METHODS: We examined 43,242 adolescent men conscribed to military service in Sweden in 1970. Self-reported data on total amount and type of alcohol (wine, beer, and spirits) and risk behaviors associated with heavy drinking were registered. Population-based registers were used to ascertain incident cases of severe liver disease (defined as cirrhosis, decompensated liver disease, liver failure, hepatocellular carcinoma, or liver-related mortality). Cox regression models were used to estimate hazard ratios for development of severe liver disease. RESULTS: During follow-up, 392 men developed severe liver disease. In multivariable analysis, after adjustment for BMI, smoking, use of narcotics, cardiovascular fitness, cognitive ability, and total amount of alcohol, an increased risk for severe liver disease was found in men who reported drinking alcohol to alleviate a hangover ("eye-opener"; aHR 1.47, 95% CI 1.02-2.11) and men who reported having been apprehended for being drunk (aHR 2.17, 95% CI 1.63-2.90), but not for any other risk behaviors. Wine consumption was not associated with a reduced risk for severe liver disease compared to beer and spirits. CONCLUSIONS: Certain risk behaviors can identify young men with a high risk of developing severe liver disease. Wine consumption was not associated with a reduced risk for severe liver disease compared to beer and spirits.

Functional variants in the sucrase-isomaltase gene associate with increased risk of irritable bowel syndrome.

OBJECTIVE: IBS is a common gut disorder of uncertain pathogenesis. Among other factors, genetics and certain foods are proposed to contribute. Congenital sucrase-isomaltase deficiency (CSID) is a rare genetic form of disaccharide malabsorption characterised by diarrhoea, abdominal pain and bloating, which are features common to IBS. We tested sucrase-isomaltase (SI) gene variants for their potential relevance in IBS. DESIGN: We sequenced SI exons in seven familial cases, and screened four CSID mutations (p.Val557Gly, p.Gly1073Asp, p.Arg1124Ter and p.Phe1745Cys) and a common SI coding polymorphism (p.Val15Phe) in a multicentre cohort of 1887 cases and controls. We studied the effect of the 15Val to 15Phe substitution on SI function in vitro. We analysed p.Val15Phe genotype in relation to IBS status, stool frequency and faecal microbiota composition in 250 individuals from the general population. RESULTS: CSID mutations were more common in patients than asymptomatic controls (p=0.074; OR=1.84) and Exome Aggregation Consortium reference sequenced individuals (p=0.020; OR=1.57). 15Phe was detected in 6/7 sequenced familial cases, and increased IBS risk in case-control and population-based cohorts, with best evidence for diarrhoea phenotypes (combined p=0.00012; OR=1.36). In the population-based sample, 15Phe allele dosage correlated with stool frequency (p=0.026) and Parabacteroides faecal microbiota abundance (p=0.0024). The SI protein with 15Phe exhibited 35% reduced enzymatic activity in vitro compared with 15Val (p<0.05). CONCLUSIONS: SI gene variants coding for disaccharidases with defective or reduced enzymatic activity predispose to IBS. This may help the identification of individuals at risk, and contribute to personalising treatment options in a subset of patients.

Alcohol consumption in late adolescence is associated with an increased risk of severe liver disease later in life.

BACKGROUND & AIMS: High alcohol consumption is associated with an increased risk of severe liver disease. Current recommendations suggest it is safe for men to consume 30 grams of alcohol per day. We investigated the association between alcohol consumption early in life and later development of severe liver disease. METHODS: We used data on alcohol consumption at conscription to military service from 43,296 men (18-20 years) in Sweden between 1969 and 1970. Outcomes were defined as incident diagnoses of severe liver disease from systematic national registration of clinical events until the end of 2009. A Cox regression model adjusted for body mass index, smoking, use of narcotics, cognitive ability and cardiovascular capacity was applied. RESULTS: During a mean follow-up of 37.8 years, 383 men developed severe liver disease. Alcohol consumption was associated with an increased risk of development of severe liver disease in a dose-response pattern (adjusted hazard ratio for every one gram/day increase 1.02; 95% CI 1.01-1.02). No evidence of a threshold effect was found. Importantly, a clear trend pointed towards an increased risk of severe liver disease in men who consumed less than 30 grams of alcohol per day. CONCLUSION: Alcohol consumption in young men is associated with an increased risk of severe liver disease, up to 39 years later in life. The risk was dose-dependent, with no sign of a threshold effect. Current guidelines for safe alcohol intake in men might have to be revised. LAY SUMMARY: We investigated more than 43,000 Swedish men in their late teens enlisted for conscription in 1969-1970. After almost 40 years of follow-up, we found that alcohol consumption was a significant risk factor for developing severe liver disease, independent of confounders. This risk was dose-dependent, and was most pronounced in men consuming two drinks per day or more.