Metagenomics analysis reveals unique gut microbiota signature of slow-transit constipation.

INTRODUCTION: Altered gut microbiota may play a role in slow-transit constipation (STC). We conducted a study of gut microbiota composition and functionality in STC using metagenomic analyses. METHODS: We assembled a clinical cohort of 24 patients with STC physiology age- and sex-matched to 24 controls. We performed shotgun metagenomic sequencing followed by prediction of metabolite composition from functional profiles. RESULTS: In a middle-aged (mean 55.3 years), predominantly female cohort, there were no significant differences in α diversity indices, but permutational multivariate analysis of variance analysis showed significant between-group differences (R2=0.050, p<0.001) between STC patients and controls. Gordonibacter pamelaeae, Bifidobacterium longum, Firmicutes bacterium CAG 94, and Anaerotruncus colihominis were more abundant in STC, while Coprococcus comes and Roseburia intestinalis were more abundant in controls. Gut-derived metabolites varying in STC relative to controls were related to bile acid and cholesterol metabolism. DISCUSSION: We found a unique metagenomic and metabolomic signature of STC.

Gut microbiome structure and function in asymptomatic diverticulosis.

BACKGROUND: Colonic diverticulosis, the most common lesion found in routine colonoscopy, affects more than 50% of individuals aged ≥ 60 years. Emerging evidence suggest that dysbiosis of gut microbiota may play an important role in the pathophysiology of diverticular disease. However, specific changes in microbial species and metabolic functions in asymptomatic diverticulosis remain unknown. METHODS: In a cohort of US adults undergoing screening colonoscopy, we analyzed the gut microbiota using shotgun metagenomic sequencing. Demographic factors, lifestyle, and medication use were assessed using a baseline questionnaire administered prior to colonoscopy. Taxonomic structures and metabolic pathway abundances were determined using MetaPhlAn3 and HUMAnN3. We used multivariate association with linear models to identify microbial species and metabolic pathways that were significantly different between asymptomatic diverticulosis and controls, while adjusting for confounders selected a priori including age at colonoscopy, sex, body mass index (BMI), and dietary pattern. RESULTS: Among 684 individuals undergoing a screening colonoscopy, 284 (42%) had diverticulosis. Gut microbiome composition explained 1.9% variation in the disease status of asymptomatic diverticulosis. We observed no significant differences in the overall diversity of gut microbiome between asymptomatic diverticulosis and controls. However, microbial species Bifidobacterium pseudocatenulatum and Prevotella copri were significantly enriched in controls (q value = 0.19 and 0.14, respectively), whereas Roseburia intestinalis, Dorea sp. CAG:317, and Clostridium sp. CAG: 299 were more abundant in those with diverticulosis (q values = 0.17, 0.24, and 0.10, respectively). We observed that the relationship between BMI and diverticulosis appeared to be limited to carriers of Bifidobacterium pseudocatenulatum and Roseburia intestinalis (Pinteraction = 0.09). CONCLUSIONS: Our study provides the first large-scale evidence supporting taxonomic and functional shifts of the gut microbiome in individuals with asymptomatic diverticulosis. The suggestive interaction between gut microbiota and BMI on prevalent diverticulosis deserves future investigations.

Towards Improved XAI-Based Epidemiological Research into the Next Potential Pandemic.

By applying AI techniques to a variety of pandemic-relevant data, artificial intelligence (AI) has substantially supported the control of the spread of the SARS-CoV-2 virus. Along with this, epidemiological machine learning studies of SARS-CoV-2 have been frequently published. While these models can be perceived as precise and policy-relevant to guide governments towards optimal containment policies, their black box nature can hamper building trust and relying confidently on the prescriptions proposed. This paper focuses on interpretable AI-based epidemiological models in the context of the recent SARS-CoV-2 pandemic. We systematically review existing studies, which jointly incorporate AI, SARS-CoV-2 epidemiology, and explainable AI approaches (XAI). First, we propose a conceptual framework by synthesizing the main methodological features of the existing AI pipelines of SARS-CoV-2. Upon the proposed conceptual framework and by analyzing the selected epidemiological studies, we reflect on current research gaps in epidemiological AI toolboxes and how to fill these gaps to generate enhanced policy support in the next potential pandemic.

Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis.

Immune checkpoint inhibitor (ICI) therapy has revolutionized oncology, but treatments are limited by immune-related adverse events, including checkpoint inhibitor colitis (irColitis). Little is understood about the pathogenic mechanisms driving irColitis, which does not readily occur in model organisms, such as mice. To define molecular drivers of irColitis, we used single-cell multi-omics to profile approximately 300,000 cells from the colon mucosa and blood of 13 patients with cancer who developed irColitis (nine on anti-PD-1 or anti-CTLA-4 monotherapy and four on dual ICI therapy; most patients had skin or lung cancer), eight controls on ICI therapy and eight healthy controls. Patients with irColitis showed expanded mucosal Tregs, ITGAEHi CD8 tissue-resident memory T cells expressing CXCL13 and Th17 gene programs and recirculating ITGB2Hi CD8 T cells. Cytotoxic GNLYHi CD4 T cells, recirculating ITGB2Hi CD8 T cells and endothelial cells expressing hypoxia gene programs were further expanded in colitis associated with anti-PD-1/CTLA-4 therapy compared to anti-PD-1 therapy. Luminal epithelial cells in patients with irColitis expressed PCSK9, PD-L1 and interferon-induced signatures associated with apoptosis, increased cell turnover and malabsorption. Together, these data suggest roles for circulating T cells and epithelial-immune crosstalk critical to PD-1/CTLA-4-dependent tolerance and barrier function and identify potential therapeutic targets for irColitis.

Avoidant/Restrictive Food Intake Disorder Symptoms Are Not as Frequent as Other Eating Disorder Symptoms When Ulcerative Colitis Is in Remission.

BACKGROUND AND AIM: Recent studies have shown that up to 53% of patients with inflammatory bowel disease [IBD] screen positive for avoidant/restrictive food intake disorder [ARFID]. There is however concern that ARFID screening rates are over-inflated in patients with active disease. We aimed to evaluate the frequency and characteristics of ARFID symptoms using the Nine Item ARFID Screen [NIAS], and to use another eating disorder measure, the Eating Disorder Examination-Questionnaire 8 [EDE-Q8], to rule-out/characterise other eating disorder cognitive and behavioural symptoms. METHODS: Participants included adults with UC who are enrolled in an ongoing cohort study with quiescent UC (Simple Clinical Colitis Activity Index [SCCAI] ≤2 or faecal calprotectin <150 µg/g with corticosteroid-free clinical remission for ≥3 months) at baseline. We used self-reported data on demographics, gastrointestinal medications, medical comorbidities, NIAS scores, and EDE-Q-8 scores. RESULTS: We included 101 participants who completed the NIAS at their baseline cohort assessment [age 49.9 ±â€…16.5 years; 55% female]. Eleven participants [11%] screened positively for ARFID on at least one NIAS subscale [n = 8 male]. Up to 30 participants [30%] screened positive for other eating disorder symptoms [EDE-Q-8 Global ≥2.3]. Overall score distributions on the EDE-Q-8 showed that participants scored highest on the Weight Concern and Shape Concern subscales. CONCLUSIONS: Among adults with UC in remission, we found a low rate of ARFID symptoms by the NIAS but a high rate of positive screens for other eating disorder symptoms.

A natural language processing algorithm accurately classifies steatotic liver disease pathology to estimate the risk of cirrhosis.

BACKGROUND: Histopathology remains the gold standard for diagnosing and staging metabolic dysfunction-associated steatotic liver disease (MASLD). The feasibility of studying MASLD progression in electronic medical records based on histological features is limited by the free-text nature of pathology reports. Here we introduce a natural language processing (NLP) algorithm to automatically score MASLD histology features. METHODS: From the Mass General Brigham health care system electronic medical record, we identified all patients (1987-2021) with steatosis on index liver biopsy after excluding excess alcohol use and other etiologies of liver disease. An NLP algorithm was constructed in Python to detect steatosis, lobular inflammation, ballooning, and fibrosis stage from pathology free-text and manually validated in >1200 pathology reports. Patients were followed from the index biopsy to incident decompensated liver disease accounting for covariates. RESULTS: The NLP algorithm demonstrated positive and negative predictive values from 93.5% to 100% for all histologic concepts. Among 3134 patients with biopsy-confirmed MASLD followed for 20,604 person-years, rates of the composite endpoint increased monotonically with worsening index fibrosis stage (p for linear trend <0.005). Compared to simple steatosis (incidence rate, 15.06/1000 person-years), the multivariable-adjusted HRs for cirrhosis were 1.04 (0.72-1.5) for metabolic dysfunction-associated steatohepatitis (MASH)/F0, 1.19 (0.92-1.54) for MASH/F1, 1.89 (1.41-2.52) for MASH/F2, and 4.21 (3.26-5.43) for MASH/F3. CONCLUSIONS: The NLP algorithm accurately scores histological features of MASLD from pathology free-text. This algorithm enabled the construction of a large and high-quality MASLD cohort across a multihospital health care system and disclosed an accelerating risk for cirrhosis based on the index MASLD fibrosis stage.

Predominantly antibody deficiency and the association with celiac disease in Sweden: A nationwide case-control study.

BACKGROUND: Predominantly antibody deficiency (PAD) is associated with noninfectious inflammatory gastrointestinal disease. Population estimates of celiac disease (CeD) risk in those with PAD are limited. OBJECTIVE: To estimate population risk of PAD in individuals with CeD. METHODS: We conducted a nationwide case-control study in Swedish individuals who received a diagnosis of CeD between 1997 and 2017 (n = 34,980), matched to population comparators by age, sex, calendar year, and county. The CeD was confirmed through the Epidemiology Strengthened by histopathology Reports in Sweden study, which provided information on biopsy specimens from each of Sweden's pathology departments. PAD was identified using International Classification of Diseases, 10th Revision coding and categorized according to the International Union of Immunologic Societies. Logistic regression was used to calculate adjusted odds ratios (aORs) and 95% CIs. RESULTS: PAD was more prevalent in CeD than in population controls (n = 105 [0.3%] vs n = 57 [0.033%], respectively). This translated to an aOR of 8.23 (95% CI 5.95-11.48). The association was strongest with common variable immunodeficiency (aOR 17.25; 95% CI 6.86-52.40), and slightly lower in other PAD (aOR 8.39; 95% CI 5.79-12.32). The risk of CeD remained increased at least 5 years after diagnosis of PAD (aOR 4.79; 95% CI 2.89-7.97, P-heterogeneity ≤ 0.001). CONCLUSION: PAD was associated with an increased risk of CeD. A particularly strong association was seen in those with CVID, although this should be interpreted cautiously given the limited understanding of the mechanisms of histopathologic changes in these patients.

Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes.

BACKGROUND AND AIMS: Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. METHODS: We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. RESULTS: We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. CONCLUSION: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.

Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution.

The human leukocyte antigen (HLA) locus plays a critical role in complex traits spanning autoimmune and infectious diseases, transplantation and cancer. While coding variation in HLA genes has been extensively documented, regulatory genetic variation modulating HLA expression levels has not been comprehensively investigated. Here we mapped expression quantitative trait loci (eQTLs) for classical HLA genes across 1,073 individuals and 1,131,414 single cells from three tissues. To mitigate technical confounding, we developed scHLApers, a pipeline to accurately quantify single-cell HLA expression using personalized reference genomes. We identified cell-type-specific cis-eQTLs for every classical HLA gene. Modeling eQTLs at single-cell resolution revealed that many eQTL effects are dynamic across cell states even within a cell type. HLA-DQ genes exhibit particularly cell-state-dependent effects within myeloid, B and T cells. For example, a T cell HLA-DQA1 eQTL ( rs3104371 ) is strongest in cytotoxic cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.

Periodontal disease is not associated with risk of inflammatory bowel disease: Results from two prospective cohort studies in the US.

AIM: To examine the relationship between periodontal disease and tooth loss and risk of inflammatory bowel disease (IBD). METHODS: We conducted a prospective cohort study of 86,602 women from the Nurses' Health Study (1992-2016) and 50,349 men from the Health Professionals Follow-up Study (1986-2016) with available data on periodontal disease and tooth loss. Cases of IBD were initially reported by participants and then confirmed by medical record review. We used Cox proportional hazards modelling to estimate multivariable-adjusted hazard ratios (aHRs) and 95% CIs. RESULTS: Through the end of follow-up, we documented 175 cases of Crohn's disease (CD) and 209 cases of ulcerative colitis (UC). After adjustment for potential risk factors, there was no association between periodontal disease and risk of CD (pooled aHR: 0.99, 95% CI: 0.65-1.52, p = 0.970) or UC (aHR: 0.99, 95% CI: 0.68-1.45, p = 0.971). Similarly, we did not observe an association between tooth loss and risk of CD (aHR: 0.72, 95% CI: 0.43-1.21, p = 0.218) or UC (aHR: 0.89, 95% CI: 0.58-1.36, p = 0.581) in the pooled analysis. The associations were not modified by sex, age, body mass index (BMI), smoking status or NSAID use (all pinteraction > 0.87). CONCLUSION: In two large prospective cohort studies, we did not observe an association between periodontal disease and tooth loss and risk of CD or UC.

Increasing healthcare costs in inflammatory bowel disease 2007-2020 in Sweden.

BACKGROUND: Inflammatory bowel disease has been linked to increasing healthcare costs, but longitudinal data on other societal costs are scarce. AIM: To assess costs, including productivity losses, in patients with prevalent Crohn's disease (CD) or ulcerative colitis (UC) in Sweden between 2007 and 2020. METHODS: We linked data from national registers on all patients with CD or UC and a matched (sex, birthyear, healthcare region and education) reference population. We assessed mean costs/year in Euros, inflation-adjusted to 2020, for hospitalisations, out-patient visits, medications, sick leave and disability pension. We defined excess costs as the mean difference between patients and matched comparators. RESULTS: Between 2007 and 2020, absolute mean annual societal costs in working-age (18-64 years) individuals decreased by 17% in CD (-24% in the comparators) and by 20% in UC (-27% in comparators), due to decreasing costs from sick leave and disability, a consequence of stricter sick leave regulations. Excess costs in 2007 were dominated by productivity losses. In 2020, excess costs were mostly healthcare costs. Absolute and excess costs increased in paediatric and elderly patients. Overall, costs for TNF inhibitors/targeted therapies increased by 274% in CD and 638% in UC, and the proportion treated increased from 5% to 26% in CD, and from 1% to 10% in UC. CONCLUSION: Between 2007 and 2020, excess costs shifted from productivity losses to direct healthcare costs; that is, the patients' compensation for sickness absence decreased, while society increased its spending on medications. Medication costs were driven both by expanding use of TNF inhibitors and by high costs for newer targeted therapies.

Association of distinct microbial signatures with premalignant colorectal adenomas.

Environmental exposures are a major risk factor for developing colorectal cancer, and the gut microbiome may serve as an integrator of such environmental risk. To study the microbiome associated with premalignant colon lesions, such as tubular adenomas (TAs) and sessile serrated adenomas (SSAs), we profiled stool samples from 971 participants undergoing colonoscopy and paired these data with dietary and medication history. The microbial signatures associated with either SSA or TA are distinct. SSA associates with multiple microbial antioxidant defense systems, whereas TA associates with a depletion of microbial methanogenesis and mevalonate metabolism. Environmental factors, such as diet and medications, link with the majority of identified microbial species. Mediation analyses found that Flavonifractor plautii and Bacteroides stercoris transmit the protective or carcinogenic effects of these factors to early carcinogenesis. Our findings suggest that the unique dependencies of each premalignant lesion may be exploited therapeutically or through dietary intervention.

Patients With Microscopic Colitis Are at Higher Risk of Major Adverse Cardiovascular Events: A Matched Cohort Study.

BACKGROUND AND AIMS: Inflammatory diseases are associated with an increased risk of incident major adverse cardiovascular events (MACE). However, data on MACE are lacking in large population-based histopathology cohorts of microscopic colitis (MC). METHODS: This study included all Swedish adults with MC without previous cardiovascular disease (1990-2017; N = 11,018). MC and subtypes (collagenous colitis and lymphocytic colitis) were defined from prospectively recorded intestinal histopathology reports from all pathology departments (n = 28) in Sweden. MC patients were matched for age, sex, calendar year, and county with up to 5 reference individuals (N = 48,371) without MC or cardiovascular disease. Sensitivity analyses included full sibling comparisons, and adjustment for cardiovascular medication and healthcare utilization. Multivariable-adjusted hazard ratios for MACE (any of ischemic heart disease, congestive heart failure, stroke, and cardiovascular mortality) were calculated using Cox proportional hazards modelling. RESULTS: Over a median of 6.6 years of follow-up, 2181 (19.8%) incident cases of MACE were confirmed in MC patients and 6661 (13.8%) in reference individuals. MC patients had a higher overall risk of MACE outcomes compared with reference individuals (adjusted hazard ratio [aHR], 1.27; 95% confidence interval [CI], 1.21-1.33) and higher risk of its components: ischemic heart disease (aHR, 1.38; 95% CI, 1.28-1.48), congestive heart failure (aHR, 1.32; 95% CI, 1.22-1.43), and stroke (aHR, 1.12; 95% CI, 1.02-1.23) but not cardiovascular mortality (aHR, 1.07; 95% CI, 0.98-1.18). The results remained robust in the sensitivity analyses. CONCLUSIONS: Compared with reference individuals, MC patients had a 27% higher risk of incident MACE, equal to 1 extra case of MACE for every 13 MC patients followed for 10 years.

Predominant Antibody Deficiency and Risk of Microscopic Colitis: a Nationwide Case-Control Study in Sweden.

PURPOSE : Predominant antibody deficiency (PAD) disorders, including common variable immunodeficiency (CVID), have been linked to increased risk of gastrointestinal infections and inflammatory bowel diseases. However, there are limited data on the relationship between PAD, specifically CVID, and risk of microscopic colitis (MC). METHODS: We performed a nationwide case-control study of Swedish adults with MC diagnosed between 1997 and 2017 (n = 13,651). Data on biopsy-verified MC were retrieved from all of Sweden's pathology departments through the Epidemiology Strengthened by histoPathology Reports in Sweden (ESPRESSO) study. We defined predominant antibody deficiency using International Union of Immunologic Societies (IUIS) phenotypic classification. Individuals with MC were matched to population controls by age, sex, calendar year, and county. We used logistic regression to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: The prevalence of PAD in MC was 0.4% as compared to 0.05% in controls. After adjustment for potential confounders, this corresponded to an aOR of 7.29 (95%CI 4.64-11.63). The magnitude of the association was higher for CVID (aOR 21.01, 95% 5.48-137.44) compared to other antibody deficiencies (aOR 6.16, 95% CI 3.79-10.14). In exploratory analyses, the association between PAD and MC was particularly strong among males (aOR 31.73, 95% CI 10.82-135.04). CONCLUSION: In this population-based study, predominant antibody deficiency was associated with increased risk of MC, particularly among males. Clinicians who encounter these patients should consider a detailed infectious history and screening for antibody deficiency.

Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution.

The human leukocyte antigen (HLA) locus plays a critical role in complex traits spanning autoimmune and infectious diseases, transplantation, and cancer. While coding variation in HLA genes has been extensively documented, regulatory genetic variation modulating HLA expression levels has not been comprehensively investigated. Here, we mapped expression quantitative trait loci (eQTLs) for classical HLA genes across 1,073 individuals and 1,131,414 single cells from three tissues, using personalized reference genomes to mitigate technical confounding. We identified cell-type-specific cis-eQTLs for every classical HLA gene. Modeling eQTLs at single-cell resolution revealed that many eQTL effects are dynamic across cell states even within a cell type. HLA-DQ genes exhibit particularly cell-state-dependent effects within myeloid, B, and T cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.

Type 1 diabetes and microscopic colitis: A nationwide matched case-control study in Sweden.

BACKGROUND AND AIMS: Microscopic colitis (MC) is a colonic inflammatory condition associated with autoimmune dysfunction. Type 1 diabetes (T1D) is a chronic disease induced by autoimmune destruction of pancreatic ß-cells. We aimed to examine the association between T1D and MC. METHODS: A matched case-control study was conducted using the nationwide ESPRESSO cohort as study base. All biopsy-confirmed MC patients born after 1940 were identified and compared to biopsy-free individuals matched from the general population for T1D diagnosis using the Swedish National Patient Register. The T1D-MC association was estimated as odds ratios (ORs) and 95% confidence intervals (CIs) by conditional logistic models, considering differences by sex and MC subtype. Full sibling comparison and adjustment for MC-associated medications were also performed. RESULTS: We identified 352 (3.7%) and 945 (2.0%) T1D diagnoses from 9,600 MC cases and 47,870 matched population controls, respectively, which corresponded to an overall OR of 1.79 (95% CI: 1.56-2.05). The association was stronger for collagenous colitis (OR, 2.15; 95% CI: 1.70-2.71) than lymphocytic colitis (OR, 1.62; 95% CI: 1.37-1.92) and remained statistically significant in full sibling comparison (OR, 1.46; 95%: 1.18-1.81). Medication adjustment attenuated the association to null among females (OR: 1.02; 95% CI: 0.82-1.27) but not among males (OR: 1.45; 95% CI: 1.11-1.90). CONCLUSION: T1D diagnosis was almost 80% more prevalent in MC patients compared to general population. This positive association did not seem to be spurious due to residual confounding shared by full siblings but may relate to consumption of medications associated with MC onset.

Celiac disease and risk of microscopic colitis: A nationwide population-based matched cohort study.

BACKGROUND: An association has been reported between celiac disease (CD) and microscopic colitis (MC). However, large, population-based cohort studies are rare. OBJECTIVE: To systematically examine the association between CD and MC in a large, nationwide cohort. METHODS: We conducted a nationwide population-based matched cohort study in Sweden of 45,138 patients with biopsy-verified CD (diagnosed in 1990-2016), 223,149 reference individuals, and 51,449 siblings of CD patients. Data on CD and MC were obtained from all (n = 28) pathology departments in Sweden. Adjusted hazard ratios (aHRs) were calculated using Cox regression. RESULTS: During follow-up, 452 CD patients and 197 reference individuals received an MC diagnosis (86.1 vs. 7.5 per 100,000 person-years). This difference corresponded to an aHR of 11.6 (95% confidence interval [CI] = 9.8-13.8) or eight extra MC cases in 1000 CD patients followed up for 10 years. Although the risk of MC was highest during the first year of follow-up (aHR 35.2; 95% CI = 20.1-61.6), it remained elevated even after 10 years (aHR 8.1; 95% CI = 6.0-10.9). Examining MC subtypes lymphocytic colitis (LC) and collagenous colitis (CC) separately, the aHR was 12.4 (95% CI = 10.0-15.3) for LC and 10.2 (95% CI = 7.7-13.6) for CC. MC was also more common before CD (adjusted odds ratio [aOR] = 52.7; 95% CI = 31.4-88.4). Compared to siblings, risk estimates decreased but remained elevated (CD and later MC: HR = 6.2; CD and earlier MC: aOR = 7.9). CONCLUSION: Our study demonstrated a very strong association of MC with CD with an increased risk of future and previous MC in CD patients. The magnitude of the associations underscores the need to consider the concomitance of these diagnoses in cases in which gastrointestinal symptoms persist or recur despite a gluten-free diet or conventional MC treatment. The comparatively lower risk estimates in sibling comparisons suggest that shared genetic and early environmental factors may contribute to the association between CD and MC.

Inflammatory Bowel Disease and Risk of Colorectal Polyps: A Nationwide Population-Based Cohort Study From Sweden.

BACKGROUND: Inflammatory bowel disease [IBD] has been linked to an increased risk of colorectal neoplasia. However, the types and risks of specific polyp types in IBD are less clear. METHODS: We identified 41 880 individuals with IBD (Crohn's disease [CD: n = 12 850]; ulcerative colitis [UC]: n = 29 030]) from Sweden matched with 41 880 reference individuals. Using Cox regression, we calculated adjusted hazard ratios [aHRs] for neoplastic colorectal polyps [tubular, serrated/sessile, advanced and villous] defined by histopathology codes. RESULTS: During follow-up, 1648 [3.9%] IBD patients and 1143 [2.7%] reference individuals had an incident neoplastic colorectal polyp, corresponding to an incidence rate of 46.1 and 34.2 per 10 000 person-years, respectively. This correlated to an aHR of 1.23 (95% confidence interval [CI] 1.12-1.35) with the highest HRs seen for sessile serrated polyps [8.50, 95% CI 1.10-65.90] and traditional serrated adenomas [1.72, 95% CI 1.02-2.91]. aHRs for colorectal polyps were particularly elevated in those diagnosed with IBD at a young age and at 10 years after diagnosis. Both absolute and relative risks of colorectal polyps were higher in UC than in CD [aHRs 1.31 vs 1.06, respectively], with a 20-year cumulative risk difference of 4.4% in UC and 1.5% in CD, corresponding to one extra polyp in 23 patients with UC and one in 67 CD patients during the first 20 years after IBD diagnosis. CONCLUSIONS: In this nationwide population-based study, there was an increased risk of neoplastic colorectal polyps in IBD patients. Colonoscopic surveillance in IBD appears important, especially in UC and after 10 years of disease.