Early Ileocecal Resection for Crohn's Disease Is Associated With Improved Long-term Outcomes Compared With Anti-Tumor Necrosis Factor Therapy: A Population-Based Cohort Study.

BACKGROUND & AIMS: Early Crohn's disease (CD) treatment involves anti-tumor necrosis factor (TNF) agents, whereas ileocecal resection (ICR) is reserved for complicated CD or treatment failure. We compared long-term outcomes of primary ICR and anti-TNF therapy for ileocecal CD. METHODS: Using cross-linked nationwide registers, we identified all individuals diagnosed with ileal or ileocecal CD between 2003 and 2018 and treated with ICR or anti-TNF agents within 1 year of diagnosis. The primary outcome was a composite of ≥1 of the following: CD-related hospitalization, systemic corticosteroid exposure, CD-related surgery, and perianal CD. We conducted adjusted Cox's proportional hazards regression analyses and determined the cumulative risk of different treatments after primary ICR or anti-TNF therapy. RESULTS: Of 16,443 individuals diagnosed with CD, 1279 individuals fulfilled the inclusion criteria. Of these, 45.4% underwent ICR and 54.6% received anti-TNF. The composite outcome occurred in 273 individuals (incidence rate, 110/1000 person-years) in the ICR group and in 318 individuals (incidence rate, 202/1000 person-years) in the anti-TNF group. The risk of the composite outcome was 33% lower with ICR compared with anti-TNF (adjusted hazard ratio, 0.67; 95% confidence interval, 0.54-0.83). ICR was associated with reduced risk of systemic corticosteroid exposure and CD-related surgery, but not other secondary outcomes. The proportion of individuals on immunomodulator, anti-TNF, who underwent subsequent resection, or were on no therapy 5 years post-ICR was 46.3%, 16.8%, 1.8%, and 49.7%, respectively. CONCLUSION: These data suggest that ICR may have a role as first-line therapy in CD management and challenge the current paradigm of reserving surgery for complicated CD refractory or intolerant to medications. Yet, given inherent biases associated with observational data, our findings should be interpreted and applied cautiously in clinical decision making.

Breastfeeding Duration Is Not Associated With Offspring Inflammatory Bowel Disease Risk in Three Population-Based Birth Cohorts.

BACKGROUND & AIMS: Breastfeeding is critical for offspring health and development. Although many observational studies report a protective effect between breastfeeding and inflammatory bowel disease (IBD), the relationship is not well-understood. METHODS: We used prospectively collected data from 3 population-based birth cohorts (Danish National Birth Cohort, Norwegian Mother, Father, and Child Cohort, and All Babies in Southeast Sweden) and cross-linked national registers to ascertain the impact of breastfeeding duration on offspring IBD risk in each country, using adjusted Cox proportional regression analyses. We performed meta-analyses to determine pooled estimates. RESULTS: We included 148,737 offspring and 169,510 offspring in analyses of exclusive and any breastfeeding duration, respectively. During median follow-up of 16.3-22.3 years, between 1996 and 2021, 543 offspring were diagnosed with IBD. In each country, there was no association between exclusive breastfeeding duration and offspring IBD risk after adjusting for birth year (Denmark), offspring sex, parental IBD status, maternal education, smoking during pregnancy, age at delivery, mode of delivery, preterm birth, and small for gestational age. The pooled adjusted hazard ratio for IBD was 1.24 (95% confidence interval, 0.94-1.62; Q = 0.16, I2 = 0.0%) and 1.02 (95% confidence interval, 0.85-1.21; Q = 1.45, I 2= 0.0%) among offspring breastfed exclusively for ≥6 months and <4 months, respectively, compared with 4-5 months. Similarly, we found null associations in pooled analyses of any breastfeeding duration and IBD, subtypes Crohn's disease and ulcerative colitis, as well as in cohort-specific analyses. CONCLUSIONS: In prospectively collected data from 3 population-based birth cohorts, the duration of exclusive or any breastfeeding was not associated with offspring IBD risk.

Increasing Incidence of Pouchitis Between 1996 and 2018: A Population-Based Danish Cohort Study.

BACKGROUND & AIMS: Current knowledge regarding the epidemiology of pouchitis is based on highly selected, mostly single-center, patient cohorts. Our objective was to prospectively determine the population-based incidence of pouchitis in patients with ulcerative colitis in the first 2 years after ileal pouch-anal anastomosis and analyze time trends of the incidence of pouchitis. METHODS: Using national registries, we established a population-based cohort of all Danish patients undergoing proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis between 1996 and 2018. The primary outcome was the development of pouchitis within the first 2 years after surgery, evaluated by time period. We used Kaplan-Meier and Cox proportional hazard modeling to evaluate the time to development of pouchitis. RESULTS: Overall, 1664 patients underwent an ileal pouch-anal anastomosis. The cumulative incidence of pouchitis in the 2 years after ileal pouch-anal anastomosis increased throughout the study period, from 40% in the period from 1996 to 2000 (95% CI, 35%-46%) to 55% in the period from 2015 to 2018 (95% CI, 48%-63%). Patients undergoing surgery between 2015 and 2018 also showed an increased risk of pouchitis compared with the earliest study period (1996-2000) after adjusting for sex, age, and socioeconomic status (hazard ratio, 1.57; 95% CI, 1.20-2.05). CONCLUSIONS: This population-based study showed a 15% absolute and 38% relative increase in the incidence of pouchitis among patients undergoing surgery between 1996 and 2018, with the greatest cumulative incidence of pouchitis shown in the most recent era (2015-2018). The striking increase in the incidence of pouchitis highlights the need for further research into causes and prevention of pouchitis.

The Rising Burden of Inflammatory Bowel Disease in Denmark Over Two Decades: A Nationwide Cohort Study.

BACKGROUND & AIMS: Shifts in epidemiological stages of inflammatory bowel disease (IBD) carry implications toward understanding IBD etiology and managing clinical care. We conducted a temporal analysis of the epidemiology of IBD between 1995 and 2016 in the Danish nationwide cohort. METHODS: We used the Danish registers to obtain data on demographics and IBD-related outpatient and inpatient contacts between 1995 and 2016. IBD diagnosis was defined as having ≥2 registrations related to Crohn's disease (CD) or ulcerative colitis (UC) within a 2-year period. We estimated overall and annual incidence rates and prevalence of CD and UC standardized with respect to age and sex. RESULTS: A total of 47,830 individuals met the criteria for IBD diagnosis, of which 33% were diagnosed with CD and 67% with UC. Between 1995 and 2016, the incidence rate (95% confidence interval) per 100,000 person-years rose from 9.1 (8.3-10.0) to 17.8 (16.8-19.0) for CD, and from 21.0 (19.8-22.3) to 28.4 (27.0-29.8) for UC. The highest increase in CD and UC incidence rates occurred in children and young adults, respectively. The prevalence of IBD doubled from 1995 to 2016; the greatest increase (2.5-fold) was in UC prevalence among individuals aged >40 years. During this period, the median age of the IBD population increased by 6 to 7 years. CONCLUSIONS: In Denmark, the incidence and prevalence of IBD have increased during the last 2 decades. The IBD population is shifting toward an older age. These findings have implications towards understanding environmental shifts as well as preparing health care systems for an aging IBD population.

Medication-Wide Study: Exploring Medication Use 10 Years Before a Diagnosis of Inflammatory Bowel Disease.

INTRODUCTION: There is growing interest in the prediagnostic phase of inflammatory bowel disease (IBD) and in the overlap of IBD with other diseases. We described and compared use of any prescription medication between individuals with and without IBD in a 10-year period preceding diagnosis. METHODS: Based on cross-linked nationwide registers, we identified 29,219 individuals diagnosed with IBD in Denmark between 2005 and 2018 and matched to 292,190 IBD-free individuals. The primary outcome was use of any prescription medication in years 1-10 before IBD diagnosis/matching date. Participants were considered as medication users if they redeemed ≥1 prescription for any medication in the World Health Organization Anatomical Therapeutic Chemical (ATC) main groups or subgroups before diagnosis/matching. RESULTS: The IBD population had a universally increased use of medications compared with the matched population before IBD diagnosis. At 10 years before diagnosis, the proportion of users was 1.1-fold to 1.8-fold higher in the IBD population in 12 of 14 ATC main groups of medication ( P -value < 0.0001). This applied across age, sex, and IBD subtypes, although it was the most pronounced for Crohn's disease (CD). Two years before diagnosis, the IBD population had a steep increase in medication use for several organ systems. When analyzing therapeutic subgroups of medication, the CD population exhibited 2.7, 2.3, 1.9, and 1.9 times more users of immunosuppressants, antianemic preparations, analgesics, and psycholeptics, respectively, than the matched population 10 years before diagnosis ( P -value < 0.0001). DISCUSSION: Our findings demonstrate universally increased medication use years before IBD, especially CD, diagnosis and indicates multiorgan involvement in IBD.

Rare and low-frequency coding variants alter human adult height.

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

Early-Life Mebendazole Exposure Increases the Risk of Adult-Onset Ulcerative Colitis: A Population-Based Cohort Study.

INTRODUCTION: According to the hygiene hypothesis, exposure to parasites may protect against inflammatory bowel disease (IBD). Our aim was to examine the risk of IBD with childhood exposure to mebendazole, a broad-spectrum antihelminthic agent. METHODS: We conducted a population-based cohort study using prospectively collected historical data of all individuals born in Denmark between 1995 and 2018. We identified mebendazole exposure at age younger than 18 years and during early life (younger than 5 years). We performed adjusted Cox proportional hazards regression analysis to determine the risk of IBD, ulcerative colitis (UC), and Crohn's disease with mebendazole exposure after adjusting for potential confounders. RESULTS: Of 1,520,290 individuals in the cohort, 615,794 had childhood or adolescence mebendazole exposure. One thousand five hundred fifty-five and 1,499 individuals were subsequently diagnosed with pediatric-onset and adult-onset IBD, respectively. On multivariable analysis, mebendazole exposure at age younger than 18 years did not affect pediatric-onset or adult-onset IBD risk (adjusted hazard ratio [aHR] 0.97, 95% confidence interval [CI] 0.87, 1.07, and 1.08, 95% CI 0.97, 1.19, respectively). On limiting mebendazole exposure to age younger than 5 years while there was no association with pediatric-onset IBD (aHR 0.98, 95% CI 0.87, 1.11), adult-onset IBD risk was increased (aHR 1.17, 95% CI 1.04, 1.31). This increase in risk was driven by UC (aHR 1.32, 95% CI 1.12, 1.55), but not Crohn's disease (1.03, 95% CI 0.87, 1.22). DISCUSSION: Early-life mebendazole exposure is associated with an increase in the risk of adult-onset UC. These findings suggest the importance of early-life exposures in shaping the risk of IBD later in life.

Predicting and elucidating the etiology of fatty liver disease: A machine learning modeling and validation study in the IMI DIRECT cohorts.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in individuals with and without type 2 diabetes (T2D). Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and, ultimately, hepatocellular carcinomas. We sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. METHODS AND FINDINGS: We utilized the baseline data from IMI DIRECT, a multicenter prospective cohort study of 3,029 European-ancestry adults recently diagnosed with T2D (n = 795) or at high risk of developing the disease (n = 2,234). Multi-omics (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI-image-derived liver fat content (<5% or ≥5%) available for 1,514 participants. We applied LASSO (least absolute shrinkage and selection operator) to select features from the different layers of omics data and random forest analysis to develop the models. The prediction models included clinical and omics variables separately or in combination. A model including all omics and clinical variables yielded a cross-validated receiver operating characteristic area under the curve (ROCAUC) of 0.84 (95% CI 0.82, 0.86; p < 0.001), which compared with a ROCAUC of 0.82 (95% CI 0.81, 0.83; p < 0.001) for a model including 9 clinically accessible variables. The IMI DIRECT prediction models outperformed existing noninvasive NAFLD prediction tools. One limitation is that these analyses were performed in adults of European ancestry residing in northern Europe, and it is unknown how well these findings will translate to people of other ancestries and exposed to environmental risk factors that differ from those of the present cohort. Another key limitation of this study is that the prediction was done on a binary outcome of liver fat quantity (<5% or ≥5%) rather than a continuous one. CONCLUSIONS: In this study, we developed several models with different combinations of clinical and omics data and identified biological features that appear to be associated with liver fat accumulation. In general, the clinical variables showed better prediction ability than the complex omics variables. However, the combination of omics and clinical variables yielded the highest accuracy. We have incorporated the developed clinical models into a web interface (see: https://www.predictliverfat.org/) and made it available to the community. TRIAL REGISTRATION: ClinicalTrials.gov NCT03814915.

Inflammatory Bowel Diseases Increase Risk of Type 2 Diabetes in a Nationwide Cohort Study.

BACKGROUND & AIMS: The intestine regulates glucose homeostasis, but it is not clear whether chronic intestinal inflammation affects risk for type 2 diabetes. We investigated the long-term risk of type 2 diabetes in patients with inflammatory bowel diseases (IBD) in a nationwide cohort study in Denmark. METHODS: In a nationwide population-based cohort of 6,028,844 persons in Denmark, we compared data from individuals with a diagnosis of IBD (Crohn's disease [CD] or ulcerative colitis UC]) with data from individuals from the general population from 1977 through 2014. Persons with type 2 diabetes were identified in the National Patient Register. Risk is presented as standardized incidence ratios (SIR) with 95% CIs. RESULTS: During 736,072 person-years of follow-up, 3436 patients with IBD developed type 2 diabetes vs 2224 expected (SIR, 1.54; 95% CI, 1.49-1.60). The risk was significantly increased in patients with UC (SIR, 1.54; 95% CI, 1.48-1.60), in patients with CD (SIR, 1.57; 95% CI, 1.47-1.67), in women (SIR, 1.51; 95% CI, 1.44-1.59), and in men (SIR, 1.57; 95% CI, 1.50-1.65). The risk was highest the first year after a diagnosis of IBD (SIR, 4.48; 95% CI, 4.16-4.83), but remained increased for 20 or more years following the diagnosis (SIR, 1.26; 95% CI, 1.16-1.38). The increased risk could not be accounted for by frequency of health care contacts or corticosteroid exposure. Patients who received a diagnosis of IBD from 2003 through 2014 (SIR, 1.79; 95% CI, 1.67-1.91) had a significantly higher risk of type 2 diabetes than patients who received a diagnosis of IBD from 1977 through 1988 (SIR, 1.47; 95% CI, 1.39-1.56) or 1989 through 2002 (SIR, 1.48; 95% CI, 1.41-1.56) (P < .001). CONCLUSIONS: In a population-based cohort study, we found an increased risk of type 2 diabetes in patients with UC or CD, with highest risk estimates from 2003 through 2014, compared with earlier years. Studies are needed to determine the effects of IBD treatment on risk of type 2 diabetes.

Stopping Mesalamine Therapy in Patients With Crohn's Disease Starting Biologic Therapy Does Not Increase Risk of Adverse Outcomes.

BACKGROUND & AIMS: Little is known about the effects of discontinuing mesalamine therapy for patients with Crohn's disease (CD) who initiate therapy with an anti-tumor necrosis factor (anti-TNF) agent. We analyzed data from 2 national population cohorts to compare outcomes of patients with CD already on mesalamine therapy who started treatment with an anti-TNF agent and then either stopped or continued mesalamine. METHODS: The primary outcome was any adverse clinical event, defined as a composite of new corticosteroid use or CD-related hospitalization or surgery. We collected data from the Truven MarketScan (IBM, Armonk, NY) health claims database in the United States and the Danish health registers. Our analysis included patients with CD who started anti-TNF therapy after at least 90 days of oral mesalamine therapy. Patients were classified as stopping mesalamine if therapy was discontinued within 90 days of starting anti-TNF. We performed multivariable Cox regression models controlling for demographics, clinical factors, and health care utilization. Adjusted hazard ratios with 95% CIs were calculated, comparing stopping mesalamine with continuing mesalamine. RESULTS: A total of 3178 patients with CD were included in our final analysis (2960 in the United States and 218 in Denmark). Stopping mesalamine after initiating anti-TNF therapy was not associated with an increased risk of adverse clinical events in the US cohort (adjusted hazard ratio, 0.89; 95% CI, 0.77-1.03; P = .13) or in the Danish cohort (adjusted hazard ratio, 1.13; 95% CI, 0.68-1.87; P = .63). Similar results were obtained from sensitivity analyses of concomitant immunomodulator use and duration of mesalamine treatment before initiation of anti-TNF therapy. CONCLUSIONS: In a retrospective analysis of 2 national databases, we found that stopping mesalamine therapy for patients with CD who were starting anti-TNF therapy did not increase their risk of adverse clinical events. These results should be validated in a prospective study.

Body mass index and risk of infections: a Mendelian randomization study of 101,447 individuals.

Body mass index (BMI) has been related to risk of infections. The aim of this study was to assess the shape of the association between BMI and risk of infections and to evaluate whether such associations represent causality. We included 101,447 individuals from The Copenhagen General Population Study who had BMI measured. Outcome was hospital contacts related to infections. The shape of the association between BMI and risk of infections was examined using restricted cubic spline Cox regression. To evaluate causality, we used Mendelian randomization, an epidemiological method that counteracts confounding and reverse causality by using genetic variation as instrumental variables. We created a genetic risk score based on five genetic variants causing lifelong higher BMI and used this score in instrumental variable analysis. During median follow-up of 8.8 years, 10,263 hospital contacts related to infections were recorded. We found a U-shaped association between BMI and risk of any infection and pneumonia, and a linear association between BMI and risk of skin infection, urinary tract infection, and sepsis. In instrumental variable analyses, higher BMI was associated with increased risk of skin infection: odds ratio 1.12 (95% CI 1.03-1.22) for a genetically induced 1 unit increase in BMI. Observationally, low as well as high BMI was associated with increased risk of any infection and pneumonia, whereas only high BMI was associated with increased risk of skin infection, urinary tract infection, and sepsis. High BMI was causally associated with increased risk of skin infection.

Gestational diabetes and the human salivary microbiota: a longitudinal study during pregnancy and postpartum.

BACKGROUND: An aberrant composition of the salivary microbiota has been found in individuals with type 2 diabetes, and in pregnant women salivary microbiota composition has been associated with preeclampsia and pre-term birth. Pregnant women, who develop gestational diabetes (GDM), have a high risk of developing type 2 diabetes after pregnancy. In the present study we assessed whether GDM is linked to variation in the oral microbial community by examining the diversity and composition of the salivary microbiota. METHOD: In this observational study the salivary microbiota of pregnant women with GDM (n = 50) and normal glucose regulation (n = 160) in third trimester and 9 months postpartum was assessed by 16S rRNA gene amplicon sequencing of the V1-V3 region. GDM was diagnosed in accordance with the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria. Cross-sectional difference in alpha diversity was assessed using Student's t-test and longitudinal changes were assessed by mixed linear regression. Cross-sectional and longitudinal difference in beta diversity was assessed by permutational multivariate analyses of variance. Differentially abundant genera and OTUs were identified by negative binomial regression. RESULTS: In the third trimester, two species-level operational taxonomic units (OTUs), while eight OTUs postpartum were differentially abundant in women with GDM compared with normoglycaemic women. OTU richness, Shannon diversity and Pielou evenness decreased from late pregnancy to 9 months after delivery regardless of glycaemic status. CONCLUSION: GDM is associated with a minor aberration of the salivary microbiota during late pregnancy and postpartum. For unknown reasons richness of the salivary microbiota decreased from late pregnancy to postpartum, which might be explained by the physiological changes of the immune system during human pregnancy.

Metformin-induced changes of the gut microbiota in healthy young men: results of a non-blinded, one-armed intervention study.

AIMS/HYPOTHESIS: Individuals with type 2 diabetes have an altered bacterial composition of their gut microbiota compared with non-diabetic individuals. However, these alterations may be confounded by medication, notably the blood-glucose-lowering biguanide, metformin. We undertook a clinical trial in healthy and previously drug-free men with the primary aim of investigating metformin-induced compositional changes in the non-diabetic state. A secondary aim was to examine whether the pre-treatment gut microbiota was related to gastrointestinal adverse effects during metformin treatment. METHODS: Twenty-seven healthy young Danish men were included in an 18-week one-armed crossover trial consisting of a pre-intervention period, an intervention period and a post-intervention period, each period lasting 6 weeks. Inclusion criteria were men of age 18-35 years, BMI between 18.5 kg/m2 and 27.5 kg/m2, HbA1c < 39 mmol/mol (5.7%) and plasma creatinine within the normal range. No prescribed medication, including antibiotics, for 2 months prior to recruitment were allowed and no previous gastrointestinal surgery, discounting appendectomy or chronic illness requiring medical treatment. During the intervention the participants were given metformin up to 1 g twice daily. Participants were examined five times in the fasting state with blood sampling and recording of gastrointestinal symptoms. Examinations took place at Frederiksberg Hospital, Denmark before and after the pre-intervention period, halfway through and immediately after the end of intervention and after the wash-out period. Faecal samples were collected at nine evenly distributed time points, and bacterial DNA was extracted and subjected to 16S rRNA gene amplicon sequencing in order to evaluate gut microbiota composition. Subjective gastrointestinal symptoms were reported at each visit. RESULTS: Data from participants who completed visit 1 (n=23) are included in analyses. For the primary outcome the relative abundance of 11 bacterial genera significantly changed during the intervention but returned to baseline levels after treatment cessation. In line with previous reports, we observed a reduced abundance of Intestinibacter spp. and Clostridium spp., as well as an increased abundance of Escherichia/Shigella spp. and Bilophila wadsworthia. The relative abundance at baseline of 12 bacterial genera predicted self-reported gastrointestinal adverse effects. CONCLUSIONS/INTERPRETATION: Intake of metformin changes the gut microbiota composition in normoglycaemic young men. The microbiota changes induced by metformin extend and validate previous reports in individuals with type 2 diabetes. Secondary analyses suggest that pre-treatment gut microbiota composition may be a determinant for development of gastrointestinal adverse effects following metformin intake. These results require further investigation and replication in larger prospective studies. TRIAL REGISTRATION: Clinicaltrialsregister.eu 2015-000199-86 and ClinicalTrials.gov NCT02546050 FUNDING: This project was funded by Danish Diabetes Association and The Novo Nordisk Foundation.

Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium.

AIMS/HYPOTHESIS: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up). METHODS: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at ~18 months (both cohorts) and at ~48 months (cohort 1) or ~36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe. RESULTS: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean ± SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m2; fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m2; fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l. CONCLUSIONS/INTERPRETATION: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.

Phosphatidylcholine and its relation to apolipoproteins A-1 and B changes after Roux-en-Y gastric bypass: a cohort study.

BACKGROUND: Phosphatidylcholine (PC), the most abundant of the phospholipids, has several metabolic functions in organs such as the liver and the intestine, important structural- and signaling functions in biological membranes, and might have a role in the effects of Roux-en-Y gastric bypass (RYGB), an operation known to ameliorate metabolic diseases, including type 2 diabetes. We hypothesized that serum PC, as a reflection of phospholipid metabolism, changes after RYGB, and that changes are related to weight loss and possibly to changes in glucose metabolism (reflected in the HbA1c-level) as well as to changes in serum Apo A1, Apo B and Apo B/Apo A1 ratio. METHODS: In a cohort of 220 RYGB patients, we studied changes in serum PC after RYGB in relation to serum Apo A1 and Apo B, the main apolipoproteins in HDL- and LDL/VLDL-particles, respectively, up to 2 years following RYGB-surgery. RESULTS: Serum PC reached its lowest levels 3 months postoperatively to later rebound to preoperative levels 24 months after RYGB. No difference was seen between patients with or without type 2 diabetes. Serum Apo A1 showed a similar pattern whereas serum Apo B concentrations stayed low after the initial decrease after RYGB. As a result, the Apo B / Apo A1 ratio constantly decreased during follow-up. There was a strong positive correlation between PC and Apo A1, and between PC and Apo B, but none between Apo A1 and Apo B. After RYGB surgery, both PC and Apo A1, but not Apo B, correlated positively to weight loss. In relation to total cholesterol, the molar ratio between serum PC and plasma cholesterol increased steadily after RYGB. CONCLUSIONS: We conclude that changes in PC and apolipoproteins after RYGB are highly dynamic, reflecting a large plasticity and capability of accommodating lipid metabolism including PC-, cholesterol- and apolipoprotein metabolism imposed by RYGB surgery, independent of glucose tolerance. We suggest that after RYGB and major weight loss, PC and Apo A1 might have a special role in the altered metabolism of lipoproteins.

Aberrant intestinal microbiota in individuals with prediabetes.

AIMS/HYPOTHESIS: Individuals with type 2 diabetes have aberrant intestinal microbiota. However, recent studies suggest that metformin alters the composition and functional potential of gut microbiota, thereby interfering with the diabetes-related microbial signatures. We tested whether specific gut microbiota profiles are associated with prediabetes (defined as fasting plasma glucose of 6.1-7.0 mmol/l or HbA1c of 42-48 mmol/mol [6.0-6.5%]) and a range of clinical biomarkers of poor metabolic health. METHODS: In the present case-control study, we analysed the gut microbiota of 134 Danish adults with prediabetes, overweight, insulin resistance, dyslipidaemia and low-grade inflammation and 134 age- and sex-matched individuals with normal glucose regulation. RESULTS: We found that five bacterial genera and 36 operational taxonomic units (OTUs) were differentially abundant between individuals with prediabetes and those with normal glucose regulation. At the genus level, the abundance of Clostridium was decreased (mean log2 fold change -0.64 (SEM 0.23), p adj = 0.0497), whereas the abundances of Dorea, [Ruminococcus], Sutterella and Streptococcus were increased (mean log2 fold change 0.51 (SEM 0.12), p adj = 5 × 10-4; 0.51 (SEM 0.11), p adj = 1 × 10-4; 0.60 (SEM 0.21), p adj = 0.0497; and 0.92 (SEM 0.21), p adj = 4 × 10-4, respectively). The two OTUs that differed the most were a member of the order Clostridiales (OTU 146564) and Akkermansia muciniphila, which both displayed lower abundance among individuals with prediabetes (mean log2 fold change -1.74 (SEM 0.41), p adj = 2 × 10-3 and -1.65 (SEM 0.34), p adj = 4 × 10-4, respectively). Faecal transfer from donors with prediabetes or screen-detected, drug-naive type 2 diabetes to germfree Swiss Webster or conventional C57BL/6 J mice did not induce impaired glucose regulation in recipient mice. CONCLUSIONS/INTERPRETATION: Collectively, our data show that individuals with prediabetes have aberrant intestinal microbiota characterised by a decreased abundance of the genus Clostridium and the mucin-degrading bacterium A. muciniphila. Our findings are comparable to observations in overt chronic diseases characterised by low-grade inflammation.

Antibiotic exposure in early life and childhood overweight and obesity: A systematic review and meta-analysis.

We conducted a systematic review and meta-analysis of observational studies investigating the association between antibiotic exposure in infancy and risk of childhood overweight and obesity. Thirteen studies, including a total of 527 504 children, were included in the systematic review and 8 were included in meta-analyses. Exposure to antibiotics in infancy was associated with an increased odds ratio (OR) of childhood overweight and obesity (OR 1.11, 95% confidence interval [CI] 1.02-1.20). Whereas exposure to 1 treatment only and exposure between 6 and 24 months were not associated with increased risk of childhood overweight and obesity, exposure to >1 treatment was associated with an OR of 1.24 (95% CI 1.09-1.43) and exposure within the first 6 months of life was associated with an OR of 1.20 (95% CI 1.04-1.37). In conclusion, antibiotic exposure in infancy was associated with a slightly increased risk of childhood overweight and obesity, mainly if children were exposed to repeated treatments or treatment within the first 6 months of life. It is unclear whether this association is mediated via direct effects of antibiotics on the gut microbiota.