Dose-Responsive Effects of Iron Supplementation on the Gut Microbiota in Middle-Aged Women.

Oral iron supplementation is the first-line treatment for addressing iron deficiency, a concern particularly relevant to women who are susceptible to sub-optimal iron levels. Nevertheless, the impact of iron supplementation on the gut microbiota of middle-aged women remains unclear. To investigate the association between iron supplementation and the gut microbiota, healthy females aged 40-65 years (n = 56, BMI = 23 ± 2.6 kg/m2) were retrospectively analyzed from the Alberta's Tomorrow Project. Fecal samples along with various lifestyle, diet, and health questionnaires were obtained. The gut microbiota was assessed by 16S rRNA sequencing. Individuals were matched by age and BMI and classified as either taking no iron supplement, a low-dose iron supplement (6-10 mg iron/day), or high-dose iron (>100 mg/day). Compositional and functional analyses of microbiome data in relation to iron supplementation were investigated using various bioinformatics tools. Results revealed that iron supplementation had a dose-dependent effect on microbial communities. Elevated iron intake (>100 mg) was associated with an augmentation of Proteobacteria and a reduction in various taxa, including Akkermansia, Butyricicoccus, Verrucomicrobia, Ruminococcus, Alistipes, and Faecalibacterium. Metagenomic prediction further suggested the upregulation of iron acquisition and siderophore biosynthesis following high iron intake. In conclusion, adequate iron levels are essential for the overall health and wellbeing of women through their various life stages. Our findings offer insights into the complex relationships between iron supplementation and the gut microbiota in middle-aged women and underscore the significance of iron dosage in maintaining optimal gut health.

Reduced incidence of diabetes during the COVID-19 pandemic in Alberta: A time-segmented longitudinal study of Alberta's Tomorrow Project.

AIM: To characterize the impact of the COVID-19 pandemic on diabetes diagnosis using data from Alberta's Tomorrow Project (ATP), a population-based cohort study of chronic diseases in Alberta, Canada. MATERIALS AND METHODS: The ATP participants who were free of diabetes on 1 April 2018 were included in the study. A time-segmented regression model was used to compare incidence rates of diabetes before the COVID-19 pandemic, during the first two COVID-19 states of emergency, and in the period when the state of emergency was relaxed, after adjusting for seasonality, sociodemographic factors, socioeconomic status, and lifestyle behaviours. RESULTS: Among 43 705 ATP participants free of diabetes (65.5% females, age 60.4 ± 9.5 years in 2018), the rate of diabetes was 4.75 per 1000 person-year (PY) during the COVID-19 pandemic (up to 31 March 2021), which was 32% lower (95% confidence interval [CI] 21%, 42%; p < 0.001) than pre-pandemic (6.98 per 1000 PY for the period 1 April 2018 to 16 March 2020). In multivariable regression analysis, the first COVID-19 state of emergency (first wave) was associated with an 87.3% (95% CI -98.6%, 13.9%; p = 0.07) reduction in diabetes diagnosis; this decreasing trend was sustained to the second COVID-19 state of emergency and no substantial rebound (increase) was observed when the COVID-19 state of emergency was relaxed. CONCLUSIONS: The COVID-19 public health emergencies had a negative impact on diabetes diagnosis in Alberta. The reduction in diabetes diagnosis was likely due to province-wide health service disruptions during the COVID-19 pandemic. Systematic plans to close the post-COVID-19 diagnostic gap are required in diabetes to avoid substantial downstream sequelae of undiagnosed disease.

Factors associated with change in moderate or severe symptoms of anxiety and depression in community-living adults and older adults during the COVID-19 pandemic.

OBJECTIVES: Few are the longitudinal studies on the changes in moderate or severe symptoms of anxiety or depression (MSS-ANXDEP) from before to during the COVID-19 pandemic in Canada. The aim was to study the change in MSS-ANXDEP and associated sociodemographic, economic, psychosocial, health behaviour and lifestyle, and clinical factors. METHODS: The current sample includes 59,997 adults aged ≥ 35 years participating in the 2018 and 2020 health surveys of the 5 established cohorts of the Canadian Partnership for Tomorrow's Health (CanPath). MSS-ANXDEP was based on a cutoff score ≥ 10 on the 7-item Generalized Anxiety Disorder Scale and Patient Health Questionnaire (PHQ-8). Change in MSS-ANXDEP was categorized as follows: no MSS-ANXDEP, remitted, incident, and persistent. Multinomial regressions were used to study MSS-ANXDEP as a function of sociodemographic, economic, psychosocial, health behaviours and lifestyle, and clinical factors. RESULTS: Sociodemographic and economic (i.e. age, gender, cohort, race/ethnicity, lower income, decreased in income, work status, being an essential worker), lifestyle and health behaviours (i.e. smoking, cannabis and alcohol use, drinking more alcohol), psychosocial (i.e. provide help to others, information and instrumental support, and change in relationships with friends, family, and partner) and clinical factors (i.e. lifetime mental disorder and multimorbidity) were associated with remitted, incident, and persistent MSS-ANXDEP. CONCLUSION: Health and socio-economic factors were associated with changes in symptoms of anxiety and depression during the pandemic, further increasing inequities in mental health needs. Public health campaigns on the importance of healthy behaviours should continue and health policies should reduce economic and social barriers to integrated substance use and mental health care.

RéSUMé: OBJECTIFS: Les études longitudinales sur l'évolution des symptômes modérés ou sévères d'anxiété ou de dépression (SMS-ANXDEP) avant et pendant la pandémie de COVID-19 au Canada sont rares. L'objectif était d'étudier l'association entre l'évolution des SMS-ANXDEP et les facteurs sociodémographiques, économiques, psychosociaux, cliniques et liés aux comportements et au mode de vie, avant et pendant la pandémie. MéTHODES: Ce grand échantillon comprend 59 997 adultes âgés de ≥ 35 ans qui ont participé aux enquêtes de santé 2018 et 2020 des 5 cohortes établies du Partenariat canadien pour la santé de demain (CanPath). La présence de SMS-ANXDEP a été définie par un résultat ≥ 10 sur les échelles Generalized Anxiety Disorder Scale à 7 items (GAD-7) et Patient Health Questionnaire (PHQ-8). Les changements dans les SMS-ANXDEP ont été catégorisés selon les patrons temporels suivants : absence, rémission, incidence et persistance de SMS-ANXDEP. Des régressions multinomiales multivariées ont été utilisées pour étudier les patrons temporels de SMS-ANXDEP en fonction, des facteurs socio-démographiques, économiques, associés au style de vie et aux comportements de santé, psychosociaux et cliniques. RéSULTATS: Les facteurs socio-démographiques et économiques (âge, genre, cohorte, race/ethnie, revenu inférieur, diminution du revenu, statut d'emploi, être un travailleur essentiel), associés au style de vie et aux comportements de santé (tabagisme, consommation de cannabis et d'alcool, consommation accrue d'alcool), psychosociaux (offrir de l'aide pendant la pandémie, soutien en information et instrumental, changement dans les relations avec les amis, la famille et la personne partenaire) et cliniques (trouble mental au cours de la vie, multimorbidité) étaient associés à la présence de SMS-ANXDEP en rémission, incident et persistant. CONCLUSION: Les patrons temporels des SMS-ANXDEP pendant la pandémie étaient associés aux facteurs socio-économiques et de santé, suggérant des inégalités accrues en matière de besoins de santé mentale. Les campagnes de santé publique sur l'importance d'adopter des comportements sains devraient continuer et les politiques de santé devraient réduire les barrières économiques et sociales aux soins intégrés de santé mentale et de toxicomanie.

Impact of Comorbidity on Hospitalization and Emergency Room Visits in Adults With Diabetes: A Longitudinal Study of Alberta's Tomorrow Project.

OBJECTIVE: Our aim in this study was to characterize the impact of comorbidities, including number and types, on hospitalization and emergency room (ER) visits in people with diabetes. METHODS: Incident cases of diabetes from Alberta's Tomorrow Project with >24 months of follow-up were included. Comorbidities, classified by Elixhauser conditions, were updated every 12 months after diagnosis. A generalized estimating equation model was used to examine the association (by incidence rate ratio [IRR]) between time-varying comorbidity profile and hospitalization and ER visits per year of follow-up after adjusting for sociodemographic factors, lifestyle behaviours, and historic health-care utilization in the previous 5 years. RESULTS: Among 2,110 incident cases of diabetes (51.0% females; median age at diagnosis: 59.5 years; median follow-up: 7.19 years), the average number of Elixhauser comorbidities was 1.9±1.6 in the first year of diagnosis and 3.3±2.0 in year 15 after diagnosis. The number of comorbidities in the previous year was positively associated with risk of hospitalization (IRR=1.33 [95% confidence interval {CI}: 1.04 to 1.70] and 2.14 [95% CI: 1.67 to 2.74] for 1 or 2 and ≥2 comorbidities, respectively) and ER visits (IRR=1.31 [95% CI: 1.15 to 1.50] and 1.62 [95% CI: 1.41 to 1.87] for 1 or 2 and ≥2 comorbidities, respectively) in the subsequent year. Cardiovascular diseases, peripheral vascular diseases, cancer, liver disease, fluid and electrolyte disorders, and depression were the conditions most typically associated with increased health-care utilization. CONCLUSIONS: The number of comorbidities was a major risk factor of health-care utilization for people with diabetes. Vascular diseases, cancer, and conditions closely related to diabetic frailty (e.g. fluid and electrolyte disorders and depression) were the main drivers of hospital care and ER visits.

Patterns and predictors of adherence to breast cancer screening recommendations in Alberta's Tomorrow Project.

Breast cancer screening is an important prevention component as it can reduce cancer mortality and improve survival. Understanding patterns of adherence to screening recommendations is essential to guide health promotion strategies and policy implementation efforts. The 1999 Alberta screening guidelines were used to determine screening status for eligible female participants in Alberta's Tomorrow Project (n = 4,972), a longitudinal province-based cohort. Screening patterns were derived based on screening status assessed at enrollment (2001-2008) and follow-up (2008-2011). Information on reason for screening was also collected at each time point. Multinomial logistic regression was used to assess potential predictors of adherence to screening recommendations. The majority of participants were up-to-date with screening at enrollment (79.3 %), and follow-up (75.2 %). Among all participants, 66.3 % were up-to-date at both time points (considered 'regular screeners'), 8.9 % were not up-to-date or never at enrollment but up-to-date at follow-up (considered 'new screeners'), 21.6 % were not up-to-date at follow-up (considered 'episodic screeners') and 3.2 % had never participated in screening (considered 'non-screeners'). Having a family doctor was the strongest factor associated with being a regular screener (OR (95 % CI): 0.37 (0.24 0.57) when compared with new screeners. Current smokers were more likely to be non-regular screeners. The primary reason for screening was routine screening or age. In conclusions, non-regular screening patterns were more prevalent among women without a family doctor. This finding suggests having a family doctor is an important mechanism to encourage screening. Further work is required to raise awareness of current recommendations and to understand and address reasons for non-adherence.

Personalized breast cancer onset prediction from lifestyle and health history information.

We propose a method to predict when a woman will develop breast cancer (BCa) from her lifestyle and health history features. To address this objective, we use data from the Alberta's Tomorrow Project of 18,288 women to train Individual Survival Distribution (ISD) models to predict an individual's Breast-Cancer-Onset (BCaO) probability curve. We show that our three-step approach-(1) filling missing data with multiple imputations by chained equations, followed by (2) feature selection with the multivariate Cox method, and finally, (3) using MTLR to learn an ISD model-produced the model with the smallest L1-Hinge loss among all calibrated models with comparable C-index. We also identified 7 actionable lifestyle features that a woman can modify and illustrate how this model can predict the quantitative effects of those changes-suggesting how much each will potentially extend her BCa-free time. We anticipate this approach could be used to identify appropriate interventions for individuals with a higher likelihood of developing BCa in their lifetime.

A dietary carbohydrate - gut Parasutterella - human fatty acid biosynthesis metabolic axis in obesity and type 2 diabetes.

Recent rodent microbiome experiments suggest that besides Akkermansia, Parasutterella sp. are important in type 2 diabetes and obesity development. In the present translational human study, we aimed to characterize Parasutterella in our European cross-sectional FoCus cohort (n = 1,544) followed by validation of the major results in an independent Canadian cohort (n = 438). In addition, we examined Parasutterella abundance in response to a weight loss intervention (n = 55). Parasutterella was positively associated with BMI and type 2 diabetes independently of the reduced microbiome α/ß diversity and low-grade inflammation commonly found in obesity. Nutritional analysis revealed a positive association with the dietary intake of carbohydrates but not with fat or protein consumption. Out of 126 serum metabolites differentially detectable by untargeted HPLC-based MS-metabolomics, L-cysteine showed the strongest reduction in subjects with high Parasutterella abundance. This is of interest, since Parasutterella is a known high L-cysteine consumer and L-cysteine is known to improve blood glucose levels in rodents. Furthermore, metabolic network enrichment analysis identified an association of high Parasutterella abundance with the activation of the human fatty acid biosynthesis pathway suggesting a mechanism for body weight gain. This is supported by a significant reduction of the Parasutterella abundance during our weight loss intervention. Together, these data indicate a role for Parasutterella in human type 2 diabetes and obesity, whereby the link to L-cysteine might be relevant in type 2 diabetes development and the link to the fatty acid biosynthesis pathway for body weight gain in response to a carbohydrate-rich diet in obesity development.

Towards refining World Cancer Research Fund/American Institute for Cancer Research cancer prevention recommendations for red and processed meat intake: insights from Alberta's Tomorrow Project cohort.

Current cancer prevention recommendations advise limiting red meat intake to <500 g/week and avoiding consumption of processed meat, but do not differentiate the source of processed meat. We examined the associations of processed meat derived from red v. non-red meats with cancer risk in a prospective cohort of 26 218 adults who reported dietary intake using the Canadian Diet History Questionnaire. Incidence of cancer was obtained through data linkage with Alberta Cancer Registry with median follow-up of 13·3 (interquartile range (IQR) 5·1) years. Multivariable Cox proportional hazards regression models were adjusted for covariates and stratified by age and sex. The median consumption (g/week) of red meat, processed meat from red meat and processed meat from non-red meat was 267·9 (IQR 269·9), 53·6 (IQR 83·3) and 11·9 (IQR 31·8), respectively. High intakes (4th Quartile) of processed meat from red meat were associated with increased risk of gastrointestinal cancer adjusted hazard ratio (AHR): 1·68 (95 % CI 1·09, 2·57) and colorectal cancers AHR: 1·90 (95 % CI 1·12, 3·22), respectively, in women. No statistically significant associations were observed for intakes of red meat or processed meat from non-red meat. Results suggest that the carcinogenic effect associated with processed meat intake may be limited to processed meat derived from red meats. The findings provide preliminary evidence towards refining cancer prevention recommendations for red and processed meat intake.

Chronic disease surveillance in Alberta's tomorrow project using administrative health data.

INTRODUCTION: Alberta's Tomorrow Project (ATP) is the largest population-based prospective cohort study of cancer and chronic diseases in Alberta, Canada. The ATP cohort data were primarily self-reported by participants on lifestyle behaviors and disease risk factors at the enrollment, which lacks sufficient and accurate data on chronic disease diagnosis for longer-term follow-up. OBJECTIVES: To characterize the occurrence rate and trend of chronic diseases in the ATP cohort by linking with administrative healthcare data. METHODS: A set of validated algorithms using ICD codes were applied to Alberta Health (AH) administrative data (October 2000-March 2018) linked to the ATP cohort to determine the prevalence and incidence of common chronic diseases. RESULTS: There were 52,770 ATP participants (51.2±9.4 years old at enrollment and 63.7% females) linked to the AH data with average follow-up of 10.1±4.4 years. In the ATP cohort, hypertension (18.5%), depression (18.1%), chronic pain (12.8%), osteoarthritis (10.1%) and cardiovascular diseases (8.7%) were the most prevalent chronic conditions. The incidence rates varied across diseases, with the highest rates for hypertension (22.1 per 1000 person-year), osteoarthritis (16.2 per 1000 person-year) and ischemic heart diseases (13.0 per 1000 person-year). All chronic conditions had increased prevalence over time (p < for trend tests), while incidence rates were relatively stable. The proportion of participants with two or more of these conditions (multi-morbidity) increased from 3.9% in 2001 to 40.3% in 2017. CONCLUSIONS: This study shows an increasing trend of chronic diseases in the ATP cohort, particularly related to cardiovascular diseases and multi-morbidity. Using administrative health data to monitor chronic diseases for large population-based prospective cohort studies is feasible in Alberta, and our approach could be further applied in a broader research area, including health services research, to enhance research capacity of these population-based studies in Canada.

Premature Mortality Due to Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, and Leukemia in Canada: A Nationwide Analysis From 1980 to 2015.

Recently, we introduced a novel measure of "average life span shortened" (ALSS) to improve comparability of premature mortality over time. In this study, we applied this novel measure to examine trends in premature mortality caused by hematological cancers in Canada from 1980 to 2015. Mortality data for Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, and leukemia were obtained from the World Health Organization mortality database. Years of life lost was calculated according to Canadian life tables. ALSS was defined as the ratio between years of life lost and expected life span. Over the study period, age-standardized rates of mortality decreased for all types of hematological cancers. Our new ALSS measure showed favorable trends in premature mortality for all types of hematological cancers among both sexes. For instance, men with non-Hodgkin lymphoma lost an average of 23.7% of their life span in 1980 versus 16.1% in 2015, while women with non-Hodgkin lymphoma lost an average of 21.7% of their life span in 1980 versus 15.5% in 2015. Results from this study showed that patients with hematological cancers experienced prolonged survival over a 35-year period although the magnitude of these life span gains varied by types of hematological cancers.

Social Jetlag and Prostate Cancer Incidence in Alberta's Tomorrow Project: A Prospective Cohort Study.

We investigated the association of social jetlag (misalignment between the internal clock and socially required timing of activities) and prostate cancer incidence in a prospective cohort in Alberta, Canada. Data were collected from 7455 cancer-free men aged 35-69 years enrolled in Alberta's Tomorrow Project (ATP) from 2001-2007. In the 2008 survey, participants reported usual bed- and wake-times on weekdays and weekend days. Social jetlag was defined as the absolute difference in waking time between weekday and weekend days, and was categorized into three groups: 0-<1 h (from 0 to anything smaller than 1), 1-<2 h (from 1 to anything smaller than 2), and 2+ h. ATP facilitated data linkage with the Alberta Cancer Registry in June 2018 to determine incident prostate cancer cases (n = 250). Hazard ratios (HR) were estimated using Cox proportional hazards regressions, adjusting for a range of covariates. Median follow-up was 9.57 years, yielding 68,499 person-years. Baseline presence of social jetlag of 1-<2 h (HR = 1.52, 95% CI: 1.10 to 2.01), and 2+ hours (HR = 1.69, 95% CI: 1.15 to 2.46) were associated with increased prostate cancer risk vs. those reporting no social jetlag (p for trend = 0.004). These associations remained after adjusting for sleep duration (p for trend = 0.006). With respect to chronotype, the association between social jetlag and prostate cancer risk remained significant in men with early chronotypes (p for trend = 0.003) but attenuated to null in men with intermediate (p for trend = 0.150) or late chronotype (p for trend = 0.381). Our findings suggest that greater than one hour of habitual social jetlag is associated with an increased risk of prostate cancer. Longitudinal studies with repeated measures of social jetlag and large samples with sufficient advanced prostate cancer cases are needed to confirm these findings.

Protein kinase C mediates enterohemorrhagic Escherichia coli O157:H7-induced attaching and effacing lesions.

Enterohemorrhagic Escherichia coli serotype O157:H7 causes outbreaks of diarrhea, hemorrhagic colitis, and the hemolytic-uremic syndrome. E. coli O157:H7 intimately attaches to epithelial cells, effaces microvilli, and recruits F-actin into pedestals to form attaching and effacing lesions. Lipid rafts serve as signal transduction platforms that mediate microbe-host interactions. The aims of this study were to determine if protein kinase C (PKC) is recruited to lipid rafts in response to E. coli O157:H7 infection and what role it plays in attaching and effacing lesion formation. HEp-2 and intestine 407 tissue culture epithelial cells were challenged with E. coli O157:H7, and cell protein extracts were then separated by buoyant density ultracentrifugation to isolate lipid rafts. Immunoblotting for PKC was performed, and localization in lipid rafts was confirmed with an anti-caveolin-1 antibody. Isoform-specific PKC small interfering RNA (siRNA) was used to determine the role of PKC in E. coli O157:H7-induced attaching and effacing lesions. In contrast to uninfected cells, PKC was recruited to lipid rafts in response to E. coli O157:H7. Metabolically active bacteria and cells with intact lipid rafts were necessary for the recruitment of PKC. PKC recruitment was independent of the intimin gene, type III secretion system, and the production of Shiga toxins. Inhibition studies, using myristoylated PKCζ pseudosubstrate, revealed that atypical PKC isoforms were activated in response to the pathogen. Pretreating cells with isoform-specific PKC siRNA showed that PKCζ plays a role in E. coli O157:H7-induced attaching and effacing lesions. We concluded that lipid rafts mediate atypical PKC signal transduction responses to E. coli O157:H7. These findings contribute further to the understanding of the complex array of microbe-eukaryotic cell interactions that occur in response to infection.

XB130 mediates cancer cell proliferation and survival through multiple signaling events downstream of Akt.

XB130, a novel adaptor protein, mediates RET/PTC chromosome rearrangement-related thyroid cancer cell proliferation and survival through phosphatidyl-inositol-3-kinase (PI3K)/Akt pathway. Recently, XB130 was found in different cancer cells in the absence of RET/PTC. To determine whether RET/PTC is required of XB130-related cancer cell proliferation and survival, WRO thyroid cancer cells (with RET/PTC mutation) and A549 lung cancer cells (without RET/PTC) were treated with XB130 siRNA, and multiple Akt down-stream signals were examined. Knocking-down of XB130 inhibited G(1)-S phase progression, and induced spontaneous apoptosis and enhanced intrinsic and extrinsic apoptotic stimulus-induced cell death. Knocking-down of XB130 reduced phosphorylation of p21Cip1/WAF1, p27Kip1, FOXO3a and GSK3ß, increased p21Cip1/WAF1protein levels and cleavages of caspase-8 and-9. However, the phosphorylation of FOXO1 and the protein levels of p53 were not affected by XB130 siRNA. We also found XB130 can be phosphorylated by multiple protein tyrosine kinases. These results indicate that XB130 is a substrate of multiple protein tyrosine kinases, and it can regulate cell proliferation and survival through modulating selected down-stream signals of PI3K/Akt pathway. XB130 could be involved in growth and survival of different cancer cells.

Claudin 1 mediates TNFα-induced gene expression and cell migration in human lung carcinoma cells.

Epithelial-mesenchymal transition (EMT) is an important mechanism in carcinogenesis. To determine the mechanisms that are involved in the regulation of EMT, it is crucial to develop new biomarkers and therapeutic targets towards cancers. In this study, when TGFß1 and TNFα were used to induce EMT in human lung carcinoma A549 cells, we found an increase in an epithelial cell tight junction marker, Claudin 1. We further identified that it was the TNFα and not the TGFß1 that induced the fibroblast-like morphology changes. TNFα also caused the increase in Claudin-1 gene expression and protein levels in Triton X-100 soluble cytoplasm fraction. Down-regulation of Claudin-1, using small interfering RNA (siRNA), inhibited 75% of TNFα-induced gene expression changes. Claudin-1 siRNA effectively blocked TNFα-induced molecular functional networks related to inflammation and cell movement. Claudin-1 siRNA was able to significantly reduce TNF-enhanced cell migration and fibroblast-like morphology. Furthermore, over expression of Claudin 1 with a Claudin 1-pcDNA3.1/V5-His vector enhanced cell migration. In conclusion, these observations indicate that Claudin 1 acts as a critical signal mediator in TNFα-induced gene expression and cell migration in human lung cancer cells. Further analyses of these cellular processes may be helpful in developing novel therapeutic strategies.

Single nucleotide polymorphisms that increase expression of the guanosine triphosphatase RAC1 are associated with ulcerative colitis.

BACKGROUND & AIMS: RAC1 is a guanosine triphosphatase that has an evolutionarily conserved role in coordinating immune defenses, from plants to mammals. Chronic inflammatory bowel diseases are associated with dysregulation of immune defenses. We studied the role of RAC1 in inflammatory bowel diseases using human genetic and functional studies and animal models of colitis. METHODS: We used a candidate gene approach to HapMap-Tag single nucleotide polymorphisms in a discovery cohort; findings were confirmed in 2 additional cohorts. RAC1 messenger RNA expression was examined from peripheral blood cells of patients. Colitis was induced in mice with conditional disruption of Rac1 in phagocytes by administration of dextran sulfate sodium. RESULTS: We observed a genetic association between RAC1 with ulcerative colitis in a discovery cohort, 2 independent replication cohorts, and in combined analysis for the single nucleotide polymorphisms rs10951982 (P(combined UC) = 3.3 × 10(-8), odds ratio = 1.43 [95% confidence interval: 1.26-1.63]) and rs4720672 (P(combined UC) = 4.7 × 10(-6), odds ratio = 1.36 [95% confidence interval: 1.19-1.58]). Patients with inflammatory bowel disease who had the rs10951982 risk allele had increased expression of RAC1 compared to those without this allele. Conditional disruption of Rac1 in macrophage and neutrophils of mice protected against dextran sulfate sodium-induced colitis. CONCLUSIONS: Human studies and knockout mice demonstrated a role for the guanosine triphosphatase RAC1 in the development of ulcerative colitis; increased expression of RAC1 was associated with susceptibility to colitis.

Osteopontin mediates Citrobacter rodentium-induced colonic epithelial cell hyperplasia and attaching-effacing lesions.

Although osteopontin (OPN) is up-regulated in inflammatory bowel diseases, its role in disease pathogenesis remains controversial. The objective of this study was to determine the role of OPN in host responses to a non-invasive bacterial pathogen, Citrobacter rodentium, which serves as a murine infectious model of colitis. OPN gene knockout and wild-type mice were infected orogastrically with either C. rodentium or Luria-Bertani (LB) broth. Mouse-derived OPN(+/+) and OPN(-/-) fibroblasts were incubated with C. rodentium and attaching-effacing lesions were demonstrated using transmission electron microscopy and immunofluorescence. Colonic expression of OPN was increased by C. rodentium infection of wild-type mice. Furthermore, colonic epithelial cell hyperplasia, the hallmark of C. rodentium infection, was reduced in OPN(-/-) mice, and spleen enlargement by infection was absent in OPN(-/-) mice. Rectal administration of OPN to OPN(-/-) mice restored these effects. There was an 8- to 17-fold reduction in bacterial colonization in OPN(-/-) mice, compared with wild-type mice, which was accompanied by reduced attaching-effacing lesions, both in infected OPN(-/-) mice and OPN(-/-) mouse fibroblasts. Moreover, adhesion pedestals were restored in OPN(-/-) cells complemented with human OPN. Therefore, lack of OPN results in decreased pedestal formation, colonization, and colonic epithelial cell hyperplasia responses to C. rodentium infection, indicating that OPN impacts disease pathogenesis through bacterial attachment and altered host immune responses.