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Engineering the gut microbiota to treat chronic diseases.
Dosoky NS, May-Zhang LS, Davies SS
(2020) Appl Microbiol Biotechnol 104: 7657-7671
MeSH Terms: Animals, Bacteria, Chronic Disease, Gastrointestinal Microbiome, Inflammation, Inflammatory Bowel Diseases, Mice
Show Abstract · Added July 25, 2020
Gut microbes play vital roles in host health and disease. A number of commensal bacteria have been used as vectors for genetic engineering to create living therapeutics. This review highlights recent advances in engineering gut bacteria for the treatment of chronic diseases such as metabolic diseases, cancer, inflammatory bowel diseases, and autoimmune disorders. KEY POINTS: • Bacterial homing to tumors has been exploited to deliver therapeutics in mice models. • Engineered bacteria show promise in mouse models of metabolic diseases. • Few engineered bacterial treatments have advanced to clinical studies.
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7 MeSH Terms
Friend or Foe in Inflammatory Bowel Disease Pathogenesis: Not All Infections Are Equal.
Shah SC
(2019) Gastroenterology 157: 1441-1442
MeSH Terms: Affect, Humans, Infant, Newborn, Infections, Inflammatory Bowel Diseases, Life
Added March 3, 2020
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Systematic review with meta-analysis: association between Helicobacter pylori CagA seropositivity and odds of inflammatory bowel disease.
Tepler A, Narula N, Peek RM, Patel A, Edelson C, Colombel JF, Shah SC
(2019) Aliment Pharmacol Ther 50: 121-131
MeSH Terms: Adolescent, Adult, Antibodies, Bacterial, Antigens, Bacterial, Bacterial Proteins, Colitis, Ulcerative, Comorbidity, Crohn Disease, Female, Helicobacter Infections, Helicobacter pylori, Humans, Inflammatory Bowel Diseases, Male, Middle Aged, Seroepidemiologic Studies, Young Adult
Show Abstract · Added March 3, 2020
BACKGROUND - Accumulating data support a protective role of Helicobacter pylori against inflammatory bowel diseases (IBD), which might be mediated by strain-specific constituents, specifically cagA expression.
AIM - To perform a systematic review and meta-analysis to more clearly define the association between CagA seropositivity and IBD.
METHODS - We identified comparative studies that included sufficient detail to determine the odds or risk of IBD, Crohn's disease (CD) or ulcerative colitis (UC) amongst individuals with vs without evidence of cagA expression (eg CagA seropositivity). Estimates were pooled using a random effects model.
RESULTS - Three clinical studies met inclusion criteria. cagA expression was represented by CagA seropositivity in all studies. Compared to CagA seronegativity overall, CagA seropositivity was associated with lower odds of IBD (OR 0.31, 95% CI 0.21-0.44) and CD (OR 0.25, 95% CI 0.17-0.38), and statistically nonsignificant lower odds for UC (OR 0.68, 95% CI 0.35-1.32). Similarly, compared to H pylori non-exposed individuals, H pylori exposed, CagA seropositive individuals had lower odds of IBD (OR 0.26, 95% CI 0.16-0.41) and CD (OR 0.23, 95% CI 0.15-0.35), but not UC (OR 0.66, 0.34-1.27). However, there was no significant difference in the odds of IBD, CD or UC between H pylori exposed, CagA seronegative and H pylori non-exposed individuals.
CONCLUSION - We found evidence for a significant association between CagA seropositive H pylori exposure and reduced odds of IBD, particularly CD, but not for CagA seronegative H pylori exposure. Additional studies are needed to confirm these findings and define underlying mechanisms.
© 2019 John Wiley & Sons Ltd.
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17 MeSH Terms
Management of Inflammatory Bowel Disease-Associated Dysplasia in the Modern Era.
Shah SC, Itzkowitz SH
(2019) Gastrointest Endosc Clin N Am 29: 531-548
MeSH Terms: Colorectal Neoplasms, Disease Management, Humans, Hyperplasia, Inflammatory Bowel Diseases, Intestines, Precancerous Conditions, Quality of Life, Risk Factors
Show Abstract · Added March 3, 2020
This article begins with a brief overview of risk factors for colorectal neoplasia in inflammatory bowel disease to concretize the approach to risk stratification. It then provides an up-to-date review of diagnosis and management of dysplasia in inflammatory bowel disease, which integrates new and emerging data in the field. This is particularly relevant in an era of increased attention to cost- and resource-containment from the health systems vantage point, coupled with a heightened prioritization of patient quality of life and shared decision-making. Also provided is a brief discussion of the status of newer therapeutic techniques, such as endoscopic submucosal dissection.
Copyright © 2019 Elsevier Inc. All rights reserved.
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Upregulated claudin-1 expression promotes colitis-associated cancer by promoting β-catenin phosphorylation and activation in Notch/p-AKT-dependent manner.
Gowrikumar S, Ahmad R, Uppada SB, Washington MK, Shi C, Singh AB, Dhawan P
(2019) Oncogene 38: 5321-5337
MeSH Terms: Animals, Biomarkers, Tumor, Cells, Cultured, Claudin-1, Colitis, Colonic Neoplasms, Gene Expression Regulation, Neoplastic, HT29 Cells, Humans, Inflammatory Bowel Diseases, Intestinal Mucosa, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation, Prognosis, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-akt, Receptors, Notch, Signal Transduction, Up-Regulation, beta Catenin
Show Abstract · Added April 24, 2019
In IBD patients, integration between a hyper-activated immune system and epithelial cell plasticity underlies colon cancer development. However, molecular regulation of such a circuity remains undefined. Claudin-1 (Cld-1), a tight-junction integral protein deregulation alters colonic epithelial cell (CEC) differentiation, and promotes colitis severity while impairing colitis-associated injury/repair. Tumorigenesis is a product of an unregulated wound-healing process and therefore we postulated that upregulated Cld-1 levels render IBD patients susceptible to the colitis-associated cancer (CAC). Villin Cld-1 mice are used to carryout overexpressed studies in mice. The role of deregulated Cld-1 expression in CAC and the underlying mechanism was determined using a well-constructed study scheme and mouse models of DSS colitis/recovery and CAC. Using an inclusive investigative scheme, we here report that upregulated Cld-1 expression promotes susceptibility to the CAC and its malignancy. Increased mucosal inflammation and defective epithelial homeostasis accompanied the increased CAC in Villin-Cld-1-Tg mice. We further found significantly increased levels of protumorigenic M2 macrophages and β-cateninSer552 (β-CatSer552) expression in the CAC in Cld-1Tg vs. WT mice. Mechanistic studies identified the role of PI3K/Akt signaling in Cld-1-dependent activation of the β-CatSer552, which, in turn, was dependent on proinflammatory signals. Our studies identify a critical role of Cld-1 in promoting susceptibility to CAC. Importantly, these effects of deregulated Cld-1 were not associated with altered tight junction integrity, but on its noncanonical role in regulating Notch/PI3K/Wnt/ β-CatSer552 signaling. Overall, outcome from our current studies identifies Cld-1 as potential prognostic biomarker for IBD severity and CAC, and a novel therapeutic target.
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22 MeSH Terms
Epidemiology and implications of concurrent diagnosis of eosinophilic oesophagitis and IBD based on a prospective population-based analysis.
Limketkai BN, Shah SC, Hirano I, Bellaguarda E, Colombel JF
(2019) Gut 68: 2152-2160
MeSH Terms: Adolescent, Adult, Aged, Child, Child, Preschool, Comorbidity, Eosinophilic Esophagitis, Female, Follow-Up Studies, Humans, Incidence, Infant, Infant, Newborn, Inflammatory Bowel Diseases, Male, Middle Aged, Population Surveillance, Prevalence, Prospective Studies, Risk Assessment, Risk Factors, United States, Young Adult
Show Abstract · Added March 3, 2020
OBJECTIVE - Eosinophilic oesophagitis (EoO) and IBD are immune-mediated diseases of the gastrointestinal tract with possible overlapping pathogenic mechanisms. Our aim was to define the epidemiology and clinical implications of concurrent EoO and IBD diagnoses.
DESIGN - We conducted a prospective cohort analysis using the Truven MarketScan database (2009-2016) to estimate the incidence and prevalence of EoO in patients with Crohn's disease (CD) or UC and vice versa. Cox proportional hazards and Kaplan-Meier methods were used to estimate the risk of EoO-related or IBD-related complications among patients with concurrent diagnoses.
RESULTS - Among 134 013 536 individuals, the incidence of EoO, CD and UC were 23.1, 51.2 and 55.2 per 100 000 person-years, respectively. The risk of EoO was higher among patients with CD (incidence rate ratio [IRR] 5.4, p<0.01; prevalence ratio (PR) 7.8, p<0.01) or UC (IRR 3.5, p<0.01; PR 5.0, p<0.01), while the risk of IBD was higher among patients with EoO (CD: IRR 5.7, p<0.01; PR 7.6, p<0.01; UC: IRR 3.4, p<0.01; PR 4.9, p<0.01) versus individuals without either diagnosis. Concurrent diagnosis of EoO and IBD was associated with greater composite risk of IBD-related complications (CD: adjusted HR (aHR) 1.09, p=0.01; UC: aHR 1.10, p=0.04) but lower composite risk of EoO-related complications (aHR 0.59; p<0.01).
CONCLUSION - Based on a population-based prospective cohort analysis, the risk of EoO is significantly higher among patients with IBD and vice versa. Concurrent diagnoses might modify the risk of IBD-related and EoO-related complications. Studies defining the mechanisms underlying these observations are needed.
© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
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Sex-based differences in the incidence of inflammatory bowel diseases-pooled analysis of population-based studies from the Asia-Pacific region.
Shah SC, Khalili H, Chen CY, Ahn HS, Ng SC, Burisch J, Colombel JF
(2019) Aliment Pharmacol Ther 49: 904-911
MeSH Terms: Adolescent, Adult, Aged, Asia, Child, Child, Preschool, Cohort Studies, Female, Humans, Incidence, Infant, Infant, Newborn, Inflammatory Bowel Diseases, Male, Middle Aged, Pacific Ocean, Population Surveillance, Risk Factors, Sex Characteristics, Young Adult
Show Abstract · Added March 3, 2020
BACKGROUND - There appear to be differences in risk factor profiles for IBD between Asia-Pacific and Western populations, which might suggest idiosyncrasies in pathogenesis. Recently, sex-based differences in IBD according to the age of diagnosis have been described in Western populations.
AIM - To identify whether sex-based differences in IBD incidence similarly exist across the age spectrum for Asia-Pacific populations.
METHODS - We identified Asia-Pacific population-based cohorts where IBD incidence data stratified by sex were available for the full age spectrum. Cohorts were included only if IBD diagnoses were confirmed and validated. We calculated incidence rate ratios of Crohn's disease (CD) and ulcerative colitis (UC) according to age and compared differences between males and females using random-effects meta-analysis.
RESULTS - Among 567.8 million people from 11 Asia-Pacific countries/provinces/nations, we identified 10 553 incident CD cases (7060 males; 3493 females) and 16 946 incident UC cases (9754 males; 7192 females). Starting in early adolescence until age 50 years, there was a 36%-64% higher incidence of CD in males vs females (P < 0.001). UC incidence ranged from 20%-42% higher in males vs females in the age groups between 15 and 65 years (P < 0.05).
CONCLUSIONS - In a pooled analysis of population-based studies from the Asia-Pacific region, we found a male predominance of both CD and UC for the majority of the age spectrum from adolescence to middle/late-middle age. Additional studies are needed to clarify biological and nonbiological determinants of sex differences in IBD, which might be distinct between Asia-Pacific and Western populations.
© 2019 John Wiley & Sons Ltd.
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20 MeSH Terms
Statin Exposure Is Not Associated with Reduced Prevalence of Colorectal Neoplasia in Patients with Inflammatory Bowel Disease.
Shah SC, Glass J, Giustino G, Hove JRT, Castaneda D, Torres J, Kumar A, Elman J, Ullman TA, Itzkowitz SH
(2019) Gut Liver 13: 54-61
MeSH Terms: Adult, Cholangitis, Sclerosing, Cohort Studies, Colitis, Colonoscopy, Colorectal Neoplasms, Early Detection of Cancer, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Inflammatory Bowel Diseases, Male, Middle Aged, Population Surveillance, Prevalence, Risk Factors, Time Factors
Show Abstract · Added March 3, 2020
Background/Aims - Statins have been postulated to lower the risk of colorectal neoplasia. No studies have examined any possible chemopreventive effect of statins in patients with inflammatory bowel disease (IBD) undergoing colorectal cancer (CRC) surveillance. This study examined the association of statin exposure with dysplasia and CRC in patients with IBD undergoing dysplasia surveillance colonoscopies.
Methods - A cohort of patients with IBD undergoing colonoscopic surveillance for dysplasia and CRC at a single academic medical center were studied. The inclusion criteria were IBD involving the colon for ≥8 years (or any colitis duration if associated with primary sclerosing cholangitis [PSC]) and at least two colonoscopic surveillance exams. The exclusion criteria were CRC or high-grade dysplasia (HGD) prior to or at enrollment, prior colectomy, or limited (<30%) colonic disease. The primary outcome was the frequency of dysplasia and/or CRC in statin-exposed versus nonexposed patients.
Results - A total of 642 patients met the inclusion criteria (57 statin-exposed and 585 nonexposed). The statin-exposed group had a longer IBD duration, longer follow-up period, and more colonoscopies but lower inflammatory scores, less frequent PSC and less use of thiopurines and biologics. There were no differences in low-grade dysplasia, HGD, or CRC development during the follow-up period between the statin-exposed and nonexposed groups (21.1%, 5.3%, 1.8% vs 19.2%, 2.9%, 2.9%, respectively). Propensity score analysis did not alter the overall findings.
Conclusions - In IBD patients undergoing surveillance colonoscopies, statin use was not associated with reduced dysplasia or CRC rates. The role of statins as chemopreventive agents in IBD remains controversial.
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Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis.
Coburn LA, Singh K, Asim M, Barry DP, Allaman MM, Al-Greene NT, Hardbower DM, Polosukhina D, Williams CS, Delgado AG, Piazuelo MB, Washington MK, Gobert AP, Wilson KT
(2019) Oncogene 38: 1067-1079
MeSH Terms: Amino Acid Transport Systems, Basic, Animals, Azoxymethane, Cell Line, Tumor, Cell Transformation, Neoplastic, Colonic Neoplasms, Inflammation, Inflammatory Bowel Diseases, Mice, Mice, Knockout, Neoplasm Proteins
Show Abstract · Added September 12, 2018
Solute carrier family 7 member 2 (SLC7A2, also known as CAT2) is an inducible transporter of the semi-essential amino acid L-arginine (L-Arg), which has been implicated in wound repair. We have reported that both SLC7A2 expression and L-Arg availability are decreased in colonic tissues from inflammatory bowel disease patients and that mice lacking Slc7a2 exhibit a more severe disease course when exposed to dextran sulfate sodium (DSS) compared to wild-type (WT) mice. Here, we present evidence that SLC7A2 plays a role in modulating colon tumorigenesis in the azoxymethane (AOM)-DSS model of colitis-associated carcinogenesis (CAC). SLC7A2 was localized predominantly to colonic epithelial cells in WT mice. Utilizing the AOM-DSS model, Slc7a2 mice had significantly increased tumor number, burden, and risk of high-grade dysplasia vs. WT mice. Tumors from Slc7a2 mice exhibited significantly increased levels of the proinflammatory cytokines/chemokines IL-1β, CXCL1, CXCL5, IL-3, CXCL2, CCL3, and CCL4, but decreased levels of IL-4, CXCL9, and CXCL10 compared to tumors from WT mice. This was accompanied by a shift toward pro-tumorigenic M2 macrophage activation in Slc7a2-deficient mice, as marked by increased colonic CD11bF4/80ARG1 cells with no alteration in CD11bF4/80NOS2 cells by flow cytometry and immunofluorescence microscopy. The shift toward M2 macrophage activation was confirmed in bone marrow-derived macrophages from Slc7a2 mice. In bone marrow chimeras between Slc7a2 and WT mice, the recipient genotype drove the CAC phenotype, suggesting the importance of epithelial SLC7A2 in abrogating neoplastic risk. These data reveal that SLC7A2 has a significant role in the protection from CAC in the setting of chronic colitis, and suggest that the decreased SLC7A2 in inflammatory bowel disease (IBD) may contribute to CAC risk. Strategies to enhance L-Arg availability by supplementing L-Arg and/or increasing L-Arg uptake could represent a therapeutic approach in IBD to reduce the substantial long-term risk of colorectal carcinoma.
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11 MeSH Terms
Microbial-Host Interactions in Inflammatory Bowel Disease, Functional Bowel Disease, Obesity and Obesity-Related Metabolic Disease.
Shah SC, Faith J, Colombel JF
(2018) Gastroenterology 155: 1283-1286
MeSH Terms: Host-Pathogen Interactions, Humans, Inflammatory Bowel Diseases, Irritable Bowel Syndrome, Metabolic Diseases, Microbiota, Obesity
Added March 3, 2020
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