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Results: 1 to 10 of 235

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Gut Epithelial Metabolism as a Key Driver of Intestinal Dysbiosis Associated with Noncommunicable Diseases.
Shelton CD, Byndloss MX
(2020) Infect Immun 88:
MeSH Terms: Animals, Colon, Disease Susceptibility, Dysbiosis, Energy Metabolism, Enterobacteriaceae, Gastrointestinal Microbiome, Humans, Intestinal Mucosa, Noncommunicable Diseases, Obesity, Oxidation-Reduction, Risk Assessment, Risk Factors
Show Abstract · Added March 30, 2020
In high-income countries, the leading causes of death are noncommunicable diseases (NCDs), such as obesity, cancer, and cardiovascular disease. An important feature of most NCDs is inflammation-induced gut dysbiosis characterized by a shift in the microbial community structure from obligate to facultative anaerobes such as This microbial imbalance can contribute to disease pathogenesis by either a depletion in or the production of microbiota-derived metabolites. However, little is known about the mechanism by which inflammation-mediated changes in host physiology disrupt the microbial ecosystem in our large intestine leading to disease. Recent work by our group suggests that during gut homeostasis, epithelial hypoxia derived from peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent β-oxidation of microbiota-derived short-chain fatty acids limits oxygen availability in the colon, thereby maintaining a balanced microbial community. During inflammation, disruption in gut anaerobiosis drives expansion of facultative anaerobic , regardless of their pathogenic potential. Therefore, our research group is currently exploring the concept that dysbiosis-associated expansion of can be viewed as a microbial signature of epithelial dysfunction and may play a greater role in different models of NCDs, including diet-induced obesity, atherosclerosis, and inflammation-associated colorectal cancer.
Copyright © 2020 American Society for Microbiology.
0 Communities
1 Members
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14 MeSH Terms
Maternal microbial molecules affect offspring health.
Ferguson J
(2020) Science 367: 978-979
MeSH Terms: Animals, Child, Child Health, Diet, High-Fat, Female, Gastrointestinal Microbiome, Mice, Obesity, Phenotype, Pregnancy
Added March 3, 2020
0 Communities
1 Members
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10 MeSH Terms
Spotlight: Gastric Intestinal Metaplasia.
Shah SC, Gupta S, Li D, Morgan D, Mustafa RA, Gawron AJ
(2020) Gastroenterology 158: 704
MeSH Terms: Algorithms, Biopsy, Endoscopy, Gastrointestinal, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Metaplasia, Population Surveillance, Practice Guidelines as Topic, Precancerous Conditions, Risk Factors, Stomach Neoplasms
Added March 3, 2020
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13 MeSH Terms
Histologic Subtyping of Gastric Intestinal Metaplasia: Overview and Considerations for Clinical Practice.
Shah SC, Gawron AJ, Mustafa RA, Piazuelo MB
(2020) Gastroenterology 158: 745-750
MeSH Terms: Biopsy, Endoscopy, Gastrointestinal, Gastric Mucosa, Health Knowledge, Attitudes, Practice, Humans, Metaplasia, Population Surveillance, Precancerous Conditions, Stomach Neoplasms
Added March 3, 2020
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1 Members
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9 MeSH Terms
Advancing the Science in Gastric Pre-Neoplasia: Study Design Considerations.
Davitkov P, Altayar O, Shah SC, Gawron AJ, Mustafa RA, Sultan S, Morgan DR
(2020) Gastroenterology 158: 751-759
MeSH Terms: Biomedical Research, Biopsy, Endoscopy, Gastrointestinal, Gastric Mucosa, Humans, Incidence, Metaplasia, Population Surveillance, Precancerous Conditions, Prevalence, Research Design, Risk Factors, Stomach Neoplasms
Added March 3, 2020
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13 MeSH Terms
AGA Technical Review on Gastric Intestinal Metaplasia-Natural History and Clinical Outcomes.
Gawron AJ, Shah SC, Altayar O, Davitkov P, Morgan D, Turner K, Mustafa RA
(2020) Gastroenterology 158: 705-731.e5
MeSH Terms: Biopsy, Disease Progression, Endoscopy, Gastrointestinal, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Metaplasia, Population Surveillance, Precancerous Conditions, Prevalence, Risk Factors, Stomach Neoplasms, United States
Added March 3, 2020
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1 Members
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14 MeSH Terms
Increased Epithelial Oxygenation Links Colitis to an Expansion of Tumorigenic Bacteria.
Cevallos SA, Lee JY, Tiffany CR, Byndloss AJ, Johnston L, Byndloss MX, Bäumler AJ
(2019) mBio 10:
MeSH Terms: Aerobiosis, Animals, Carcinogenesis, Colitis, Colorectal Neoplasms, Dextran Sulfate, Escherichia coli, Escherichia coli Infections, Female, Gastrointestinal Microbiome, Mice, Mice, Inbred C57BL, Oxygen, Peptides, Polyketides
Show Abstract · Added March 30, 2020
Intestinal inflammation is a risk factor for colorectal cancer formation, but the underlying mechanisms remain unknown. Here, we investigated whether colitis alters the colonic microbiota to enhance its cancer-inducing activity. Colitis increased epithelial oxygenation in the colon of mice and drove an expansion of within the gut-associated microbial community through aerobic respiration. An aerobic expansion of colibactin-producing was required for the cancer-inducing activity of this pathobiont in a mouse model of colitis-associated colorectal cancer formation. We conclude that increased epithelial oxygenation in the colon is associated with an expansion of a prooncogenic driver species, thereby increasing the cancer-inducing activity of the microbiota. One of the environmental factors important for colorectal cancer formation is the gut microbiota, but the habitat filters that control its cancer-inducing activity remain unknown. Here, we show that chemically induced colitis elevates epithelial oxygenation in the colon, thereby driving an expansion of colibactin-producing , a prooncogenic driver species. These data suggest that elevated epithelial oxygenation is a potential risk factor for colorectal cancer formation because the consequent changes in the gut habitat escalate the cancer-inducing activity of the microbiota.
Copyright © 2019 Cevallos et al.
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15 MeSH Terms
Utilizing Untargeted Ion Mobility-Mass Spectrometry To Profile Changes in the Gut Metabolome Following Biliary Diversion Surgery.
Poland JC, Schrimpe-Rutledge AC, Sherrod SD, Flynn CR, McLean JA
(2019) Anal Chem 91: 14417-14423
MeSH Terms: Anastomosis, Surgical, Animals, Bile Acids and Salts, Bile Ducts, Cholesterol, Chromatography, Liquid, Duodenum, Fatty Acids, Volatile, Feces, Gastrointestinal Microbiome, Ileum, Jejunum, Male, Mass Spectrometry, Mice, Inbred C57BL
Show Abstract · Added December 17, 2019
Obesity and obesity-related disorders are a global epidemic affecting over 10% of the world's population. Treatment of these diseases has become increasingly challenging and expensive. The most effective and durable treatment for Class III obesity (body mass index ≥35 kg/m) is bariatric surgery, namely, Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy. These procedures are associated with increased circulating bile acids, molecules that not only facilitate intestinal fat absorption but are also potent hormones regulating numerous metabolic pathways. We recently reported on a novel surgical procedure in mice, termed distal gallbladder bile diversion to the ileum (GB-IL), that emulates the altered bile flow after RYGB without other manipulations of gastrointestinal anatomy. GB-IL improves oral glucose tolerance in mice made obese with high-fat diet. This is accompanied by fat malabsorption and weight loss, which complicates studying the role of elevated circulating bile acids in metabolic control. A less aggressive surgery in which the gallbladder bile is diverted to the proximal ileum, termed GB-IL, also improves glucose control but is not accompanied by fat malabsorption. To better understand the differential effects achieved by these bile diversion procedures, an untargeted ultraperformance liquid chromatography-ion mobility-mass spectrometry (UPLC-IM-MS) method was optimized for fecal samples derived from mice that have undergone bile diversion surgery. Utilizing the UPLC-IM-MS method, we were able to identify dysregulation of bile acids, short-chain fatty acids, and cholesterol derivatives that contribute to the differential metabolism resulting from these surgeries.
0 Communities
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15 MeSH Terms
A Role for the Orphan Human Cytochrome P450 2S1 in Polyunsaturated Fatty Acid -1 Hydroxylation Using an Untargeted Metabolomic Approach.
Fekry MI, Xiao Y, Berg JZ, Guengerich FP
(2019) Drug Metab Dispos 47: 1325-1332
MeSH Terms: Animals, Cytochrome P-450 CYP4A, Cytochrome P-450 Enzyme System, Fatty Acids, Unsaturated, Female, Gastrointestinal Tract, Humans, Hydroxylation, Isotope Labeling, Metabolomics, Rats
Show Abstract · Added March 3, 2020
Cytochrome P450 (P450) 2S1 is one of the orphan P450s, known to be expressed but not having a defined function with an endogenous substrate or in drug oxidations. Although it has been clearly demonstrated to catalyze reductive reactions, its role in NADPH-dependent oxidations has been ambiguous. In our efforts to characterize orphan human P450 enzymes, we used an untargeted liquid chromatography-mass spectromterymetabolomic approach with recombinant human P450 2S1 and extracts of rat stomach and intestine, sites of P450 2S1 localization in humans and animals. The search yielded several candidates, including the product 19-hydroxyarachidonic acid. Subsequent O analysis and in vitro studies with commercial arachidonic acid and 19-hydroxyarachidonic acid were used to validate -1 hydroxylation of the former molecule as a NADPH- and O-dependent reaction. Steady-state kinetic assays were done for -1 hydroxylation reactions of P450 2S1 with several other long-chain fatty acids, including arachidonic, linoleic, -linolenic, eicosapentaenoic, and docosapentaenoic acids. Rates of hydroxylation were slow, but no detectable activity was seen with either medium-chain length or saturated fatty acids. P450 2S1 is known to be expressed, at least at the mRNA level, to the extent of some other non-3A subfamily P450s in the human gastrointestinal tract, and the activity may be relevant. We conclude that P450 2S1 is a fatty acid -1 hydroxylase, although the physiologic relevance of these oxidations remains to be established. The metabolomic approaches we employed in this study are feasible for orphan P450s and other enzymes, in regard to annotation of function, in mammals and other organisms. SIGNIFICANCE STATEMENT: An untargeted mass spectrometry approach was utilized to identify -1 hydroxylation of arachidonic acid as an oxidative reaction catalyzed by human cytochrome P450 2S1. The enzyme also catalyzes the relatively slow -1 hydroxylation of several other unsaturated long-chain fatty acids.
Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.
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11 MeSH Terms
Gut Microbiome and Response to Cardiovascular Drugs.
Tuteja S, Ferguson JF
(2019) Circ Genom Precis Med 12: 421-429
MeSH Terms: Animals, Bacteria, Biotransformation, Cardiovascular Agents, Gastrointestinal Microbiome, Gastrointestinal Tract, Humans
Show Abstract · Added March 3, 2020
The gut microbiome is emerging as an important contributor to both cardiovascular disease risk and metabolism of xenobiotics. Alterations in the intestinal microbiota are associated with atherosclerosis, dyslipidemia, hypertension, and heart failure. The microbiota have the ability to metabolize medications, which can results in altered drug pharmacokinetics and pharmacodynamics or formation of toxic metabolites which can interfere with drug response. Early evidence suggests that the gut microbiome modulates response to statins and antihypertensive medications. In this review, we will highlight mechanisms by which the gut microbiome facilitates the biotransformation of drugs and impacts pharmacological efficacy. A better understanding of the complex interactions of the gut microbiome, host factors, and response to medications will be important for the development of novel precision therapeutics for targeting CVD.
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7 MeSH Terms