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An alternative N-terminal fold of the intestine-specific annexin A13a induces dimerization and regulates membrane-binding.
McCulloch KM, Yamakawa I, Shifrin DA, McConnell RE, Foegeding NJ, Singh PK, Mao S, Tyska MJ, Iverson TM
(2019) J Biol Chem 294: 3454-3463
MeSH Terms: Animals, Annexins, Cell Membrane, Epithelial Cells, Humans, Hydrogen-Ion Concentration, Intestinal Mucosa, Intestines, Liposomes, Mice, Models, Molecular, Organ Specificity, Protein Binding, Protein Conformation, alpha-Helical, Protein Multimerization, Protein Structure, Quaternary, Protein Transport
Show Abstract · Added April 1, 2019
Annexin proteins function as Ca-dependent regulators of membrane trafficking and repair that may also modulate membrane curvature. Here, using high-resolution confocal imaging, we report that the intestine-specific annexin A13 (ANX A13) localizes to the tips of intestinal microvilli and determined the crystal structure of the ANX A13a isoform to 2.6 Å resolution. The structure revealed that the N terminus exhibits an alternative fold that converts the first two helices and the associated helix-loop-helix motif into a continuous α-helix, as stabilized by a domain-swapped dimer. We also found that the dimer is present in solution and partially occludes the membrane-binding surfaces of annexin, suggesting that dimerization may function as a means for regulating membrane binding. Accordingly, as revealed by binding and cellular localization assays, ANX A13a variants that favor a monomeric state exhibited increased membrane association relative to variants that favor the dimeric form. Together, our findings support a mechanism for how the association of the ANX A13a isoform with the membrane is regulated.
© 2019 McCulloch et al.
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17 MeSH Terms
Role of Bile Acids and GLP-1 in Mediating the Metabolic Improvements of Bariatric Surgery.
Albaugh VL, Banan B, Antoun J, Xiong Y, Guo Y, Ping J, Alikhan M, Clements BA, Abumrad NN, Flynn CR
(2019) Gastroenterology 156: 1041-1051.e4
MeSH Terms: Anastomosis, Surgical, Animals, Anticholesteremic Agents, Bariatric Surgery, Bile Acids and Salts, Blood Glucose, Cholestyramine Resin, Diet, High-Fat, Gallbladder, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Glucose Tolerance Test, Ileum, Insulin Resistance, Intestines, Lymph, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Cytoplasmic and Nuclear, Receptors, G-Protein-Coupled, Signal Transduction, Verrucomicrobia, Weight Loss
Show Abstract · Added January 4, 2019
BACKGROUND & AIMS - Bile diversion to the ileum (GB-IL) has strikingly similar metabolic and satiating effects to Roux-en-Y gastric bypass (RYGB) in rodent obesity models. The metabolic benefits of these procedures are thought to be mediated by increased bile acids, although parallel changes in body weight and other confounding variables limit this interpretation.
METHODS - Global G protein-coupled bile acid receptor-1 null (Tgr5) and intestinal-specific farnesoid X receptor null (Fxr) mice on high-fat diet as well as wild-type C57BL/6 and glucagon-like polypeptide 1 receptor deficient (Glp-1r) mice on chow diet were characterized following GB-IL.
RESULTS - GB-IL induced weight loss and improved oral glucose tolerance in Tgr5, but not Fxr mice fed a high-fat diet, suggesting a role for intestinal Fxr. GB-IL in wild-type, chow-fed mice prompted weight-independent improvements in glycemia and glucose tolerance secondary to augmented insulin responsiveness. Improvements were concomitant with increased levels of lymphatic GLP-1 in the fasted state and increased levels of intestinal Akkermansia muciniphila. Improvements in fasting glycemia after GB-IL were mitigated with exendin-9, a GLP-1 receptor antagonist, or cholestyramine, a bile acid sequestrant. The glucoregulatory effects of GB-IL were lost in whole-body Glp-1r mice.
CONCLUSIONS - Bile diversion to the ileum improves glucose homeostasis via an intestinal Fxr-Glp-1 axis. Altered intestinal bile acid availability, independent of weight loss, and intestinal Akkermansia muciniphila appear to mediate the metabolic changes observed after bariatric surgery and might be manipulated for treatment of obesity and diabetes.
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
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25 MeSH Terms
Loss of MYO5B Leads to Reductions in Na Absorption With Maintenance of CFTR-Dependent Cl Secretion in Enterocytes.
Engevik AC, Kaji I, Engevik MA, Meyer AR, Weis VG, Goldstein A, Hess MW, Müller T, Koepsell H, Dudeja PK, Tyska M, Huber LA, Shub MD, Ameen N, Goldenring JR
(2018) Gastroenterology 155: 1883-1897.e10
MeSH Terms: Animals, Aquaporins, Chlorides, Cystic Fibrosis Transmembrane Conductance Regulator, Duodenum, Enterocytes, Gene Silencing, Humans, Intestinal Mucosa, Intestines, Malabsorption Syndromes, Mice, Mice, Knockout, Microvilli, Mucolipidoses, Myosin Type V, Protein Transport, Sodium-Glucose Transporter 1, Sodium-Hydrogen Exchanger 3, Sodium-Hydrogen Exchangers, Sucrase-Isomaltase Complex, Tamoxifen
Show Abstract · Added February 7, 2019
BACKGROUND & AIMS - Inactivating mutations in MYO5B cause microvillus inclusion disease (MVID), but the physiological cause of the diarrhea associated with this disease is unclear. We investigated whether loss of MYO5B results in aberrant expression of apical enterocyte transporters.
METHODS - We studied alterations in apical membrane transporters in MYO5B-knockout mice, as well as mice with tamoxifen-inducible, intestine-specific disruption of Myo5b (VilCre;Myo5b mice) or those not given tamoxifen (controls). Intestinal tissues were collected from mice and analyzed by immunostaining, immunoelectron microscopy, or cultured enteroids were derived. Functions of brush border transporters in intestinal mucosa were measured in Ussing chambers. We obtained duodenal biopsy specimens from individuals with MVID and individuals without MVID (controls) and compared transporter distribution by immunocytochemistry.
RESULTS - Compared to intestinal tissues from littermate controls, intestinal tissues from MYO5B-knockout mice had decreased apical localization of SLC9A3 (also called NHE3), SLC5A1 (also called SGLT1), aquaporin (AQP) 7, and sucrase isomaltase, and subapical localization of intestinal alkaline phosphatase and CDC42. However, CFTR was present on apical membranes of enterocytes from MYO5B knockout and control mice. Intestinal biopsies from patients with MVID had subapical localization of NHE3, SGLT1, and AQP7, but maintained apical CFTR. After tamoxifen administration, VilCre;Myo5b mice lost apical NHE3, SGLT1, DRA, and AQP7, similar to germline MYO5B knockout mice. Intestinal tissues from VilCre;Myo5b mice had increased CFTR in crypts and CFTR localized to the apical membranes of enterocytes. Intestinal mucosa from VilCre;Myo5b mice given tamoxifen did not have an intestinal barrier defect, based on Ussing chamber analysis, but did have decreased SGLT1 activity and increased CFTR activity.
CONCLUSIONS - Although trafficking of many apical transporters is regulated by MYO5B, trafficking of CFTR is largely independent of MYO5B. Decreased apical localization of NHE3, SGLT1, DRA, and AQP7 might be responsible for dysfunctional water absorption in enterocytes of patients with MVID. Maintenance of apical CFTR might exacerbate water loss by active secretion of chloride into the intestinal lumen.
Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Bacterial DNA is present in the fetal intestine and overlaps with that in the placenta in mice.
Martinez KA, Romano-Keeler J, Zackular JP, Moore DJ, Brucker RM, Hooper C, Meng S, Brown N, Mallal S, Reese J, Aronoff DM, Shin H, Dominguez-Bello MG, Weitkamp JH
(2018) PLoS One 13: e0197439
MeSH Terms: Amniotic Fluid, Animals, DNA, Bacterial, Female, Intestinal Mucosa, Intestines, Mice, Placenta, Pregnancy, RNA, Ribosomal, 16S, Vagina
Show Abstract · Added May 18, 2018
Bacterial DNA has been reported in the placenta and amniotic fluid by several independent groups of investigators. However, it's taxonomic overlap with fetal and maternal bacterial DNA in different sites has been poorly characterized. Here, we determined the presence of bacterial DNA in the intestines and placentas of fetal mice at gestational day 17 (n = 13). These were compared to newborn intestines (n = 15), maternal sites (mouth, n = 6; vagina, n = 6; colon, n = 7; feces, n = 8), and negative controls to rule out contamination. The V4 region of the bacterial 16S rRNA gene indicated a pattern of bacterial DNA in fetal intestine similar to placenta but with higher phylogenetic diversity than placenta or newborn intestine. Firmicutes were the most frequently assignable phylum. SourceTracker analysis suggested the placenta as the most commonly identifiable origin for fetal bacterial DNA, but also over 75% of fetal gut genera overlapped with maternal oral and vaginal taxa but not with maternal or newborn feces. These data provide evidence for the presence of bacterial DNA in the mouse fetus.
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11 MeSH Terms
Shear stress induces noncanonical autophagy in intestinal epithelial monolayers.
Kim SW, Ehrman J, Ahn MR, Kondo J, Lopez AAM, Oh YS, Kim XH, Crawley SW, Goldenring JR, Tyska MJ, Rericha EC, Lau KS
(2017) Mol Biol Cell 28: 3043-3056
MeSH Terms: Actins, Autophagy, Caco-2 Cells, Cell Culture Techniques, Epithelium, Humans, Intestinal Mucosa, Intestines, Microvilli, Stress, Physiological, Vacuoles
Show Abstract · Added April 3, 2018
Flow of fluids through the gut, such as milk from a neonatal diet, generates a shear stress on the unilaminar epithelium lining the lumen. We report that exposure to physiological levels of fluid shear stress leads to the formation of large vacuoles, containing extracellular contents within polarizing intestinal epithelial cell monolayers. These observations lead to two questions: how can cells lacking primary cilia transduce shear stress, and what molecular pathways support the formation of vacuoles that can exceed 80% of the cell volume? We find that shear forces are sensed by actin-rich microvilli that eventually generate the apical brush border, providing evidence that these structures possess mechanosensing ability. Importantly, we identified the molecular pathway that regulates large vacuole formation downstream from mechanostimulation to involve central components of the autophagy pathway, including ATG5 and LC3, but not Beclin. Together our results establish a novel link between the actin-rich microvilli, the macroscopic transport of fluids across cells, and the noncanonical autophagy pathway in organized epithelial monolayers.
© 2017 Kim et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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Oleoylethanolamide: A fat ally in the fight against obesity.
Brown JD, Karimian Azari E, Ayala JE
(2017) Physiol Behav 176: 50-58
MeSH Terms: Animals, Anti-Obesity Agents, Eating, Endocannabinoids, Humans, Intestinal Mucosa, Intestines, Obesity, Oleic Acids, Reward
Show Abstract · Added October 23, 2017
Obesity is a pandemic, gateway disease that has thrived in modern, sedentary, high calorie-eating societies. Left unchecked, obesity and obesity-related diseases will continue to plague future generations with heavy burdens on economies, healthcare systems, and the quality of life of billions. There is a significant need to elucidate basic physiological mechanisms and therapies that address this global health care crisis. Oleoylethanolamide (OEA) is an endocannabinoid-like lipid that induces hypophagia and reduces fat mass in rodents. For over a decade, PPAR-α has been the most widely accepted mediator of the hypophagic action of OEA via signaling to homeostatic brain centers. Recent evidence suggests that OEA may also reduce food intake via effects on dopamine and endocannabinoid signaling within hedonic brain centers. Limited study of OEA supplementation in humans has provided some encouraging insight into OEA-based weight loss therapy, but more thorough, controlled investigations are needed. As a potential link between homeostatic and hedonic regulation of food intake, OEA is a prime starting point for the development of more effective obesity therapies.
Copyright © 2017 Elsevier Inc. All rights reserved.
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10 MeSH Terms
The human intestinal microbiota of constipated-predominant irritable bowel syndrome patients exhibits anti-inflammatory properties.
Gobert AP, Sagrestani G, Delmas E, Wilson KT, Verriere TG, Dapoigny M, Del'homme C, Bernalier-Donadille A
(2016) Sci Rep 6: 39399
MeSH Terms: Animals, Anti-Inflammatory Agents, Colitis, Cytokines, Dextran Sulfate, Dysbiosis, Gastrointestinal Microbiome, Humans, Inflammation, Intestines, Irritable Bowel Syndrome, Mice, Mice, Inbred C57BL, Microbiota, Rats
Show Abstract · Added December 17, 2016
The intestinal microbiota of patients with constipated-predominant irritable bowel syndrome (C-IBS) displays chronic dysbiosis. Our aim was to determine whether this microbial imbalance instigates perturbation of the host intestinal mucosal immune response, using a model of human microbiota-associated rats (HMAR) and dextran sulfate sodium (DSS)-induced experimental colitis. The analysis of the microbiota composition revealed a decrease of the relative abundance of Bacteroides, Roseburia-Eubacterium rectale and Bifidobacterium and an increase of Enterobacteriaceae, Desulfovibrio sp., and mainly Akkermansia muciniphila in C-IBS patients compared to healthy individuals. The bacterial diversity of the gut microbiota of healthy individuals or C-IBS patients was maintained in corresponding HMAR. Animals harboring a C-IBS microbiota had reduced DSS colitis with a decreased expression of pro-inflammatory cytokines from innate, Th1, and Th17 responses. The pre-treatment of conventional C57BL/6 mice or HMAR with A. muciniphila, but not with Escherichia coli, prior exposure to DSS also resulted in a reduction of colitis severity, highlighting that the anti-inflammatory effect of the gut microbiota of C-IBS patients is mediated, in part, by A. muciniphila. This work highlights a novel aspect of the crosstalk between the gut microbiota of C-IBS patients and host intestinal homeostasis.
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15 MeSH Terms
Salmonella Mitigates Oxidative Stress and Thrives in the Inflamed Gut by Evading Calprotectin-Mediated Manganese Sequestration.
Diaz-Ochoa VE, Lam D, Lee CS, Klaus S, Behnsen J, Liu JZ, Chim N, Nuccio SP, Rathi SG, Mastroianni JR, Edwards RA, Jacobo CM, Cerasi M, Battistoni A, Ouellette AJ, Goulding CW, Chazin WJ, Skaar EP, Raffatellu M
(2016) Cell Host Microbe 19: 814-25
MeSH Terms: Animals, Anti-Bacterial Agents, Antioxidants, Bacterial Proteins, Chelating Agents, Escherichia coli, Gastroenteritis, Intestinal Mucosa, Intestines, Leukocyte L1 Antigen Complex, Manganese, Mice, Mice, Inbred C57BL, Neutrophils, Oxidative Stress, Reactive Oxygen Species, Salmonella Infections, Salmonella typhimurium, Symbiosis, Zinc
Show Abstract · Added April 8, 2017
Neutrophils hinder bacterial growth by a variety of antimicrobial mechanisms, including the production of reactive oxygen species and the secretion of proteins that sequester nutrients essential to microbes. A major player in this process is calprotectin, a host protein that exerts antimicrobial activity by chelating zinc and manganese. Here we show that the intestinal pathogen Salmonella enterica serovar Typhimurium uses specialized metal transporters to evade calprotectin sequestration of manganese, allowing the bacteria to outcompete commensals and thrive in the inflamed gut. The pathogen's ability to acquire manganese in turn promotes function of SodA and KatN, enzymes that use the metal as a cofactor to detoxify reactive oxygen species. This manganese-dependent SodA activity allows the bacteria to evade neutrophil killing mediated by calprotectin and reactive oxygen species. Thus, manganese acquisition enables S. Typhimurium to overcome host antimicrobial defenses and support its competitive growth in the intestine.
Copyright © 2016 Elsevier Inc. All rights reserved.
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20 MeSH Terms
Neonatal colonization of mice with LGG promotes intestinal development and decreases susceptibility to colitis in adulthood.
Yan F, Liu L, Cao H, Moore DJ, Washington MK, Wang B, Peek RM, Acra SA, Polk DB
(2017) Mucosal Immunol 10: 117-127
MeSH Terms: Animals, Animals, Newborn, Cell Proliferation, Cells, Cultured, Colitis, Dextran Sulfate, Disease Models, Animal, Female, Gastrointestinal Microbiome, Humans, Immunoglobulin A, Intestinal Mucosa, Intestines, Lactobacillus rhamnosus, Mice, Mice, Inbred C57BL, Pregnancy, Probiotics, Symbiosis, Tight Junctions
Show Abstract · Added April 26, 2016
Development of the intestinal microbiota during early life serves as a key regulatory stage in establishing the host-microbial relationship. This symbiotic relationship contributes to developing host immunity and maintaining health throughout the life span. This study was to develop an approach to colonize conventionally raised mice with a model probiotic bacterium, Lactobacillus rhamnosus GG (LGG), and to determine the effects of LGG colonization on intestinal development and prevention of colitis in adulthood. LGG colonization in conventionally raised was established by administering LGG to pregnant mice starting at gestational day 18 and pups at postnatal days 1- 5. LGG colonization promoted bodyweight gain and increased diversity and richness of the colonic mucosa-associated microbiota before weaning. Intestinal epithelial cell proliferation, differentiation, tight junction formation, and mucosal IgA production were all significantly enhanced in LGG-colonized mice. Adult mice colonized with LGG showed increased IgA production and decreased susceptibility to intestinal injury and inflammation induced in the dextran sodium sulfate model of colitis. Thus, neonatal colonization of mice with LGG enhances intestinal functional maturation and IgA production and confers lifelong health consequences on protection from intestinal injury and inflammation. This strategy might be applied for benefiting health in the host.
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20 MeSH Terms
BVES Regulates Intestinal Stem Cell Programs and Intestinal Crypt Viability after Radiation.
Reddy VK, Short SP, Barrett CW, Mittal MK, Keating CE, Thompson JJ, Harris EI, Revetta F, Bader DM, Brand T, Washington MK, Williams CS
(2016) Stem Cells 34: 1626-36
MeSH Terms: Animals, Cell Adhesion Molecules, Cell Survival, Down-Regulation, Female, Gamma Rays, Gene Deletion, Homeostasis, Intestines, Male, Mice, Inbred C57BL, Muscle Proteins, Radiation Tolerance, Spheroids, Cellular, Stem Cells, Wnt Signaling Pathway
Show Abstract · Added February 22, 2016
Blood vessel epicardial substance (BVES/Popdc1) is a junctional-associated transmembrane protein that is underexpressed in a number of malignancies and regulates epithelial-to-mesenchymal transition. We previously identified a role for BVES in regulation of the Wnt pathway, a modulator of intestinal stem cell programs, but its role in small intestinal (SI) biology remains unexplored. We hypothesized that BVES influences intestinal stem cell programs and is critical to SI homeostasis after radiation injury. At baseline, Bves(-/-) mice demonstrated increased crypt height, as well as elevated proliferation and expression of the stem cell marker Lgr5 compared to wild-type (WT) mice. Intercross with Lgr5-EGFP reporter mice confirmed expansion of the stem cell compartment in Bves(-/-) mice. To examine stem cell function after BVES deletion, we used ex vivo 3D-enteroid cultures. Bves(-/-) enteroids demonstrated increased stemness compared to WT, when examining parameters such as plating efficiency, stem spheroid formation, and retention of peripheral cystic structures. Furthermore, we observed increased proliferation, expression of crypt-base columnar "CBC" and "+4" stem cell markers, amplified Wnt signaling, and responsiveness to Wnt activation in the Bves(-/-) enteroids. Bves expression was downregulated after radiation in WT mice. Moreover, after radiation, Bves(-/-) mice demonstrated significantly greater SI crypt viability, proliferation, and amplified Wnt signaling in comparison to WT mice. Bves(-/-) mice also demonstrated elevations in Lgr5 and Ascl2 expression, and putative damage-responsive stem cell populations marked by Bmi1 and TERT. Therefore, BVES is a key regulator of intestinal stem cell programs and mucosal homeostasis. Stem Cells 2016;34:1626-1636.
© 2016 AlphaMed Press.
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16 MeSH Terms