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https://www.readbyqxmd.com/read/28102757/dysbiosis-in-crohn-s-disease-joint-action-of-stochastic-injuries-and-focal-inflammation-in-the-gut
#1
Ludovica F Buttó, Dirk Haller
Gut homeostasis involves interrelated biological networks that include the immune system, specialized cells of the epithelium, such as Paneth and goblet cells, as well as triggers derived from the microbiota. Disruption of these homeostatic interactions may lead to the pathogenesis of inflammatory bowel diseases (IBD). To develop more targeted and individual treatments in Crohn's disease and ulcerative colitis, it becomes more and more important to link key mechanisms of the disease pathogenesis to distinct IBD subsets...
January 19, 2017: Gut Microbes
https://www.readbyqxmd.com/read/28097227/a-xenogeneic-free-system-generating-functional-human-gut-organoids-from-pluripotent-stem-cells
#2
Hajime Uchida, Masakazu Machida, Takumi Miura, Tomoyuki Kawasaki, Takuya Okazaki, Kengo Sasaki, Seisuke Sakamoto, Noriaki Ohuchi, Mureo Kasahara, Akihiro Umezawa, Hidenori Akutsu
Functional intestines are composed of cell types from all 3 primary germ layers and are generated through a highly orchestrated and serial developmental process. Directed differentiation of human pluripotent stem cells (hPSCs) has been shown to yield gut-specific cell types; however, these structures do not reproduce critical functional interactions between cell types of different germ layers. Here, we developed a simple protocol for the generation of mature functional intestinal organoids from hPSCs under xenogeneic-free conditions...
January 12, 2017: JCI Insight
https://www.readbyqxmd.com/read/28070680/a-disturbance-of-intestinal-epithelial-cell-population-and-kinetics-in-apc1638t-mice
#3
Tuya Wang, Takanori Onouchi, Nami O Yamada, Shuji Matsuda, Takao Senda
The adenomatous polyposis coli (APC) is a multifunctional protein as well as a tumor suppressor. To determine the functions of the C-terminal domain of APC, we explored APC (1638T/1638T) (APC1638T) mice that express a truncated APC lacking the C-terminal domain. The APC1638T mice were tumor free and exhibited growth retardation. In the present study, we compared small intestinal crypt-villus cells homeostasis in APC (+/+) (WT) mice and APC1638T mice. The body weight of APC1638T mice was significantly smaller than that of WT mice at all ages...
January 9, 2017: Medical Molecular Morphology
https://www.readbyqxmd.com/read/28067516/elucidating-the-bacterial-membrane-disruption-mechanism-of-human-%C3%AE-defensin-5-a-theoretical-study
#4
Sang Won Jung, Juho Lee, Art E Cho
Human α-defensin 5 (HD5) is a broad-spectrum antibacterial peptide produced by small intestinal Paneth cells. Despite considerable experimental evidence for the correlation between bacterial membrane destruction and the antibacterial activity of HD5, its membrane disruption mechanism remains unclear. Using all-atom molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis, we demonstrate the membrane disruption mechanism of HD5 based on the intrinsic binding of HD5 to Gram-negative (GN) bacterial inner-membrane...
January 9, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28002460/metformin-improves-ileal-epithelial-barrier-function-in-interleukin-10-deficient-mice
#5
Yansong Xue, Hanying Zhang, Xiaofei Sun, Mei-Jun Zhu
BACKGROUND AND AIMS: The impairment of intestinal epithelial barrier is the main etiologic factor of inflammatory bowel disease. The proper intestinal epithelial proliferation and differentiation is crucial for maintaining intestinal integrity. Metformin is a common anti-diabetic drug. The objective is to evaluate the protective effects of metformin on ileal epithelial barrier integrity using interleukin-10 deficient (IL10KO) mice. METHODS: Wild-type and IL10KO mice were fed with/without metformin for 6 weeks and then ileum was collected for analyses...
2016: PloS One
https://www.readbyqxmd.com/read/27939219/induced-quiescence-of-lgr5-stem-cells-in-intestinal-organoids-enables-differentiation-of-hormone-producing-enteroendocrine-cells
#6
Onur Basak, Joep Beumer, Kay Wiebrands, Hiroshi Seno, Alexander van Oudenaarden, Hans Clevers
Lgr5+ adult intestinal stem cells are highly proliferative throughout life. Single Lgr5+ stem cells can be cultured into three-dimensional organoids containing all intestinal epithelial cell types at near-normal ratios. Conditions to generate the main cell types (enterocyte, goblet cells, Paneth cells, and M cells) are well established, but signals to induce the spectrum of hormone-producing enteroendocrine cells (EECs) have remained elusive. Here, we induce Lgr5+ stem cell quiescence in vitro by blocking epidermal growth factor receptor (EGFR) or mitogen-associated protein kinase (MAPK) signaling pathways in organoids and show that their quiescent state is readily reverted...
November 17, 2016: Cell Stem Cell
https://www.readbyqxmd.com/read/27935584/ketogenesis-contributes-to-intestinal-cell-differentiation
#7
Qingding Wang, Yuning Zhou, Piotr Rychahou, Teresa W-M Fan, Andrew N Lane, Heidi L Weiss, B Mark Evers
The intestinal epithelium undergoes a continual process of proliferation, differentiation and apoptosis. Previously, we have shown that the PI3K/Akt/mTOR pathway has a critical role in intestinal homeostasis. However, the downstream targets mediating the effects of mTOR in intestinal cells are not known. Here, we show that the ketone body β-hydroxybutyrate (βHB), an endogenous inhibitor of histone deacetylases (HDACs) induces intestinal cell differentiation as noted by the increased expression of differentiation markers (Mucin2 (MUC2), lysozyme, IAP, sucrase-isomaltase, KRT20, villin, Caudal-related homeobox transcription factor 2 (CDX2) and p21(Waf1))...
December 9, 2016: Cell Death and Differentiation
https://www.readbyqxmd.com/read/27930931/deficiency-in-duox2-activity-alleviates-ileitis-in-gpx1-and-gpx2-knockout-mice-without-affecting-apoptosis-incidence-in-the-crypt-epithelium
#8
Fong-Fong Chu, R Steven Esworthy, James H Doroshow, Helmut Grasberger, Agnes Donko, Thomas L Leto, Qiang Gao, Binghui Shen
Mice deficient in glutathione peroxidase (GPx)-1 and -2 (GPx1(-/-)GPx2(-/-) double knockout or DKO mice) develop very-early-onset (VEO) ileocolitis, suggesting that lack of defense against reactive oxygen species (ROS) renders susceptibility to intestinal inflammation. Two members of ROS-generating NADPH oxidase family, NOX1 and DUOX2, are highly inducible in the intestinal epithelium. Previously, we reported that Nox1 deficiency ameliorated the pathology in DKO mice (Nox1-TKO). The role of Duox2 in ileocolitis of the DKO mice is evaluated here in Duoxa-TKO mice by breeding DKO mice with Duoxa(-/-) mice (Duoxa-TKO), which do not have Duox2 activity...
November 22, 2016: Redox Biology
https://www.readbyqxmd.com/read/27895587/vitamin-d-signaling-through-induction-of-paneth-cell-defensins-maintains-gut-microbiota-and-improves-metabolic-disorders-and-hepatic-steatosis-in-animal-models
#9
Danmei Su, Yuanyang Nie, Airu Zhu, Zishuo Chen, Pengfei Wu, Li Zhang, Mei Luo, Qun Sun, Linbi Cai, Yuchen Lai, Zhixiong Xiao, Zhongping Duan, Sujun Zheng, Guihui Wu, Richard Hu, Hidekazu Tsukamoto, Aurelia Lugea, Zhenqui Liu, Stephen J Pandol, Yuan-Ping Han
Metabolic syndrome (MetS), characterized as obesity, insulin resistance, and non-alcoholic fatty liver diseases (NAFLD), is associated with vitamin D insufficiency/deficiency in epidemiological studies, while the underlying mechanism is poorly addressed. On the other hand, disorder of gut microbiota, namely dysbiosis, is known to cause MetS and NAFLD. It is also known that systemic inflammation blocks insulin signaling pathways, leading to insulin resistance and glucose intolerance, which are the driving force for hepatic steatosis...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27867006/intercellular-coupling-of-the-cell-cycle-and-circadian-clock-in-adult-stem-cell-culture
#10
Toru Matsu-Ura, Andrey Dovzhenok, Eitaro Aihara, Jill Rood, Hung Le, Yan Ren, Andrew E Rosselot, Tongli Zhang, Choogon Lee, Karl Obrietan, Marshall H Montrose, Sookkyung Lim, Sean R Moore, Christian I Hong
Circadian clock-gated cell division cycles are observed from cyanobacteria to mammals via intracellular molecular connections between these two oscillators. Here we demonstrate WNT-mediated intercellular coupling between the cell cycle and circadian clock in 3D murine intestinal organoids (enteroids). The circadian clock gates a population of cells with heterogeneous cell-cycle times that emerge as 12-hr synchronized cell division cycles. Remarkably, we observe reduced-amplitude oscillations of circadian rhythms in intestinal stem cells and progenitor cells, indicating an intercellular signal arising from differentiated cells governing circadian clock-dependent synchronized cell division cycles...
December 1, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27866962/distribution-of-muscarinic-acetylcholine-receptor-subtypes-in-the-murine-small-intestine
#11
Eleanor D Muise, Neeru Gandotra, John J Tackett, Michaela C Bamdad, Robert A Cowles
AIMS: Serotonin stimulates enterocyte turnover in the small intestine and studies suggest this is mediated by neuronal signaling via a cholinergic pathway. Distribution of the five known muscarinic receptor subtypes (mAChRs) in the small intestine has not been fully studied, and their role in intestinal growth is unknown. We hypothesized that mAChRs have distinct anatomic distributions within the bowel, and that mAChRs present within intestinal crypts mediate the effects of acetylcholine on the small intestinal mucosa...
November 17, 2016: Life Sciences
https://www.readbyqxmd.com/read/27791005/single-cell-lineage-tracing-reveals-a-role-for-tgf%C3%AE-r2-in-intestinal-stem-cell-dynamics-and-differentiation
#12
Jared M Fischer, Peter P Calabrese, Ashleigh J Miller, Nina M Muñoz, William M Grady, Darryl Shibata, R Michael Liskay
Intestinal stem cells (ISCs) are maintained by a niche mechanism, in which multiple ISCs undergo differential fates where a single ISC clone ultimately occupies the niche. Importantly, mutations continually accumulate within ISCs creating a potential competitive niche environment. Here we use single cell lineage tracing following stochastic transforming growth factor β receptor 2 (TgfβR2) mutation to show cell autonomous effects of TgfβR2 loss on ISC clonal dynamics and differentiation. Specifically, TgfβR2 mutation in ISCs increased clone survival while lengthening times to monoclonality, suggesting that Tgfβ signaling controls both ISC clone extinction and expansion, independent of proliferation...
October 25, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27788929/circulating-inflammatory-associated-proteins-in-the-first-month-of-life-and-cognitive-impairment-at-age-10-years-in-children-born-extremely-preterm
#13
Karl C K Kuban, Robert M Joseph, Thomas M O'Shea, Timothy Heeren, Raina N Fichorova, Laurie Douglass, Hernan Jara, Jean A Frazier, Deborah Hirtz, Julie Vanier Rollins, Nigel Paneth
OBJECTIVES: To evaluate whether in children born extremely preterm, indicators of sustained systemic inflammation in the first month of life are associated with cognitive impairment at school age. STUDY DESIGN: A total of 873 of 966 eligible children previously enrolled in the multicenter Extremely Low Gestational Age Newborn Study from 2002 to 2004 were evaluated at age 10 years. We analyzed the relationship between elevated blood concentrations of inflammation-associated proteins in the first 2 weeks ("early elevations"; n = 812) and the third and fourth week ("late elevations"; n = 532) of life with neurocognition...
January 2017: Journal of Pediatrics
https://www.readbyqxmd.com/read/27753990/ed-05-2-interaction-of-gut-dysbiosis-and-innate-immune-dysfunction-in-the-development-of-metabolic-syndrome
#14
Myung-Shik Lee
Low-grade systemic inflammation in adipose tissues or liver, is an important etiologic factor in insulin resistance. LPS is an important element causing such metabolic inflammation, and intestinal flora is considered a major source of systemic LPS. We studied changes of intestinal microbiota associated with high-fat diet (HFD) that causes insulin resistance and metabolic stress. 16S rRNA gene sequencing showed that HFD significantly decreased the abundance of a mucin-degrading bacterium Akkermansia muciniphila compared to control diet...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27736879/zinc-transporter-slc39a7-zip7-promotes-intestinal-epithelial-self-renewal-by-resolving-er-stress
#15
Wakana Ohashi, Shunsuke Kimura, Toshihiko Iwanaga, Yukihiro Furusawa, Tarou Irié, Hironori Izumi, Takashi Watanabe, Atsushi Hijikata, Takafumi Hara, Osamu Ohara, Haruhiko Koseki, Toshiro Sato, Sylvie Robine, Hisashi Mori, Yuichi Hattori, Hiroshi Watarai, Kenji Mishima, Hiroshi Ohno, Koji Hase, Toshiyuki Fukada
Zinc transporters play a critical role in spatiotemporal regulation of zinc homeostasis. Although disruption of zinc homeostasis has been implicated in disorders such as intestinal inflammation and aberrant epithelial morphology, it is largely unknown which zinc transporters are responsible for the intestinal epithelial homeostasis. Here, we show that Zrt-Irt-like protein (ZIP) transporter ZIP7, which is highly expressed in the intestinal crypt, is essential for intestinal epithelial proliferation. Mice lacking Zip7 in intestinal epithelium triggered endoplasmic reticulum (ER) stress in proliferative progenitor cells, leading to significant cell death of progenitor cells...
October 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27732932/the-first-investigation-of-wilms-tumour-atomic-structure-nitrogen-and-carbon-isotopic-composition-as-a-novel-biomarker-for-the-most-individual-approach-in-cancer-disease
#16
Katarzyna Taran, Tomasz FrÄ Czek, Anita Sikora-Szubert, Anna Sitkiewicz, Wojciech Må Ynarski, Józef Kobos, Piotr Paneth
The paper describes a novel approach to investigating Wilms' tumour (nephroblastoma) biology at the atomic level. Isotope Ratio Mass Spectrometry (IRMS) was used to directly assess the isotope ratios of nitrogen and carbon in 84 Wilms' tumour tissue samples from 28 cases representing the histological spectrum of nephroblastoma. Marked differences in nitrogen and carbon isotope ratios were found between nephroblastoma histological types and along the course of cancer disease, with a breakout in isotope ratio of the examined elements in tumour tissue found between stages 2 and 3...
October 8, 2016: Oncotarget
https://www.readbyqxmd.com/read/27729212/paneth-cell-alterations-in-the-development-and-phenotype-of%C3%A2-crohn-s-disease
#17
Thaddeus S Stappenbeck, Dermot P B McGovern
Pathogenesis of Crohn's disease (CD) involves immune and microbial dysregulation, induced by environmental factors in genetically susceptible individuals. There are believed to be multiple subtypes of CD, which contributes to its observed clinical heterogeneity. This concept has been reinforced by recognition of the complexity of the genetic, microbial, immune, and environmental factors that affect risk for CD. Paneth cells mediate immunity and maintain the small intestinal epithelium; defects in activities of these cells have been observed in high proportions of patients with CD, and are associated with a more aggressive CD phenotype...
February 2017: Gastroenterology
https://www.readbyqxmd.com/read/27703457/nod2-a-critical-regulator-of-ileal-microbiota-and-crohn-s-disease
#18
Tabasum Sidiq, Sayuri Yoshihama, Isaac Downs, Koichi S Kobayashi
The human intestinal tract harbors large bacterial community consisting of commensal, symbiotic, and pathogenic strains, which are constantly interacting with the intestinal immune system. This interaction elicits a non-pathological basal level of immune responses and contributes to shaping both the intestinal immune system and bacterial community. Recent studies on human microbiota are revealing the critical role of intestinal bacterial community in the pathogenesis of both systemic and intestinal diseases, including Crohn's disease (CD)...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27699268/paneth-cell-defects-in-crohn-s-disease-patients-promote-dysbiosis
#19
Ta-Chiang Liu, Bhaskar Gurram, Megan T Baldridge, Richard Head, Vy Lam, Chengwei Luo, Yumei Cao, Pippa Simpson, Michael Hayward, Mary L Holtz, Pavlos Bousounis, Joshua Noe, Diana Lerner, Jose Cabrera, Vincent Biank, Michael Stephens, Curtis Huttenhower, Dermot P B McGovern, Ramnik J Xavier, Thaddeus S Stappenbeck, Nita H Salzman
BACKGROUND: Paneth cell dysfunction has been implicated in a subset of Crohn's disease (CD) patients. We previously stratified clinical outcomes of CD patients by using Paneth cell phenotypes, which we defined by the intracellular distribution of antimicrobial proteins. Animal studies suggest that Paneth cells shape the intestinal microbiome. However, it is unclear whether Paneth cell phenotypes alter the microbiome complexity in CD subjects. Therefore, we analyzed the correlation of Paneth cell phenotypes with mucosal microbiome composition and ileal RNA expression in pediatric CD and noninflammatory bowel disease (non-IBD) patients...
June 2, 2016: JCI Insight
https://www.readbyqxmd.com/read/27685631/mesenchymal-stem-cells-stimulate-intestinal-stem-cells-to-repair-radiation-induced-intestinal-injury
#20
Wei Gong, Mengzheng Guo, Zhibo Han, Yan Wang, Ping Yang, Chang Xu, Qin Wang, Liqing Du, Qian Li, Hui Zhao, Feiyue Fan, Qiang Liu
The loss of stem cells residing in the base of the intestinal crypt has a key role in radiation-induced intestinal injury. In particular, Lgr5(+) intestinal stem cells (ISCs) are indispensable for intestinal regeneration following exposure to radiation. Mesenchymal stem cells (MSCs) have previously been shown to improve intestinal epithelial repair in a mouse model of radiation injury, and, therefore, it was hypothesized that this protective effect is related to Lgr5(+) ISCs. In this study, it was found that, following exposure to radiation, transplantation of MSCs improved the survival of the mice, ameliorated intestinal injury and increased the number of regenerating crypts...
2016: Cell Death & Disease
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