Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn's disease
Objective Although genome wide association studies have partly uncovered the genetic basis of Crohn's disease (CD), it remains a challenge to link genetic polymorphisms to functional intestinal phenotypes. Paneth cells are specialised antimicrobial epithelial cells localised to the small-intest...
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| Veröffentlicht in: | Gut 2014-07, Vol.63 (7), p.1081-1091 |
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| creator | Deuring, J Jasper Fuhler, Gwenny M Konstantinov, Sergey R Peppelenbosch, Maikel P Kuipers, Ernst J de Haar, Colin van der Woude, C Janneke |
| description | Objective Although genome wide association studies have partly uncovered the genetic basis of Crohn's disease (CD), it remains a challenge to link genetic polymorphisms to functional intestinal phenotypes. Paneth cells are specialised antimicrobial epithelial cells localised to the small-intestinal crypt-base. Here, we investigate whether genomic variations in ATG16L1 affect Paneth cell function. Design Genomic variation of ATG16L1 (T300A, rs2241880) was determined in DNA from 78 patients with CD and 12 healthy controls. Paraffin-embedded ileal biopsies from patients with genotype AA (n=17), GA (n=38) and patients with the GG allele (n=23) were stained for GRP78, phospho-EIF2α, lysozyme, cleaved-caspase 3, phosphohistone H3, phospho-IκB, p65, phospho-p38MAPK and PHLDA1. Microbial composition of biopsies was assessed by PCR. Disease phenotype was scored. Results In patients with quiescent disease but with an ATG16L1 risk allele, the endoplasmic reticulum (ER) stress markers GRP78 and pEIF2α were highly expressed in Paneth cells. Other CD risk gene variations did not correlate with Paneth cell ER stress. Functionally, patients with ER-stressed Paneth cells showed no changes in intestinal epithelial cells proliferation or apoptosis, Paneth cell or stem cell numbers, p65, phospho-IκB and phospho-p38 staining. However, a significantly increased presence of adherent-invasive Escherichia coli was observed in biopsies from patients with ER-stressed Paneth cells. Phenotypically, patients with GRP78 positive Paneth cells have relatively less colonic disease over ileal disease (−21%, p=0.04), more fistulas (+21%, p=0.05) and an increased need for intestinal surgery (+38%, p=0.002). Conclusions The ATG16L1 T300A polymorphism defines a specific subtype of patients with CD, characterised by Paneth cell ER stress even during quiescent disease. Paneth cell ER stress correlates with bacterial persistence, and is thus likely to modulate antimicrobial functionality of this cell type in patients with CD. |
| doi_str_mv | 10.1136/gutjnl-2012-303527 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1687664240</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1687664240</sourcerecordid><originalsourceid>FETCH-LOGICAL-b402t-9cca6a61ccc4bbb73b9046f4442caa255234c4c2d75b0cc0297c435c642fc23a3</originalsourceid><addsrcrecordid>eNqNkU1LJDEQhoO46Oj6BzxIwINeslv56KRzlEFHYWBF3MOeQromoz32hybdB__9Zmj14EVPBeGpl7fyEHLM4RfnUv9-GIdN1zABXDAJshBmh8y40iWToix3yQyAG1YYZffJQUobAChLy_fIvpBWK7B2Rv4tQte3NdKL-wXXS05jnZ6ob5rQBBZDGmKNQ1jRW9-F4ZFiaBp6eUfze0iJ1h19GeuQMHQDncf-sTtLdFWn4FP4SX6sfZPC0ds8JH-vLu_n12z5Z3Ezv1iySoEYmEX02muOiKqqKiMrC0qvlVICvRdFIaRChWJligoQQViDShaolVijkF4ekvMp9zn2L2Nu7No6bXvmxv2YHNel0ZlW8DVaSJW_z0CZ0dNP6KYfY5cPcdwYqzRwLjIlJgpjn1IMa_cc69bHV8fBbR25yZHbOnKTo7x08hY9Vm1Yfay8S8kAm4Cq3Xwn8D9xd5p1</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1779460112</pqid></control><display><type>article</type><title>Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn's disease</title><source>MEDLINE</source><source>BMJ Journals - NESLi2</source><source>PubMed Central</source><creator>Deuring, J Jasper ; Fuhler, Gwenny M ; Konstantinov, Sergey R ; Peppelenbosch, Maikel P ; Kuipers, Ernst J ; de Haar, Colin ; van der Woude, C Janneke</creator><creatorcontrib>Deuring, J Jasper ; Fuhler, Gwenny M ; Konstantinov, Sergey R ; Peppelenbosch, Maikel P ; Kuipers, Ernst J ; de Haar, Colin ; van der Woude, C Janneke</creatorcontrib><description>Objective Although genome wide association studies have partly uncovered the genetic basis of Crohn's disease (CD), it remains a challenge to link genetic polymorphisms to functional intestinal phenotypes. Paneth cells are specialised antimicrobial epithelial cells localised to the small-intestinal crypt-base. Here, we investigate whether genomic variations in ATG16L1 affect Paneth cell function. Design Genomic variation of ATG16L1 (T300A, rs2241880) was determined in DNA from 78 patients with CD and 12 healthy controls. Paraffin-embedded ileal biopsies from patients with genotype AA (n=17), GA (n=38) and patients with the GG allele (n=23) were stained for GRP78, phospho-EIF2α, lysozyme, cleaved-caspase 3, phosphohistone H3, phospho-IκB, p65, phospho-p38MAPK and PHLDA1. Microbial composition of biopsies was assessed by PCR. Disease phenotype was scored. Results In patients with quiescent disease but with an ATG16L1 risk allele, the endoplasmic reticulum (ER) stress markers GRP78 and pEIF2α were highly expressed in Paneth cells. Other CD risk gene variations did not correlate with Paneth cell ER stress. Functionally, patients with ER-stressed Paneth cells showed no changes in intestinal epithelial cells proliferation or apoptosis, Paneth cell or stem cell numbers, p65, phospho-IκB and phospho-p38 staining. However, a significantly increased presence of adherent-invasive Escherichia coli was observed in biopsies from patients with ER-stressed Paneth cells. Phenotypically, patients with GRP78 positive Paneth cells have relatively less colonic disease over ileal disease (−21%, p=0.04), more fistulas (+21%, p=0.05) and an increased need for intestinal surgery (+38%, p=0.002). Conclusions The ATG16L1 T300A polymorphism defines a specific subtype of patients with CD, characterised by Paneth cell ER stress even during quiescent disease. Paneth cell ER stress correlates with bacterial persistence, and is thus likely to modulate antimicrobial functionality of this cell type in patients with CD.</description><identifier>ISSN: 0017-5749</identifier><identifier>EISSN: 1468-3288</identifier><identifier>DOI: 10.1136/gutjnl-2012-303527</identifier><identifier>PMID: 23964099</identifier><identifier>CODEN: GUTTAK</identifier><language>eng</language><publisher>England: BMJ Publishing Group LTD</publisher><subject>Autophagy ; Autophagy-Related Proteins ; Biopsy ; Carrier Proteins - genetics ; Case-Control Studies ; Cells, Cultured ; Crohn Disease - genetics ; Crohn Disease - metabolism ; Crohn Disease - microbiology ; Crohn Disease - pathology ; Crohn's disease ; DNA, Bacterial - analysis ; Endoplasmic reticulum ; Endoplasmic Reticulum Stress - genetics ; Endoplasmic Reticulum Stress - physiology ; Escherichia coli ; Escherichia coli - genetics ; Escherichia coli - isolation & purification ; Genetic Markers ; Genetic Predisposition to Disease ; Genomes ; Genotype & phenotype ; Genotyping Techniques ; Humans ; Ileum - metabolism ; Ileum - microbiology ; Ileum - pathology ; Inflammation ; Inflammatory bowel disease ; Microbiota ; Morphology ; Multivariate Analysis ; Paneth Cells - metabolism ; Paneth Cells - microbiology ; Paneth Cells - pathology ; Patients ; Phenotype ; Polymorphism, Single Nucleotide ; Protein folding ; Risk Factors ; Rodents ; Small intestine ; Stem cells ; Studies</subject><ispartof>Gut, 2014-07, Vol.63 (7), p.1081-1091</ispartof><rights>Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions</rights><rights>Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.</rights><rights>Copyright: 2014 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b402t-9cca6a61ccc4bbb73b9046f4442caa255234c4c2d75b0cc0297c435c642fc23a3</citedby><cites>FETCH-LOGICAL-b402t-9cca6a61ccc4bbb73b9046f4442caa255234c4c2d75b0cc0297c435c642fc23a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttp://gut.bmj.com/content/63/7/1081.full.pdf$$EPDF$$P50$$Gbmj$$H</linktopdf><linktohtml>$$Uhttp://gut.bmj.com/content/63/7/1081.full$$EHTML$$P50$$Gbmj$$H</linktohtml><link.rule.ids>114,115,314,776,780,3183,23550,27901,27902,77343,77374</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23964099$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Deuring, J Jasper</creatorcontrib><creatorcontrib>Fuhler, Gwenny M</creatorcontrib><creatorcontrib>Konstantinov, Sergey R</creatorcontrib><creatorcontrib>Peppelenbosch, Maikel P</creatorcontrib><creatorcontrib>Kuipers, Ernst J</creatorcontrib><creatorcontrib>de Haar, Colin</creatorcontrib><creatorcontrib>van der Woude, C Janneke</creatorcontrib><title>Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn's disease</title><title>Gut</title><addtitle>Gut</addtitle><description>Objective Although genome wide association studies have partly uncovered the genetic basis of Crohn's disease (CD), it remains a challenge to link genetic polymorphisms to functional intestinal phenotypes. Paneth cells are specialised antimicrobial epithelial cells localised to the small-intestinal crypt-base. Here, we investigate whether genomic variations in ATG16L1 affect Paneth cell function. Design Genomic variation of ATG16L1 (T300A, rs2241880) was determined in DNA from 78 patients with CD and 12 healthy controls. Paraffin-embedded ileal biopsies from patients with genotype AA (n=17), GA (n=38) and patients with the GG allele (n=23) were stained for GRP78, phospho-EIF2α, lysozyme, cleaved-caspase 3, phosphohistone H3, phospho-IκB, p65, phospho-p38MAPK and PHLDA1. Microbial composition of biopsies was assessed by PCR. Disease phenotype was scored. Results In patients with quiescent disease but with an ATG16L1 risk allele, the endoplasmic reticulum (ER) stress markers GRP78 and pEIF2α were highly expressed in Paneth cells. Other CD risk gene variations did not correlate with Paneth cell ER stress. Functionally, patients with ER-stressed Paneth cells showed no changes in intestinal epithelial cells proliferation or apoptosis, Paneth cell or stem cell numbers, p65, phospho-IκB and phospho-p38 staining. However, a significantly increased presence of adherent-invasive Escherichia coli was observed in biopsies from patients with ER-stressed Paneth cells. Phenotypically, patients with GRP78 positive Paneth cells have relatively less colonic disease over ileal disease (−21%, p=0.04), more fistulas (+21%, p=0.05) and an increased need for intestinal surgery (+38%, p=0.002). Conclusions The ATG16L1 T300A polymorphism defines a specific subtype of patients with CD, characterised by Paneth cell ER stress even during quiescent disease. Paneth cell ER stress correlates with bacterial persistence, and is thus likely to modulate antimicrobial functionality of this cell type in patients with CD.</description><subject>Autophagy</subject><subject>Autophagy-Related Proteins</subject><subject>Biopsy</subject><subject>Carrier Proteins - genetics</subject><subject>Case-Control Studies</subject><subject>Cells, Cultured</subject><subject>Crohn Disease - genetics</subject><subject>Crohn Disease - metabolism</subject><subject>Crohn Disease - microbiology</subject><subject>Crohn Disease - pathology</subject><subject>Crohn's disease</subject><subject>DNA, Bacterial - analysis</subject><subject>Endoplasmic reticulum</subject><subject>Endoplasmic Reticulum Stress - genetics</subject><subject>Endoplasmic Reticulum Stress - physiology</subject><subject>Escherichia coli</subject><subject>Escherichia coli - genetics</subject><subject>Escherichia coli - isolation & purification</subject><subject>Genetic Markers</subject><subject>Genetic Predisposition to Disease</subject><subject>Genomes</subject><subject>Genotype & phenotype</subject><subject>Genotyping Techniques</subject><subject>Humans</subject><subject>Ileum - metabolism</subject><subject>Ileum - microbiology</subject><subject>Ileum - pathology</subject><subject>Inflammation</subject><subject>Inflammatory bowel disease</subject><subject>Microbiota</subject><subject>Morphology</subject><subject>Multivariate Analysis</subject><subject>Paneth Cells - metabolism</subject><subject>Paneth Cells - microbiology</subject><subject>Paneth Cells - pathology</subject><subject>Patients</subject><subject>Phenotype</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Protein folding</subject><subject>Risk Factors</subject><subject>Rodents</subject><subject>Small intestine</subject><subject>Stem cells</subject><subject>Studies</subject><issn>0017-5749</issn><issn>1468-3288</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkU1LJDEQhoO46Oj6BzxIwINeslv56KRzlEFHYWBF3MOeQromoz32hybdB__9Zmj14EVPBeGpl7fyEHLM4RfnUv9-GIdN1zABXDAJshBmh8y40iWToix3yQyAG1YYZffJQUobAChLy_fIvpBWK7B2Rv4tQte3NdKL-wXXS05jnZ6ob5rQBBZDGmKNQ1jRW9-F4ZFiaBp6eUfze0iJ1h19GeuQMHQDncf-sTtLdFWn4FP4SX6sfZPC0ds8JH-vLu_n12z5Z3Ezv1iySoEYmEX02muOiKqqKiMrC0qvlVICvRdFIaRChWJligoQQViDShaolVijkF4ekvMp9zn2L2Nu7No6bXvmxv2YHNel0ZlW8DVaSJW_z0CZ0dNP6KYfY5cPcdwYqzRwLjIlJgpjn1IMa_cc69bHV8fBbR25yZHbOnKTo7x08hY9Vm1Yfay8S8kAm4Cq3Xwn8D9xd5p1</recordid><startdate>20140701</startdate><enddate>20140701</enddate><creator>Deuring, J Jasper</creator><creator>Fuhler, Gwenny M</creator><creator>Konstantinov, Sergey R</creator><creator>Peppelenbosch, Maikel P</creator><creator>Kuipers, Ernst J</creator><creator>de Haar, Colin</creator><creator>van der Woude, C Janneke</creator><general>BMJ Publishing Group LTD</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>BTHHO</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20140701</creationdate><title>Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn's disease</title><author>Deuring, J Jasper ; Fuhler, Gwenny M ; Konstantinov, Sergey R ; Peppelenbosch, Maikel P ; Kuipers, Ernst J ; de Haar, Colin ; van der Woude, C Janneke</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b402t-9cca6a61ccc4bbb73b9046f4442caa255234c4c2d75b0cc0297c435c642fc23a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Autophagy</topic><topic>Autophagy-Related Proteins</topic><topic>Biopsy</topic><topic>Carrier Proteins - genetics</topic><topic>Case-Control Studies</topic><topic>Cells, Cultured</topic><topic>Crohn Disease - genetics</topic><topic>Crohn Disease - metabolism</topic><topic>Crohn Disease - microbiology</topic><topic>Crohn Disease - pathology</topic><topic>Crohn's disease</topic><topic>DNA, Bacterial - analysis</topic><topic>Endoplasmic reticulum</topic><topic>Endoplasmic Reticulum Stress - genetics</topic><topic>Endoplasmic Reticulum Stress - physiology</topic><topic>Escherichia coli</topic><topic>Escherichia coli - genetics</topic><topic>Escherichia coli - isolation & purification</topic><topic>Genetic Markers</topic><topic>Genetic Predisposition to Disease</topic><topic>Genomes</topic><topic>Genotype & phenotype</topic><topic>Genotyping Techniques</topic><topic>Humans</topic><topic>Ileum - metabolism</topic><topic>Ileum - microbiology</topic><topic>Ileum - pathology</topic><topic>Inflammation</topic><topic>Inflammatory bowel disease</topic><topic>Microbiota</topic><topic>Morphology</topic><topic>Multivariate Analysis</topic><topic>Paneth Cells - metabolism</topic><topic>Paneth Cells - microbiology</topic><topic>Paneth Cells - pathology</topic><topic>Patients</topic><topic>Phenotype</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Protein folding</topic><topic>Risk Factors</topic><topic>Rodents</topic><topic>Small intestine</topic><topic>Stem cells</topic><topic>Studies</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Deuring, J Jasper</creatorcontrib><creatorcontrib>Fuhler, Gwenny M</creatorcontrib><creatorcontrib>Konstantinov, Sergey R</creatorcontrib><creatorcontrib>Peppelenbosch, Maikel P</creatorcontrib><creatorcontrib>Kuipers, Ernst J</creatorcontrib><creatorcontrib>de Haar, Colin</creatorcontrib><creatorcontrib>van der Woude, C Janneke</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>BMJ Journals</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Gut</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Deuring, J Jasper</au><au>Fuhler, Gwenny M</au><au>Konstantinov, Sergey R</au><au>Peppelenbosch, Maikel P</au><au>Kuipers, Ernst J</au><au>de Haar, Colin</au><au>van der Woude, C Janneke</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn's disease</atitle><jtitle>Gut</jtitle><addtitle>Gut</addtitle><date>2014-07-01</date><risdate>2014</risdate><volume>63</volume><issue>7</issue><spage>1081</spage><epage>1091</epage><pages>1081-1091</pages><issn>0017-5749</issn><eissn>1468-3288</eissn><coden>GUTTAK</coden><abstract>Objective Although genome wide association studies have partly uncovered the genetic basis of Crohn's disease (CD), it remains a challenge to link genetic polymorphisms to functional intestinal phenotypes. Paneth cells are specialised antimicrobial epithelial cells localised to the small-intestinal crypt-base. Here, we investigate whether genomic variations in ATG16L1 affect Paneth cell function. Design Genomic variation of ATG16L1 (T300A, rs2241880) was determined in DNA from 78 patients with CD and 12 healthy controls. Paraffin-embedded ileal biopsies from patients with genotype AA (n=17), GA (n=38) and patients with the GG allele (n=23) were stained for GRP78, phospho-EIF2α, lysozyme, cleaved-caspase 3, phosphohistone H3, phospho-IκB, p65, phospho-p38MAPK and PHLDA1. Microbial composition of biopsies was assessed by PCR. Disease phenotype was scored. Results In patients with quiescent disease but with an ATG16L1 risk allele, the endoplasmic reticulum (ER) stress markers GRP78 and pEIF2α were highly expressed in Paneth cells. Other CD risk gene variations did not correlate with Paneth cell ER stress. Functionally, patients with ER-stressed Paneth cells showed no changes in intestinal epithelial cells proliferation or apoptosis, Paneth cell or stem cell numbers, p65, phospho-IκB and phospho-p38 staining. However, a significantly increased presence of adherent-invasive Escherichia coli was observed in biopsies from patients with ER-stressed Paneth cells. Phenotypically, patients with GRP78 positive Paneth cells have relatively less colonic disease over ileal disease (−21%, p=0.04), more fistulas (+21%, p=0.05) and an increased need for intestinal surgery (+38%, p=0.002). Conclusions The ATG16L1 T300A polymorphism defines a specific subtype of patients with CD, characterised by Paneth cell ER stress even during quiescent disease. Paneth cell ER stress correlates with bacterial persistence, and is thus likely to modulate antimicrobial functionality of this cell type in patients with CD.</abstract><cop>England</cop><pub>BMJ Publishing Group LTD</pub><pmid>23964099</pmid><doi>10.1136/gutjnl-2012-303527</doi><tpages>11</tpages></addata></record> |
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| subjects | Autophagy Autophagy-Related Proteins Biopsy Carrier Proteins - genetics Case-Control Studies Cells, Cultured Crohn Disease - genetics Crohn Disease - metabolism Crohn Disease - microbiology Crohn Disease - pathology Crohn's disease DNA, Bacterial - analysis Endoplasmic reticulum Endoplasmic Reticulum Stress - genetics Endoplasmic Reticulum Stress - physiology Escherichia coli Escherichia coli - genetics Escherichia coli - isolation & purification Genetic Markers Genetic Predisposition to Disease Genomes Genotype & phenotype Genotyping Techniques Humans Ileum - metabolism Ileum - microbiology Ileum - pathology Inflammation Inflammatory bowel disease Microbiota Morphology Multivariate Analysis Paneth Cells - metabolism Paneth Cells - microbiology Paneth Cells - pathology Patients Phenotype Polymorphism, Single Nucleotide Protein folding Risk Factors Rodents Small intestine Stem cells Studies |
| title | Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn's disease |
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