دورية أكاديمية
Spontaneous episodic inflammation in the intestines of mice lacking HNF4A is driven by microbiota and associated with early life microbiota alterations.
| العنوان: | Spontaneous episodic inflammation in the intestines of mice lacking HNF4A is driven by microbiota and associated with early life microbiota alterations. |
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| المؤلفون: | Kelly C; Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine , Durham, North Carolina, USA., Jawahar J; Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine , Durham, North Carolina, USA., Davey L; Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine , Durham, North Carolina, USA.; Department of Immunology, Duke University School of Medicine , Durham, North Carolina, USA., Everitt JI; Department of Pathology, Research Animal Pathology Core, Duke University School of Medicine , Durham, North Carolina, USA., Galanko JA; Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina, USA., Anderson C; Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina, USA., Avendano JE; Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine , Durham, North Carolina, USA., McCann JR; Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine , Durham, North Carolina, USA., Sartor RB; Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina, USA., Valdivia RH; Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine , Durham, North Carolina, USA.; Department of Immunology, Duke University School of Medicine , Durham, North Carolina, USA., Rawls JF; Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine , Durham, North Carolina, USA. |
| المصدر: | MBio [mBio] 2023 Aug 31; Vol. 14 (4), pp. e0150423. Date of Electronic Publication: 2023 Aug 01. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 101519231 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2150-7511 (Electronic) NLM ISO Abbreviation: mBio Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Society for Microbiology |
| مواضيع طبية MeSH: | Colitis*/chemically induced , Hepatocyte Nuclear Factor 4*/genetics , Inflammatory Bowel Diseases*/genetics , Microbiota*, Animals ; Humans ; Mice ; Anti-Bacterial Agents ; Inflammation/pathology ; Intestines ; RNA, Ribosomal, 16S/genetics |
| مستخلص: | The inflammatory bowel diseases (IBD) occur in genetically susceptible individuals who mount inappropriate immune responses to their microbiota leading to chronic intestinal inflammation. Whereas IBD clinical presentation is well described, how interactions between microbiota and host genotype impact early subclinical stages of the disease remains unclear. The transcription factor hepatocyte nuclear factor 4 alpha (HNF4A) has been associated with human IBD, and deletion of Hnf4a in intestinal epithelial cells (IECs) in mice ( Hnf4a ΔIEC ) leads to spontaneous colonic inflammation by 6-12 mo of age. Here, we tested if pathology in Hnf4a ΔIEC mice begins earlier in life and if microbiota contribute to that process. Longitudinal analysis revealed that Hnf4a ΔIEC mice reared in specific pathogen-free (SPF) conditions develop episodic elevated fecal lipocalin 2 (Lcn2) and loose stools beginning by 4-5 wk of age. Lifetime cumulative Lcn2 levels correlated with histopathological features of colitis at 12 mo. Antibiotic and gnotobiotic tests showed that these phenotypes in Hnf4a ΔIEC mice were dependent on microbiota. Fecal 16S rRNA gene sequencing in SPF Hnf4a ΔIEC and control mice disclosed that genotype significantly contributed to differences in microbiota composition by 12 mo, and longitudinal analysis of the Hnf4a ΔIEC mice with the highest lifetime cumulative Lcn2 revealed that microbial community differences emerged early in life when elevated fecal Lcn2 was first detected. These microbiota differences included enrichment of a novel phylogroup of Akkermansia muciniphila in Hnf4a ΔIEC mice. We conclude that HNF4A functions in IEC to shape composition of the gut microbiota and protect against episodic inflammation induced by microbiota throughout the lifespan. IMPORTANCE The inflammatory bowel diseases (IBD), characterized by chronic inflammation of the intestine, affect millions of people around the world. Although significant advances have been made in the clinical management of IBD, the early subclinical stages of IBD are not well defined and are difficult to study in humans. This work explores the subclinical stages of disease in mice lacking the IBD-associated transcription factor HNF4A in the intestinal epithelium. Whereas these mice do not develop overt disease until late in adulthood, we find that they display episodic intestinal inflammation, loose stools, and microbiota changes beginning in very early life stages. Using germ-free and antibiotic-treatment experiments, we reveal that intestinal inflammation in these mice was dependent on the presence of microbiota. These results suggest that interactions between host genotype and microbiota can drive early subclinical pathologies that precede the overt onset of IBD and describe a mouse model to explore those important processes. Competing Interests: The authors declare no conflict of interest. |
| References: | J Clin Invest. 2022 Mar 1;132(5):. (PMID: 35077396) Am J Pathol. 1997 Jan;150(1):91-7. (PMID: 9006326) PLoS One. 2009 Oct 29;4(10):e7609. (PMID: 19898610) J Exp Med. 1998 Nov 16;188(10):1929-39. (PMID: 9815270) Microorganisms. 2021 May 14;9(5):. (PMID: 34068994) Sci Rep. 2022 Dec 16;12(1):21747. (PMID: 36526682) Am J Gastroenterol. 2005 Dec;100(12):2730-6. (PMID: 16393227) PLoS One. 2012;7(9):e44328. (PMID: 22957064) Nature. 2012 Nov 1;491(7422):119-24. (PMID: 23128233) Gastroenterology. 2003 Jun;124(7):1728-37. (PMID: 12806605) Infect Immun. 1998 Nov;66(11):5224-31. (PMID: 9784526) Nat Microbiol. 2016 Jan 27;1:15021. (PMID: 27571978) Gut. 2016 Feb;65(2):225-37. (PMID: 25887379) Curr Opin Pharmacol. 2020 Dec;55:110-115. (PMID: 33221629) Gut. 2016 Mar;65(3):426-36. (PMID: 26100928) Aliment Pharmacol Ther. 2016 Jun;43(12):1300-10. (PMID: 27117843) Diabetes. 1997 Oct;46(10):1652-7. (PMID: 9313765) Cell. 2007 Oct 5;131(1):33-45. (PMID: 17923086) J Cell Sci. 2017 Jan 15;130(2):307-314. (PMID: 28062847) Nature. 1996 Dec 5;384(6608):458-60. (PMID: 8945471) Gastroenterology. 2022 Nov;163(5):1364-1376.e10. (PMID: 35850197) Nat Rev Gastroenterol Hepatol. 2021 Jan;18(1):7-23. (PMID: 33024279) Mol Cell Biol. 2014 Sep;34(17):3291-304. (PMID: 24980432) Genome Biol. 2020 Dec 16;21(1):292. (PMID: 33323122) J Exp Med. 2022 Aug 1;219(8):. (PMID: 35792863) Science. 2002 Mar 1;295(5560):1726-9. (PMID: 11872843) Gastroenterology. 2000 Dec;119(6):1740-4. (PMID: 11113095) Gastroenterology. 2014 Dec;147(6):1363-77.e17. (PMID: 25172014) Cell Mol Gastroenterol Hepatol. 2023;15(3):593-612. (PMID: 36464209) J Exp Med. 1998 Feb 2;187(3):389-402. (PMID: 9449719) Cell Host Microbe. 2010 Sep 16;8(3):292-300. (PMID: 20833380) Gut Microbes. 2021 Jan-Dec;13(1):1-18. (PMID: 33645438) J Infect Dis. 2021 Apr 23;223(8):1478-1487. (PMID: 32830227) Cell Rep. 2017 Jun 6;19(10):2174. (PMID: 28591587) Front Immunol. 2021 Oct 21;12:717723. (PMID: 34745096) J Clin Invest. 2007 Dec;117(12):3909-21. (PMID: 18008007) Nat Genet. 2019 May;51(5):777-785. (PMID: 30988513) BMC Microbiol. 2021 Oct 29;21(1):298. (PMID: 34715771) PLoS One. 2022 Apr 6;17(4):e0266066. (PMID: 35385524) Gastroenterology. 2020 Mar;158(4):985-999.e9. (PMID: 31759926) J Clin Invest. 1996 Aug 15;98(4):945-53. (PMID: 8770866) Genes Immun. 2012 Oct;13(7):556-65. (PMID: 22914433) Infect Immun. 2014 Jun;82(6):2239-46. (PMID: 24643531) Nat Commun. 2021 May 17;12(1):2886. (PMID: 34001900) Am J Physiol Gastrointest Liver Physiol. 2009 Jul;297(1):G124-34. (PMID: 19389805) Inflamm Bowel Dis. 2019 May 16;25(Suppl 2):S5-S12. (PMID: 31095706) Gastroenterology. 1990 Mar;98(3):694-702. (PMID: 1688816) Genome Res. 2017 Jul;27(7):1195-1206. (PMID: 28385711) Cells. 2019 Sep 21;8(10):. (PMID: 31546615) Clin Gastroenterol Hepatol. 2017 Sep;15(9):1413-1418.e1. (PMID: 28286191) Am J Gastroenterol. 2007 Jan;102(1):132-6. (PMID: 17100982) Cell. 1993 Oct 22;75(2):263-74. (PMID: 8402911) J Biol Chem. 2015 Jan 16;290(3):1850-60. (PMID: 25488664) Gastroenterology. 2006 Jul;131(1):117-29. (PMID: 16831596) Science. 2019 Jun 21;364(6446):1179-1184. (PMID: 31221858) mBio. 2021 May 18;12(3):. (PMID: 34006653) Genome Med. 2021 Nov 11;13(1):181. (PMID: 34758847) J Crohns Colitis. 2020 Jul 15;:. (PMID: 32667962) Gastroenterology. 2017 Feb;152(2):327-339.e4. (PMID: 27769810) Cell. 2016 Nov 17;167(5):1339-1353.e21. (PMID: 27863247) Inflamm Bowel Dis. 2017 Oct;23(10):1718-1729. (PMID: 28885228) Int J Mol Sci. 2018 Sep 18;19(9):. (PMID: 30231491) J Allergy Clin Immunol. 2020 Jan;145(1):16-27. (PMID: 31910984) Nat Rev Gastroenterol Hepatol. 2014 Feb;11(2):88-98. (PMID: 24345891) Mucosal Immunol. 2020 Jan;13(1):96-109. (PMID: 31628426) Front Cell Infect Microbiol. 2022 Oct 07;12:1010853. (PMID: 36275026) ISME J. 2014 Jun;8(6):1323-35. (PMID: 24553467) Immunity. 1999 Mar;10(3):387-98. (PMID: 10204494) J Gastroenterol Hepatol. 2017 Jan;32(1):128-135. (PMID: 27640344) Gastroenterology. 2017 Sep;153(3):772-786. (PMID: 28552621) Inflamm Bowel Dis. 2011 Dec;17(12):2566-84. (PMID: 21557393) N Engl J Med. 2020 Dec 31;383(27):2652-2664. (PMID: 33382932) Inflamm Bowel Dis. 2008 Jul;14(7):908-20. (PMID: 18338782) Gut Microbes. 2015 Jul 4;6(4):279-83. (PMID: 26067589) Nat Genet. 2009 Dec;41(12):1330-4. (PMID: 19915572) Am J Physiol. 1999 Jun;276(6):G1461-72. (PMID: 10362650) Front Med (Lausanne). 2021 Dec 20;8:765474. (PMID: 34988090) Cell Host Microbe. 2014 Mar 12;15(3):382-392. (PMID: 24629344) Mol Cell Biol. 2009 Dec;29(23):6294-308. (PMID: 19805521) mSystems. 2017 Sep 5;2(5):. (PMID: 28904997) J Exp Med. 1995 Nov 1;182(5):1281-90. (PMID: 7595199) |
| معلومات مُعتمدة: | F31-DK121392 HHS | National Institutes of Health (NIH); P01-DK094779 HHS | National Institutes of Health (NIH); P30-DK034987 HHS | National Institutes of Health (NIH); P40-OD010955 HHS | National Institutes of Health (NIH) |
| فهرسة مساهمة: | Keywords: HNF4A; NR2A1; gut inflammation; gut microbiome; inflammatory bowel disease; longitudinal analysis; transcription factors |
| المشرفين على المادة: | 0 (Anti-Bacterial Agents) 0 (Hepatocyte Nuclear Factor 4) 0 (RNA, Ribosomal, 16S) 0 (Hnf4a protein, mouse) |
| تواريخ الأحداث: | Date Created: 20230801 Date Completed: 20230927 Latest Revision: 20230927 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC10470520 |
| DOI: | 10.1128/mbio.01504-23 |
| PMID: | 37526424 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2150-7511 |
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| DOI: | 10.1128/mbio.01504-23 |