Alicia S Wellman1, Mallikarjuna R Metukuri1, Nevzat Kazgan1, Xiaojiang Xu2, Qing Xu1, Natalie S X Ren1, Agnieszka Czopik3, Michael T Shanahan4, Ashley Kang5, Willa Chen1, M Andrea Azcarate-Peril6, Ajay S Gulati4, David C Fargo2, Leonard Guarente3, Xiaoling Li7. 1. Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina. 2. Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina. 3. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts. 4. Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 5. Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina; NIEHS Scholars Connect Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina. 6. Department of Medicine, Division of Gastroenterology and Hepatology and Microbiome Core Facility, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 7. Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina. Electronic address: lix3@niehs.nih.gov.
Abstract
BACKGROUND & AIMS: Intestinal epithelial homeostasis is maintained by complex interactions among epithelial cells, commensal gut microorganisms, and immune cells. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD), but the mechanisms of this process are not clear. We investigated how Sirtuin 1 (SIRT1), a conserved mammalian NAD+-dependent protein deacetylase, senses environmental stress to alter intestinal integrity. METHODS: We performed studies of mice with disruption of Sirt1 specifically in the intestinal epithelium (SIRT1 iKO, villin-Cre+, Sirt1flox/flox mice) and control mice (villin-Cre-, Sirt1flox/flox) on a C57BL/6 background. Acute colitis was induced in some mice by addition of 2.5% dextran sodium sulfate to drinking water for 5-9 consecutive days. Some mice were given antibiotics via their drinking water for 4 weeks to deplete their microbiota. Some mice were fed with a cholestyramine-containing diet for 7 days to sequester their bile acids. Feces were collected and proportions of microbiota were analyzed by 16S rRNA amplicon sequencing and quantitative PCR. Intestines were collected from mice and gene expression profiles were compared by microarray and quantitative PCR analyses. We compared levels of specific mRNAs between colon tissues from age-matched patients with ulcerative colitis (n=10) vs without IBD (n=8, controls). RESULTS: Mice with intestinal deletion of SIRT1 (SIRT1 iKO) had abnormal activation of Paneth cells starting at the age of 5-8 months, with increased activation of NF-κB, stress pathways, and spontaneous inflammation at 22-24 months of age, compared with control mice. SIRT1 iKO mice also had altered fecal microbiota starting at 4-6 months of age compared with control mice, in part because of altered bile acid metabolism. Moreover, SIRT1 iKO mice with defective gut microbiota developed more severe colitis than control mice. Intestinal tissues from patients with ulcerative colitis expressed significantly lower levels of SIRT1 mRNA than controls. Intestinal tissues from SIRT1 iKO mice given antibiotics, however, did not have signs of inflammation at 22-24 months of age, and did not develop more severe colitis than control mice at 4-6 months. CONCLUSIONS: In analyses of intestinal tissues, colitis induction, and gut microbiota in mice with intestinal epithelial disruption of SIRT1, we found this protein to prevent intestinal inflammation by regulating the gut microbiota. SIRT1 might therefore be an important mediator of host-microbiome interactions. Agents designed to activate SIRT1 might be developed as treatments for IBDs.
BACKGROUND & AIMS: Intestinal epithelial homeostasis is maintained by complex interactions among epithelial cells, commensal gut microorganisms, and immune cells. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD), but the mechanisms of this process are not clear. We investigated how Sirtuin 1 (SIRT1), a conserved mammalianNAD+-dependent protein deacetylase, senses environmental stress to alter intestinal integrity. METHODS: We performed studies of mice with disruption of Sirt1 specifically in the intestinal epithelium (SIRT1 iKO, villin-Cre+, Sirt1flox/floxmice) and control mice (villin-Cre-, Sirt1flox/flox) on a C57BL/6 background. Acute colitis was induced in some mice by addition of 2.5% dextran sodium sulfate to drinking water for 5-9 consecutive days. Some mice were given antibiotics via their drinking water for 4 weeks to deplete their microbiota. Some mice were fed with a cholestyramine-containing diet for 7 days to sequester their bile acids. Feces were collected and proportions of microbiota were analyzed by 16S rRNA amplicon sequencing and quantitative PCR. Intestines were collected from mice and gene expression profiles were compared by microarray and quantitative PCR analyses. We compared levels of specific mRNAs between colon tissues from age-matched patients with ulcerative colitis (n=10) vs without IBD (n=8, controls). RESULTS:Mice with intestinal deletion of SIRT1 (SIRT1 iKO) had abnormal activation of Paneth cells starting at the age of 5-8 months, with increased activation of NF-κB, stress pathways, and spontaneous inflammation at 22-24 months of age, compared with control mice. SIRT1 iKO mice also had altered fecal microbiota starting at 4-6 months of age compared with control mice, in part because of altered bile acid metabolism. Moreover, SIRT1 iKO mice with defective gut microbiota developed more severe colitis than control mice. Intestinal tissues from patients with ulcerative colitis expressed significantly lower levels of SIRT1 mRNA than controls. Intestinal tissues from SIRT1 iKO mice given antibiotics, however, did not have signs of inflammation at 22-24 months of age, and did not develop more severe colitis than control mice at 4-6 months. CONCLUSIONS: In analyses of intestinal tissues, colitis induction, and gut microbiota in mice with intestinal epithelial disruption of SIRT1, we found this protein to prevent intestinal inflammation by regulating the gut microbiota. SIRT1 might therefore be an important mediator of host-microbiome interactions. Agents designed to activate SIRT1 might be developed as treatments for IBDs.
Authors: R Caruso; I Marafini; E Franzè; C Stolfi; F Zorzi; I Monteleone; F Caprioli; A Colantoni; M Sarra; S Sedda; L Biancone; P Sileri; G S Sica; T T MacDonald; F Pallone; G Monteleone Journal: Mucosal Immunol Date: 2014-05-21 Impact factor: 7.313
Authors: C N Jacobsen; V Rosenfeldt Nielsen; A E Hayford; P L Møller; K F Michaelsen; A Paerregaard; B Sandström; M Tvede; M Jakobsen Journal: Appl Environ Microbiol Date: 1999-11 Impact factor: 4.792
Authors: Anna Biason-Lauber; Marianne Böni-Schnetzler; Basil P Hubbard; Karim Bouzakri; Andrea Brunner; Claudia Cavelti-Weder; Cornelia Keller; Monika Meyer-Böni; Daniel T Meier; Caroline Brorsson; Katharina Timper; Gil Leibowitz; Andrea Patrignani; Remy Bruggmann; Gino Boily; Henryk Zulewski; Andreas Geier; Jennifer M Cermak; Peter Elliott; James L Ellis; Christoph Westphal; Urs Knobel; Jyrki J Eloranta; Julie Kerr-Conte; François Pattou; Daniel Konrad; Christian M Matter; Adriano Fontana; Gerhard Rogler; Ralph Schlapbach; Camille Regairaz; José M Carballido; Benjamin Glaser; Michael W McBurney; Flemming Pociot; David A Sinclair; Marc Y Donath Journal: Cell Metab Date: 2013-03-05 Impact factor: 27.287
Authors: Núria Planell; Juan J Lozano; Rut Mora-Buch; M Carme Masamunt; Mireya Jimeno; Ingrid Ordás; Miriam Esteller; Elena Ricart; Josep M Piqué; Julián Panés; Azucena Salas Journal: Gut Date: 2012-11-07 Impact factor: 23.059
Authors: Timon E Adolph; Michal F Tomczak; Lukas Niederreiter; Hyun-Jeong Ko; Janne Böck; Eduardo Martinez-Naves; Jonathan N Glickman; Markus Tschurtschenthaler; John Hartwig; Shuhei Hosomi; Magdalena B Flak; Jennifer L Cusick; Kenji Kohno; Takao Iwawaki; Susanne Billmann-Born; Tim Raine; Richa Bharti; Ralph Lucius; Mi-Na Kweon; Stefan J Marciniak; Augustine Choi; Susan J Hagen; Stefan Schreiber; Philip Rosenstiel; Arthur Kaser; Richard S Blumberg Journal: Nature Date: 2013-10-02 Impact factor: 49.962
Authors: Zhou Zhou; Ting Jie Ye; Elizabeth DeCaro; Brian Buehler; Zachary Stahl; Gregory Bonavita; Michael Daniels; Min You Journal: Am J Pathol Date: 2019-10-11 Impact factor: 4.307