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Intestinal Epithelial Sirtuin 1 Regulates Intestinal Inflammation During Aging in Mice by Altering the Intestinal Microbiota.

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-?B, 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.

SUBMITTER: Wellman AS

PROVIDER: S-EPMC5581719 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Intestinal Epithelial Sirtuin 1 Regulates Intestinal Inflammation During Aging in Mice by Altering the Intestinal Microbiota.

Wellman Alicia S AS Metukuri Mallikarjuna R MR Kazgan Nevzat N Xu Xiaojiang X Xu Qing Q Ren Natalie S X NSX Czopik Agnieszka A Shanahan Michael T MT Kang Ashley A Chen Willa W Azcarate-Peril M Andrea MA Gulati Ajay S AS Fargo David C DC Guarente Leonard L Li Xiaoling X

Gastroenterology 20170526 3

<h4>Background & aims</h4>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<sup>+</sup>-dependent protein deacetylase, senses environmental stress to alter intestinal integrity.<h4>Methods< ...[more]

PMID: 28552621

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Project description:Background & aimsMice lacking the receptor Toll-like receptor 5 (TLR5-null mice), which recognizes flagellin, have an altered intestinal microbiota composition compared with wild-type mice; they develop low-grade inflammation and metabolic syndrome and are prone to colitis. The relative roles of intestinal epithelial cell (IEC) vs dendritic cell (DC) TLR5 in mediating these phenotypes are not clear; modification of intestinal microbiota composition has been reported to reflect animal husbandry practices rather than loss of TLR5. We generated mice with specific disruption of Tlr5 in IECs or DCs by using a breeding scheme that allows comparison with cohoused siblings as controls.MethodsWe generated C57BL/6 mice with LoxP sites flanking Tlr5. These mice were crossed with mice expressing Cre recombinase, regulated by the villin or CD11c promoters, to generate mice that lacked expression of TLR5 by IECs (TLR5(ΔIEC)) or DCs (TLR5(ΔDC)), respectively. Tlr5(fl/fl) siblings were used as controls. On weaning, mice were housed by sex and genotype or by sex only (genotypes cohoused). Mice were examined for basal phenotypes, including microbiota composition; we also analyzed responses to pathobiont challenge, administration of dextran sodium sulfate, and high-fat diets.ResultsSimilar to previous findings from TLR5-null mice, TLR5(ΔIEC) mice had low-grade inflammation (mild splenomegaly, shortened colons, and increased fecal levels of lipocalin 2), metabolic syndrome, and an inability to clear pathobionts and were prone to developing colitis compared with their sibling controls under both housing conditions. Development of this inflammation in the TLR5(ΔIEC) mice was eliminated by administration of antibiotics and associated with alterations in localization of microbiota and levels of fecal lipopolysaccharide and flagellin. The composition of the microbiota clustered more closely according to genotype than housing. Loss of TLR5 from DCs did not associate with development of inflammation-associated phenotypes or alterations in the composition of the microbiota but resulted in complete loss of flagellin-induced production of interleukin-22.ConclusionsIn mice, flagellin activation of TLR5 on DCs leads to production of interleukin-22. Expression of TLR5 on IECs regulates the composition and localization of the intestinal microbiota, preventing diseases associated with intestinal inflammation.

Project description:ObjectiveObesity increases morbidity and resource utilization in sepsis patients. Sepsis transitions from early/hyper-inflammatory to late/hypo-inflammatory phase. Majority of sepsis-mortality occurs during the late sepsis; no therapies exist to treat late sepsis. In lean mice, we have shown that sirtuins (SIRTs) modulate this transition. Here, we investigated the role of sirtuins, especially the adipose-tissue abundant SIRT-2 on transition from early to late sepsis in obese with sepsis.MethodsSepsis was induced using cecal ligation and puncture (CLP) in ob/ob mice. We measured microvascular inflammation in response to lipopolysaccharide/normal saline re-stimulation as a "second-hit" (marker of immune function) at different time points to track phases of sepsis in ob/ob mice. We determined SIRT-2 expression during different phases of sepsis. We studied the effect of SIRT-2 inhibition during the hypo-inflammatory phase on immune function and 7-day survival. We used a RAW264.7 (RAW) cell model of sepsis for mechanistic studies. We confirmed key findings in diet induced obese (DIO) mice with sepsis.ResultsWe observed that the ob/ob-septic mice showed an enhanced early inflammation and a persistent and prolonged hypo-inflammatory phase when compared to WT mice. Unlike WT mice that showed increased SIRT1 expression, we found that SIRT2 levels were increased in ob/ob mice during hypo-inflammation. SIRT-2 inhibition in ob/ob mice during the hypo-inflammatory phase of sepsis reversed the repressed microvascular inflammation in vivo via activation of endothelial cells and circulating leukocytes and significantly improved survival. We confirmed the key finding of the role of SIRT2 during hypo-inflammatory phase of sepsis in this project in DIO-sepsis mice. Mechanistically, in the sepsis cell model, SIRT-2 expression modulated inflammatory response by deacetylation of NFκBp65.ConclusionSIRT-2 regulates microvascular inflammation in obese mice with sepsis and may provide a novel treatment target for obesity with sepsis.

Dataset Information

Intestinal Epithelial Sirtuin 1 Regulates Intestinal Inflammation During Aging in Mice by Altering the Intestinal Microbiota.

Publications

Intestinal Epithelial Sirtuin 1 Regulates Intestinal Inflammation During Aging in Mice by Altering the Intestinal Microbiota.

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