Methyl-deficient diet promotes colitis and SIRT1-mediated endoplasmic reticulum stress

Melhem, Hassan; Hansmannel, Franck; Bressenot, Aude; Battaglia-Hsu, Syue-Fang; Billioud, Vincent; Alberto, Jean-Marc; Guéant, Jean Louis; Peyrin–Biroulet, Laurent

doi:10.1136/gutjnl-2014-307030

Cited by 57 publications

(48 citation statements)

References 49 publications

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“…The differential alterations of these gut microorganisms in these two studies may directly lead to distinct responses of SIRT1 iKO mice to DSS-induced colitis. Nevertheless, our observations in the present study are consistent with previous reports that reduced SIRT1 expression, inhibition of SIRT1 activity, or a SIRT1 mutation that decreases its activity, is associated with intestinal inflammation and colitis in both humans and rodents, whereas activation of SIRT1 by resveratrol, Cay10591, or SRT1720 prevents and cures experimental colitis 9-12 . Our findings provide a direct link between SIRT1, gut microbiota, and intestinal inflammation, and highlight the therapeutic potential of SIRT1-activating compounds in the treatment of human IBD.…”

Section: Discussionsupporting

confidence: 93%

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

et al. 2017

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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, 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 (villinCre-, 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 inflammatory bowel disease (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 due to 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 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 inflammatory bowel diseases.

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Section: Discussionsupporting

confidence: 93%

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

et al. 2017

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“…Considering that ELAVL1/HuR export is also altered in patient fibroblasts and in hippocampal neurons of the Cd320 KO mice (the experimental systems without the presence of G418), we conclude that cellular response to stress mediated by ELAVL1/HuR-containing hnRNP complex shuttling is impaired in both human and mouse under aberrant Cbl metabolism. Together with the previous evidence that in TO and OT model cell system, cellular Cbl deficit produced non-adapted unfolded protein response due to decreased SIRT1 activity (5,13,31), our data here provide a mechanistic link between anti-stress responses mediated by ELAVL1/HuR and SIRT1 activity. A major consequence of ELAVL1/HuR nuclear retention is the confinement of ELAVL1/HuR target mRNAs like Sirt1 in the nucleus, hence reduced translation of ELAVL1/HuR-relevant stress response proteins.…”

Section: Discussionsupporting

confidence: 84%

“…A major consequence of ELAVL1/HuR nuclear retention is the confinement of ELAVL1/HuR target mRNAs like Sirt1 in the nucleus, hence reduced translation of ELAVL1/HuR-relevant stress response proteins. A decreased expression and activity of SIRT1 is a key component of the non-adapted response to the ER stress of the TO cells and the rats subjected to Cbl and folate deficient diet (5,12,13,31), as reduced SIRT1 protein expression leads to HSF1 hyperacetylation, the latter in turn reduces the expression of heat shock proteins (HSPs) (32). Besides HSPs, other gene function may also be affected as decreased SIRT1activity can contribute to dysregulated nuclear receptor co-regulation via deacetylated PGC1α, as observed in the brain, heart and gut of rats deficient in Cbl and folate (10–14,31).…”

Section: Discussionmentioning

confidence: 99%

Inherited disorders of cobalamin metabolism disrupt nucleocytoplasmic transport of mRNA through impaired methylation/phosphorylation of ELAVL1/HuR

Battaglia-Hsu

Ghemrawi

Coelho

et al. 2018

Nucleic Acids Research

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The molecular mechanisms that underlie the neurological manifestations of patients with inherited diseases of vitamin B12 (cobalamin) metabolism remain to date obscure. We observed transcriptomic changes of genes involved in RNA metabolism and endoplasmic reticulum stress in a neuronal cell model with impaired cobalamin metabolism. These changes were related to the subcellular mislocalization of several RNA binding proteins, including the ELAVL1/HuR protein implicated in neuronal stress, in this cell model and in patient fibroblasts with inborn errors of cobalamin metabolism and Cd320 knockout mice. The decreased interaction of ELAVL1/HuR with the CRM1/exportin protein of the nuclear pore complex and its subsequent mislocalization resulted from hypomethylation at R-217 produced by decreased S-adenosylmethionine and protein methyl transferase CARM1 and dephosphorylation at S221 by increased protein phosphatase PP2A. The mislocalization of ELAVL1/HuR triggered the decreased expression of SIRT1 deacetylase and genes involved in brain development, neuroplasticity, myelin formation, and brain aging. The mislocalization was reversible upon treatment with siPpp2ca, cobalamin, S-adenosylmethionine, or PP2A inhibitor okadaic acid. In conclusion, our data highlight the key role of the disruption of ELAVL1/HuR nuclear export, with genomic changes consistent with the effects of inborn errors of Cbl metabolisms on brain development, neuroplasticity and myelin formation.

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“…The activation of SIRT1 by resveratrol, NAD+, or calorie restriction could attenuate ER stress via the PERK/eIF2α, ATF6/CHOP, or IRE1α/ JNK-mediated pathways. [52][53][54][55][56] In this study, we observed the downregulation of SIRT1 in macrophages treated with both TiPs and CoPs, and the treatment of resveratrol showed a similar effect on the inflammatory response with an ER stress inhibitor. Those results suggest a correlation between ER stress and SIRT1 in the pathological process of aseptic loosening.…”

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confidence: 63%

The metal nanoparticle-induced inflammatory response is regulated by SIRT1 through NF-κB deacetylation in aseptic loosening

Deng¹,

Jin²,

Wang³

et al. 2017

IJN

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Aseptic loosening is the most common cause of total hip arthroplasty (THA) failure, and osteolysis induced by wear particles plays a major role in aseptic loosening. Various pathways in multiple cell types contribute to the pathogenesis of osteolysis, but the role of Sirtuin 1 (SIRT1), which can regulate inflammatory responses through its deacetylation, has never been investigated. We hypothesized that the downregulation of SIRT1 in macrophages induced by metal nanoparticles was one of the reasons for osteolysis in THA failure. In this study, the expression of SIRT1 was examined in macrophages stimulated with metal nanoparticles from materials used in prosthetics and in specimens from patients suffering from aseptic loosening. To address whether SIRT1 downregulation triggers these inflammatory responses, the effects of the SIRT1 activator resveratrol on the expression of inflammatory cytokines in metal nanoparticle-stimulated macrophages were tested. The results demonstrated that SIRT1 expression was significantly downregulated in metal nanoparticle-stimulated macrophages and clinical specimens of prosthesis loosening. Pharmacological activation of SIRT1 dramatically reduced the particle-induced expression of inflammatory cytokines in vitro and osteolysis in vivo. Furthermore, SIRT1 regulated particle-induced inflammatory responses through nuclear factor kappa B (NF-κB) acetylation. Thus, the results of this study suggest that SIRT1 plays a key role in metal nanoparticle-induced inflammatory responses and that targeting the SIRT1 pathway may lead to novel therapeutic approaches for the treatment of aseptic prosthesis loosening.

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Methyl-deficient diet promotes colitis and SIRT1-mediated endoplasmic reticulum stress

Abstract: SIRT1 is a master regulator of ER stress and severity of experimental colitis in case of MDD. It could deserve further interest as a therapeutic target of IBD.

Cited by 57 publications

References 49 publications

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

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

Inherited disorders of cobalamin metabolism disrupt nucleocytoplasmic transport of mRNA through impaired methylation/phosphorylation of ELAVL1/HuR

The metal nanoparticle-induced inflammatory response is regulated by SIRT1 through NF-κB deacetylation in aseptic loosening

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Methyl-deficient diet promotes colitis and SIRT1-mediated endoplasmic reticulum stress

Abstract: SIRT1 is a master regulator of ER stress and severity of experimental colitis in case of MDD. It could deserve further interest as a therapeutic target of IBD.

Cited by 57 publications

References 49 publications

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

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

Inherited disorders of cobalamin metabolism disrupt nucleocytoplasmic transport of mRNA through impaired methylation/phosphorylation of ELAVL1/HuR

The metal nanoparticle-induced inflammatory response is regulated by SIRT1 through NF-&kappa;B deacetylation in aseptic loosening

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The metal nanoparticle-induced inflammatory response is regulated by SIRT1 through NF-κB deacetylation in aseptic loosening