Abstract
Dysfunction of Paneth and goblet cells in the intestine contributes to inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). Here, we report a role for the NAD+-dependent histone deacetylase SIRT1 in the control of anti-bacterial defense. Mice with an intestinal specific Sirt1 deficiency (Sirt1int-/-) have more Paneth and goblet cells with a consequent rearrangement of the gut microbiota. From a mechanistic point of view, the effects on mouse intestinal cell maturation are mediated by SIRT1-dependent changes in the acetylation status of SPDEF, a master regulator of Paneth and goblet cells. Our results suggest that targeting SIRT1 may be of interest in the management of IBD and CAC.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / metabolism
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism
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Cell Differentiation
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Cell Line
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Colitis / chemically induced
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Colitis / complications
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Colitis / genetics*
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Colitis / pathology
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Colorectal Neoplasms / chemically induced
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Colorectal Neoplasms / etiology
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Colorectal Neoplasms / genetics*
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Colorectal Neoplasms / pathology
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Gene Deletion
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Gene Expression Regulation, Neoplastic*
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Goblet Cells / metabolism*
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Goblet Cells / pathology
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Humans
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Mice
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Mice, Knockout
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Paneth Cells / metabolism*
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Paneth Cells / pathology
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Proto-Oncogene Proteins c-ets / genetics
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Proto-Oncogene Proteins c-ets / metabolism
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Signal Transduction
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Sirtuin 1 / deficiency
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Sirtuin 1 / genetics*
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Sodium Dodecyl Sulfate
Substances
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Caenorhabditis elegans Proteins
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Proto-Oncogene Proteins c-ets
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Spdef protein, mouse
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Sodium Dodecyl Sulfate
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Sirt1 protein, mouse
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Sirtuin 1