Loss of Sirt1 Function Improves Intestinal Anti-Bacterial Defense and Protects from Colitis-Induced Colorectal Cancer

Elena Katsyuba,Michael O Hottiger,Kristina Schoonjans,Samodha C Fernando,Giuseppe Lo Sasso,Dongryeol Ryu,Alessandra Piersigilli,Christopher L Anderson,Laurent Mouchiroud,Johan Auwerx

doi:10.1371/journal.pone.0102495

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.

Highlights

Paneth and goblet cells are highly specialized small intestinal epithelial cells that synthesize and secrete anti-microbial peptides and mucus
We evaluated whether Sirt1 is correlated to the genes involved in anti-bacterial defense using the BXD mouse genetic reference population [30]
Intestinal Sirt1 deletion protects from colitis and colitis-induced colorectal cancer Given these last observations, we studied the impact of Sirt1 on the pathogenesis of both colitis and CAC

Summary

Introduction

Paneth and goblet cells are highly specialized small intestinal epithelial cells that synthesize and secrete anti-microbial peptides and mucus. These factors represent the first line of defense against pathogens and are essential to maintain the subtle balance among different bacterial species that colonize the mammalian gut [1]. The differentiation and maturation of Paneth and goblet cells is controlled by the Wnt and Notch signaling cascades that cooperate to promote the specification of the different cell lineages [3]. The SAM pointed domain containing ETS transcription factor (SPDEF), a downstream effector of both Wnt and Notch pathways, is known to enhance the differentiation of both Paneth and goblet cells from their common progenitor [4]. SPDEF was initially identified as a regulator of the prostatespecific antigen [5], but later associated to breast, lung, and intestine epithelium, with possible involvement in cancer progression in those tissues [6,7]

Methods

Results

Conclusion