Crosstalk between gut microbiota and Sirtuin-3 in colonic inflammation and tumorigenesis

Abstract

Colorectal cancer (CRC) is a disease involving a variety of genetic and environmental factors. Sirtuin-3 (Sirt3) is expressed at a low level in cancer tissues of CRC, but it is unclear how Sirt3 modulates colonic tumorigenesis. In this study, we found that gut microbiota play a central role in the resistance to CRC tumor formation in wild-type (WT) mice through APC (Adenomatous Polyposis Coli)-mutant mouse microbiota transfer via Wnt signaling. We also found that Sirt3-deficient mice were hypersusceptible to colonic inflammation and tumor development through altered intestinal integrity and p38 signaling, respectively. Furthermore, susceptibility to colorectal tumorigenesis was aggravated by initial commensal microbiota deletion via Wnt signaling. Mice with Sirt3-deficient microbiota transfer followed by chemically induced colon tumorigenesis had low Sirt3 expression compared to WT control microbiome transfer, mainly due to a decrease in Escherichia/Shigella, as well as an increase in Lactobacillus reuteri and Lactobacillus taiwanensis. Collectively, our data revealed that Sirt3 is an anti-inflammatory and tumor-suppressing gene that interacts with the gut microbiota during colon tumorigenesis.

The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer

“…To investigate this, we first characterized human enteroids derived from term male fetuses and "normal" colon biopsies from elderly male subjects ( Fig 3A) for transcript expression levels of SIRTs 1 and 6, two key aging/longevity related families of proteins with either mono-ADP-ribosyltransferase or deacylase activity, that is, sirtuins because previous lifespan studies carried out using yeast, worms, and flies as model organisms have demonstrated that sirtuins are evolutionarily conserved mediators of longevity (Kaeberlein et al, 1999;Tissenbaum & Guarente, 2001;Rogina & Helfand, 2004). Both SIRTs have been shown to regulate inflammation in the gut (Akimova et al, 2014;Lo Sasso et al, 2014;Wellman et al, 2017;Zhang et al, 2018). We found that compared with fetal EDMs, aged EDMs expressed less SIRT1 and 6 ( Fig 3B-Left, Middle), consistent with the previous observations of their decline in the aged gut (Liu et al, 2017a;Igarashi et al, 2019).…”

“…A compromised gut barrier allows microbes and unwanted antigens to cross the epithelium and generate inflammation (systemic endotoxemia), which may contribute to a variety of diseases, ranging from metabolic syndrome and chronic organ dysfunctions to neurodegenerative diseases and cancers (Yacyshyn et al, 1996;Barbara, 2006;Camilleri & Gorman, 2007;Sandek et al, 2007Sandek et al, , 2008Sandek et al, , 2012Alam et al, 2014;Bischoff et al, 2014;Nouri et al, 2014;Samsam et al, 2014;van De Sande et al, 2014;Clairembault et al, 2015;Lee et al, 2015;Buscarinu et al, 2016;Xue et al, 2016;Ghosh, 2017). Evidence also shows that aging-related genes, that is, the sirtuins (SIRTs1, 3, 6), are critical for the integrity of the gut barrier and for controlling inflammation in the gut (Akimova et al, 2014;Akbulut et al, 2015;Liu et al, 2017b;Zhang et al, 2018). Despite the traction and the discovery of plausible targets to strengthen the barrier, for example, myosin light-chain kinase (Cunningham & Turner, 2012), our knowledge of the underlying mechanism(s) that reinforce the barrier when faced with stressors is incomplete, and practical strategies for pharmacologic modulation of the gut barrier remains unrealized.…”

SIRT3 Deficiency Promotes High‐Fat Diet‐Induced Nonalcoholic Fatty Liver Disease in Correlation with Impaired Intestinal Permeability through Gut Microbial Dysbiosis

“…Our investigation revealed that SIRT3 deficiency resulted in an impaired intestinal barrier and inflammation in mice following the HFD. It has been reported that SIRT3KO mice were susceptible to colonic inflammation through altered intestinal integrity . Recent data suggest that microbial butyrate can improve intestinal barrier function.…”

Identification of Intestinal Flora-Related Key Genes and Therapeutic Drugs in Colorectal Cancer

“…Previous studies have con rmed that alteration of intestinal ora can promote CRC development by inducing in ammation, immune suppression, and attacking the gut barrier system [19][20][21]. Moreover, intestinal ora has been proven to promote tumorigenesis and chemoresistance of CRC via regulating gene expression [22][23][24]. Therefore, the mechanism of intestinal ora contributing to the development of CRC is complex and multifaceted.…”