Bifidobacterium infantis Maintains Genome Stability in Ulcerative Colitis via Regulating Anaphase-Promoting Complex Subunit 7.

Taotao Han,Jingnan Li,Kemin Li,Di Zhang,Xiaomin Hu,Yan Zhang

doi:10.3389/fmicb.2021.761113

Abstract

Probiotics represents a promising intestinal microbiota-targeted therapeutic method for the treatment of ulcerative colitis (UC). Several lines of evidence implicate that Bifidobacterium infantis serves as a probiotic strain with proven efficacy in maintaining the remission of UC. However, the exact mechanisms underlying the beneficial effects of B. infantis on UC progression have yet to be elucidated. Herein, we provide evidence that B. infantis acts as a key predisposing factor for the maintenance of host genome stability. First, we showed that the fecal microbiota transplantation (FMT) of UC-derived feces contributes to more severely DNA damage in dextran sodium sulfate (DSS)-induced mice likely due to mucosa-associated microbiota alterations, as reflected by the rapid appearance of DNA double strand breaks (DSBs), a typical marker of genome instability. Genomic DNA damage analysis of colon tissues derived from healthy controls, patients with UC or dysplasia, and colitis associated cancer (CAC) patients, revealed an enhanced level of DSBs with aggravation in the degree of the intestinal mucosal lesions. To evaluate whether B. infantis modulates the host genome stability, we employed the DSS-induced colitis model and a TNFα-induced intestinal epithelial cell model. Following the administration of C57BL/6 mice with B. infantis via oral gavage, we found that the development of DSS-induced colitis in mice was significantly alleviated, in contrast to the colitis model group. Notably, B. infantis administration decreased DSB levels in both DSS-induced colitis and TNF-treated colonial cell model. Accordingly, our bioinformatic and functional studies demonstrated that B. infantis altered signal pathways involved in ubiquitin-mediated proteolysis, transcriptional misregulation in cancer, and the bacterial invasion of epithelial cells. Mechanistically, B. infantis upregulated anaphase-promoting complex subunit 7 (APC7), which was significantly suppressed in colitis condition, to activate the DNA repair pathway and alter the genome stability, while downregulation of APC7 abolished the efficiency of B. infantis treatment to induce a decrease in the level of DSBs in TNFα-induced colonial cells. Collectively, our results support that B. infantis orchestrates a molecular network involving in APC7 and genome stability, to control UC development at the clinical, biological, and mechanistic levels. Supplying B. infantis and targeting its associated pathway will yield valuable insight into the clinical management of UC patients.

Highlights

Ulcerative colitis (UC), is a chronic inflammatory condition of the colon and is associated with an increased risk for the development of colorectal cancer (CRC)
To further clarify the genetic alterations in UC patients, various of studies depicted the genomic and molecular landscape of inflammatory bowel disease (IBD)-associated CRC, and shown that the main genomic alterations in IBD-CRC, including p53 mutation, p53 loss of heterozygosity (LOH), chromosomic instability, and a high incidence of microsatellite instability (MSI) accompanied by telomere shortening (O’Sullivan et al, 2002), in long standing UC patients with severe inflammation, reflecting genomic instability caused by repeated inflammatory stress (Park et al, 1998; Ishitsuka et al, 2001)
Since previous studies reported that genome instability is an early event during the progression of UC-related neoplasia (Willenbucher et al, 1999), we aimed to test whether the progression of UC was associated with genome instability, by evaluating the expression of S139-phosphorylation of histone H2Ax, a sensitive marker of double strand breaks (DSBs), using immunohistology

Summary

Introduction

Ulcerative colitis (UC), is a chronic inflammatory condition of the colon and is associated with an increased risk for the development of colorectal cancer (CRC). Epidemiological studies demonstrate that more than 20% of worldwide cancers are caused by chronic inflammatory conditions (Grivennikov et al, 2010; Trinchieri, 2012). This increased cancer risk is thought to develop via a multistep process involving in cellular genome instability and the progressive accumulation of genetic alterations induced by the chronic inflammation (Loeb and Loeb, 1999). As a critical component of APC, the dysregulation of anaphase-promoting complex subunit 7 (APC7) may contribute to the pathogenesis of acute myeloid leukemia (AML) (Rahimi et al, 2015), the function roles of APC7 involving in the development of UC remain unclear

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