The gut microbiota acts as a real organ. The symbiotic interactions between resident micro-organisms and the digestive tract highly contribute to maintain the gut homeostasis. However, alterations to the microbiome caused by environmental changes (e.g., infection, diet and/or lifestyle) can disturb this symbiotic relationship and promote disease, such as inflammatory bowel diseases and cancer. Colorectal cancer is a complex association of tumoral cells, non-neoplastic cells and a large amount of micro-organisms, and the involvement of the microbiota in colorectal carcinogenesis is becoming increasingly clear. Indeed, many changes in the bacterial composition of the gut microbiota have been reported in colorectal cancer, suggesting a major role of dysbiosis in colorectal carcinogenesis. Some bacterial species have been identified and suspected to play a role in colorectal carcinogenesis, such as Streptococcus bovis, Helicobacter pylori, Bacteroides fragilis, Enterococcus faecalis, Clostridium septicum, Fusobacterium spp. and Escherichia coli. The potential pro-carcinogenic effects of these bacteria are now better understood. In this review, we discuss the possible links between the bacterial microbiota and colorectal carcinogenesis, focusing on dysbiosis and the potential pro-carcinogenic properties of bacteria, such as genotoxicity and other virulence factors, inflammation, host defenses modulation, bacterial-derived metabolism, oxidative stress and anti-oxidative defenses modulation. We lastly describe how bacterial microbiota modifications could represent novel prognosis markers and/or targets for innovative therapeutic strategies.

These data reveal a new paradigm for carcinogenesis, in which colibactin-induced senescence has an important role.

Purpose: The intestinal microbiota is potentially involved in the development of colorectal carcinoma via various mechanisms. Escherichia coli are commensal bacteria of the human gut microbiota, but some pathogenic strains have acquired the ability to induce chronic inflammation and/or produce toxins, such as cyclomodulin, which could participate in the carcinogenesis process. Here, we analyzed the E. coli population associated with mucosa of patients with colon cancer in relation to clinicopathologic characteristics. We assessed carcinogenic properties of a colon cancer-associated E. coli strain in multiple intestinal neoplasia (Min) mice.Experimental design: Mucosa-associated or internalized E. coli were quantified and characterized from tumors and mucosa of patients with colon cancer and the healthy mucosa of diverticulosis controls. Min mice were inoculated with a colon cancer-associated E. coli strain (11G5). The number of colonic polyps was evaluated at 7 weeks after infection.Results: An increased level of mucosa-associated and internalized E. coli was observed in the tumors compared with normal tissue. A relationship between poor prognostic factors for colon cancer (tumornode-metastasis stage) and colonization of mucosa by E. coli was observed. Pathogenic cyclomodulinpositive E. coli strains were more prevalent on mucosa of patients with stages III/IV than those with stage I colon cancer. Proliferative index and E. coli colonization level of the mucosa distant from the tumor significantly correlated. Min mice infected with the E. coli strain 11G5 displayed a marked increase in the number of visible colonic polyps compared with controls.Conclusion: These findings support that pathogenic E. coli could be a cofactor in pathogenesis of colorectal cancer. Clin Cancer Res; 20(4); 859-67. Ó2013 AACR.

BASIC AND TRANSLATIONAL AT increase in mean histologic score, than infected Apc Min/þ mice. Increased levels of Il6, Tnf, and Cxcl1 mRNAs, decreased level of Il10 mRNA, and increased markers of DNA double-strand breaks and proliferation were observed in the colonic mucosa of 11G5-infected Apc Min/þ /Atg16l1 DIEC mice vs 11G5-infected Apc Min/þ mice. CONCLUSION: Infection of IECs and susceptible mice with CoPEC promotes autophagy, which is required to prevent colorectal tumorigenesis. Loss of ATG16L1 from IECs increases markers of inflammation, DNA damage, and cell proliferation and increases colorectal tumorigenesis in 11G5-infected Apc Min/þ mice. These findings indicate the importance of autophagy in response to CoPEC infection, and strategies to induce autophagy might be developed for patients with CRC and CoPEC colonization.

Recent studies suggest that colonization of colonic mucosa by pathogenic could be involved in the development of colorectal cancer (CRC), especially through the production of genotoxins such as colibactin and/or by interfering with the DNA mismatch repair (MMR) pathway that leads to microsatellite instability (MSI). The present study, performed on 88 CRC patients, revealed a significant increase in colonization in the MSI CRC phenotype. In the same way, persistence and internalization were increased in MMR-deficient cells. Moreover, we demonstrated that colibactin-producing induce inhibition of the mutL homologue 1 (MLH1) MMR proteins, which could lead to genomic instability. However, colibactin-producing were more frequently identified in microsatellite stable (MSS) CRC. The present study suggests differences in the involvement of colibactin-producing in colorectal carcinogenesis according to the CRC phenotype. Further host-pathogen interactions studies should take into account CRC phenotypes.

Thrombotic occlusion of a modified Blalock-Taussig (BT) shunt is rare, leading to life-threatening hypoxemia. Rescue percutaneous interventions may allow recanalization of the systemic-to-pulmonary shunt but data on large patients' scales are lacking. We aimed to describe safety and effectiveness of catheter-based interventions to restore modified BT shunt patency. All patients who attempted transcatheter intervention for thrombotic occlusion of a modified BT shunt at our Institution from 1994 to 2014 were reviewed. Characteristics, management, and outcomes of the 28 identified patients were analyzed. Thirty-three procedures were performed at a median age of 0.6 years old (range 0.03-32.1 years) and a median weight of 5.8 kg (range 2.2-82 kg). Percutaneous intervention consisted in 33 balloon angioplasty (100 %) and 14 stent implantations (42.4 %). Thrombolytic agents were also used in 6.1 % cases. No peri-procedural death occurred but complications were observed in five patients (15.2 %), including one catheter-induced transient complete atrioventricular block, one cardiac tamponade, and one massive thrombo-embolic stroke. Early procedural success was obtained in 28 patients (84.8 %) and remained long-lasting in 26 patients (78.8 %). A young age and a low body-weight at the time of the procedure were significantly associated with procedural failure (p = 0.0364 and p = 0.0247, respectively). Although technically challenging and carrying potential major complications, transcatheter intervention can be considered as an efficient rescue strategy to restore patency in case of thrombotic obstruction of a modified BT shunt.

BackgroundRecent evidence has suggested that Alzheimer’s disease (AD)-associated neuronal loss may occur via the caspase-independent route of programmed cell death (PCD) in addition to caspase-dependent mechanisms. However, the brain region specificity of caspase-independent PCD in AD-associated neurodegeneration is unknown. We therefore used the transgenic CRND8 (TgCRND8) AD mouse model to explore whether the apoptosis inducing factor (AIF), a key mediator of caspase-independent PCD, contributes to cell loss in selected brain regions in the course of aging.ResultsIncreased expression of truncated AIF (tAIF), which is directly responsible for cell death induction, was observed at both 4- and 6-months of age in the cortex. Concomitant with the up-regulation of tAIF was an increase in the nuclear translocation of this protein. Heightened tAIF expression or translocation was not observed in the hippocampus or cerebellum, which were used as AD-vulnerable and relatively AD-spared regions, respectively. The cortical alterations in tAIF levels were accompanied by increased Bax expression and mitochondrial translocation. This effect was preceded by a significant reduction in ATP content and an increase in reactive oxygen species (ROS) production, detectable at 2 months of age despite negligible amounts of amyloid-beta peptides (Aβ).ConclusionsTaken together, these data suggest that AIF is likely to play a region-specific role in AD-related caspase-independent PCD, which is consistent with aging-associated mitochondrial impairment and oxidative stress.

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