Sporadic colorectal cancer (CRC) is a result of complex interactions between the host and its environment. Environmental stressors act by causing host cell DNA alterations implicated in the onset of cancer. Here we investigate the stressor ability of CRC-associated gut dysbiosis as causal agent of host DNA alterations. The epigenetic nature of these alterations was investigated in humans and in mice. Germ-free mice receiving fecal samples from subjects with normal colonoscopy or from CRC patients were monitored for 7 or 14 wk. Aberrant crypt foci, luminal microbiota, and DNA alterations (colonic exome sequencing and methylation patterns) were monitored following human feces transfer. CRC-associated microbiota induced higher numbers of hypermethylated genes in murine colonic mucosa (vs. healthy controls’ microbiota recipients). Several gene promoters including SFRP1,2,3, PENK, NPY, ALX4, SEPT9, and WIF1 promoters were found hypermethylated in CRC but not in normal tissues or effluents from fecal donors. In a pilot study (n = 266), the blood methylation levels of 3 genes (Wif1, PENK, and NPY) were shown closely associated with CRC dysbiosis. In a validation study (n = 1,000), the cumulative methylation index (CMI) of these genes was significantly higher in CRCs than in controls. Further, CMI appeared as an independent risk factor for CRC diagnosis as shown by multivariate analysis that included fecal immunochemical blood test. Consequently, fecal bacterial species in individuals with higher CMI in blood were identified by whole metagenomic analysis. Thus, CRC-related dysbiosis induces methylation of host genes, and corresponding CMIs together with associated bacteria are potential biomarkers for CRC.

No abstract

Background Antibiotic-impregnated external ventricular drains (AI-EVDs) have a debated efficacy in clinical studies. Objectives Our aim was to assess the durability of antimicrobial activity of AI-EVDs used in clinical settings. Methods From April 2017 to January 2018, all consecutive AI-EVDs (Bactiseal™) inserted in adult patients were prospectively included. After removal, each AI-EVD was cultured and assessed for antimicrobial activity on both internal and external sides of AI-EVDs. Catheters were each challenged with a single Staphylococcus strain [MSSA, MRSA or methicillin-resistant Staphylococcus epidermidis (MRSE)]. MS was used to measure residual concentrations of rifampicin and clindamycin. Results Sixty-five AI-EVDs were included (56 patients). Among these, 21 were challenged with MSSA, 23 with MRSA and 21 with MRSE. Five ventriculostomy-related colonizations (9%) and two ventriculostomy-related infections (4%) occurred. Staphylococcus was the main bacterium responsible for colonization (4/5). AI-EVD inhibition decreased significantly against MRSA and MRSE according to duration of catheterization (for external and internal sides, P < 0.02) and overall volume of CSF drained (P < 0.005 for both sides against MRSE, P < 0.005 for external side against MRSA), but not against MSSA. Clindamycin concentration was not correlated with duration of catheterization or CSF volume drained, but <20% of initial concentration was recovered even after 5 days of AI-EVD dwelling. Conversely, rifampicin concentration showed a rapid and significant decline correlated to duration and CSF volume (P < 0.001 and P = 0.03, respectively). Conclusions Antimicrobial activity of AI-EVDs dropped quickly in vivo. Antimicrobial impregnation did not prevent AI-EVD colonization by susceptible strains in 9% of the cases.