Brandl, K. et al. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature 455, 804-807

Infectious Diseases Service, Department of Medicine, Immunology Program, Sloan-Kettering Institute, New York, New York, USA.
Nature (Impact Factor: 41.46). 09/2008; 455(7214):804-7. DOI: 10.1038/nature07250
Source: PubMed


Infection with antibiotic-resistant bacteria, such as vancomycin-resistant Enterococcus (VRE), is a dangerous and costly complication of broad-spectrum antibiotic therapy. How antibiotic-mediated elimination of commensal bacteria promotes infection by antibiotic-resistant bacteria is a fertile area for speculation with few defined mechanisms. Here we demonstrate that antibiotic treatment of mice notably downregulates intestinal expression of RegIIIgamma (also known as Reg3g), a secreted C-type lectin that kills Gram-positive bacteria, including VRE. Downregulation of RegIIIgamma markedly decreases in vivo killing of VRE in the intestine of antibiotic-treated mice. Stimulation of intestinal Toll-like receptor 4 by oral administration of lipopolysaccharide re-induces RegIIIgamma, thereby boosting innate immune resistance of antibiotic-treated mice against VRE. Compromised mucosal innate immune defence, as induced by broad-spectrum antibiotic therapy, can be corrected by selectively stimulating mucosal epithelial Toll-like receptors, providing a potential therapeutic approach to reduce colonization and infection by antibiotic-resistant microbes.

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    • "neomysin, norfloxacin and ciprofloxacin [35,36]. However, long-term use of antibiotics may lead to an increase of pathogenic bacteria in the gut [37] and to increased antibiotic resistance [38,39]. In experimental studies, probiotics (Bifidobacterium spp., Lactobacillus spp.), have restored normal gut homeostasis and have inhibited excessive growth of gram-negative bacteria [40-42]. "
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    ABSTRACT: The liver is the first line of defence against continuously occurring influx of microbial-derived products and bacteria from the gut. Intestinal bacteria have been implicated in the pathogenesis of alcoholic liver cirrhosis. Escape of intestinal bacteria into the ascites is involved in the pathogenesis of spontaneous bacterial peritonitis, which is a common complication of liver cirrhosis. The association between faecal bacterial populations and alcoholic liver cirrhosis has not been resolved. Relative ratios of major commensal bacterial communities (Bacteroides spp., Bifidobacterium spp., Clostridium leptum group, Enterobactericaea and Lactobacillus spp.) were determined in faecal samples from post mortem examinations performed on 42 males, including cirrhotic alcoholics (n = 13), non-cirrhotic alcoholics (n = 15), non-alcoholic controls (n = 14) and in 7 healthy male volunteers using real-time quantitative PCR (RT-qPCR). Translocation of bacteria into liver in the autopsy cases and into the ascites of 12 volunteers with liver cirrhosis was also studied with RT-qPCR. CD14 immunostaining was performed for the autopsy liver samples. Relative ratios of faecal bacteria in autopsy controls were comparable to those of healthy volunteers. Cirrhotics had in median 27 times more bacterial DNA of Enterobactericaea in faeces compared to the healthy volunteers (p = 0.011). Enterobactericaea were also the most common bacteria translocated into cirrhotic liver, although there were no statistically significant differences between the study groups. Of the ascites samples from the volunteers with liver cirrhosis, 50% contained bacterial DNA from Enterobactericaea, Clostridium leptum group or Lactobacillus spp.. The total bacterial DNA in autopsy liver was associated with the percentage of CD14 expression (p = 0.045). CD14 expression percentage in cirrhotics was significantly higher than in the autopsy controls (p = 0.004). Our results suggest that translocation of intestinal bacteria into liver may be involved as a one factor in the pathogenesis of alcoholic liver cirrhosis.
    BMC Gastroenterology 02/2014; 14(1):40. DOI:10.1186/1471-230X-14-40 · 2.37 Impact Factor
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    • "There is an urgent need to uncover bacterial drugresistant mechanisms to combat the antibiotic-resistant pathogens and cure the consequently infectious diseases. A line of evidences has indicated that bacteria developed several strategies to cope with antibiotic treatments, including gene mutation of target protein, transferring of antibiotic resistance plasmids, modifications of enzymatically degrading and target sites, decreasing of permeability, and activation of efflux system [1] [2] [3]. In particular, Gram-negative bacteria, which "
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    ABSTRACT: We previously revealed a negative regulation of LamB in chlortetracycline-resistant Escherichia coli strain. In the present study, we first showed that the negative regulation, which was characterized by decreased abundance of LamB with elevated growth of its gene-deleted mutant in medium with antibiotics, was a general response in resistance to different classes of antibiotics using 2-DE based proteomics or/and genetically gene-deletion mutant of LamB. Then, we revealed the interaction of LamB and Odp1 which catalyzes the overall conversion of pyruvate to acetyl-CoA and CO2, and found the decrease of the complex in antibiotic-resistant strains with a minimum inhibitory concentration dose-dependent manner. Further spectrofluorometry assay indicated that LamB served as a porin to influx an antibiotic. Finally, we showed that the decreased expression of LamB and Odp1 was detected in almost of 34 multidrug-resistant strains, which suggested that LamB and Odp1 were biomarkers for identification of antibiotic-resistance E. coli. Our results indicated that the interaction of an outer membrane protein with an energy metabolic enzyme constructed an efficient pathway to resist antibiotics. These findings provide novel insights into the mechanisms of antibiotics resistance. Our data indicate that the negative regulation by LamB is widely detected in antibiotic-resistant E. coli. LamB serves as a porin to influx an antibiotic and is interacted with Odp1. The complex decreases in antibiotic-resistant strains with a MIC dose-dependent manner. Our findings indicate that interaction of outer membrane protein with energy metabolic enzyme constructs an efficient pathway to resist antibiotics and provides novel insights into the mechanisms of antibiotics resistance.
    Journal of proteomics 01/2014; 98. DOI:10.1016/j.jprot.2013.12.024 · 3.89 Impact Factor
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    • "The loss of SFB may not only facilitate colonization by a Gram-negative pathogen such as S. Typhimurium as shown by Croswell et al. [65], but may also predispose the host to the outgrowth of opportunistic Gram-positive bacteria. This possibility is suggested by the strong induction by SFB of the microbicide peptide Reg3␥ [30] [45] [54], the downregulation of which after antibiotic therapy was shown to promote colonization by Vancomycin-resistant enterococcus [66]. The mechanism(s) of the barrier effect of SFB is (are), however, not delineated and more studies are necessary to define whether SFB interferes directly with pathogens by blocking their attachment or competing for nutrients or indirectly by stimulating host defense. "
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    ABSTRACT: Segmented Filamentous Bacteria (SFB) are present in the gut microbiota of a large number of vertebrate species where they are found intimately attached to the intestinal epithelium. SFB has recently attracted considerable attention due to its outstanding capacity to stimulate innate and adaptive host immune responses without causing pathology. Recent genomic analysis placed SFB between obligate and facultative symbionts, unraveled its highly auxotrophic needs, and provided a rationale for the complex SFB life-style in close contact with the epithelium. Herein, we examine how the SFB life-style may underlie its potent immunostimulatory properties and discuss how the trade-off set up between SFB and its hosts can simultaneously help to establish and maintain the ecological niche of SFB in the intestine and drive the post-natal maturation of the host gut immune barrier.
    Seminars in Immunology 10/2013; 25(5). DOI:10.1016/j.smim.2013.09.001 · 5.17 Impact Factor
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