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      Pathogen elimination by probiotic Bacillus via signaling interference

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          Abstract

          Probiotic nutrition is frequently claimed to improve human health. In particular, live probiotic bacteria obtained with food are believed to reduce pathogen colonization and thus, susceptibility to infection. However, the underlying mechanisms remain poorly understood. Here, we report that the consumption of probiotic Bacillus bacteria comprehensively abolishes colonization with the dangerous pathogen, Staphylococcus aureus. We discovered that the widespread fengycin class of Bacillus lipopeptides achieves colonization resistance by inhibiting the S. aureus Agr quorum-sensing signaling system. Our study presents a detailed molecular mechanism underlining the importance of probiotic nutrition in reducing infectious disease. Notably, we provide human evidence supporting the biological significance of probiotic bacterial interference and show for the first time that such interference can be achieved by blocking a pathogen’s signaling system. Furthermore, our findings suggest a probiotic-based method for S. aureus decolonization and new ways to fight S. aureus infections.

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          Most cited references41

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          Interactions between commensal intestinal bacteria and the immune system.

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            Probiotic Mechanisms of Action

            Probiotics are live microorganisms that provide health benefits to the host when ingested in adequate amounts. The strains most frequently used as probiotics include lactic acid bacteria and bifidobacteria. Probiotics have demonstrated significant potential as therapeutic options for a variety of diseases, but the mechanisms responsible for these effects have not been fully elucidated yet. Several important mechanisms underlying the antagonistic effects of probiotics on various microorganisms include the following: modification of the gut microbiota, competitive adherence to the mucosa and epithelium, strengthening of the gut epithelial barrier and modulation of the immune system to convey an advantage to the host. Accumulating evidence demonstrates that probiotics communicate with the host by pattern recognition receptors, such as toll-like receptors and nucleotide-binding oligomerization domain-containing protein-like receptors, which modulate key signaling pathways, such as nuclear factor-ĸB and mitogen-activated protein kinase, to enhance or suppress activation and influence downstream pathways. This recognition is crucial for eliciting measured antimicrobial responses with minimal inflammatory tissue damage. A clear understanding of these mechanisms will allow for appropriate probiotic strain selection for specific applications and may uncover novel probiotic functions. The goal of this systematic review was to explore probiotic modes of action focusing on how gut microbes influence the host.
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              Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA.

              Methicillin-resistant Staphylococcus aureus (MRSA) remains a major human pathogen. Traditionally, MRSA infections occurred exclusively in hospitals and were limited to immunocompromised patients or individuals with predisposing risk factors. However, recently there has been an alarming epidemic caused by community-associated (CA)-MRSA strains, which can cause severe infections that can result in necrotizing fasciitis or even death in otherwise healthy adults outside of healthcare settings. In the US, CA-MRSA is now the cause of the majority of infections that result in trips to the emergency room. It is unclear what makes CA-MRSA strains more successful in causing human disease compared with their hospital-associated counterparts. Here we describe a class of secreted staphylococcal peptides that have a remarkable ability to recruit, activate and subsequently lyse human neutrophils, thus eliminating the main cellular defense against S. aureus infection. These peptides are produced at high concentrations by standard CA-MRSA strains and contribute significantly to the strains' ability to cause disease in animal models of infection. Our study reveals a previously uncharacterized set of S. aureus virulence factors that account at least in part for the enhanced virulence of CA-MRSA.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                12 September 2018
                10 October 2018
                October 2018
                10 April 2019
                : 562
                : 7728
                : 532-537
                Affiliations
                [1 ]Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health, 50 South Drive, Bethesda, Maryland 20814, USA
                [2 ]Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok 10700, Thailand
                [3 ]Faculty of Veterinary Science, Rajamangala University of Technology Srivijaya, Nakhon Si Thammarat Campus, 133 M.5 Thung Yai District, Nakhon Si Thammarat 80240, Thailand
                Author notes
                [$]

                Current address: Duksung Women’s University, College of Natural Sciences, Department of Pre-PharmMed, 33 Samyang-ro 144-gil, Dobong-gu, Seoul 01369, South Korea

                Contributions

                P.P., S.P. and S.K. collected human samples and analyzed bacterial isolates by MALDI-TOF. Y.Z., H.J. and M.O. performed analytical and preparative chromatography. P.P., T.H.N., E.L.F., R.L.H., J.C., and G.Y.C.C. performed animal studies. S.W.D. constructed the agrBD and A.E.V. all other S. aureus agr mutant and complemented strains. K.A.G., A.E.V. and B.L. performed MLST. P.P. performed reporter assays, the microbiome study, and all further analyses not specifically mentioned. P.K. supervised the human, and M.O. all other parts of the study.</author_notes>

                [* ]Corresponding Author 50 South Drive, Bethesda, MD 20814, USA, motto@ 123456niaid.nih.gov
                Article
                NIHMS1503935
                10.1038/s41586-018-0616-y
                6202238
                30305736
                0e6fcbb1-fa93-4b9e-a852-bea2c5db6de6

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