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      Associations of microbiota and toll-like receptor signaling pathway in esophageal adenocarcinoma

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          Abstract

          Background

          Toll-like receptors (TLRs) recognize known molecules from microbes and have an established role in tumorigenesis. Using a rat model of esophageal adenocarcinoma, and human clinical samples, we investigated genes central to TLR-mediated signal transduction and characterized the esophageal microbiome across the spectrum of esophageal adenocarcinoma carcinogenesis.

          Methods

          We surgically induced bile/acid reflux in rats and their esophagi were harvested at 40 weeks post-surgery. Tissue samples from the model were selected for gene expression profiling. Additionally, for rat and human samples microbiome analysis was performed using PCR-ESI-MS-TOF technology with validation by fluorescence in situ hybridization.

          Results

          Gene expression results in the rat model indicated a significant upregulation of TLRs 1-3, 6, 7 and 9 in EAC compared to normal epithelium. PCR-ESI-MS-TOF analysis revealed a prevalence of Escherichia coli in Barrett’s esophagus (60 %) and esophageal adenocarcinoma (100 %), which was validated by fluorescence in situ hybridization. In the human clinical samples, Streptococcus pneumonia was detected in high abundance in gastroesophageal reflux disease and Barrett’s esophagus (50–70 %) in comparison to tumor adjacent normal epithelium, dysplasia, and esophageal adenocarcinoma (20–30 %). E. coli was detected in the Barrett’s esophagus and esophageal adenocarcinoma groups but was absent in the tumor adjacent normal epithelium, dysplasia, and the gastroesophageal reflux disease groups.

          Conclusions

          We demonstrated an association between the TLR signaling pathway and E. coli hinting towards possible early molecular changes being mediated by microbes in the rat model of esophageal adenocarcinoma carcinogenesis. Studies on human clinical samples also corroborate results to some extent; however, a study with larger sample size is needed to further explore this association.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12885-016-2093-8) contains supplementary material, which is available to authorized users.

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          Most cited references23

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          Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function.

          MyD88, originally isolated as a myeloid differentiation primary response gene, is shown to act as an adaptor in interleukin-1 (IL-1) signaling by interacting with both the IL-1 receptor complex and IL-1 receptor-associated kinase (IRAK). Mice generated by gene targeting to lack MyD88 have defects in T cell proliferation as well as induction of acute phase proteins and cytokines in response to IL-1. Increases in interferon-gamma production and natural killer cell activity in response to IL-18 are abrogated. In vivo Th1 response is also impaired. Furthermore, IL-18-induced activation of NF-kappaB and c-Jun N-terminal kinase (JNK) is blocked in MyD88-/- Th1-developing cells. Taken together, these results demonstrate that MyD88 is a critical component in the signaling cascade that is mediated by IL-1 receptor as well as IL-18 receptor.
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            Inferences, questions and possibilities in Toll-like receptor signalling.

            The Toll-like receptors (TLRs) are the key proteins that allow mammals--whether immunologically naive or experienced--to detect microbes. They lie at the core of our inherited resistance to disease, initiating most of the phenomena that occur in the course of infection. Quasi-infectious stimuli that have been used for decades to study inflammatory mechanisms can activate the TLR family of proteins. And it now seems that many inflammatory processes, both sterile and infectious, may depend on TLR signalling. We are in a good position to apply our understanding of TLR signalling to a range of challenges in immunology and medicine.
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              Inflammation and intestinal metaplasia of the distal esophagus are associated with alterations in the microbiome.

              Gastroesophageal reflux causes inflammation and intestinal metaplasia and its downstream sequelum adenocarcinoma in the distal esophagus. The incidence of esophageal adenocarcinoma has increased approximately 6-fold in the United States since the 1970s, accompanied with a significant increase in the prevalence of gastroesophageal reflux disease (GERD). Despite extensive epidemiologic study, the cause for GERD and the unexpected increases remain unexplainable. Microbes are among the environmental factors that may contribute to the etiology of GERD, but very little research has been done on the esophageal microbiome, particularly in its relation to GERD. This is the first comprehensive reported correlation between a change in the esophageal microbiome and esophageal diseases. Biopsy samples of the distal esophagus were collected from 34 patients. Host phenotypes were histologically defined as normal, esophagitis, or Barrett's esophagus (intestinal metaplasia). Microbiomes from the biopsy samples were analyzed by bacterial 16S ribosomal RNA gene survey and classified into types using unsupervised cluster analysis and phenotype-guided analyses. Independence between host phenotypes and microbiome types were analyzed by Fisher exact test. Esophageal microbiomes can be classified into 2 types. The type I microbiome was dominated by the genus Streptococcus and concentrated in the phenotypically normal esophagus. Conversely, the type II microbiome contained a greater proportion of gram-negative anaerobes/microaerophiles and primarily correlated with esophagitis (odds ratio, 15.4) and Barrett's esophagus (odds ratio, 16.5). In the human distal esophagus, inflammation and intestinal metaplasia are associated with global alteration of the microbiome. These findings raise the issue of a possible role for dysbiosis in the pathogenesis of reflux-related disorders.
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                Author and article information

                Contributors
                412-578-1342 , azaidi@wpahs.org
                lkelly7@wpahs.org
                rkreft1@wpahs.org
                mbarlek@gmail.com
                aomstead@wpahs.org
                dmatsui@wpahs.org
                nboyd@wpahs.org
                kgazarik@wpahs.org
                mheit1@wpahs.org
                lnistico@wpahs.org
                pashtoon.kasi@gmail.com
                tspirk@wpahs.org
                bbyers1@wpahs.org
                elloyd1@wpahs.org
                rlandren@wpahs.org
                bjobe1@wpahs.org
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                2 February 2016
                2 February 2016
                2016
                : 16
                : 52
                Affiliations
                [ ]Esophageal and Lung Institute, Allegheny Health Network, 4600 North Tower, 4800 Friendship Avenue, Pittsburgh, PA 15224 USA
                [ ]Center of Excellence in Biofilm Research, Allegheny Health Network, Pittsburgh, PA USA
                [ ]Department of Medicine, Mayo Clinic, Rochester, Minnesota USA
                Article
                2093
                10.1186/s12885-016-2093-8
                4739094
                26841926
                aba2dff4-5867-4df5-b09b-bafddffe10bb
                © Zaidi et al. 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 21 July 2015
                : 28 January 2016
                Funding
                Funded by: David E. Gold and Irene Blumenkranz
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2016

                Oncology & Radiotherapy
                esophageal adenocarcinoma,microbiota,toll-like receptors,levrat model
                Oncology & Radiotherapy
                esophageal adenocarcinoma, microbiota, toll-like receptors, levrat model

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