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Chemical and pathogen-induced inflammation disrupt the murine intestinal microbiome.

ABSTRACT: BACKGROUND:Salmonella is one of the most significant food-borne pathogens to affect humans and agriculture. While it is well documented that Salmonella infection triggers host inflammation, the impacts on the gut environment are largely unknown. A CBA/J mouse model was used to evaluate intestinal responses to Salmonella-induced inflammation. In parallel, we evaluated chemically induced inflammation by dextran sodium sulfate (DSS) and a non-inflammation control. We profiled gut microbial diversity by sequencing 16S ribosomal ribonucleic acid (rRNA) genes from fecal and cecal samples. These data were correlated to the inflammation marker lipocalin-2 and short-chain fatty acid concentrations. RESULTS:We demonstrated that inflammation, chemically or biologically induced, restructures the chemical and microbial environment of the gut over a 16-day period. We observed that the ten mice within the Salmonella treatment group had a variable Salmonella relative abundance, with three high responding mice dominated by >46% Salmonella at later time points and the remaining seven mice denoted as low responders. These low- and high-responding Salmonella groups, along with the chemical DSS treatment, established an inflammation gradient with chemical and low levels of Salmonella having at least 3 log-fold lower lipocalin-2 concentration than the high-responding Salmonella mice. Total short-chain fatty acid and individual butyrate concentrations each negatively correlated with inflammation levels. Microbial communities were also structured along this inflammation gradient. Low levels of inflammation, regardless of chemical or biological induction, enriched for Akkermansia spp. in the Verrucomicrobiaceae and members of the Bacteroidetes family S24-7. Relative to the control or low inflammation groups, high levels of Salmonella drastically decreased the overall microbial diversity, specifically driven by the reduction of Alistipes and Lachnospiraceae in the Bacteroidetes and Firmicutes phyla, respectively. Conversely, members of the Enterobacteriaceae and Lactobacillus were positively correlated to high levels of Salmonella-induced inflammation. CONCLUSIONS:Our results show that enteropathogenic infection and intestinal inflammation are interrelated factors modulating gut homeostasis. These findings may prove informative with regard to prophylactic or therapeutic strategies to prevent disruption of microbial communities, or promote their restoration.

SUBMITTER: Borton MA

PROVIDER: S-EPMC5408407 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Chemical and pathogen-induced inflammation disrupt the murine intestinal microbiome.

Borton Mikayla A MA Sabag-Daigle Anice A Wu Jikang J Solden Lindsey M LM O'Banion Bridget S BS Daly Rebecca A RA Wolfe Richard A RA Gonzalez Juan F JF Wysocki Vicki H VH Ahmer Brian M M BMM Wrighton Kelly C KC

Microbiome 20170427 1

<h4>Background</h4>Salmonella is one of the most significant food-borne pathogens to affect humans and agriculture. While it is well documented that Salmonella infection triggers host inflammation, the impacts on the gut environment are largely unknown. A CBA/J mouse model was used to evaluate intestinal responses to Salmonella-induced inflammation. In parallel, we evaluated chemically induced inflammation by dextran sodium sulfate (DSS) and a non-inflammation control. We profiled gut microbial ...[more]

PMID: 28449706

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Project description:Background & aimsWe studied interactions among proteins of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, which interact with microbes, and transforming growth factor beta (TGFB) signaling pathway, which is often altered in colorectal cancer cells. We investigated mechanisms by which CEACAM proteins inhibit TGFB signaling and alter the intestinal microbiome to promote colorectal carcinogenesis.MethodsWe collected data on DNA sequences, messenger RNA expression levels, and patient survival times from 456 colorectal adenocarcinoma cases, and a separate set of 594 samples of colorectal adenocarcinomas, in The Cancer Genome Atlas. We performed shotgun metagenomic sequencing analyses of feces from wild-type mice and mice with defects in TGFB signaling (Sptbn1+/- and Smad4+/-/Sptbn1+/-) to identify changes in microbiota composition before development of colon tumors. CEACAM protein and its mutants were overexpressed in SW480 and HCT116 colorectal cancer cell lines, which were analyzed by immunoblotting and proliferation and colony formation assays.ResultsIn colorectal adenocarcinomas, high expression levels of genes encoding CEACAM proteins, especially CEACAM5, were associated with reduced survival times of patients. There was an inverse correlation between expression of CEACAM genes and expression of TGFB pathway genes (TGFBR1, TGFBR2, and SMAD3). In colorectal adenocarcinomas, we also found an inverse correlation between expression of genes in the TGFB signaling pathway and genes that regulate stem cell features of cells. We found mutations encoding L640I and A643T in the B3 domain of human CEACAM5 in colorectal adenocarcinomas; structural studies indicated that these mutations would alter the interaction between CEACAM5 and TGFBR1. Overexpression of these mutants in SW480 and HCT116 colorectal cancer cell lines increased their anchorage-independent growth and inhibited TGFB signaling to a greater extent than overexpression of wild-type CEACAM5, indicating that they are gain-of-function mutations. Compared with feces from wild-type mice, feces from mice with defects in TGFB signaling had increased abundance of bacterial species that have been associated with the development of colon tumors, including Clostridium septicum, and decreased amounts of beneficial bacteria, such as Bacteroides vulgatus and Parabacteroides distasonis.ConclusionWe found expression of CEACAMs and genes that regulate stem cell features of cells to be increased in colorectal adenocarcinomas and inversely correlated with expression of TGFB pathway genes. We found colorectal adenocarcinomas to express mutant forms of CEACAM5 that inhibit TGFB signaling and increase proliferation and colony formation. We propose that CEACAM proteins disrupt TGFB signaling, which alters the composition of the intestinal microbiome to promote colorectal carcinogenesis.

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Chemical and pathogen-induced inflammation disrupt the murine intestinal microbiome.

Publications

Chemical and pathogen-induced inflammation disrupt the murine intestinal microbiome.

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