Functional Changes in the Gut Microbiome Contribute to Transforming Growth Factor β-Deficient Colon Cancer

Daniel, Scott G.; Ball, Corbie; Besselsen, David G.; Doetschman, Tom; Hurwitz, Bonnie

doi:10.1128/msystems.00065-17

Cited by 54 publications

(50 citation statements)

References 93 publications

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“…During colorectal cancer (CRC) development, functional differences in the microbiome related to specific bacterial species, emerge from four pathways: lipopolysaccharide (LPS) production, polyamine synthesis, butyrate metabolism, and oxidative phosphorylation. Notably, an LPS production-related gene, specific for M. schaedleri, is dramatically upregulated in a CRC mouse model [33], supporting the differential expression of genes in M. schaedleri, also observed in our study.…”

Section: Discussionsupporting

confidence: 90%

“…To date, several reports have shown microbiota structure and microbiome function in the mouse gut under various environmental conditions by metatranscriptomic analysis [22,24,[27][28][29][30][31][32][33][34][35][36][37]. In particular, metatranscriptomic analysis of the mouse gut microbiome during targeted exposure to lard and primary bile acid diet [29], a high-protein diet [31], and vitamin and mineral deficiencies [32] uncovered significant alterations in both bacterial community structure and their gene expression profiles.…”

Section: Discussionmentioning

confidence: 99%

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Functional dynamics of bacterial species in the mouse gut microbiome revealed by metagenomic and metatranscriptomic analyses

et al. 2020

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BackgroundMicrobial communities of the mouse gut have been extensively studied; however, their functional roles and regulation are yet to be elucidated. Metagenomic and metatranscriptomic analyses may allow us a comprehensive profiling of bacterial composition and functions of the complex gut microbiota. The present study aimed to investigate the active functions of the microbial communities in the murine cecum by analyzing both metagenomic and metatranscriptomic data on specific bacterial species within the microbial communities, in addition to the whole microbiome. ResultsBacterial composition of the healthy mouse gut microbiome was profiled using the following three different approaches: 16S rRNA-based profiling based on amplicon and shotgun sequencing data, and genome-based profiling based on shotgun sequencing data. Consistently, Bacteroidetes, Firmicutes, and Deferribacteres emerged as the major phyla. Based on NCBI taxonomy, Muribaculaceae, Lachnospiraceae, and Deferribacteraceae were the predominant families identified in each phylum. The genes for carbohydrate metabolism were upregulated in Muribaculaceae, while genes for cofactors and vitamin metabolism and amino acid metabolism were upregulated in Deferribacteraceae. The genes for translation were commonly enhanced in all three families. Notably, combined analysis of metagenomic and metatranscriptomic sequencing data revealed that the functions of translation and metabolism were largely upregulated in all three families in the mouse gut environment. The ratio of the genes in the metagenome and their expression in the metatranscriptome PLOS ONE | https://doi.indicated higher expression of carbohydrate metabolism in Muribaculum, Duncaniella, and Mucispirillum. ConclusionsWe demonstrated a fundamental methodology for linking genomic and transcriptomic datasets to examine functional activities of specific bacterial species in a complicated microbial environment. We investigated the normal flora of the mouse gut using three different approaches and identified Muribaculaceae, Lachnospiraceae, and Deferribacteraceae as the predominant families. The functional distribution of these families was reflected in the entire microbiome. By comparing the metagenomic and metatranscriptomic data, we found that the expression rates differed for different functional categories in the mouse gut environment. Application of these methods to track microbial transcription in individuals over time, or before and after administration of a specific stimulus will significantly facilitate future development of diagnostics and treatments.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Functional dynamics of bacterial species in the mouse gut microbiome revealed by metagenomic and metatranscriptomic analyses

et al. 2020

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“…Green and Hudson (36) have reviewed the roles of several signaling pathways implicated in the development of colon cancers. KRAS-dependent tumorigenesis is inhibited by DFMO in human Caco-2 xenografts (37), and colon carcinogenesis in transforming growth factor ␤ (TGF␤)-deficient mice is associated with changes in the polyamine and other metabolic pathways in the gut microbiome of these mice (38). The role of the microbiome will be discussed further in a subsequent section of this Minireview.…”

Section: Polyamines As Mediators Of Colon Carcinogenesismentioning

confidence: 99%

Cancer pharmacoprevention: Targeting polyamine metabolism to manage risk factors for colon cancer

Gerner

Bruckheimer

Cohen

2018

Journal of Biological Chemistry

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Edited by Eric R. Fearon Cancer is a set of diseases characterized by uncontrolled cell growth. In certain cancers of the gastrointestinal tract, the adenomatous polyposis coli (APC) tumor suppressor gene is altered in either germline or somatic cells and causes formation of risk factors, such as benign colonic or intestinal neoplasia, which can progress to invasive cancer. APC is a key component of the WNT pathway, contributing to normal GI tract development, and APC alteration results in dysregulation of the pathway for production of polyamines, which are ubiquitous cations essential for cell growth. Studies with mice have identified nonsteroidal anti-inflammatory drugs (NSAIDs) and difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, as potent inhibitors of colon carcinogenesis. Moreover, gene expression profiling has uncovered that NSAIDs activate polyamine catabolism and export. Several DFMO-NSAID combination strategies are effective and safe methods for reducing risk factors in clinical trials with patients having genetic or sporadic risk of colon cancer. These strategies affect cancer stem cells, inflammation, immune surveillance, and the microbiome. Pharmacotherapies consisting of drug combinations targeting the polyamine pathway provide a complementary approach to surgery and cytotoxic cancer treatments for treating patients with cancer risk factors. In this Minireview, we discuss the role of polyamines in colon cancer and highlight the mechanisms of select pharmacoprevention agents to delay or prevent carcinogenesis in humans.

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“…2). Interestingly, the abundance of several of the genera in the microbiomes in the Nlrp1b –/– mice are associated with more commensal and pathogenic species known to be associated with inflammation and cancer in the GI tract, including H. pylori [32], H. hepaticus [33], M. schaedleri [34], and C. difficile [35]. It is tempting to speculate that the previously reported increased sensitivity of these knockout animals in models of experimental colitis and colitis-associated tumorigenesis could be due to changes in their microbiome composition [9].…”

Section: Resultsmentioning

confidence: 99%

Maternal Influence and Murine Housing Confound Impact of NLRP1 Inflammasome on Microbiome Composition

Ringel‐Scaia

Qin²,

Thomas

et al. 2019

J Innate Immun

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The NLRP1 inflammasome attenuates inflammatory bowel disease (IBD) progression and colitis-associated tumorigenesis. A possible mechanism postulates that the lack of the NLRP1 inflammasome creates permissive niches in the gut for pathogenic bacteria to flourish, causing dysbiosis and increased IBD susceptibility. To evaluate this hypothesis, we characterized the gut microbiome of wild-type, Nlrp1b–/–, and Asc–/– mice under naïve conditions by sequencing the V3 region of the 16s rRNA gene. For both genetically modified mouse lines, the microbiome composition reflected overrepresentation of bacteria associated with dysbiosis relative to wild-type animals. Measurement of short- and medium-chain fatty acids by mass spectrometry further revealed significant differences between genotypes. However, prior to concluding that the NLRP1 inflammasome plays a role in regulating the composition of the microbiome, we evaluated two additional strategies for cohousing wild-type and Nlrp1b–/– mice: breeding homozygous parents and cohousing at weaning, and breeding from heterozygous parents and cohousing littermates. We found that maternal influence was the greater predictor of microbiome composition rather than genotype. With the rise in microbiome research across disciplines, our study should be viewed as a cautionary example that illustrates the importance of careful breeding and housing strategies when evaluating host-microbiome interactions.

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Functional Changes in the Gut Microbiome Contribute to Transforming Growth Factor β-Deficient Colon Cancer

Cited by 54 publications

References 93 publications

Functional dynamics of bacterial species in the mouse gut microbiome revealed by metagenomic and metatranscriptomic analyses

Functional dynamics of bacterial species in the mouse gut microbiome revealed by metagenomic and metatranscriptomic analyses

Cancer pharmacoprevention: Targeting polyamine metabolism to manage risk factors for colon cancer

Maternal Influence and Murine Housing Confound Impact of NLRP1 Inflammasome on Microbiome Composition

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