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Cancer Cell Feb 2022Microbial dysbiosis is a colorectal cancer (CRC) hallmark and contributes to inflammation, tumor growth, and therapy response. Gut microbes signal via metabolites, but...
Microbial dysbiosis is a colorectal cancer (CRC) hallmark and contributes to inflammation, tumor growth, and therapy response. Gut microbes signal via metabolites, but how the metabolites impact CRC is largely unknown. We interrogated fecal metabolites associated with mouse models of colon tumorigenesis with varying mutational load. We find that microbial metabolites from healthy mice or humans are growth-repressive, and this response is attenuated in mice and patients with CRC. Microbial profiling reveals that Lactobacillus reuteri and its metabolite, reuterin, are downregulated in mouse and human CRC. Reuterin alters redox balance, and reduces proliferation and survival in colon cancer cells. Reuterin induces selective protein oxidation and inhibits ribosomal biogenesis and protein translation. Exogenous Lactobacillus reuteri restricts colon tumor growth, increases tumor reactive oxygen species, and decreases protein translation in vivo. Our findings indicate that a healthy microbiome and specifically, Lactobacillus reuteri, is protective against CRC through microbial metabolite exchange.
Topics: Animals; Biomarkers; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Disease Models, Animal; Energy Metabolism; Gastrointestinal Microbiome; Glutathione; Glyceraldehyde; Host Microbial Interactions; Humans; Intestinal Mucosa; Metabolomics; Metagenomics; Mice; Models, Biological; Oxidation-Reduction; Oxidative Stress; Propane; Signal Transduction; Xenograft Model Antitumor Assays
PubMed: 34951957
DOI: 10.1016/j.ccell.2021.12.001 -
Cell Metabolism Jan 2020Iron is a central micronutrient needed by all living organisms. Competition for iron in the intestinal tract is essential for the maintenance of indigenous microbial...
Iron is a central micronutrient needed by all living organisms. Competition for iron in the intestinal tract is essential for the maintenance of indigenous microbial populations and for host health. How symbiotic relationships between hosts and native microbes persist during times of iron limitation is unclear. Here, we demonstrate that indigenous bacteria possess an iron-dependent mechanism that inhibits host iron transport and storage. Using a high-throughput screen of microbial metabolites, we found that gut microbiota produce metabolites that suppress hypoxia-inducible factor 2α (HIF-2α) a master transcription factor of intestinal iron absorption and increase the iron-storage protein ferritin, resulting in decreased intestinal iron absorption by the host. We identified 1,3-diaminopropane (DAP) and reuterin as inhibitors of HIF-2α via inhibition of heterodimerization. DAP and reuterin effectively ameliorated systemic iron overload. This work provides evidence of intestine-microbiota metabolic crosstalk that is essential for systemic iron homeostasis.
Topics: Adolescent; Animals; Anti-Bacterial Agents; Basic Helix-Loop-Helix Transcription Factors; Cell Line; Cell Proliferation; Diamines; Dimerization; Duodenum; Feces; Female; Ferritins; Gastrointestinal Microbiome; Glyceraldehyde; Homeostasis; Humans; Iron; Lactobacillus; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Organoids; Probiotics; Propane; Signal Transduction
PubMed: 31708445
DOI: 10.1016/j.cmet.2019.10.005 -
Microbial Cell Factories Nov 2020The development of sustainable routes to the bio-manufacture of gaseous hydrocarbons will contribute widely to future energy needs. Their realisation would contribute... (Review)
Review
The development of sustainable routes to the bio-manufacture of gaseous hydrocarbons will contribute widely to future energy needs. Their realisation would contribute towards minimising over-reliance on fossil fuels, improving air quality, reducing carbon footprints and enhancing overall energy security. Alkane gases (propane, butane and isobutane) are efficient and clean-burning fuels. They are established globally within the transportation industry and are used for domestic heating and cooking, non-greenhouse gas refrigerants and as aerosol propellants. As no natural biosynthetic routes to short chain alkanes have been discovered, de novo pathways have been engineered. These pathways incorporate one of two enzymes, either aldehyde deformylating oxygenase or fatty acid photodecarboxylase, to catalyse the final step that leads to gas formation. These new pathways are derived from established routes of fatty acid biosynthesis, reverse β-oxidation for butanol production, valine biosynthesis and amino acid degradation. Single-step production of alkane gases in vivo is also possible, where one recombinant biocatalyst can catalyse gas formation from exogenously supplied short-chain fatty acid precursors. This review explores current progress in bio-alkane gas production, and highlights the potential for implementation of scalable and sustainable commercial bioproduction hubs.
Topics: Alkanes; Biofuels; Biosynthetic Pathways; Butanes; Carboxy-Lyases; Fatty Acids; Gases; Genetic Engineering; Industrial Microbiology; Metabolic Engineering; Oxidation-Reduction; Oxygenases; Propane; Synthetic Biology
PubMed: 33187524
DOI: 10.1186/s12934-020-01470-6 -
Nature Genetics Nov 2020Epidemiological studies have identified many environmental agents that appear to significantly increase cancer risk in human populations. By analyzing tumor genomes from...
Epidemiological studies have identified many environmental agents that appear to significantly increase cancer risk in human populations. By analyzing tumor genomes from mice chronically exposed to 1 of 20 known or suspected human carcinogens, we reveal that most agents do not generate distinct mutational signatures or increase mutation burden, with most mutations, including driver mutations, resulting from tissue-specific endogenous processes. We identify signatures resulting from exposure to cobalt and vinylidene chloride and link distinct human signatures (SBS19 and SBS42) with 1,2,3-trichloropropane, a haloalkane and pollutant of drinking water, and find these and other signatures in human tumor genomes. We define the cross-species genomic landscape of tumors induced by an important compendium of agents with relevance to human health.
Topics: Animals; Carcinogenesis; Carcinogens; DNA Mutational Analysis; Environmental Pollutants; Female; Genome; Humans; Male; Mice; Mutation; Mutation Rate; Propane; Species Specificity
PubMed: 32989322
DOI: 10.1038/s41588-020-0692-4 -
IUCrData Feb 2023The title compound, CHNO, crystallizes in the space group 2 with two mol-ecules in the asymmetric unit. The crystal packing shows O⋯π inter-actions between the two...
The title compound, CHNO, crystallizes in the space group 2 with two mol-ecules in the asymmetric unit. The crystal packing shows O⋯π inter-actions between the two mol-ecules.
PubMed: 36911082
DOI: 10.1107/S2414314623001049