The microbial gbu gene cluster links microbial L-carnitine catabolism to red meat diet-enhanced cardiovascular disease risk
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PROVIDER: PRJEB44883 | ENA |
REPOSITORIES: ENA
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Project description:Choline is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which upon absorption by the host is converted in the liver to trimethylamine N-oxide (TMAO). Recent studies revealed that TMAO exacerbates atherosclerosis in mice, and positively correlates with the severity of this disease in human. However, which microbes contribute to TMA production in the human gut; the extent to which host factors, e.g., genotype and diet, affect TMA production and colonization of these microbes; as well as the effects TMA-producing microbes have on bioavailability of dietary choline remain largely unknown. We screened a collection of 78 sequenced human intestinal isolates encompassing the major phyla found in the human gut and identified eight strains capable of producing TMA from choline in vitro. Gnotobiotic mouse studies showed that TMAO accumulates in the serum of animals colonized with TMA-producing species, but not in the serum of animals colonized with intestinal isolates that do not generate TMA from choline in vitro. Remarkably, low levels of colonization of TMA-producing bacteria significantly reduced choline levels available to the host. This effect was more pronounced as the abundance of TMA-producing bacteria increased. Our findings provide a framework for designing strategies aimed at changing the representation or activity of TMA-producing bacteria in the human gut and suggest the TMA producing status of the gut microbiota should be considered when making recommendations about choline intake requirements for humans.
2015-04-02 | GSE63461 | GEO
Project description:Eubacterium limosum ATCC 8486 makes acetate and butyrate from various substrates and is found in the human intestine. The proteome of L-carnitine-grown Eubacterium limosum was obtained in order to identify enzymes required for growth on L-carnitine, in particular to identify components that are unique to growth on L-carnitine in comparison to other substrates for acetogenesis, such as lactic acid. L-carnitine and derviatives are converted to trimethylamine (TMA) by certain members of the gut microbiome, metabolism of TMA is now tied to progression of cardiovascular disease. Demethylation of carnitine is observed during growth of Eubacterium limosum on this substrate, and does not produce TMA. Carnitine demethylation by organisms like Eubacterium limosum could lessen TMA production in the gut, thereby lessening the propensity towards atherorsclerosis caused by metabolism of TMA in the body. The carnitine proteome led to the description of a carnitine:tetrahydrofolate methyltransferase system. The key carnitine demethylating enzyme is a member of the widespread TMA methyltransferase protein superfamily.
2020-06-19 | PXD013961 | Pride
Project description:Trimethylamine (TMA) is an important gut microbial metabolite strongly associated with human disease. There are prominent gaps in our understanding of how TMA is produced from the essential dietary nutrient L-carnitine, particularly in the anoxic environment of the human gut where oxygen-dependent L-carnitine-metabolizing enzymes are likely inactive. Here, we elucidate the chemical and genetic basis for anaerobic TMA generation from the L-carnitine-derived metabolite γ-butyrobetaine (γbb) by the human gut bacterium Emergencia timonensis. We identify a set of genes upregulated by γbb and demonstrate that the enzymes encoded by the induced γbb utilization (bbu) gene cluster convert γbb to TMA. The key TMA-generating step is catalyzed by a previously unknown type of TMA-lyase enzyme that utilizes a flavin cofactor to catalyze a redox neutral transformation. We identify additional cultured and uncultured host-associated bacteria that possess the bbu gene cluster, providing insights into the distribution of anaerobic γbb metabolism. Lastly, we present genetic, transcriptional, and metabolomic evidence that confirms the relevance of this metabolic pathway in the human gut microbiota. These analyses indicate that the anaerobic pathway is a more substantial contributor to TMA generation from L-carnitine in the human gut than the previously proposed aerobic pathway. The discovery and characterization of the bbu pathway provides the critical missing link in anaerobic metabolism of L-carnitine to TMA, enabling investigation into the connection between this microbial function and human disease.
2021-02-03 | GSE165976 | GEO
Project description:Despite this large body of evidence from clinical studies that an improvement of carnitine status has beneficial effects on metabolic health, serious safety concerns with carnitine supplementation have been raised based on the recent observation that longterm carnitine supplementation (from weaning to 5 mo of age) in a transgenic mouse model of atherosclerosis (Apoe-/- mice) promotes atherosclerosis through gut microbiota-dependent formation of trimethylamine (TMA) and subsequent hepatic conversion into proatherogenic TMA-N-oxide (TMAO) (Koeth et al., 2013). In addition, Lu et al. (2017) found that carnitine supplementation to normal mice for 3 mo induces oxidative stress, liver inflammation, liver lipid accumulation and even liver damage as well as hypercholesterinemia. However, it has to be mentioned that the carnitine dose administered to the mice in the abovementioned studies was extremely high. In order to address whether safety concerns are founded under conditions of longterm supplementation of a carnitine dose used in clinical trials, the present study aimed to investigate the effect of almost lifelong daily administration of a carnitine-supplemented diet (1 g/kg diet) to mice from weaning to 18 mo of age. Considering a body weight of 50 g for an adult mice and a daily feed intake of 5 g, the daily intake of this diet results in a daily carnitine dose of 100 mg/kg body weight which better reflects the dose used in clinical trials. In order to evaluate possible detrimental effects of carnitine supplementation, we investigated parameters of lipid metabolism and stress signaling pathways in the liver and performed a genome-wide transcriptome analysis of skeletal muscle in the mice at advanced age.
2018-09-19 | GSE120120 | GEO
Project description:TMAO is gut microbiota dependent metabolite catalyzed by monooxygenase FMO3 from TMA. TMAO is positively assocaited with different metabolic diseases such as diabetes, chronic kidney disease, and atherosclerosis. We used microarray to analyze the genes regulated by TMAO treatment in primary rat hepatocytes to further understand the mechanistic view of TMAO action.
2019-08-22 | GSE135856 | GEO
Project description:Circulating levels of the gut microbe-derived metabolite trimethylamine-N-oxide(TMAO) have recently been linked to cardiovascular disease (CVD) risk. Here we performed transcriptional profiling in mouse models of altered reverse cholesterol transport (RCT), and serendipitously identified the TMAO-generating enzyme flavin monooxygenase 3 (FMO3) as a powerful modifier of cholesterol metabolism and RCT. Knockdown of FMO3 in cholesterol-fed mice alters biliary lipid secretion, blunts intestinal cholesterol absorption, and limits the production of hepatic oxysterols and cholesteryl esters. Furthermore, FMO3 knockdown stimulates basal and liver X receptor (LXR)-stimulated macrophage RCT, thereby improving cholesterol balance. Conversely, FMO3 knockdown exacerbates hepatic ER stress and inflammation in part by decreasing hepatic oxysterol levels and subsequent LXR activation. FMO3 is thus identified as a central integrator of hepatic cholesterol and triacylglycerol metabolism, inflammation, and ER stress. These studies suggest that the gut microbiota-driven TMA/FMO3/TMAO pathway is a key regulator of lipid metabolism and inflammation.
2014-12-19 | GSE64326 | GEO
Project description:Eubacterium limosum ATCC 8486 makes acetate and butyrate from various substrates and is found in the human intestine. The proteome of choline -grown Eubacterium limosum was obtained in order to identify enzymes required for growth on choline, in particular to identify components that are unique to growth on choline in comparison to other substrates for acetogenesis, such as lactic acid, L-carnitine, or proline betaine. Choline is converted to trimethylamine (TMA) by certain members of the gut microbiome. Subsequent liver metabolism of TMA is now tied to progression of cardiovascular disease. Demethylation of choline is observed during growth of Eubacterium limosum on this substrate, and does not produce TMA. Choline demethylation by organisms like Eubacterium limosum could lessen TMA production in the gut, thereby lessening the propensity towards atherosclerosis caused by metabolism of TMA in the body. This proteome led to discovery of a phosphocholine:tetrahydrofolate methyltransferase system. The key choline demethylating enzyme is a member of the widespread TMA methyltransferase protein superfamily.
2025-06-16 | PXD033467 | Pride
Project description:Circulating levels of the gut microbe-derived metabolite trimethylamine-N-oxide(TMAO) have recently been linked to cardiovascular disease (CVD) risk. Here we performed transcriptional profiling in mouse models of altered reverse cholesterol transport (RCT), and serendipitously identified the TMAO-generating enzyme flavin monooxygenase 3 (FMO3) as a powerful modifier of cholesterol metabolism and RCT. Knockdown of FMO3 in cholesterol-fed mice alters biliary lipid secretion, blunts intestinal cholesterol absorption, and limits the production of hepatic oxysterols and cholesteryl esters. Furthermore, FMO3 knockdown stimulates basal and liver X receptor (LXR)-stimulated macrophage RCT, thereby improving cholesterol balance. Conversely, FMO3 knockdown exacerbates hepatic ER stress and inflammation in part by decreasing hepatic oxysterol levels and subsequent LXR activation. FMO3 is thus identified as a central integrator of hepatic cholesterol and triacylglycerol metabolism, inflammation, and ER stress. These studies suggest that the gut microbiota-driven TMA/FMO3/TMAO pathway is a key regulator of lipid metabolism and inflammation. To identify potential regulators of macrophage reverse cholesterol transport (RCT), liver was isolated from two independent mouse models where the non-biliary RCT pathway known as transintestinal cholesterol excretion (TICE) was either chronically (NPC1L1-liver-transgenic mice) or acutely (ACAT2 antisense oligonucleotide treatment) stimulated. Total RNA was isolated and gene expression levels were profiled on the Affymetrix GeneAtlas MG-430 PM Array Strip (Affymetrix; Santa Clara, CA, USA)
2014-12-19 | E-GEOD-64326 | biostudies-arrayexpress
Project description:Eubacterium limosum ATCC 8486 makes acetate and butyrate from various substrates and is found in the human intestine. The proteome of gamma-butyrobetaine -grown Eubacterium limosum was obtained in order to identify enzymes required for growth on gamma-butyrobetaine, in particular to identify components that are unique to growth on gamma-butyrobetaine in comparison to other substrates for acetogenesis, such as lactic acid, L-carnitine, or proline betaine. Gamma-butyrobetaine is converted to trimethylamine (TMA) by certain members of the gut microbiome. Subsequent liver metabolism of TMA is now tied to progression of cardiovascular disease. Demethylation of gamma-butyrobetaine is observed during growth of Eubacterium limosum on this substrate, and does not produce TMA. Gamma-butyrobetaine demethylation by organisms like Eubacterium limosum could lessen TMA production in the gut, thereby lessening the propensity towards atherosclerosis caused by metabolism of TMA in the body. This proteome led to discovery of gamma-butyrobetaine:tetrahydrofolate methyltransferase system. The key gamma-butyrobetaine demethylating enzyme is a member of the widespread TMA methyltransferase protein superfamily.
2021-11-04 | PXD020152 | Pride
Project description:The composition of the gut microbiome controls innate and adaptive immunity and has emerged as a key regulator of tumor growth and the success of immune checkpoint blockade (ICB) therapy. However, the underlying mechanisms remain unclear. Pancreatic ductal adenocarcinoma (PDAC) tends to be refractory to therapy, including ICB. We found that the gut microbe-derived metabolite trimethylamine N-oxide (TMAO) enhances anti-tumor immunity to PDAC. Delivery of TMAO given intraperitoneally or via dietary choline supplement to PDAC-bearing mice reduces tumor growth and is associated with an immunostimulatory tumor-associated macrophage (TAM) phenotype and activated effector T cell response in the tumor microenvironment. Mechanistically, TMAO signals through potentiating type-I interferon (IFN) pathway and confers anti-tumor effects in a type-I IFN dependent manner. Notably, delivering TMAO-primed macrophages alone produced similar anti-tumor effects. Combining TMAO with ICB (anti-PD1 and/or anti-Tim3) significantly reduced tumor burden and improved survival beyond TMAO or ICB alone. Finally, the levels of trimethylamine (TMA)-producing bacteria and of CutC gene expression associate with improved survivorship and response to anti-PD1 in cancer patients. Together, our study identifies the gut microbial metabolite TMAO as an important driver of anti-tumor immunity and lays the groundwork for new therapeutic strategies.
2022-07-22 | GSE207946 | GEO