Dataset Information

A methylotrophic bacterium growing with the antidiabetic drug metformin as its sole carbon, nitrogen and energy source

ABSTRACT: Metformin is one of the most prescribed antidiabetic agents worldwide, and also considered for other therapeutic applications including cancer and endocrine disorders. Metformin is largely unmetabolised by human enzymes, and its mechanisms of action, likely also involving the microbiome, are not yet well characterised. Increasing presence of metformin in the environment has raised concerns, with reported toxic effects on aquatic life and potentially also on humans. We report on the isolation and characterisation of strain MD1, an aerobic methylotrophic bacterium growing with metformin as its sole carbon, nitrogen and energy source. Sequence analysis of its fully assembled genome allows its affiliation to Aminobacter niigataensis. Strain MD1 degrades metformin into dimethylamine used for growth, leaving guanylurea as a side-product. Differential proteomics and transcriptomics, as well as minitransposon mutagenesis of the strain, point to genes and proteins potentially associated with hydrolytic C-N cleavage of metformin, transport of metformin and guanylurea, and associated regulatory processes. Our results will inform future research on the fate of metformin and its degradation products in the human gut and the environment, and to identify microbial players and enzymes involved in the transformation of pharmaceuticals.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Unclassified Aminobacter

SUBMITTER: Lauriane Kuhn

LAB HEAD: Stéphane Vuilleumier

PROVIDER: PXD036621 | Pride | 2023-03-11

REPOSITORIES: Pride

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Publications

A Methylotrophic Bacterium Growing with the Antidiabetic Drug Metformin as Its Sole Carbon, Nitrogen and Energy Source.

Chaignaud Pauline P Gruffaz Christelle C Borreca Adrien A Fouteau Stéphanie S Kuhn Lauriane L Masbou Jérémy J Rouy Zoé Z Hammann Philippe P Imfeld Gwenaël G Roche David D Vuilleumier Stéphane S

Microorganisms 20221121 11

Metformin is one of the most prescribed antidiabetic agents worldwide and is also considered for other therapeutic applications including cancer and endocrine disorders. It is largely unmetabolized by human enzymes and its presence in the environment has raised concern, with reported toxic effects on aquatic life and potentially also on humans. We report on the isolation and characterisation of strain MD1, an aerobic methylotrophic bacterium growing with metformin as its sole carbon, nitrogen an ...[more]

PMID: 36422372

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Project description:Metformin is a type 2 diabetes medication which extends life span across species when given from young adulthood onwards; late life effects of metformin are not well understood. Here we used C. elegans to investigate the outcome of metformin treatment initiated late in life. We found that, contrary to young age administration, old age metformin treatment interferes with energy homeostasis and shortens life span by aggravating age-associated mitochondrial dysfunction. Nematode mutants defective in mitochondrial respiration, mitochondrial biogenesis and mitochondrial quality control were highly susceptible to metformin killing already at young age while insulin receptor deficient nematodes carrying healthier mitochondria were protected from late life metformin toxicity. In the mammalian cell culture model of replicative senescence metformin killing correlated with loss of mitochondrial membrane potential and strong reduction of systemic ATP levels. Reduced ATP levels and depletion of lipid stores consistent with energy deficit were observed also in nematodes following late life metformin treatment. At the molecular level young animals responded to metformin by inducing adaptive stress responses and longevity-assurance pathways while old nematodes demonstrated a protein expression signature consistent with lipid turnover and energy deficit. Ectopic ATP supplementation was sufficient to alleviate metformin toxicity in human skin fibroblasts highlighting the key contribution of energy deficit to the detrimental effect of metformin. Also, co-exposure with rapamycin, known to stabilize cellular ATP levels under conditions of mitochondrial failure, significantly reduced metformin-inflicted lethality in both cells and old animals. In summary we uncovered a novel negative synergism between metformin treatment and mitochondrial dysfunction which gains importance late in life and may limit therapeutic benefits of metformin for older patients; these side effects can partially be overcome by co-treatment with agents stabilizing cellular ATP levels such as rapamycin.

Project description:The grass-fed cattle obtain nutrients directly from pastures containing limited assimilable energy but abundant amount of fiber; by contrast, grain-fed steers receive a diet that is comprised mainly of grains and serves as an efficient source of high-digestible energy. Besides energy, these two types of diet differ in a large number of nutritional components. Additionally, animals maintained on rich-energy regimen are more likely to develop metabolic disorders and infectious diseases than pasture raised individuals. Thus, we hypothesize that spleenâ??the main immune organâ??may function differently under disparate regimes. The objective of this study was to find the differentially expressed genes in the spleen of grass-fed and grain-fed steers, and furtherly explore the potential involved biopathways. Through RNA sequencing (RNA-Seq), we detected 123 differentially expressed genes. Based on these genes, we performed an Ingenuity Pathway Analysis (IPA) and identified 9 significant molecular networks and 13 enriched biological pathways. Two of the pathways, Nur77 signaling in T lymphocytes and calcium-induced T lymphocyte apoptosis which are immune related, contain a pair of genes HLA-DRA and NR4A1 with dramatically altered expression level. Collectively, our results provided valuable insights into understanding the molecular mechanism of spleen under varied feeding regimens. We collected spleen samples from two randomly chosen animals per group, totaling four samples. The animals were born and raised at the Wye Angus farm, which has produced genetically similar progenies. The genetic resemblance among individuals permitted us to better control the variation between experimental individuals, constituting an excellent resource to perform scientific research. All animals included in this study received the same diet until weaning. Next, we assigned the animals to one certain diet at random, and exclusively raised them under that regimen until termination. The diet of grain-fed group consisted of soybean, shelled corn, corn silage and trace minerals. The grass-fed steers normally received alfalfa harvested from land without any fertilizers, pesticides or other chemicals; during wintertime, bailage was supplied. Grass-fed individuals ate no animal, agricultural or industrial byproducts and never consumed any type of grain. Grain-fed animals reached the market weight around 14 month-old; however, grass-fed steers needed approximately 200 additional days to achieve the same weight. Immediately after termination at the Old Line Custom Meat Company (Baltimore, MD), a small piece of spleen was incised, washed and frozen at -80Â°C for posterior processing.

Dataset Information

A methylotrophic bacterium growing with the antidiabetic drug metformin as its sole carbon, nitrogen and energy source

Publications

A Methylotrophic Bacterium Growing with the Antidiabetic Drug Metformin as Its Sole Carbon, Nitrogen and Energy Source.

Similar Datasets

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