Metformin decreases bacterial trimethylamine production and trimethylamine N-oxide levels in db/db mice.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
03 09 2020
03 09 2020
Historique:
received:
26
03
2020
accepted:
17
08
2020
entrez:
5
9
2020
pubmed:
5
9
2020
medline:
9
3
2021
Statut:
epublish
Résumé
The current study aimed to explore whether metformin, the most widely prescribed oral medication for the treatment of type 2 diabetes, alters plasma levels of cardiometabolic disease-related metabolite trimethylamine N-oxide (TMAO) in db/db mice with type 2 diabetes. TMAO plasma concentration was up to 13.2-fold higher in db/db mice when compared to control mice, while in db/db mice fed choline-enriched diet, that mimics meat and dairy product intake, TMAO plasma level was increased 16.8-times. Metformin (250 mg/kg/day) significantly decreased TMAO concentration by up to twofold in both standard and choline-supplemented diet-fed db/db mice plasma. In vitro, metformin significantly decreased the bacterial production rate of trimethylamine (TMA), the precursor of TMAO, from choline up to 3.25-fold in K. pneumoniae and up to 26-fold in P. Mirabilis, while significantly slowing the growth of P. Mirabilis only. Metformin did not affect the expression of genes encoding subunits of bacterial choline-TMA-lyase microcompartment, the activity of the enzyme itself and choline uptake, suggesting that more complex regulation beyond the choline-TMA-lyase is present. To conclude, the TMAO decreasing effect of metformin could be an additional mechanism behind the clinically observed cardiovascular benefits of the drug.
Identifiants
pubmed: 32884086
doi: 10.1038/s41598-020-71470-4
pii: 10.1038/s41598-020-71470-4
pmc: PMC7471276
doi:
Substances chimiques
Methylamines
0
Metformin
9100L32L2N
trimethyloxamine
FLD0K1SJ1A
trimethylamine
LHH7G8O305
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
14555Références
Karlsson, F. H. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103. https://doi.org/10.1038/nature12198 (2013).
doi: 10.1038/nature12198
pubmed: 23719380
pmcid: 23719380
Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60. https://doi.org/10.1038/nature11450 (2012).
doi: 10.1038/nature11450
pubmed: 23023125
pmcid: 23023125
Tang, W. H. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368, 1575–1584. https://doi.org/10.1056/NEJMoa1109400 (2013).
doi: 10.1056/NEJMoa1109400
pubmed: 23614584
pmcid: 3701945
Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63. https://doi.org/10.1038/nature09922 (2011).
doi: 10.1038/nature09922
pubmed: 21475195
pmcid: 21475195
Dambrova, M. et al. Diabetes is associated with higher trimethylamine N-oxide plasma levels. Exp. Clin. Endocrinol Diabetes 124, 251–256. https://doi.org/10.1055/s-0035-1569330 (2016).
doi: 10.1055/s-0035-1569330
pubmed: 27123785
Lever, M. et al. Betaine and trimethylamine-N-oxide as predictors of cardiovascular outcomes show different patterns in diabetes mellitus: an observational study. PLoS ONE 9, e114969. https://doi.org/10.1371/journal.pone.0114969 (2014).
doi: 10.1371/journal.pone.0114969
pubmed: 25493436
pmcid: 4262445
Miao, J. et al. Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis. Nat. Commun. 6, 6498. https://doi.org/10.1038/ncomms7498 (2015).
doi: 10.1038/ncomms7498
pubmed: 25849138
pmcid: 4391288
Chen, S. et al. Trimethylamine N-oxide binds and activates PERK to promote metabolic dysfunction. Cell Metab. https://doi.org/10.1016/j.cmet.2019.08.021 (2019).
doi: 10.1016/j.cmet.2019.08.021
pubmed: 31801057
pmcid: 6720459
Flory, J. H., Keating, S. J., Siscovick, D. & Mushlin, A. I. Identifying prevalence and risk factors for metformin non-persistence: a retrospective cohort study using an electronic health record. BMJ Open 8, e021505. https://doi.org/10.1136/bmjopen-2018-021505 (2018).
doi: 10.1136/bmjopen-2018-021505
pubmed: 30037872
pmcid: 6059278
Forslund, K. et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266. https://doi.org/10.1038/nature15766 (2015).
doi: 10.1038/nature15766
pubmed: 4681099
pmcid: 4681099
Wu, H. et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 23, 850–858. https://doi.org/10.1038/nm.4345 (2017).
doi: 10.1038/nm.4345
pubmed: 28530702
Lee, H. et al. Modulation of the gut microbiota by metformin improves metabolic profiles in aged obese mice. Gut Microbes 9, 155–165. https://doi.org/10.1080/19490976.2017.1405209 (2018).
doi: 10.1080/19490976.2017.1405209
pubmed: 29157127
pmcid: 5989809
Bauer, P. V. et al. Metformin alters upper small intestinal microbiota that impact a glucose-SGLT1-sensing glucoregulatory pathway. Cell Metab. 27, 101–117. https://doi.org/10.1016/j.cmet.2017.09.019 (2018).
doi: 10.1016/j.cmet.2017.09.019
pubmed: 29056513
Proctor, W. R., Bourdet, D. L. & Thakker, D. R. Mechanisms underlying saturable intestinal absorption of metformin. Drug Metab. Dispos 36, 1650–1658. https://doi.org/10.1124/dmd.107.020180 (2008).
doi: 10.1124/dmd.107.020180
pubmed: 18458049
Han, Y. et al. Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis. Cardiovasc. Diabetol. 18, 96. https://doi.org/10.1186/s12933-019-0900-7 (2019).
doi: 10.1186/s12933-019-0900-7
pubmed: 31362743
pmcid: 6668189
Luo, F. et al. Metformin in patients with and without diabetes: a paradigm shift in cardiovascular disease management. Cardiovasc. Diabetol. 18, 54. https://doi.org/10.1186/s12933-019-0860-y (2019).
doi: 10.1186/s12933-019-0860-y
pubmed: 31029144
pmcid: 6486984
Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585. https://doi.org/10.1038/nm.3145 (2013).
doi: 10.1038/nm.3145
pubmed: 23563705
pmcid: 3650111
Koeth, R. A. et al. gamma-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metab. 20, 799–812. https://doi.org/10.1016/j.cmet.2014.10.006 (2014).
doi: 10.1016/j.cmet.2014.10.006
pubmed: 25440057
pmcid: 4255476
Kuka, J. et al. Suppression of intestinal microbiota-dependent production of pro-atherogenic trimethylamine N-oxide by shifting L-carnitine microbial degradation. Life Sci. 117, 84–92. https://doi.org/10.1016/j.lfs.2014.09.028 (2014).
doi: 10.1016/j.lfs.2014.09.028
pubmed: 25301199
Wu, W. K. et al. Identification of TMAO-producer phenotype and host-diet-gut dysbiosis by carnitine challenge test in human and germ-free mice. Gut 68, 1439–1449. https://doi.org/10.1136/gutjnl-2018-317155 (2019).
doi: 10.1136/gutjnl-2018-317155
pubmed: 30377191
Martinez-del Campo, A. et al. Characterization and detection of a widely distributed gene cluster that predicts anaerobic choline utilization by human gut bacteria. mBio https://doi.org/10.1128/mBio.00042-15 (2015).
doi: 10.1128/mBio.00042-15
pubmed: 25873372
pmcid: 4453576
Craciun, S., Marks, J. A. & Balskus, E. P. Characterization of choline trimethylamine-lyase expands the chemistry of glycyl radical enzymes. ACS Chem. Biol. 9, 1408–1413. https://doi.org/10.1021/cb500113p (2014).
doi: 10.1021/cb500113p
pubmed: 24854437
Kalnins, G. et al. Structure and function of CutC choline lyase from human microbiota bacterium Klebsiella pneumoniae. J. Biol. Chem. 290, 21732–21740. https://doi.org/10.1074/jbc.M115.670471 (2015).
doi: 10.1074/jbc.M115.670471
pubmed: 26187464
pmcid: 4571895
Madiraju, A. K. et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510, 542–546. https://doi.org/10.1038/nature13270 (2014).
doi: 10.1038/nature13270
pubmed: 24847880
pmcid: 24847880
McCreight, L. J., Bailey, C. J. & Pearson, E. R. Metformin and the gastrointestinal tract. Diabetologia 59, 426–435. https://doi.org/10.1007/s00125-015-3844-9 (2016).
doi: 10.1007/s00125-015-3844-9
pubmed: 26780750
pmcid: 4742508
Stynen, B. et al. Changes of cell biochemical states are revealed in protein homomeric complex dynamics. Cell 175, 1418–1429. https://doi.org/10.1016/j.cell.2018.09.050 (2018).
doi: 10.1016/j.cell.2018.09.050
pubmed: 30454649
pmcid: 6242466
Al-Obaide, M. A. I. et al. Gut microbiota-dependent trimethylamine-N-oxide and serum biomarkers in patients with T2DM and advanced CKD. J. Clin. Med. https://doi.org/10.3390/jcm6090086 (2017).
doi: 10.3390/jcm6090086
pubmed: 28925931
pmcid: 5615279
Chou, R. H. et al. Trimethylamine N-oxide, circulating endothelial progenitor cells, and endothelial function in patients with stable angina. Sci. Rep. 9, 4249. https://doi.org/10.1038/s41598-019-40638-y (2019).
doi: 10.1038/s41598-019-40638-y
pubmed: 30862856
pmcid: 6414518
Li, T., Chen, Y., Gua, C. & Li, X. Elevated circulating trimethylamine N-oxide levels contribute to endothelial dysfunction in aged rats through vascular inflammation and oxidative stress. Front Physiol. 8, 350. https://doi.org/10.3389/fphys.2017.00350 (2017).
doi: 10.3389/fphys.2017.00350
pubmed: 28611682
pmcid: 5447752
Nafisa, A. et al. Endothelial function and dysfunction: impact of metformin. Pharmacol. Ther. 192, 150–162. https://doi.org/10.1016/j.pharmthera.2018.07.007 (2018).
doi: 10.1016/j.pharmthera.2018.07.007
pubmed: 30056057
Sardu, C. et al. Effects of metformin therapy on coronary endothelial dysfunction in patients with prediabetes with stable angina and nonobstructive coronary artery stenosis: the CODYCE multicenter prospective study. Diabetes Care 42, 1946–1955. https://doi.org/10.2337/dc18-2356 (2019).
doi: 10.2337/dc18-2356
pubmed: 30796109
Eskens, B. J., Zuurbier, C. J., van Haare, J., Vink, H. & van Teeffelen, J. W. Effects of two weeks of metformin treatment on whole-body glycocalyx barrier properties in db/db mice. Cardiovasc. Diabetol. 12, 175. https://doi.org/10.1186/1475-2840-12-175 (2013).
doi: 10.1186/1475-2840-12-175
pubmed: 24308370
pmcid: 3866460
Hamidi Shishavan, M. et al. Metformin improves endothelial function and reduces blood pressure in diabetic spontaneously hypertensive rats independent from glycemia control: comparison to vildagliptin. Sci. Rep. 7, 10975. https://doi.org/10.1038/s41598-017-11430-7 (2017).
doi: 10.1038/s41598-017-11430-7
pubmed: 28887562
pmcid: 5591199
Beli, E., Prabakaran, S., Krishnan, P., Evans-Molina, C. & Grant, M. B. Loss of diurnal oscillatory rhythms in gut microbiota correlates with changes in circulating metabolites in type 2 diabetic db/db mice. Nutrients https://doi.org/10.3390/nu11102310 (2019).
doi: 10.3390/nu11102310
pubmed: 31569518
pmcid: 6835667
Huo, T. et al. Metabonomic study of biochemical changes in the serum of type 2 diabetes mellitus patients after the treatment of metformin hydrochloride. J. Pharm. Biomed. Anal. 49, 976–982. https://doi.org/10.1016/j.jpba.2009.01.008 (2009).
doi: 10.1016/j.jpba.2009.01.008
pubmed: 19249171
Velebova, K. et al. The effect of metformin on serum levels of Trimethylamine-N-oxide in patients with type 2 diabetes/prediabetes and chronic heart failure. Diabetologia 59, S533. https://doi.org/10.1007/s00125-016-4046-9 (2016).
doi: 10.1007/s00125-016-4046-9
Latkovskis, G. et al. Loop diuretics decrease the renal elimination rate and increase the plasma levels of trimethylamine-N-oxide. Br. J. Clin. Pharmacol. 84, 2634–2644. https://doi.org/10.1111/bcp.13728 (2018).
doi: 10.1111/bcp.13728
pubmed: 30069897
pmcid: 6177719
Bailey, C. J., Wilcock, C. & Scarpello, J. H. Metformin and the intestine. Diabetologia 51, 1552–1553. https://doi.org/10.1007/s00125-008-1053-5 (2008).
doi: 10.1007/s00125-008-1053-5
pubmed: 18528677
Herring, T. I., Harris, T. N., Chowdhury, C., Mohanty, S. K. & Bobik, T. A. A Bacterial microcompartment is used for choline fermentation by Escherichia coli 536. J. Bacteriol. https://doi.org/10.1128/JB.00764-17 (2018).
doi: 10.1128/JB.00764-17
pubmed: 29507086
pmcid: 5915781
Kilkenny, C. et al. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br. J. Pharmacol. 160, 1577–1579. https://doi.org/10.1111/j.1476-5381.2010.00872.x (2010).
doi: 10.1111/j.1476-5381.2010.00872.x
pubmed: 20649561
pmcid: 2936830
McGrath, J. C., Drummond, G. B., McLachlan, E. M., Kilkenny, C. & Wainwright, C. L. Guidelines for reporting experiments involving animals: the ARRIVE guidelines. Br. J. Pharmacol. 160, 1573–1576. https://doi.org/10.1111/j.1476-5381.2010.00873.x (2010).
doi: 10.1111/j.1476-5381.2010.00873.x
pubmed: 20649560
pmcid: 2936829
Dambrova, M. et al. Meldonium decreases the diet-increased plasma levels of trimethylamine N-oxide, a metabolite associated with atherosclerosis. J. Clin. Pharmacol. 53, 1095–1098. https://doi.org/10.1002/jcph.135 (2013).
doi: 10.1002/jcph.135
pubmed: 23893520
Sack, J. S. et al. Structural basis for the high-affinity binding of pyrrolotriazine inhibitors of p38 MAP kinase. Acta Crystallogr. D Biol. Crystallogr. D64, 705–710. https://doi.org/10.1107/S0907444908010032 (2008).
doi: 10.1107/S0907444908010032
pubmed: 18566506
Seim, H., Löster, H., Claus, R., Kleber, H.-P. & Strack, E. Formation of γ-butyrobetaine and trimethylamine from quaternary ammonium compounds structure-related to l-carnitine and choline by Proteus vulgaris. FEMS Microbiol. Lett. 13, 201–205. https://doi.org/10.1111/j.1574-6968.1982.tb08256.x (1982).
doi: 10.1111/j.1574-6968.1982.tb08256.x
Rose, R. L. Measurements of flavin-containing monooxygenase (FMO) activities. Curr Protoc Toxicol Chapter 4, Unit4 9, https://doi.org/10.1002/0471140856.tx0409s13 (2002).
Roberts, A. B. et al. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat. Med. 24, 1407–1417. https://doi.org/10.1038/s41591-018-0128-1 (2018).
doi: 10.1038/s41591-018-0128-1
pubmed: 30082863
pmcid: 6129214
Liepinsh, E. et al. Decreased acylcarnitine content improves insulin sensitivity in experimental mice models of insulin resistance. Pharmacol. Res. 113, 788–795. https://doi.org/10.1016/j.phrs.2015.11.014 (2016).
doi: 10.1016/j.phrs.2015.11.014
pubmed: 26621248
Ferrand, J. et al. Comparison of seven methods for extraction of bacterial DNA from fecal and cecal samples of mice. J. Microbiol. Methods 105, 180–185. https://doi.org/10.1016/j.mimet.2014.07.029 (2014).
doi: 10.1016/j.mimet.2014.07.029
pubmed: 25093756
Ye, J. et al. Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinform. 13, 134. https://doi.org/10.1186/1471-2105-13-134 (2012).
doi: 10.1186/1471-2105-13-134