A mutation in mouse Krüppel-like factor 15 alters the gut microbiome and response to obesogenic diet


Autoři: Karen L. Svenson aff001;  Lauren L. Long aff002;  Steven L. Ciciotte aff001;  Mark D. Adams aff002
Působiště autorů: The Jackson Laboratory, Bar Harbor, Maine, United States of America aff001;  The Jackson Laboratory, Farmington, Connecticut, United States of America aff002
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0222536

Souhrn

We identified a mouse strain, HLB444, carrying an N-ethyl-N-nitrosourea (ENU)-induced mutation in a highly conserved C2H2 zinc-finger DNA binding motif of the transcriptional regulator KLF15 that exhibits resistance to diet-induced obesity. Characterization of the HLB444 mutant model on high-fat and chow diets revealed a number of phenotypic differences compared to wild-type controls. When fed a high fat diet, HLB444 had lower body fat, resistance to hepatosteatosis, lower circulating glucose and improved insulin sensitivity compared to C57BL/6J controls. Gut microbial profiles in HLB444 generated from 16S rRNA sequencing of fecal samples differed from controls under both chow and high fat diets. HLB444 shares similar phenotypic traits with engineered full- and adipose-specific Klf15 knockout strains; however, some phenotypic differences between this mutant and the other models suggest that the Klf15 mutation in HLB444 is a hypomorphic variant. The HLB444 model will inform further annotation of transcriptional functions of KLF15, especially with respect to the role of the first zinc-finger domain.

Klíčová slova:

Blood plasma – Diet – Fats – Gene expression – Glucose – Insulin – Mouse models – Obesity


Zdroje

1. Lim S, Eckel RH. Pharmacological treatment and therapeutic perspectives of metabolic syndrome. Rev Endocr Metab Disord. 2014. Epub 2014/10/25. doi: 10.1007/s11154-014-9298-4 25342235.

2. Moore JX, Chaudhary N, Akinyemiju T. Metabolic Syndrome Prevalence by Race/Ethnicity and Sex in the United States, National Health and Nutrition Examination Survey, 1988–2012. Prev Chronic Dis. 2017;14:E24. Epub 2017/03/17. doi: 10.5888/pcd14.160287 28301314; PubMed Central PMCID: PMC5364735.

3. Svenson KL, Bogue M.A., Peters L.L. Identifying new mouse models of cardiovascular disease: A review of high-throughput screens of mutagenized and inbred strains. Journal of Applied Physiology. 2003;94(4):1650–9. doi: 10.1152/japplphysiol.01029.2003 12626479

4. Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 1998;81(4A):7B–12B. Epub 1998/04/04. doi: 10.1016/s0002-9149(98)00031-9 9526807.

5. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet. 2014;384(9943):626–35. Epub 2014/08/19. doi: 10.1016/S0140-6736(14)61177-6 25131982.

6. Bradberry JC, Hilleman DE. Overview of omega-3 Fatty Acid therapies. P T. 2013;38(11):681–91. Epub 2014/01/07. 24391388; PubMed Central PMCID: PMC3875260.

7. Feingold KR, Grunfeld C. Triglyceride Lowering Drugs. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, et al., editors. Endotext. South Dartmouth (MA)2000.

8. Ravussin Y, Koren O, Spor A, Leduc C, Gutman R, Stombaugh J, et al. Responses of Gut Microbiota to Diet Composition and Weight Loss in Lean and Obese Mice. Obesity (Silver Spring). 2011. Epub 2011/05/20. oby2011111 [pii] doi: 10.1038/oby.2011.111 21593810.

9. Turnbaugh PJ, Gordon JI. An invitation to the marriage of metagenomics and metabolomics. Cell. 2008;134(5):708–13. Epub 2008/09/09. S0092-8674(08)01070-2 [pii] doi: 10.1016/j.cell.2008.08.025 18775300.

10. Turnbaugh PJ, Gordon JI. The core gut microbiome, energy balance and obesity. J Physiol. 2009;587(Pt 17):4153–8. Epub 2009/06/06. jphysiol.2009.174136 [pii] doi: 10.1113/jphysiol.2009.174136 19491241; PubMed Central PMCID: PMC2754355.

11. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, et al. A core gut microbiome in obese and lean twins. Nature. 2009;457(7228):480–4. Epub 2008/12/02. nature07540 [pii] doi: 10.1038/nature07540 19043404.

12. Gray S, Wang B, Orihuela Y, Hong EG, Fisch S, Haldar S, et al. Regulation of gluconeogenesis by Kruppel-like factor 15. Cell Metab. 2007;5(4):305–12. doi: 10.1016/j.cmet.2007.03.002 17403374; PubMed Central PMCID: PMC1892530.

13. Fisch S, Gray S, Heymans S, Haldar SM, Wang B, Pfister O, et al. Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A. 2007;104(17):7074–9. Epub 2007/04/18. doi: 10.1073/pnas.0701981104 17438289; PubMed Central PMCID: PMC1855421.

14. Matoba K, Lu Y, Zhang R, Chen ER, Sangwung P, Wang B, et al. Adipose KLF15 Controls Lipid Handling to Adapt to Nutrient Availability. Cell Rep. 2017;21(11):3129–40. doi: 10.1016/j.celrep.2017.11.032 29241541.

15. Nagare T, Sakaue H, Matsumoto M, Cao Y, Inagaki K, Sakai M, et al. Overexpression of KLF15 transcription factor in adipocytes of mice results in down-regulation of SCD1 protein expression in adipocytes and consequent enhancement of glucose-induced insulin secretion. J Biol Chem. 2011;286(43):37458–69. doi: 10.1074/jbc.M111.242651 21862590; PubMed Central PMCID: PMC3199492.

16. Peters LL, Cheever EM, Ellis HR, Magnani PA, Svenson KL, Von Smith R, et al. Large-scale, high-throughput screening for coagulation and hematologic phenotypes in mice. Physiol Genomics. 2002;11(3):185–93. doi: 10.1152/physiolgenomics.00077.2002 12419856.

17. Svenson KL, Ahituv N, Durgin RS, Savage H, Magnani PA, Foreman O, et al. A new mouse mutant for the LDL receptor identified using ENU mutagenesis. J Lipid Res. 2008;49(11):2452–62. Epub 2008/07/18. M800303-JLR200 [pii] doi: 10.1194/jlr.M800303-JLR200 18632552; PubMed Central PMCID: PMC2563210.

18. Arends D, Prins P, Jansen RC, Broman KW. R/qtl: high-throughput multiple QTL mapping. Bioinformatics. 2010;26(23):2990–2. Epub 2010/10/23. doi: 10.1093/bioinformatics/btq565 20966004; PubMed Central PMCID: PMC2982156.

19. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754–60. Epub 2009/05/20. doi: 10.1093/bioinformatics/btp324 19451168; PubMed Central PMCID: PMC2705234.

20. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. Epub 2014/12/18. doi: 10.1186/s13059-014-0550-8 25516281; PubMed Central PMCID: PMC4302049.

21. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545–50. Epub 2005/10/04. doi: 10.1073/pnas.0506580102 16199517; PubMed Central PMCID: PMC1239896.

22. Liberzon A, Subramanian A, Pinchback R, Thorvaldsdottir H, Tamayo P, Mesirov JP. Molecular signatures database (MSigDB) 3.0. Bioinformatics. 2011;27(12):1739–40. Epub 2011/05/07. doi: 10.1093/bioinformatics/btr260 21546393; PubMed Central PMCID: PMC3106198.

23. Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1(6):417–25. Epub 2016/01/16. doi: 10.1016/j.cels.2015.12.004 26771021; PubMed Central PMCID: PMC4707969.

24. The Gene Ontology C. Expansion of the Gene Ontology knowledgebase and resources. Nucleic Acids Res. 2017;45(D1):D331–D8. Epub 2016/12/03. doi: 10.1093/nar/gkw1108 27899567; PubMed Central PMCID: PMC5210579.

25. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30(15):2114–20. Epub 2014/04/04. doi: 10.1093/bioinformatics/btu170 24695404; PubMed Central PMCID: PMC4103590.

26. Magoc T, Salzberg SL. FLASH: fast length adjustment of short reads to improve genome assemblies. Bioinformatics. 2011;27(21):2957–63. Epub 2011/09/10. doi: 10.1093/bioinformatics/btr507 21903629; PubMed Central PMCID: PMC3198573.

27. Edgar RC, Haas BJ, Clemente JC, Quince C, Knight R. UCHIME improves sensitivity and speed of chimera detection. Bioinformatics. 2011;27(16):2194–200. Epub 2011/06/28. doi: 10.1093/bioinformatics/btr381 21700674; PubMed Central PMCID: PMC3150044.

28. Cole JR, Wang Q, Fish JA, Chai B, McGarrell DM, Sun Y, et al. Ribosomal Database Project: data and tools for high throughput rRNA analysis. Nucleic Acids Res. 2014;42(Database issue):D633–42. Epub 2013/11/30. doi: 10.1093/nar/gkt1244 24288368; PubMed Central PMCID: PMC3965039.

29. Wang Q, Garrity GM, Tiedje JM, Cole JR. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl Environ Microbiol. 2007;73(16):5261–7. Epub 2007/06/26. doi: 10.1128/AEM.00062-07 17586664; PubMed Central PMCID: PMC1950982.

30. Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, et al. Clustal W and Clustal X version 2.0. Bioinformatics. 2007;23(21):2947–8. Epub 2007/09/12. doi: 10.1093/bioinformatics/btm404 17846036.

31. Kumar S, Stecher G, Tamura K. MEGA7: Molecular Evolutionary Genetics Analysis Version 7.0 for Bigger Datasets. Mol Biol Evol. 2016;33(7):1870–4. Epub 2016/03/24. doi: 10.1093/molbev/msw054 27004904.

32. Anderson MJ, Crist TO, Chase JM, Vellend M, Inouye BD, Freestone AL, et al. Navigating the multiple meanings of beta diversity: a roadmap for the practicing ecologist. Ecol Lett. 2011;14(1):19–28. Epub 2010/11/13. doi: 10.1111/j.1461-0248.2010.01552.x 21070562.

33. McMurdie PJ, Holmes S. phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS One. 2013;8(4):e61217. Epub 2013/05/01. doi: 10.1371/journal.pone.0061217 23630581; PubMed Central PMCID: PMC3632530.

34. Oksanen J, Blanchet, G., Friendly, M, Kindt, R., Legendre, P., McGlinn, et al. vegan: Community Ecology Package. R package version 2.5–3. https://CRAN.R-project.org/package=vegan2018.

35. Anderson MJ. Permanova: A Frtran Computer Program for Permutational Multivariate Analusis of Variance. Aukland: Department of Statistics, University of Aukland; 2005.

36. Ericsson AC, Davis JW, Spollen W, Bivens N, Givan S, Hagan CE, et al. Effects of vendor and genetic background on the composition of the fecal microbiota of inbred mice. PLoS One. 2015;10(2):e0116704. Epub 2015/02/13. doi: 10.1371/journal.pone.0116704 25675094; PubMed Central PMCID: PMC4326421.

37. Benjamini Y, Hochberg H. Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society. 1995;57(No. 1):289–300.

38. Bieker JJ. Kruppel-like factors: three fingers in many pies. J Biol Chem. 2001;276(37):34355–8. doi: 10.1074/jbc.R100043200 11443140.

39. McConnell BB, Yang VW. Mammalian Kruppel-like factors in health and diseases. Physiol Rev. 2010;90(4):1337–81. doi: 10.1152/physrev.00058.2009 20959618; PubMed Central PMCID: PMC2975554.

40. Svenson KL, Paigen B, Von Smith R, Bogue MA, Barker JE, Naggert JK, et al. Comprehensive characterization of 40 inbred mouse strains reveals broad diversity in cardiovascular phenotypes. Circulation. 2002;Abstract ID: 109540; Publishing ID: 1041.

41. Reifsnyder PC, Churchill G, Leiter EH. Maternal environment and genotype interact to establish diabesity in mice. Genome Res. 2000;10(10):1568–78. Epub 2000/10/24. doi: 10.1101/gr.147000 11042154; PubMed Central PMCID: PMC310941.

42. Lodhi IJ, Yin L, Jensen-Urstad AP, Funai K, Coleman T, Baird JH, et al. Inhibiting adipose tissue lipogenesis reprograms thermogenesis and PPARgamma activation to decrease diet-induced obesity. Cell Metab. 2012;16(2):189–201. Epub 2012/08/07. doi: 10.1016/j.cmet.2012.06.013 22863804; PubMed Central PMCID: PMC3467338.

43. Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science. 2001;294(5549):2166–70. Epub 2001/12/12. doi: 10.1126/science.1066285 11739957.

44. Mori T, Sakaue H, Iguchi H, Gomi H, Okada Y, Takashima Y, et al. Role of Kruppel-like factor 15 (KLF15) in transcriptional regulation of adipogenesis. J Biol Chem. 2005;280(13):12867–75. Epub 2005/01/25. doi: 10.1074/jbc.M410515200 15664998.

45. Fu S, Watkins SM, Hotamisligil GS. The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab. 2012;15(5):623–34. Epub 2012/05/09. doi: 10.1016/j.cmet.2012.03.007 22560215.

46. Nakagawa H, Umemura A, Taniguchi K, Font-Burgada J, Dhar D, Ogata H, et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell. 2014;26(3):331–43. Epub 2014/08/19. doi: 10.1016/j.ccr.2014.07.001 25132496; PubMed Central PMCID: PMC4165611.

47. Hodin CM, Lenaerts K, Grootjans J, de Haan JJ, Hadfoune M, Verheyen FK, et al. Starvation compromises Paneth cells. Am J Pathol. 2011;179(6):2885–93. Epub 2011/10/12. doi: 10.1016/j.ajpath.2011.08.030 21986443; PubMed Central PMCID: PMC3260859.

48. Kaser A, Flak MB, Tomczak MF, Blumberg RS. The unfolded protein response and its role in intestinal homeostasis and inflammation. Exp Cell Res. 2011;317(19):2772–9. Epub 2011/08/09. doi: 10.1016/j.yexcr.2011.07.008 21821022; PubMed Central PMCID: PMC3392150.

49. Jung DY, Chalasani U, Pan N, Friedline RH, Prosdocimo DA, Nam M, et al. KLF15 is a molecular link between endoplasmic reticulum stress and insulin resistance. PLoS One. 2013;8(10):e77851. doi: 10.1371/journal.pone.0077851 24167585; PubMed Central PMCID: PMC3805598.

50. Zhang L, Prosdocimo DA, Bai X, Fu C, Zhang R, Campbell F, et al. KLF15 Establishes the Landscape of Diurnal Expression in the Heart. Cell Rep. 2015;13(11):2368–75. Epub 2015/12/22. doi: 10.1016/j.celrep.2015.11.038 26686628.

51. Aggarwal A, Costa MJ, Rivero-Gutierrez B, Ji L, Morgan SL, Feldman BJ. The Circadian Clock Regulates Adipogenesis by a Per3 Crosstalk Pathway to Klf15. Cell Rep. 2017;21(9):2367–75. Epub 2017/12/01. doi: 10.1016/j.celrep.2017.11.004 29186676; PubMed Central PMCID: PMC5728416.

52. Neve B, Fernandez-Zapico ME, Ashkenazi-Katalan V, Dina C, Hamid YH, Joly E, et al. Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function. Proc Natl Acad Sci U S A. 2005;102(13):4807–12. Epub 2005/03/19. doi: 10.1073/pnas.0409177102 PubMed Central PMCID: PMC554843. 15774581

53. Cao S, Fernandez-Zapico ME, Jin D, Puri V, Cook TA, Lerman LO, et al. KLF11-mediated repression antagonizes Sp1/sterol-responsive element-binding protein-induced transcriptional activation of caveolin-1 in response to cholesterol signaling. J Biol Chem. 2005;280(3):1901–10. Epub 2004/11/09. doi: 10.1074/jbc.M407941200 15531587.

54. Pabona JM, Zeng Z, Simmen FA, Simmen RC. Functional differentiation of uterine stromal cells involves cross-regulation between bone morphogenetic protein 2 and Kruppel-like factor (KLF) family members KLF9 and KLF13. Endocrinology. 2010;151(7):3396–406. Epub 2010/04/23. doi: 10.1210/en.2009-1370 20410205; PubMed Central PMCID: PMC2903926.

55. Gray S, Feinberg MW, Hull S, Kuo CT, Watanabe M, Sen-Banerjee S, et al. The Kruppel-like factor KLF15 regulates the insulin-sensitive glucose transporter GLUT4. J Biol Chem. 2002;277(37):34322–8. Epub 2002/07/05. doi: 10.1074/jbc.M201304200 12097321.

56. Carmody RN, Gerber GK, Luevano JM Jr., Gatti DM, Somes L, Svenson KL, et al. Diet dominates host genotype in shaping the murine gut microbiota. Cell Host Microbe. 2015;17(1):72–84. Epub 2014/12/24. doi: 10.1016/j.chom.2014.11.010 25532804; PubMed Central PMCID: PMC4297240.

57. Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013;110(22):9066–71. Epub 2013/05/15. doi: 10.1073/pnas.1219451110 23671105; PubMed Central PMCID: PMC3670398.

58. Friswell MK, Gika H, Stratford IJ, Theodoridis G, Telfer B, Wilson ID, et al. Site and strain-specific variation in gut microbiota profiles and metabolism in experimental mice. PLoS One. 2010;5(1):e8584. Epub 2010/01/07. doi: 10.1371/journal.pone.0008584 20052418; PubMed Central PMCID: PMC2798964.

59. Pan F, Zhang L, Li M, Hu Y, Zeng B, Yuan H, et al. Predominant gut Lactobacillus murinus strain mediates anti-inflammaging effects in calorie-restricted mice. Microbiome. 2018;6(1):54. Epub 2018/03/23. doi: 10.1186/s40168-018-0440-5 29562943; PubMed Central PMCID: PMC5863386.

60. Parks BW, Nam E, Org E, Kostem E, Norheim F, Hui ST, et al. Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice. Cell metabolism. 2013;17(1):141–52. Epub 2013/01/15. doi: 10.1016/j.cmet.2012.12.007 23312289; PubMed Central PMCID: PMC3545283.

61. Rothschild D, Weissbrod O, Barkan E, Kurilshikov A, Korem T, Zeevi D, et al. Environment dominates over host genetics in shaping human gut microbiota. Nature. 2018;555(7695):210–5. Epub 2018/03/01. doi: 10.1038/nature25973 29489753.

62. McMurdie PJ, Holmes S. Waste not, want not: why rarefying microbiome data is inadmissible. PLoS Comput Biol. 2014;10(4):e1003531. Epub 2014/04/05. doi: 10.1371/journal.pcbi.1003531 24699258; PubMed Central PMCID: PMC3974642.

63. Sheng L, Jena PK, Liu HX, Hu Y, Nagar N, Bronner DN, et al. Obesity treatment by epigallocatechin-3-gallate-regulated bile acid signaling and its enriched Akkermansia muciniphila. FASEB J. 2018:fj201800370R. doi: 10.1096/fj.201800370R 29882708; PubMed Central PMCID: PMC6219838.

64. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Microbial ecology: human gut microbes associated with obesity. Nature. 2006;444(7122):1022–3. Epub 2006/12/22. doi: 10.1038/4441022a 17183309.

65. Haldar SM, Jeyaraj D, Anand P, Zhu H, Lu Y, Prosdocimo DA, et al. Kruppel-like factor 15 regulates skeletal muscle lipid flux and exercise adaptation. Proc Natl Acad Sci U S A. 2012;109(17):6739–44. Epub 2012/04/12. doi: 10.1073/pnas.1121060109 22493257; PubMed Central PMCID: PMC3340075.

66. Chaillou T, Lee JD, England JH, Esser KA, McCarthy JJ. Time course of gene expression during mouse skeletal muscle hypertrophy. J Appl Physiol (1985). 2013;115(7):1065–74. Epub 2013/07/23. doi: 10.1152/japplphysiol.00611.2013 23869057; PubMed Central PMCID: PMC3798821.

67. Otteson DC, Liu Y, Lai H, Wang C, Gray S, Jain MK, et al. Kruppel-like factor 15, a zinc-finger transcriptional regulator, represses the rhodopsin and interphotoreceptor retinoid-binding protein promoters. Invest Ophthalmol Vis Sci. 2004;45(8):2522–30. Epub 2004/07/28. doi: 10.1167/iovs.04-0072 15277472; PubMed Central PMCID: PMC2660604.

68. Prosdocimo DA, Anand P, Liao X, Zhu H, Shelkay S, Artero-Calderon P, et al. Kruppel-like factor 15 is a critical regulator of cardiac lipid metabolism. J Biol Chem. 2014;289(9):5914–24. Epub 2014/01/11. doi: 10.1074/jbc.M113.531384 24407292; PubMed Central PMCID: PMC3937660.

69. Leenders JJ, Wijnen WJ, van der Made I, Hiller M, Swinnen M, Vandendriessche T, et al. Repression of cardiac hypertrophy by KLF15: underlying mechanisms and therapeutic implications. PLoS One. 2012;7(5):e36754. Epub 2012/05/16. doi: 10.1371/journal.pone.0036754 22586493; PubMed Central PMCID: PMC3346753.

70. Jeyaraj D, Haldar SM, Wan X, McCauley MD, Ripperger JA, Hu K, et al. Circadian rhythms govern cardiac repolarization and arrhythmogenesis. Nature. 2012;483(7387):96–9. Epub 2012/03/01. doi: 10.1038/nature10852 22367544; PubMed Central PMCID: PMC3297978.

71. Rodriguez E, Martignetti JA. The Kruppel traffic report: cooperative signals direct KLF8 nuclear transport. Cell Res. 2009;19(9):1041–3. Epub 2009/09/04. doi: 10.1038/cr.2009.103 19727130; PubMed Central PMCID: PMC3059494.

72. Han S, Ray JW, Pathak P, Sweet DR, Zhang R, Gao H, et al. KLF15 regulates endobiotic and xenobiotic metabolism. Nature Metabolism. 2019;1(4):422–30. doi: 10.1038/s42255-019-0054-7

73. Clarke SF, Murphy EF, Nilaweera K, Ross PR, Shanahan F, O'Toole PW, et al. The gut microbiota and its relationship to diet and obesity: new insights. Gut Microbes. 2012;3(3):186–202. Epub 2012/05/11. doi: 10.4161/gmic.20168 22572830; PubMed Central PMCID: PMC3427212.

74. Dao MC, Everard A, Aron-Wisnewsky J, Sokolovska N, Prifti E, Verger EO, et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2016;65(3):426–36. Epub 2015/06/24. doi: 10.1136/gutjnl-2014-308778 26100928.


Článek vyšel v časopise

PLOS One


2019 Číslo 9

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Kurzy

Zvyšte si kvalifikaci online z pohodlí domova

Léčba bolesti v ordinaci praktického lékaře
nový kurz
Autoři: MUDr. PhDr. Zdeňka Nováková, Ph.D.

Revmatoidní artritida: včas a k cíli
Autoři: MUDr. Heřman Mann

Jistoty a nástrahy antikoagulační léčby aneb kardiolog - neurolog - farmakolog - nefrolog - právník diskutují
Autoři: doc. MUDr. Štěpán Havránek, Ph.D., prof. MUDr. Roman Herzig, Ph.D., doc. MUDr. Karel Urbánek, Ph.D., prim. MUDr. Jan Vachek, MUDr. et Mgr. Jolana Těšínová, Ph.D.

Léčba akutní pooperační bolesti
Autoři: doc. MUDr. Jiří Málek, CSc.

Nové antipsychotikum kariprazin v léčbě schizofrenie
Autoři: prof. MUDr. Cyril Höschl, DrSc., FRCPsych.

Všechny kurzy
Kurzy Doporučená témata Časopisy
Přihlášení
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se