Hyperlipidemia and gut microbiota: the role of prebiotics, probiotics, statins and fibrates

   Aim of the study was to characterize the intestinal microbiota and its metabolites in hyperlipidemia and analyze the associations between the intestinal microbiota and some biological (prebiotics and probiotics) and lipid-lowering (statins, fibrates) drugs in the treatment of hyperlipidemia.

   In hyperlipidemia, the number of bacteria producing toxic metabolites such as lipopolysaccharide and trimethylamine-N-oxide (TMAO) is increased (Bacillota (former Firmicutes), Pseudomonadota (former Proteobacteria), Desulfovibrionaceae) and the number of intestinal producers of beneficial short-chain fatty acids and bile salt hydrolase is decreased (Bacteroidota (former Bacteroidetes), Verrucomicrobia, Bifidobacterium, Lactobacillus, Streptococcus, Eubacterium). Prebiotics can improve lipid metabolism, but the mechanisms of such effect remain unknown. Probiotics (the best studied are Lactobacillus and Bifidobacterium) can remove cholesterol from circulation (by adsorbing and assimilating it on cell membranes), reduce intestinal absorption of cholesterol (by stimulating de novo bile acid synthesis), and modulate cholesterol synthesis (by inhibiting HMG-CoA reductase and reducing the expression of the ATP-associated cassette transporter type A1 gene family). Lactobacillus, in addition to improving the intestinal microbial profile and lipid metabolism, reduces body weight, blood pressure, inflammation, and insulin resistance. Statins and the intestinal microbiota demonstrate mutual influence: a better response to statin treatment is associated with a higher diversity of microbiota, statins are also able to restore the microbiota altered due to pathology to a healthier state (reduce the number of potential pathogens, such as Parabacteroides merdae, and increase the number of beneficial bacteria – Bifidobacterium longum, Bifidobacterium bifidum, Anaerostipes hadrus, Faecalibacterium prausnitzii, Akkermansia muciniphila and the genus Oscillospira, and reduce plasma TMAO levels). Moreover, the effect of statins on the composition and function of the gut microbiota does not depend on a decrease in cholesterol level. The data on the effects of fibrates on the microbiota, studied in mice, are contradictory: in some studies, fenofibrate can reduce caused by a high-fat diet systemic inflammation and lipid metabolism disorders, while in others, on the contrary, it can increase obesity and inflammation.

   Conclusions. The gut microbiome opens up fundamentally new approaches to the treatment of cardiometabolic diseases in the era of precision medicine.

1. Ezhov M.V., Kukharchuk V.V., Sergienko I.V., Alieva A.S., Antsiferov M.B., Ansheles A.A., Arabidze G.G., Aronov D.M., Arutyunov G.P., Akhmedzhanov N.M., … Shlyakhto E.V. Disorders of lipid metabolism. Clinical Guidelines 2023. Rossiyskiy kardiologicheskiy zhurnal = Russian Journal of Cardiology. 2023;28(5): 250–297. [In Russian]. doi: 10.15829/1560-4071-2023-5471

2. Song J.J., Tian W.J., Kwok L.Y., Wang Y.L., Shang Y.N., Menghe B., Wang J.G. Effects of microencapsulated Lactobacillus plantarum LIP-1 on the gut microbiota of hyperlipidaemic rats. Br. J. Nutr. 2017;118(7):481–492. doi: 10.1017/S0007114517002380

3. Huang F., Zheng X., Ma X., Jiang R., Zhou W., Zhou S., Zhang Y., Lei S., Wang S., Kuang J., … Jia W. Theabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism. Nat. Commun. 2019;10(1):4971. doi: 10.1038/s41467-019-12896-x

4. Grigorieva I.N. Atherosclerosis and trimethylamine-N-oxide – the gut microbiota potential. Rossiyskiy kardiologicheskiy zhurnal = Russian Journal of Cardiology. 2022;27(9):142–147. [In Russian]. doi: 10.15829/1560-4071-2022-5038

5. Robitzki D. Newly Renamed Prokaryote Phyla Cause Uproar. Available at: clck.ru/3M3Y2r

6. Kappel B.A., de Angelis L., Puetz A., Ballanti M., Menghini R., Marx N., Federici M. Antibiotic-induced gut microbiota depletion exacerbates host hypercholesterolemia. Pharmacol. Res. 2023;187:106570. doi: 10.1016/j.phrs.2022.106570

7. Jie Z., Xia H., Zhong S.L., Feng Q., Li S., Liang S., Zhong H., Liu Z., Gao Y., Zhao H., … Kristiansen K. The gut microbiome in atherosclerotic cardiovascular disease. Nat. Commun. 2017;8(1):845. doi: 10.1038/s41467-017-00900-1

8. Kaddurah-Daouk R., Baillie R.A., Zhu H., Zeng Z.B., Wiest M.M., Nguyen U.T., Wojnoonski K., Watkins S.M., Trupp M., Krauss R.M. Enteric microbiome metabolites correlate with response to simvastatin treatment. PLoS One. 2011;6(10):e25482. doi: 10.1371/journal.pone.0025482

9. Zhang Y., Jia X.B., Liu Y.C., Yu W.Q., Si Y.H., Guo S.D. Fenofibrate enhances lipid deposition via modulating PPARγ, SREBP-1c, and gut microbiota in ob/ob mice fed a high-fat diet. Front. Nutr. 2022;9:971581. doi: 10.3389/fnut.2022.971581

10. Caparrós-Martín J.A., Maher P., Ward N.C., Saladié M., Agudelo-Romero P., Stick S.M., Chan D.C., Watts G.F., O’Gara F. An analysis of the gut microbiota and related metabolites following PCSK9 inhibition in statin-treated patients with elevated levels of lipoprotein(a). Microorganisms. 2024;12(1):170. doi: 10.3390/microorganisms12010170

11. Jia X., Xu W., Zhang L., Li X., Wang R., Wu S. Impact of gut microbiota and microbiota-related metabolites on hyperlipidemia. Front. Cell. Infect. Microbiol. 2021;11:634780. doi: 10.3389/fcimb.2021.634780

12. Delzenne N.M., Williams C.M. Prebiotics and lipid metabolism. Curr. Opin. Lipidol. 2002;13(1):61–67. doi: 10.1097/00041433-200202000-00009

13. Liu F., Prabhakar M., Ju J., Long H., Zhou H.W. Effect of inulin-type fructans on blood lipid profile and glucose level: a systematic review and meta-analysis of randomized controlled trials. Eur. J. Clin. Nutr. 2017;71(1):9–20. doi: 10.1038/ejcn.2016.156

14. Chen K., Xie K., Liu Z., Nakasone Y., Sakao K., Hossain A., Hou D.X. Preventive effects and mechanisms of garlic on dyslipidemia and gut microbiome dysbiosis. Nutrients. 2019;11(6):1225. doi: 10.3390/nu11061225

15. McRorie J.W., Gibb R.D., McKeown N.M. Inulin-type fructans have no significant beneficial effects on lipid or glucose metabolism. Eur. J. Clin. Nutr. 2017;71(5):677. doi: 10.1038/ejcn.2017.15

16. Li L., Li P., Xu L. Assessing the effects of inulin-type fructan intake on body weight, blood glucose, and lipid profile : A systematic review and meta-analysis of randomized controlled trials. Food Sci. Nutr. 2021;9(8):4598–4616. doi: 10.1002/fsn3.2403

17. Miremadi F., Sherkat F., Stojanovska L. Hypocholesterolaemic effect and anti-hypertensive properties of probiotics and prebiotics : A review. J. Funct. Foods. 2016;25:497–510. doi: 10.1016/j.jff.2016.06.016

18. Abdi M., Esmaeili Gouvarchin Ghaleh H., Ranjbar R. Lactobacilli and Bifidobacterium as anti-atherosclerotic agents. Iran. J. Basic Med. Sci. 2022;25(8):934–946. doi: 10.22038/IJBMS.2022.63860.14073

19. Cho Y.A., Kim J. Effect of probiotics on blood lipid concentrations: A meta-analysis of randomized controlled trials. Medicine (Baltimore). 2015;94(43):e1714. doi: 10.1097/MD.0000000000001714

20. Wang L., Guo M.J., Gao Q., Yang J.F., Yang L., Pang X.L., Jiang X.J. The effects of probiotics on total cholesterol: A meta-analysis of randomized controlled trials. Medicine (Baltimore). 2018;97(5):e9679. doi: 10.1097/MD.0000000000009679

21. Sun J., Buys N. Effects of probiotics consumption on lowering lipids and CVD risk factors : a systematic review and meta-analysis of randomized controlled trials. Ann. Med. 2015;47(6):430–440. doi: 10.3109/07853890.2015.1071872

22. Wu Y., Zhang Q., Ren Y., Ruan Z. Effect of probiotic Lactobacillus on lipid profile : A systematic review and meta-analysis of randomized, controlled trials. PLoS One. 2017;12(6):e0178868. doi: 10.1371/journal.pone.0178868

23. Shimizu M., Hashiguchi M., Shiga T., Tamura H.O., Mochizuki M. Meta-analysis: effects of probiotic supplementation on lipid profiles in normal to mildly hypercholesterolemic individuals. PLoS One. 2015;10(10):e0139795. doi: 10.1371/journal.pone.0139795

24. Fuentes M.C., Lajo T., Carrión J.M., Cuñé J. Cholesterol-lowering efficacy of Lactobacillus plantarum CECT 7527, 7528 and 7529 in hypercholesterolaemic adults. Br. J. Nutr. 2013;109(10):1866–1872. doi: 10.1017/S000711451200373X

25. Kang Y., Kang X., Yang H., Liu H., Yang X., Liu Q., Tian H., Xue Y., Ren P., Kuang X., … Fan W. Lactobacillus acidophilus ameliorates obesity in mice through modulation of gut microbiota dysbiosis and intestinal permeability. Pharmacol. Res. 2022;175:106020. doi: 10.1016/j.phrs.2021.106020

26. Costabile A., Buttarazzi I., Kolida S., Quercia S., Baldini J., Swann J.R., Brigidi P., Gibson G.R. An in vivo assessment of the cholesterol-lowering efficacy of Lactobacillus plantarum ECGC 13110402 in normal to mildly hypercholesterolaemic adults. PLoS One. 2017;12(12):e0187964. doi: 10.1371/journal.pone.0187964

27. Lye H.S., Rahmat-Ali G.R., Liong M.T. Mechanisms of cholesterol removal by lactobacilli under conditions that mimic the human gastrointestinal tract. International Dairy Journal. 2010;20(3):169–175. doi: 10.1016/j.idairyj.2009.10.003

28. Wang K., Yu X., Li Y., Guo Y., Ge L., Pu F., Ma X., Cui W., Marrota F., He F., Li M. Bifidobacterium bifidum TMC3115 can characteristically influence glucose and lipid profile and intestinal microbiota in the middle-aged and elderly. Probiotics Antimicrob. Proteins. 2019;11(4):1182–1194. doi: 10.1007/s12602-018-9441-8

29. Guardamagna O., Amaretti A., Puddu P.E., Raimondi S., Abello F., Cagliero P., Rossi M. Bifidobacteria supplementation: effects on plasma lipid profiles in dyslipidemic children. Nutrition. 2014;30(7-8):831–836. doi: 10.1016/j.nut.2014.01.014

30. Kim Y., Yoon S., Lee S.B., Han H.W., Oh H., Lee W.J., Lee S.M. Fermentation of soy milk via Lactobacillus plantarum improves dysregulated lipid metabolism in rats on a high cholesterol diet. PLoS One. 2014;9(2):e88231. doi: 10.1371/journal.pone.0088231

31. Qiu L., Tao X., Xiong H., Yu J., Wei H. Lactobacillus plantarum ZDY04 exhibits a strain-specific property of lowering TMAO via the modulation of gut microbiota in mice. Food Funct. 2018;9(8):4299–4309. doi: 10.1039/C8FO00349A

32. Hatakka K., Mutanen M., Holma R., Saxelin M., Korpela R. Lactobacillus rhamnosus LC705 together with Propionibacterium freudenreichii ssp shermanii JS administered in capsules is ineffective in lowering serum lipids. J. Am. Coll. Nutr. 2008;27(4):441–447. doi: 10.1080/07315724.2008.10719723

33. Lewis S.J., Burmeister S. A double-blind placebo-controlled study of the effects of Lactobacillus acidophilus on plasma lipids. Eur. J. Clin. Nutr. 2005;59(6):776–780. doi: 10.1038/sj.ejcn.1602139

34. Ebrahimi Z.S., Nasli-Esfahani E., Nadjarzade A., Mozaffari-Khosravi H. Effect of symbiotic supplementation on glycemic control, lipid profiles and microalbuminuria in patients with non-obese type 2 diabetes: a randomized, double-blind, clinical trial. J. Diabetes Metab. Disord. 2017;16:23. doi: 10.1186/s40200-017-0304-8

35. Song M., Yun B., Moon J.H., Park D.J., Lim K., Oh S. Characterization of selected Lactobacillus strains for use as probiotics. Korean J. Food Sci. Anim. Resour. 2015;35(4):551–556. doi: 10.5851/kosfa.2015.35.4.551

36. Korcz E., Kerényi Z., Varga L. Dietary fibers, prebiotics, and exopolysaccharides produced by lactic acid bacteria: potential health benefits with special regard to cholesterol-lowering effects. Food Funct. 2018;9(6):3057–3068. doi: 10.1039/c8fo00118a

37. Sasikumar K., Kozhummal Vaikkath D., Devendra L., Nampoothiri K.M. An exopolysaccharide (EPS) from a Lactobacillus plantarum BR2 with potential benefits for making functional foods. Bioresour. Technol. 2017;241:1152–1156. doi: 10.1016/j.biortech.2017.05.075

38. Grigor’eva I.N., Notova T.E., Suvorova T.S., Nepomnyashchikh D.L. Polymorphisms of the ATP-binding cassette sterol efflux transporter genes g5 and g8 in cardiovascular diseases and type 2 diabetes mellitus. Ateroscleroz = Atherosclerosis. 2024;20(1):6–15. [In Russian]. doi: 10.52727/2078-256X-2024-20-1-6-15

39. Lim F.T., Lim S.M., Ramasamy K. Pediococcus acidilactici LAB4 and Lactobacillus plantarum LAB12 assimilate cholesterol and modulate ABCA1, CD36, NPC1L1 and SCARB1 in vitro. Benef. Microbes. 2017;8(1):97–109. doi: 10.3920/BM2016.0048

40. Chen K., Li S., Chen F., Li J., Luo X. Regulation of the Lactobacillus strains on HMGCoA reductase gene transcription in human HepG2 cells via nuclear factor-κB. J. Microbiol. Biotechnol. 2016;26(2):402–407. doi: 10.4014/jmb.1507.07086

41. Wang P., Li D., Ke W., Liang D., Hu X., Chen F. Resveratrol-induced gut microbiota reduces obesity in high-fat diet-fed mice. Int. J. Obes. (Lond). 2020;44(1):213–225. doi: 10.1038/s41366-019-0332-1

42. Yadegar A., Bar-Yoseph H., Monaghan T.M., Pakpour S., Severino A., Kuijper E.J., Smits W.K., Terveer E.M., Neupane S., Nabavi-Rad A., … Kao D. Fecal microbiota transplantation: current challenges and future landscapes. Clin. Microbiol. Rev. 2024;37(2):e0006022. doi: 10.1128/cmr.00060-22

43. Sun C., Chen L., Shen Z. Mechanisms of gastrointestinal microflora on drug metabolism in clinical practice. Saudi Pharm. J. 2019;27(8):1146–1156. doi: 10.1016/j.jsps.2019.09.011

44. Kim J., Lee H., An J., Song Y., Lee C.K., Kim K., Kong H. Alterations in gut microbiota by statin therapy and possible intermediate effects on hyperglycemia and hyperlipidemia. Front. Microbiol. 2019;10:1947. doi: 10.3389/fmicb.2019.01947

45. Hu X., Li H., Zhao X., Zhou R., Liu H., Sun Y., Fan Y., Shi Y., Qiao S., Liu S., Liu H., Zhang S. Multi-omics study reveals that statin therapy is associated with restoration of gut microbiota homeostasis and improvement in outcomes in patients with acute coronary syndrome. Theranostics. 2021;11(12):5778–5793. doi: 10.7150/thno.55946

46. Sun B., Li L., Zhou X. Comparative analysis of the gut microbiota in distinct statin response patients in East China. J. Microbiol. 2018;56(12):886–892. doi: 10.1007/s12275-018-8152-x

47. Liu Y., Song X., Zhou H., Zhou X., Xia Y., Dong X., Zhong W., Tang S., Wang L., Wen S., Xiao J., Tang L. Gut microbiome associates with lipid-lowering effect of rosuvastatin in vivo. Front. Microbiol. 2018;9:530. doi: 10.3389/fmicb.2018.00530

48. Khan T.J., Ahmed Y.M., Zamzami M.A., Siddiqui A.M., Khan I., Baothman O.A.S., Mehanna M.G., Kuerban A., Kaleemuddin M., Yasir M. Atorvastatin treatment modulates the gut microbiota of the hypercholesterolemic patients. OMICS. 2018;22(2):154–163. doi: 10.1089/omi.2017.0130

49. He X., Zheng N., He J., Liu C., Feng J., Jia W., Li H. Gut microbiota modulation attenuated the hypolipidemic effect of simvastatin in high-fat/cholesterol-diet fed mice. J. Proteome Res. 2017;16(5):1900–1910. doi: 10.1021/acs.jproteome.6b00984

50. Wang L., Wang Y., Wang H., Zhou X., Wei X., Xie Z., Zhang Z., Wang K., Mu J. The influence of the intestinal microflora to the efficacy of Rosuvastatin. Lipids Health Dis. 2018;17(1):151. doi: 10.1186/s12944-018-0801-x

51. Yoo D.H., Kim I.S., Van Le T.K., Jung I.H., Yoo H.H., Kim D.H. Gut microbiota-mediated drug interactions between lovastatin and antibiotics. Drug Metab. Dispos. 2014;42(9):1508–1513. doi: 10.1124/dmd.114.058354

52. Chen C., Mireles R.J., Campbell S.D., Lin J., Mills J.B., Xu J.J., Smolarek T.A. Differential interaction of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab. Dispos. 2005;33(4):537–546. doi: 10.1124/dmd.104.002477

53. Wan Y., Zuo T. Interplays between drugs and the gut microbiome. Gastroenterol. Rep. (Oxf). 2022;10:goac009. doi: 10.1093/gastro/goac009

54. Li D.Y., Li X.S., Chaikijurajai T., Li L., Wang Z., Hazen S.L., Tang W.H.W. Relation of statin use to gut microbial trimethylamine n-oxide and cardiovascular risk. Am. J. Cardiol. 2022;178:26–34. doi: 10.1016/j.amjcard.2022.05.010

55. Caparrós-Martín J.A., Lareu R.R., Ramsay J.P., Peplies J., Reen F.J., Headlam H., Ward N.C., Croft K.D., Newsholme P., Hughes J.D., O’Gara F. Statin therapy causes gut dysbiosis in mice through a PXR-dependent mechanism. Microbiome. 2017;5(1):95. doi: 10.1186/s40168-017-0312-4

56. Dias A.M., Cordeiro G., Estevinho M.M., Veiga R., Figueira L., Reina-Couto M., Magro F.; the Clinical Pharmacology Unit, São João Hospital University Centre. Gut bacterial microbiome composition and statin intake – A systematic review. Pharmacol. Res. Perspect. 2020;8(3):e00601. doi: 10.1002/prp2.601

57. Grigor’eva I.N. Gallstone disease, obesity and the firmicutes/bacteroidetes ratio as a possible biomarker of gut dysbiosis. J. Pers. Med. 2020;11(1):13. doi: 10.3390/jpm11010013

58. Xiang J.Y., Chi Y.Y., Han J.X., Kong P., Liang Z., Wang D., Xiang H., Xie Q. Litchi chinensis seed prevents obesity and modulates the gut microbiota and mycobiota compositions in high-fat diet-induced obese zebrafish. Food Funct. 2022;13(5):2832–2845. doi: 10.1039/d1fo03991a

59. Wang X., Yu C., Liu X., Yang J., Feng Y., Wu Y., Xu Y., Zhu Y., Li W. Fenofibrate ameliorated systemic and retinal inflammation and modulated gut microbiota in high-fat diet-induced mice. Front. Cell. Infect. Microbiol. 2022;12:839592. doi: 10.3389/fcimb.2022.839592

60. de Vos W.M., Tilg H., Van Hul M., Cani P.D. Gut microbiome and health: mechanistic insights. Gut. 2022;71(5):1020–1032. doi: 10.1136/gutjnl-2021-326789

61. Machate D.J., Figueiredo P.S., Marcelino G., Guimarães R.C.A., Hiane P.A., Bogo D., Pinheiro V.A.Z., Oliveira L.C.S., Pott A. Fatty acid diets: regulation of gut microbiota composition and obesity and its related metabolic dysbiosis. Int. J. Mol. Sci. 2020;21(11):4093. doi: 10.3390/ijms21114093

62. Zhang D., Ma Y., Liu J., Wang D., Geng Z., Wen D., Chen H., Wang H., Li L., Zhu X., … Ma L. Fenofibrate improves hepatic steatosis, insulin resistance, and shapes the gut microbiome via TFEB-autophagy in NAFLD mice. Eur. J. Pharmacol. 2023;960:176159. doi: 10.1016/j.ejphar.2023.176159

63. Lu S., Zhang T., Gu W., Yang X., Lu J., Zhao R., Yu J. Volatile oil of Amomum villosum inhibits nonalcoholic fatty liver disease via the gut-liver axis. Biomed. Res. Int. 2018;2018:3589874. doi: 10.1155/2018/3589874