Conjugated linoleic acid ameliorates hepatic steatosis by modulating intestinal permeability and gut microbiota in ob/ob mice

  • Shengli Gao Biomedical Center, Qingdao Medical College, Qingdao University, Qingdao, China
  • Yingying He Key Laboratory of Marine Eco- Environmental Science and Technology, First Institute of Oceanography, Ministry of Natural Resource, Qingdao, China
  • Liping Zhang Key Laboratory of Marine Eco- Environmental Science and Technology, First Institute of Oceanography, Ministry of Natural Resource, Qingdao, China; and Department of Special Medicine, School of Basic Medicine, Qingdao University
  • Lina Liu Department of Special Medicine, School of Basic Medicine, Qingdao University
  • Changfeng Qu Key Laboratory of Marine Eco- Environmental Science and Technology, First Institute of Oceanography, Ministry of Natural Resource, Qingdao, Chin; and Qingdao Key Laboratory of Marine Natural Products Research and Development, Qingdao, China; 5Guangxi Academy of Sciences, Nanning, China
  • Zhou Zheng Key Laboratory of Marine Eco- Environmental Science and Technology, First Institute of Oceanography, Ministry of Natural Resource, Qingdao, Chin; and Qingdao Key Laboratory of Marine Natural Products Research and Development, Qingdao, China; 5Guangxi Academy of Sciences, Nanning, China
  • Jinlai Miao Key Laboratory of Marine Eco- Environmental Science and Technology, First Institute of Oceanography, Ministry of Natural Resource, Qingdao, China; Department of Special Medicine, School of Basic Medicine, Qingdao University; Qingdao Key Laboratory of Marine Natural Products Research and Development, Qingdao, China; Guangxi Academy of Sciences, Nanning, China
Keywords: Conjugated linoleic acid; Obesity; hepatic steatosis; intestinal permeability; gut microbiota

Abstract

Background: Conjugated linoleic acid (CLA) is an effective supplement for reducing fat mass, but its effect on hepatic steatosis remains controversial.

Objective: This study aims to evaluate the effect of CLA on liver fat accumulation, inflammation, gut microbiome, and intestinal barrier integrity.

Design: Wild-type (WT) mice and ob/ob (OB) mice were randomly divided into four groups according to the treatment with/without 1% CLA: WT, WT mice treated with CLA (WT-CLA), OB, and OB mice treated with CLA (OB-CLA). Lipid metabolism and hepatic fat accumulation were evaluated by changes in histological and biochemical parameters. Gene expressions related to liver inflammation and intestinal barrier integrity were examined. The effect of CLA on the gut microbiota population was investigated.

Results: The body weight, fatty tissue mass, and serum lipid levels of the WT-CLA group and OB-CLA group were separately lower than those of the WT group and OB group, but the livers of the WT-CLA group had more fatty lipids, higher triglyceride properties, and saturated fatty acid (FA) composition than those of the WT group, which was contrary to the effect of CLA on OB mice. Real time quantitative PCR results showed that CLA increased hepatic inflammation and intestinal permeability in the WT mice, while it significantly decreased the mRNA expression of liver TNF-α, IFN-γ, and IL-1β and markedly ameliorated intestinal tight junction proteins in the OB mice. The gut microbiota testing indicated a higher abundance of beneficial bacteria (e.g., LachnoclostridiumRoseburiaDubosiellaOscillibacter, and Anaerostipes) and a lower abundance of pro-inflammatory bacteria (e.g., Tyzzerella and Alistipes) in the OB-CLA group than those of the OB group. Correlation analysis suggested that gut microbiota correlated with liver inflammation, intestinal permeability, and hepatic FA composition.

Conclusion: CLA potentially contributed to ameliorating hepatic steatosis in OB mice via modulating liver inflammation, intestinal permeability, and gut microbiota, which suggests CLA is more suitable for people with obesity or overweight.

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References


  1. Zabala A, Portillo MP, Macarulla MT, Rodriguez VM, Fernandez-Quintela A. Effects of cis-9, trans-11 and trans-10, cis-12 CLA isomers on liver and adipose tissue fatty acid profile in hamsters. Lipids 2006; 41(11): 993–1001. doi: 10.1007/s11745-006-5050-5

  2. den Hartigh LJ. Conjugated linoleic acid effects on cancer, obesity, and atherosclerosis: a review of pre-clinical and human trials with current perspectives. Nutrients 2019; 11(2): 370. doi: 10.3390/nu11020370

  3. den Hartigh LJ, Wang S, Goodspeed L, Wietecha T, Houston B, Omer M, et al. Metabolically distinct weight loss by 10,12 CLA and caloric restriction highlight the importance of subcutaneous white adipose tissue for glucose homeostasis in mice. PLoS One 2017; 12(2): e0172912. doi: 10.1371/journal.pone.0172912

  4. Bezan PN, Holland H, de Castro GS, Cardoso JFR, Ovidio PP, Calder PC, et al. High dose of a conjugated linoleic acid mixture increases insulin resistance in rats fed either a low fat or a high fat diet. Exp Clin Endocrinol Diabetes 2018; 126(6): 379–86 doi: 10.1055/s-0043-118348

  5. Fu C, Zhang Y, Yao Q, Wei X, Shi T, Yan P, et al. Maternal conjugated linoleic acid alters hepatic lipid metabolism via the AMPK signaling pathway in chick embryos. Poult Sci 2020; 99(1): 224–34. doi: 10.3382/ps/pez462

  6. Vyas D, Kadegowda AK, Erdman RA. Dietary conjugated linoleic Acid and hepatic steatosis: species-specific effects on liver and adipose lipid metabolism and gene expression. J Nutr Metab 2012; 2012: 932928. doi: 10.1155/2012/932928

  7. Stout MB, Liu LF, Belury MA. Hepatic steatosis by dietary-conjugated linoleic acid is accompanied by accumulation of diacylglycerol and increased membrane-associated protein kinase C epsilon in mice. Mol Nutr Food Res 2011; 55(7): 1010–7. doi: 10.1002/mnfr.201000413

  8. Wendel AA, Purushotham A, Liu LF, Belury MA. Conjugated linoleic acid fails to worsen insulin resistance but induces hepatic steatosis in the presence of leptin in ob/ob mice. J Lipid Res 2008; 49(1): 98–106. doi: 10.1194/jlr.M700195-JLR200

  9. Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver disease: pathophysiological basis for therapy. J Hepatol 2020; 72(3): 558–77. doi: 10.1016/j.jhep.2019.10.003

  10. Duan Y, Llorente C, Lang S, Brandl K, Chu H, Jiang L, et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature 2019; 575(7783): 505–511. doi: 10.1038/s41586-019-1742-x

  11. Todoric J, Di Caro G, Reibe S, Henstridge DC, Green CR, Vrbanac A, et al. Fructose stimulated de novo lipogenesis is promoted by inflammation. Nat Metab 2020; 2(10): 1034–45. doi: 10.1038/s42255-020-0261-2

  12. Barron LK, Bao JW, Aladegbami BG, Colasanti JJ, Guo J, Erwin CR, et al. Toll-like receptor 4 is critical for the development of resection-associated hepatic steatosis. J Pediatr Surg 2017; 52(6): 1014–19. doi: 10.1016/j.jpedsurg.2017.03.026

  13. Han Y-H, Onufer EJ, Huang L-H, Sprung RW, Davidson WS, Czepielewski RS, et al. Enterically derived high-density lipoprotein restrains liver injury through the portal vein. Science 2021; 373(6553). doi: 10.1126/science.abe6729

  14. Chen Y, Yang B, Ross RP, Jin Y, Stanton C, Zhao J, et al. Orally administered CLA ameliorates DSS-induced colitis in mice via intestinal barrier improvement, oxidative stress reduction, and inflammatory cytokine and gut microbiota modulation. J Agric Food Chem 2019; 67(48): 13282–98. doi: 10.1021/acs.jafc.9b05744

  15. Kim YJ, Lee KW, Lee S, Kim H, Lee HJ. The production of high-purity conjugated linoleic acid (CLA) using two-step urea-inclusion crystallization I and hydrophilic arginine-CLA complex. J Food Sci 2003; 68(6): 1948–51. doi: 10.1111/j.1365-2621.2003.tb06999.x

  16. Aldai N, Delmonte P, Alves SP, Bessa RJB, Kramer JKG. Evidence for the initial steps of DHA biohydrogenation by mixed ruminal microorganisms from sheep involves formation of conjugated fatty acids. J Agric Food Chem 2018; 66(4): 842–55. doi: 10.1021/acs.jafc.7b04563

  17. Banni S, Carta G, Angioni E, Murru E, Scanu P, Melis MP, et al. Distribution of conjugated linoleic acid and metabolites in different lipid fractions in the rat liver. J Lipid Res 2001; 42(7): 1056–61. doi: 10.1016/S0022-2275(20)31594-7

  18. Lei F, Zhang XN, Wang W, Xing DM, Xie WD, Su H, et al. Evidence of anti-obesity effects of the pomegranate leaf extract in high-fat diet induced obese mice. Int J Obes (Lond) 2007; 31(6): 1023–9. doi: 10.1038/sj.ijo.0803502

  19. Devaligoda GKYP, Hemantha S, Tharanga T. Determination of adipocyte cell size by H & E stained adipose tissue and collagenase digested isolated adipocytes. Curr Trends Biotechnol Pharm 2018; 12(2): 139–46.

  20. Jin T, Jiang Z, Luan X, Qu Z, Guo F, Gao S, et al. Exogenous orexin-A microinjected into central nucleus of the amygdala modulates feeding and gastric motility in rats. Front Neurosci. 2020; 14: 274. doi: 10.3389/fnins.2020.00274

  21. Parlee SD, Lentz SI, Mori H, MacDougald OA. Quantifying size and number of adipocytes in adipose tissue. Methods Enzymol 2014; 537: 93–122. doi: 10.1016/B978-0-12-411619-1.00006-9

  22. Nahar A, Baker AL, Nichols DS, Bowman JP, Britz ML. Application of thin-layer chromatography-flame ionization detection (TLC-FID) to total lipid quantitation in mycolic-acid synthesizing Rhodococcus and Williamsia species. Int J Mol Sci 2020; 21(5): 1670. doi: 10.3390/ijms21051670

  23. Pang LQ, Liang QL, Wang YM, Ping L, Luo GA. Simultaneous determination and quantification of seven major phospholipid classes in human blood using normal-phase liquid chromatography coupled with electrospray mass spectrometry and the application in diabetes nephropathy. J Chromatogr B Anal Technol Biomed Life Sci 2008; 869(1–2): 118–25. doi: 10.1016/j.jchromb.2008.05.027

  24. Sebedio JL, Juaneda P, Dobson G, Ramilison I, Martin JC, Chardigny JM, et al. Metabolites of conjugated isomers of linoleic acid (CLA) in the rat. Biochim Biophys Acta. 1997; 1345(1): 5–10. doi: 10.1016/s0005-2760(97)00015-5

  25. Guo F, Xu L, Gao S, Sun X, Zhang N, Gong Y. Effect of orexin-A in the arcuate nucleus on cisplatin-induced gastric side effects in rats. Neurosci Res 2019; 143: 53–60. doi: 10.1016/j.neures.2018.06.001

  26. Jarvinen KM, Konstantinou GN, Pilapil M, Arrieta MC, Noone S, Sampson HA, et al. Intestinal permeability in children with food allergy on specific elimination diets. Pediatr Allergy Immunol 2013; 24(6): 589–95. doi: 10.1111/pai.12106

  27. Yang B, Chen HQ, Gao H, Wang JT, Stanton C, Ross RP, et al. Bifidobacterium breve CCFM683 could ameliorate DSS-induced colitis in mice primarily via conjugated linoleic acid production and gut microbiota modulation. J Funct Foods 2018; 49: 61–72. doi: 10.1016/j.jff.2018.08.014

  28. Ma H, Zhang B, Hu Y, Wang J, Liu J, Qin R, et al. Correlation analysis of intestinal redox state with the gut microbiota reveals the positive intervention of tea polyphenols on hyperlipidemia in high fat diet fed mice. J Agric Food Chem 2019; 67(26): 7325–35. doi: 10.1021/acs.jafc.9b02211

  29. Kim JH, Kim YJ, Park Y. Conjugated linoleic acid and postmenopausal women’s health. J Food Sci 2015; 80(6): R1137-43. doi: 10.1111/1750-3841.12905

  30. Han X, Fink MP, Yang R, Delude RL. Increased iNOS activity is essential for intestinal epithelial tight junction dysfunction in endotoxemic mice. Shock 2004; 21(3): 261–70. doi: 10.1097/01.shk.0000112346.38599.10

  31. Wiersema ML, Koester LR, Schmitz-Esser S, Koltes DA. Comparison of intestinal permeability, morphology, and ileal microbial communities of commercial hens housed in conventional cages and cage-free housing systems. Poult Sci 2021; 100(2): 1178–91. doi: 10.1016/j.psj.2020.10.052

  32. Rincel M, Olier M, Minni A, Monchaux de Oliveira C, Matime Y, Gaultier E, et al. Pharmacological restoration of gut barrier function in stressed neonates partially reverses long-term alterations associated with maternal separation. Psychopharmacology (Berl). 2019; 236(5): 1583–96. doi: 10.1007/s00213-019-05252-w

  33. Ascher S, Reinhardt C. The gut microbiota: an emerging risk factor for cardiovascular and cerebrovascular disease. Eur J Immunol 2018; 48(4): 564–75. doi: 10.1002/eji.201646879

  34. Marques TM, Wall R, O’Sullivan O, Fitzgerald GF, Shanahan F, Quigley EM, et al. Dietary trans-10, cis-12-conjugated linoleic acid alters fatty acid metabolism and microbiota composition in mice. Br J Nutr 2015; 113(5): 728–38. doi: 10.1017/S0007114514004206

  35. Belury MA, Kempa-Steczko A. Conjugated linoleic acid modulates hepatic lipid composition in mice. Lipids 1997; 32(2): 199–204. doi: 10.1007/s11745-997-0025-0

  36. Sebedio JL, Angioni E, Chardigny JM, Gregoire S, Juaneda P, Berdeaux O. The effect of conjugated linoleic acid isomers on fatty acid profiles of liver and adipose tissues and their conversion to isomers of 16:2 and 18:3 conjugated fatty acids in rats. Lipids 2001; 36(6): 575–82. doi: 10.1007/s11745-001-0759-8

  37. Liang J, Chen S, Hu Y, Yang Y, Yuan J, Wu Y, et al. Protective roles and mechanisms of Dendrobium officinal polysaccharides on secondary liver injury in acute colitis. Int J Biol Macromol 2018; 107(Pt B): 2201–10. doi: 10.1016/j.ijbiomac.2017.10.085

  38. Lam YY, Ha CW, Campbell CR, Mitchell AJ, Dinudom A, Oscarsson J, et al. Increased gut permeability and microbiota change associate with mesenteric fat inflammation and metabolic dysfunction in diet-induced obese mice. PLoS One 2012; 7(3): e34233. doi: 10.1371/journal.pone.0034233

  39. Damms-Machado A, Louis S, Schnitzer A, Volynets V, Rings A, Basrai M, et al. Gut permeability is related to body weight, fatty liver disease, and insulin resistance in obese individuals undergoing weight reduction. Am J Clin Nutr 2017; 105(1): 127–35. doi: 10.3945/ajcn.116.131110

  40. Li B, Lee C, Chuslip S, Lee D, Biouss G, Wu R, et al. Intestinal epithelial tight junctions and permeability can be rescued through the regulation of endoplasmic reticulum stress by amniotic fluid stem cells during necrotizing enterocolitis. FASEB J 2021; 35(1): e21265. doi: 10.1096/fj.202001426R

  41. den Hartigh LJ, Gao Z, Goodspeed L, Wang S, Das AK, Burant CF, et al. Obese mice losing weight due to trans-10, cis-12 conjugated linoleic acid supplementation or food restriction harbor distinct gut microbiota. J Nutr 2018; 148(4): 562–72. doi: 10.1093/jn/nxy011

  42. Zhao L, Huang Y, Lu L, Yang W, Huang T, Lin Z, et al. Saturated long-chain fatty acid-producing bacteria contribute to enhanced colonic motility in rats. Microbiome 2018; 6(1): 107. doi: 10.1186/s40168-018-0492-6

  43. Reinoso Webb C, den Bakker H, Koboziev I, Jones-Hall Y, Rao Kottapalli K, Ostanin D, et al., Differential susceptibility to T cell-induced colitis in mice: role of the intestinal microbiota. Inflamm Bowel Dis 2018; 24(2): 361–79. doi: 10.1093/ibd/izx014

  44. Benitez-Paez A, Gomez Del Pugar EM, Lopez-Almela I, Moya-Perez A, Codoner-Franch P, Sanz Y. Depletion of Blautia species in the microbiota of obese children relates to intestinal inflammation and metabolic phenotype worsening. mSystems 2020; 5(2): e00857–19. doi: 10.1128/mSystems.00857-19

  45. Parker BJ, Wearsch PA, Veloo ACM, Rodriguez-Palacios A. The genus alistipes: gut bacteria with emerging implications to inflammation, cancer, and mental health. Front Immunol 2020; 11: 906. doi: 10.3389/fimmu.2020.00906

  46. Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol 2014; 12(10): 661–72. doi: 10.1038/nrmicro3344

  47. Yan F, Li N, Shi J, Li H, Yue Y, Jiao W, et al. Lactobacillus acidophilus alleviates type 2 diabetes by regulating hepatic glucose, lipid metabolism and gut microbiota in mice. Food Funct 2019; 10(9): 5804–15. doi: 10.1039/c9fo01062a

  48. Zeng Q, Li D, He Y, Li Y, Yang Z, Zhao X, et al. Discrepant gut microbiota markers for the classification of obesity-related metabolic abnormalities. Sci Rep 2019; 9(1): 13424. doi: 10.1038/s41598-019-49462-w

Published
2022-03-03
How to Cite
Gao S., He Y., Zhang L., Liu L., Qu C., Zheng Z., & Miao J. (2022). Conjugated linoleic acid ameliorates hepatic steatosis by modulating intestinal permeability and gut microbiota in ob/ob mice. Food & Nutrition Research, 66. https://doi.org/10.29219/fnr.v66.8226
Section
Original Articles