Milk polar lipids favorably alter circulating and intestinal ceramide and sphingomyelin species in postmenopausal women
Mélanie Le Barz, Cécile Vors, Emmanuel Combe, Laurie Joumard-Cubizolles, Manon Lecomte, Florent Joffre, Michèle Trauchessec, Sandra Pesenti, Emmanuelle Loizon, Anne-Esther Breyton, Emmanuelle Meugnier, Karène Bertrand, Jocelyne Drai, Chloé Robert, Annie Durand, Charlotte Cuerq, Patrice Gaborit, Nadine Leconte, Annick Bernalier-Donadille, Eddy Cotte, Martine Laville, Stéphanie Lambert-Porcheron, Lemlih Ouchchane, Hubert Vidal, Corinne Malpuech-Brugère, David Cheillan, Marie-Caroline Michalski, Mélanie Le Barz, Cécile Vors, Emmanuel Combe, Laurie Joumard-Cubizolles, Manon Lecomte, Florent Joffre, Michèle Trauchessec, Sandra Pesenti, Emmanuelle Loizon, Anne-Esther Breyton, Emmanuelle Meugnier, Karène Bertrand, Jocelyne Drai, Chloé Robert, Annie Durand, Charlotte Cuerq, Patrice Gaborit, Nadine Leconte, Annick Bernalier-Donadille, Eddy Cotte, Martine Laville, Stéphanie Lambert-Porcheron, Lemlih Ouchchane, Hubert Vidal, Corinne Malpuech-Brugère, David Cheillan, Marie-Caroline Michalski
Abstract
BACKGROUNDHigh circulating levels of ceramides (Cer) and sphingomyelins (SM) are associated with cardiometabolic diseases. The consumption of whole fat dairy products, naturally containing such polar lipids (PL), is associated with health benefits, but the impact on sphingolipidome remains unknown.METHODSIn a 4-week randomized controlled trial, 58 postmenopausal women daily consumed milk PL-enriched cream cheese (0, 3, or 5 g of milk PL). Postprandial metabolic explorations were performed before and after supplementation. Analyses included SM and Cer species in serum, chylomicrons, and feces. The ileal contents of 4 ileostomy patients were also explored after acute milk PL intake.RESULTSMilk PL decreased serum atherogenic C24:1 Cer, C16:1 SM, and C18:1 SM species (Pgroup < 0.05). Changes in serum C16+18 SM species were positively correlated with the reduction of cholesterol (r = 0.706), LDL-C (r = 0.666), and ApoB (r = 0.705) (P < 0.001). Milk PL decreased chylomicron content in total SM and C24:1 Cer (Pgroup < 0.001), parallel to a marked increase in total Cer in feces (Pgroup < 0.001). Milk PL modulated some specific SM and Cer species in both ileal efflux and feces, suggesting differential absorption and metabolization processes in the gut.CONCLUSIONMilk PL supplementation decreased atherogenic SM and Cer species associated with the improvement of cardiovascular risk markers. Our findings bring insights on sphingolipid metabolism in the gut, especially Cer, as signaling molecules potentially participating in the beneficial effects of milk PL.TRIAL REGISTRATIONClinicalTrials.gov, NCT02099032, NCT02146339.FUNDINGANR-11-ALID-007-01; PHRCI-2014: VALOBAB, no. 14-007; CNIEL; GLN 2018-11-07; HCL (sponsor).
Keywords: Cardiovascular disease; Cholesterol; Clinical Trials; Lipid rafts; Metabolism.
Conflict of interest statement
Conflict of interest: This work was supported in part by a grant from the French Dairy Interbranch Organisation (CNIEL). MCM has received research funding for other research projects from CNIEL, Danone-Nutricia Research, and Sodiaal-Candia R&D. MCM has consultancy activities for food, fats and oils, and dairy companies. MCM is a member of the scientific advisory board of ITERG, the Industrial Technical Centre for the oils and fats business sector. These activities had no link with the present study. FJ was, and KB is, an employee of ITERG. PG is an employee of ACTALIA Produits Laitiers, an Agri-Food Technical Institute, with a strong specialization in dairy research and development, and food safety. ML had research collaborations with Mondelez and Bridor without link with the present study. HV has research collaborations with PiLeJe and Roquette without link with the present study.
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References
- Iqbal J, et al. Sphingolipids and lipoproteins in health and metabolic disorders. Trends Endocrinol Metab. 2017;28(7):506–518. doi: 10.1016/j.tem.2017.03.005.
- Norris GH, Blesso CN. Dietary and endogenous sphingolipid metabolism in chronic inflammation. Nutrients. 2017;9(11):1180. doi: 10.3390/nu9111180.
- Duan R-D. Physiological functions and clinical implications of sphingolipids in the gut. J Dig Dis. 2011;12(2):60–70. doi: 10.1111/j.1751-2980.2011.00481.x.
- Gault CR, et al. An overview of sphingolipid metabolism: from synthesis to breakdown. Adv Exp Med Biol. 2010;688:1–23. doi: 10.1007/978-1-4419-6741-1_1.
- Hannun YA, Obeid LM. Sphingolipids and their metabolism in physiology and disease. Nat Rev Mol Cell Biol. 2018;19(3):175–191. doi: 10.1038/nrm.2017.107.
- Meikle PJ, Summers SA. Sphingolipids and phospholipids in insulin resistance and related metabolic disorders. Nat Rev Endocrinol. 2017;13(2):79–91. doi: 10.1038/nrendo.2016.169.
- Gorden DL, et al. Biomarkers of NAFLD progression: a lipidomics approach to an epidemic. J Lipid Res. 2015;56(3):722–736. doi: 10.1194/jlr.P056002.
- Borodzicz S, et al. Sphingolipids in cardiovascular diseases and metabolic disorders. Lipids Health Dis. 2015;14:55.
- Mantovani A, Dugo C. Ceramides and risk of major adverse cardiovascular events: a meta-analysis of longitudinal studies. J Clin Lipidol. 2020;14(2):176–185. doi: 10.1016/j.jacl.2020.01.005.
- de Carvalho LP, et al. Plasma ceramides as prognostic biomarkers and their arterial and myocardial tissue correlates in acute myocardial infarction. JACC Basic Transl Sci. 2018;3(2):163–175. doi: 10.1016/j.jacbts.2017.12.005.
- Wang DD, et al. Plasma ceramides, Mediterranean diet, and incident cardiovascular disease in the PREDIMED Trial (prevención con dieta Mediterránea) Circulation. 2017;135(21):2028–2040. doi: 10.1161/CIRCULATIONAHA.116.024261.
- Laaksonen R. Identifying new Risk markers and potential targets for coronary artery disease: the value of the lipidome and metabolome. Cardiovasc Drugs Ther. 2016;30(1):19–32. doi: 10.1007/s10557-016-6651-8.
- Jiang XC, et al. Plasma sphingomyelin level as a risk factor for coronary artery disease. Arterioscler Thromb Vasc Biol. 2000;20(12):2614–2618. doi: 10.1161/01.ATV.20.12.2614.
- Choi S, Snider AJ. Sphingolipids in high fat diet and obesity-related diseases. Mediators Inflamm. 2015;2015:520618.
- Hilvo M, et al. Ceramides and ceramide scores: clinical applications for cardiometabolic risk stratification. Front Endocrinol (Lausanne) 2020;11:570628.
- Le Barz M, et al. Alterations of endogenous sphingolipid metabolism in cardiometabolic diseases: towards novel therapeutic approaches. Biochimie. 2020;169:133–143. doi: 10.1016/j.biochi.2019.10.003.
- Vesper H, et al. Sphingolipids in food and the emerging importance of sphingolipids to nutrition. J Nutr. 1999;129(7):1239–1250. doi: 10.1093/jn/129.7.1239.
- Drouin-Chartier J-P, et al. Comprehensive review of the impact of dairy foods and dairy fat on cardiometabolic risk. Adv Nutr. 2016;7(6):1041–1051. doi: 10.3945/an.115.011619.
- Thorning TK, et al. Whole dairy matrix or single nutrients in assessment of health effects: current evidence and knowledge gaps. Am J Clin Nutr. 2017;105(5):1033–1045. doi: 10.3945/ajcn.116.151548.
- Norris GH, et al. Milk sphingomyelin improves lipid metabolism and alters gut microbiota in high fat diet-fed mice. J Nutr Biochem. 2016;30:93–101. doi: 10.1016/j.jnutbio.2015.12.003.
- Lecomte M, et al. Milk polar lipids affect in vitro digestive lipolysis and postprandial lipid metabolism in mice. J Nutr. 2015;145(8):1770–1777. doi: 10.3945/jn.115.212068.
- Lecomte M, et al. Dietary emulsifiers from milk and soybean differently impact adiposity and inflammation in association with modulation of colonic goblet cells in high-fat fed mice. Mol Nutr Food Res. 2016;60(3):609–620. doi: 10.1002/mnfr.201500703.
- Eckhardt ERM, et al. Dietary sphingomyelin suppresses intestinal cholesterol absorption by decreasing thermodynamic activity of cholesterol monomers. Gastroenterology. 2002;122(4):948–956. doi: 10.1053/gast.2002.32539.
- Wat E, et al. Dietary phospholipid-rich dairy milk extract reduces hepatomegaly, hepatic steatosis and hyperlipidemia in mice fed a high-fat diet. Atherosclerosis. 2009;205(1):144–150. doi: 10.1016/j.atherosclerosis.2008.12.004.
- Milard M, et al. Acute effects of milk polar lipids on intestinal tight junction expression: towards an impact of sphingomyelin through the regulation of IL-8 secretion? J Nutr Biochem. 2019;65:128–138. doi: 10.1016/j.jnutbio.2018.12.007.
- Milard M, et al. Milk polar lipids in a high-fat diet can prevent body weight gain: modulated abundance of gut bacteria in relation with fecal loss of specific fatty acids. Mol Nutr Food Res. 2019;63(4):e1801078.
- Bourlieu-Lacanal C, et al. Polar lipid composition of bioactive dairy co-products buttermilk and butterserums: emphasis on sphingolipid and ceramide isoforms. Food Chem. 2018;240:67–74. doi: 10.1016/j.foodchem.2017.07.091.
- Conway V, et al. Buttermilk: much more than a source of milk phospholipids. Anim Front. 2014;4(2):44–51. doi: 10.2527/af.2014-0014.
- Vors C, et al. Milk polar lipids reduce lipid cardiovascular risk factors in overweight postmenopausal women: towards a gut sphingomyelin-cholesterol interplay. Gut. 2020;69(3):487–501. doi: 10.1136/gutjnl-2018-318155.
- Nyberg L, et al. Localization and capacity of sphingomyelin digestion in the rat intestinal tract. J Nutr Biochem. 1997;8(3):112–118. doi: 10.1016/S0955-2863(97)00010-7.
- Chaurasia B, Summers SA. Ceramides — lipotoxic inducers of metabolic disorders. Trends Endocrinol Metab. 2015;26(10):538–550. doi: 10.1016/j.tem.2015.07.006.
- Galadari S, et al. Role of ceramide in diabetes mellitus: evidence and mechanisms. Lipids Health Dis. 2013;12:98.
- Bergman BC, et al. Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans. Am J Physiol Endocrinol Metab. 2015;309(4):E398–E408. doi: 10.1152/ajpendo.00134.2015.
- Nilsson A, Duan R-D. Absorption and lipoprotein transport of sphingomyelin. J Lipid Res. 2006;47(1):154–171. doi: 10.1194/jlr.M500357-JLR200.
- Nilsson A, Duan RD. Alkaline sphingomyelinases and ceramidases of the gastrointestinal tract. Chem Phys Lipids. 1999;102(1–2):97–105.
- Ohlsson L, et al. Sphingolipids in human ileostomy content after meals containing milk sphingomyelin. Am J Clin Nutr. 2010;91(3):672–678. doi: 10.3945/ajcn.2009.28311.
- Trošt K, et al. Describing the fecal metabolome in cryogenically collected samples from healthy participants. Sci Rep. 2020;10(1):885. doi: 10.1038/s41598-020-57888-w.
- Bowden J, et al. Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950-metabolites in frozen human plasma. J Lipid Res. 2017;58(12):2275–2288. doi: 10.1194/jlr.M079012.
- Olsen I, Jantzen E. Sphingolipids in bacteria and fungi. Anaerobe. 2001;7(2):103–112. doi: 10.1006/anae.2001.0376.
- Geiger O, et al. Bacterial Sphingolipids and Sulfonolipids. In: Geiger O, eds. Biogenesis of Fatty Acids, Lipids and Membranes. Springer; 2019:123–137.
- doi: 10.1194/jlr.RA120000950. Lee M-T, et al. Dietary sphinganine is selectively assimilated by members of the mammalian gut microbiome [published online July 9, 2020]. J Lipid Res .
- Heaver SL, et al. Sphingolipids in host-microbial interactions. Curr Opin Microbiol. 2018;43:92–99. doi: 10.1016/j.mib.2017.12.011.
- Pan W, et al. Elevation of ceramide and activation of secretory acid sphingomyelinase in patients with acute coronary syndromes. Coron Artery Dis. 2014;25(3):230–235. doi: 10.1097/MCA.0000000000000079.
- Abdel Hadi L, et al. Fostering inflammatory bowel disease: sphingolipid strategies to join forces. Mediators Inflamm. 2016;2016:3827684.
- Feng D, et al. Generating ceramide from sphingomyelin by alkaline sphingomyelinase in the gut enhances sphingomyelin-induced inhibition of cholesterol uptake in Caco-2 cells. Dig Dis Sci. 2010;55(12):3377–3383. doi: 10.1007/s10620-010-1202-9.
- Zhang P, et al. Alkaline sphingomyelinase (NPP7) promotes cholesterol absorption by affecting sphingomyelin levels in the gut: a study with NPP7 knockout mice. Am J Physiol Gastrointest Liver Physiol. 2014;306(10):G903–G908. doi: 10.1152/ajpgi.00319.2013.
- Norris GH, Blesso CN. Dietary sphingolipids: potential for management of dyslipidemia and nonalcoholic fatty liver disease. Nutr Rev. 2017;75(4):274–285. doi: 10.1093/nutrit/nux004.
- Norris GH, et al. Dietary sphingomyelin attenuates hepatic steatosis and adipose tissue inflammation in high-fat-diet-induced obese mice. J Nutr Biochem. 2017;40:36–43. doi: 10.1016/j.jnutbio.2016.09.017.
- Chung RWS, et al. Dietary sphingomyelin lowers hepatic lipid levels and inhibits intestinal cholesterol absorption in high-fat-fed mice. PLoS One. 2013;8(2):e55949–e55949. doi: 10.1371/journal.pone.0055949.
- Hammad SM, et al. Blood sphingolipidomics in healthy humans: impact of sample collection methodology. J Lipid Res. 2010;51(10):3074–3087. doi: 10.1194/jlr.D008532.
- Eich C, et al. Changes in membrane sphingolipid composition modulate dynamics and adhesion of integrin nanoclusters. Sci Rep. 2016;6:20693.
- Gassi JY, et al. Preparation and characterisation of a milk polar lipids enriched ingredient from fresh industrial liquid butter serum: Combination of physico-chemical modifications and technological treatments. Elsevier. 2016;52:26–34.
- Vors C, et al. Modulating absorption and postprandial handling of dietary fatty acids by structuring fat in the meal: a randomized crossover clinical trial. Am J Clin Nutr. 2013;97(1):23–36. doi: 10.3945/ajcn.112.043976.
- Folch J, et al. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957;226(1):497–509. doi: 10.1016/S0021-9258(18)64849-5.
- Becart I, et al. Quantitative analysis of phospholipids by HPLC with a light scattering evaporating detector — application to raw materials for cosmetic use. Journal of High Resolution Chromatography. 1990;13(2):126–129. doi: 10.1002/jhrc.1240130210.
- Rombaut R, et al. Analysis of phospho- and sphingolipids in dairy products by a new HPLC method. J Dairy Sci. 2005;88(2):482–488. doi: 10.3168/jds.S0022-0302(05)72710-7.
- Kyrklund T. Two procedures to remove polar contaminants from a crude brain lipid extract by using prepacked reversed-phase columns. Lipids. 1987;22(4):274–277. doi: 10.1007/BF02533991.
- Sullards MC, et al. Analysis of mammalian sphingolipids by liquid chromatography tandem mass spectrometry (LC-MS/MS) and tissue imaging mass spectrometry (TIMS) Biochim Biophys Acta. 2011;1811(11):838–853.
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