Digestive Diseases and Sciences

, Volume 63, Issue 12, pp 3317–3328 | Cite as

Altered Metabolic Profile of Triglyceride-Rich Lipoproteins in Gut-Lymph of Rodent Models of Sepsis and Gut Ischemia-Reperfusion Injury

  • Jiwon HongEmail author
  • Shorena Nachkebia
  • Soe Min Tun
  • Amorita Petzer
  • John A. Windsor
  • Anthony J. Hickey
  • Anthony R. Phillips
Original Article



Triglyceride-rich lipoproteins are important in dietary lipid absorption and subsequent energy distribution in the body. Their importance in the gut-lymph may have been overlooked in sepsis, the most common cause of critical illness, and in gut ischemia-reperfusion injury, a common feature of many critical illnesses.


We aimed to undertake an exploratory study of triglyceride-rich lipoprotein fractions in gut-lymph using untargeted metabolic profiling to identify altered metabolites in sepsis or gut ischemia-reperfusion.


The gut-lymph was collected from rodent sham, sepsis, and gut ischemia-reperfusion models. The triglyceride-rich lipoprotein-enriched fractions isolated from the gut-lymph were subjected to a dual metabolomics analysis approach: non-polar metabolite analysis by ultra-high performance liquid chromatography–mass spectrometry and polar metabolite analysis by gas chromatography–mass spectrometry.


The metabolite analysis of gut-lymph triglyceride-rich lipoprotein fractions revealed a significant increase (FDR-adjusted P value < 0.05) in myo-inositol in the sepsis group and monoacylglycerols [(18:1) and (18:2)] in gut ischemia-reperfusion. There were no significantly increased specific metabolites in the lipoprotein-enriched fractions of both sepsis and gut ischemia-reperfusion. In contrast, there was a widespread decrease in multiple lipid species in sepsis (35 out of 190; adjusted P < 0.05), but not in the gut ischemia-reperfusion.


Increased levels of myo-inositol and monoacylglycerols, and decreased multiple lipid species in the gut-lymph triglyceride-rich lipoprotein fraction could be candidates for new biomarkers and/or involved in the progression of sepsis and gut ischemia-reperfusion pathobiology.


Metabolomics Lipoproteins Lymph Gut Critical illness 







Gas chromatography–mass spectrometry










Mean arterial pressure


Multiple organ dysfunction syndrome








Quality control




Triglyceride-rich lipoprotein


Ultra-high performance liquid chromatography–mass spectrometry


Very low-density lipoprotein



We wish to thank C Keven of the Liggins Institute, University of Auckland, for the biochemical analyte measurements; S Church and P Begley from the Centre for Advanced Discovery and Experimental Therapeutics, Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health at the University of Manchester, UK (supported by the NIHR Manchester Biomedical Research Centre), for their technical assistance with the metabolomic analyses.

Author’s contributions

JH, ARP, AJH, and JAW designed the studies. SN, SMT, and AP performed animal surgery. JH interpreted the data and wrote the manuscript, and ARP, AJH, and JAW edited the manuscript. All authors approved the manuscript.


This work was supported by the Early Careers Academic Grants, Association of Commonwealth Universities; Maurice and Phyllis Paykel Trust; Performance-Based Research Fund, University of Auckland; Auckland Medical Research Foundation; Faculty Research Development Fund, University of Auckland; and Health Research Council of New Zealand.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Supplementary material

10620_2018_5270_MOESM1_ESM.xlsx (155 kb)
Supplementary material 1 (XLSX 155 kb)
10620_2018_5270_MOESM2_ESM.docx (932 kb)
Supplementary material 2 (DOCX 931 kb)


  1. 1.
    Urden LD, Stacy KM, Lough ME. Critical Care Nursing: Diagnosis and Management. 7th ed. Amsterdam: Elsevier; 2014.Google Scholar
  2. 2.
    Dewar D, Moore FA, Moore EE, Balogh Z. Postinjury multiple organ failure. Injury. 2009;40:912–918.CrossRefGoogle Scholar
  3. 3.
    Swank GM, Deitch EA. Role of the gut in multiple organ failure: bacterial translocation and permeability changes. World J Surg. 1996;20:411–417.CrossRefGoogle Scholar
  4. 4.
    Deitch EA, Xu D, Kaise VL. Role of the gut in the development of injury- and shock induced SIRS and MODS: the gut-lymph hypothesis, a review. Front Biosci. 2006;11:520–528.CrossRefGoogle Scholar
  5. 5.
    Bisgaier CL, Glickman RM. Intestinal synthesis, secretion, and transport of lipoproteins. Annu Rev Physiol. 1983;45:625–636.CrossRefGoogle Scholar
  6. 6.
    Ockner RK, Hughes FB, Isselbacher KJ. Very low density lipoproteins in intestinal lymph: origin, composition, and role in lipid transport in the fasting state. J Clin Invest. 1969;48:2079–2088.CrossRefPubMedCentralGoogle Scholar
  7. 7.
    Green PH, Glickman RM, Saudek CD, Blum CB, Tall AR. Human intestinal lipoproteins. Studies in chyluric subjects. J Clin Invest. 1979;64:233–242.CrossRefPubMedCentralGoogle Scholar
  8. 8.
    Jonas A, Phillips MC. Lipoprotein structure. In: Vance DE, ed. Biochemistry of Lipids, Lipoproteins and Membranes. 5th ed. Vance JE: Elsevier B.V; 2008:485–506.CrossRefGoogle Scholar
  9. 9.
    Lo CM, Nordskog BK, Nauli AM, et al. Why does the gut choose apolipoprotein B48 but not B100 for chylomicron formation? Am J Physiol Gastrointest Liver Physiol. 2008;294:G344–G352.CrossRefGoogle Scholar
  10. 10.
    Ali Abdelhamid Y, Cousins CE, Sim JA, et al. Effect of critical illness on triglyceride absorption. JPEN J Parenter Enteral Nutr. 2015;39:966–972.CrossRefPubMedCentralGoogle Scholar
  11. 11.
    Lind L, Lithell H. Impaired glucose and lipid metabolism seen in intensive care patients is related to severity of illness and survival. Clin Intensive Care. 1994;5:100–105.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Wishart DS, Knox C, Guo AC, et al. HMDB: a knowledgebase for the human metabolome. Nucleic Acids Res. 2009;37:D603–D610.CrossRefPubMedCentralGoogle Scholar
  13. 13.
    Otero-Anton E, Gonzalez-Quintela A, Lopez-Soto A, et al. Cecal ligation and puncture as a model of sepsis in the rat: influence of the puncture size on mortality, bacteremia, endotoxemia and tumor necrosis factor alpha levels. Eur Surg Res. 2001;33:77–79.CrossRefPubMedCentralGoogle Scholar
  14. 14.
    Akcakaya A, Alimoglu O, Sahin M, Abbasoglu SD. Ischemia-reperfusion injury following superior mesenteric artery occlusion and strangulation obstruction. J Surg Res. 2002;108:39–43.CrossRefPubMedCentralGoogle Scholar
  15. 15.
    Windmueller HG, Levy RI. Production of beta-lipoprotein by intestine in the rat. J Biol Chem. 1968;243:4878–4884.PubMedGoogle Scholar
  16. 16.
    Cox RA, García-Palmieri MR. Cholesterol, Triglycerides, and Associated Lipoproteins. Boston: Butterworth Publishers; 1990.Google Scholar
  17. 17.
    Oikawa S, Mizunuma Y, Iwasaki Y, Tharwat M. Changes of very low-density lipoprotein concentration in hepatic blood from cows with fasting-induced hepatic lipidosis. Can J Vet Res. 2010;74:317–320.PubMedPubMedCentralGoogle Scholar
  18. 18.
    R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.
  19. 19.
    Dunn WB, Broadhurst D, Begley P, et al. Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry. Nat Protoc. 2011;6:1060–1083.CrossRefGoogle Scholar
  20. 20.
    Begley P, Francis-McIntyre S, Dunn WB, et al. Development and performance of a gas chromatography-time-of-flight mass spectrometry analysis for large-scale nontargeted metabolomic studies of human serum. Anal Chem. 2009;81:7038–7046.CrossRefPubMedCentralGoogle Scholar
  21. 21.
    Hui DY. Intestinal phospholipid and lysophospholipid metabolism in cardiometabolic disease. Curr Opin Lipidol. 2016;27:507–512.CrossRefPubMedCentralGoogle Scholar
  22. 22.
    Morishita K, Aiboshi J, Kobayashi T, et al. Lipidomics analysis of mesenteric lymph after trauma and hemorrhagic shock. J Trauma Acute Care Surg. 2012;72:1541–1547.CrossRefPubMedCentralGoogle Scholar
  23. 23.
    Flint RS, Phillips AR, Power SE, et al. Acute pancreatitis severity is exacerbated by intestinal ischemia-reperfusion conditioned mesenteric lymph. Surgery. 2008;143:404–413.CrossRefPubMedCentralGoogle Scholar
  24. 24.
    Deitch EA. Gut lymph and lymphatics: a source of factors leading to organ injury and dysfunction. Ann N Y Acad Sci. 2010;1207:E103–E111.CrossRefPubMedCentralGoogle Scholar
  25. 25.
    Qin X, Dong W, Sharpe SM, et al. Role of lipase-generated free fatty acids in converting mesenteric lymph from a noncytotoxic to a cytotoxic fluid. Am J Physiol Gastrointest Liver Physiol. 2012;303:G969–G978.CrossRefPubMedCentralGoogle Scholar
  26. 26.
    Lavy A, Ben Amotz A, Aviram M. Increased susceptibility to undergo lipid peroxidation of chylomicrons and low-density lipoprotein in celiac disease. Ann Nutr Metab. 1993;37:68–74.CrossRefPubMedCentralGoogle Scholar
  27. 27.
    Khan M, Pelengaris S, Cooper M, et al. Oxidised lipoproteins may promote inflammation through the selective delay of engulfment but not binding of apoptotic cells by macrophages. Atherosclerosis. 2003;171:21–29.CrossRefPubMedCentralGoogle Scholar
  28. 28.
    Sachinidis A, Kettenhofen R, Seewald S, et al. Evidence that lipoproteins are carriers of bioactive factors. Arterioscler Thromb Vasc Biol. 1999;19:2412–2421.CrossRefPubMedCentralGoogle Scholar
  29. 29.
    Kauppi AM, Edin A, Ziegler I, et al. Metabolites in blood for prediction of bacteremic sepsis in the emergency room. PLoS ONE. 2016;11:e0147670.CrossRefPubMedCentralGoogle Scholar
  30. 30.
    Beloborodova NV, Olenin AY, Pautova AK. Metabolomic findings in sepsis as a damage of host-microbial metabolism integration. J Crit Care. 2018;43:246–255.CrossRefGoogle Scholar
  31. 31.
    Park DW, Kwak DS, Park YY, et al. Impact of serial measurements of lysophosphatidylcholine on 28-day mortality prediction in patients admitted to the intensive care unit with severe sepsis or septic shock. J Crit Care. 2014;29:882 e885-811.CrossRefGoogle Scholar
  32. 32.
    Ferrario M, Cambiaghi A, Brunelli L, et al. Mortality prediction in patients with severe septic shock: a pilot study using a target metabolomics approach. Sci Rep. 2016;6:20391.CrossRefPubMedCentralGoogle Scholar
  33. 33.
    Cambiaghi A, Pinto BB, Brunelli L, et al. Characterization of a metabolomic profile associated with responsiveness to therapy in the acute phase of septic shock. Sci Rep. 2017;7:9748.CrossRefPubMedCentralGoogle Scholar
  34. 34.
    Evangelatos N, Bauer P, Reumann M, et al. Metabolomics in sepsis and its impact on public health. Public Health Genom. 2017;20:274–285.CrossRefGoogle Scholar
  35. 35.
    Su L, Huang Y, Zhu Y, et al. Discrimination of sepsis stage metabolic profiles with an LC/MS–MS-based metabolomics approach. BMJ Open Respir Res. 2014;1:e000056.CrossRefPubMedCentralGoogle Scholar
  36. 36.
    Eckerle M, Ambroggio L, Puskarich MA, et al. Metabolomics as a driver in advancing precision medicine in sepsis. Pharmacotherapy. 2017;37:1023–1032.CrossRefPubMedCentralGoogle Scholar
  37. 37.
    Ludwig KR, Hummon AB. Mass spectrometry for the discovery of biomarkers of sepsis. Mol Biosyst. 2017;13:648–664.CrossRefPubMedCentralGoogle Scholar
  38. 38.
    Mickiewicz B, Vogel HJ, Wong HR, Winston BW. Metabolomics as a novel approach for early diagnosis of pediatric septic shock and its mortality. Am J Respir Crit Care Med. 2013;187:967–976.CrossRefPubMedCentralGoogle Scholar
  39. 39.
    Izquierdo-Garcia JL, Nin N, Ruiz-Cabello J, et al. A metabolomic approach for diagnosis of experimental sepsis. Intensive Care Med. 2011;37:2023–2032.CrossRefGoogle Scholar
  40. 40.
    Mickiewicz B, Tam P, Jenne CN, et al. Integration of metabolic and inflammatory mediator profiles as a potential prognostic approach for septic shock in the intensive care unit. Crit Care. 2015;19:11.CrossRefPubMedCentralGoogle Scholar
  41. 41.
    Stringer KA, Serkova NJ, Karnovsky A, et al. Metabolic consequences of sepsis-induced acute lung injury revealed by plasma H-1-nuclear magnetic resonance quantitative metabolomics and computational analysis. Am J Physiol Lung Cell Mol Physiol. 2011;300:L4–L11.CrossRefGoogle Scholar
  42. 42.
    Fahrner R, Beyoglu D, Beldi G, Idle JR. Metabolomic markers for intestinal ischemia in a mouse model. J Surg Res. 2012;178:879–887.CrossRefPubMedCentralGoogle Scholar
  43. 43.
    Khadaroo RG, Churchill TA, Tso V, et al. Metabolomic profiling to characterize acute intestinal ischemia/reperfusion injury. PLoS ONE. 2017;12:e0179326.CrossRefPubMedCentralGoogle Scholar
  44. 44.
    Li Y, Hou M, Wang JG, et al. Changes of lymph metabolites in a rat model of sepsis induced by cecal ligation and puncture. J Trauma Acute Care Surg. 2012;73:1545–1552.CrossRefGoogle Scholar
  45. 45.
    Holub BJ. Metabolism and function of myo-inositol and inositol phospholipids. Annu Rev Nutr. 1986;6:563–597.CrossRefGoogle Scholar
  46. 46.
    Croze ML, Soulage CO. Potential role and therapeutic interests of myo-inositol in metabolic diseases. Biochimie. 2013;95:1811–1827.CrossRefGoogle Scholar
  47. 47.
    Hayashi E, Maeda T, Tomita T. The effect of myo-inositol deficiency on lipid metabolism in rats. I. The alteration of lipid metabolism in myo-inositol deficient rats. Biochim Biophys Acta. 1974;360:134–145.CrossRefGoogle Scholar
  48. 48.
    Nakanishi T, Burg MB. Osmoregulatory fluxes of myo-inositol and betaine in renal cells. Am J Physiol. 1989;257:C964–C970.CrossRefGoogle Scholar
  49. 49.
    Holub BJ. The nutritional significance, metabolism, and function of myo-inositol and phosphatidylinositol in health and disease. Adv Nutr Res. 1982;4:107–141.CrossRefGoogle Scholar
  50. 50.
    Caspary WF, Crane RK. Active transport of myo-inositol and its relation to the sugar transport system in hamster small intestine. Biochim Biophys Acta. 1970;203:308–316.CrossRefPubMedCentralGoogle Scholar
  51. 51.
    Konietzny U, Greiner R. Molecular and catalytic properties of phytate-degrading enzymes (phytases). Int J Food Sci Technol. 2002;37:791–812.CrossRefGoogle Scholar
  52. 52.
    Haak BW, Wiersinga WJ. The role of the gut microbiota in sepsis. Lancet Gastroenterol Hepatol. 2017;2:135–143.CrossRefPubMedCentralGoogle Scholar
  53. 53.
    Van Cromphaut SJ, Vanhorebeek I, Van den Berghe G. Glucose metabolism and insulin resistance in sepsis. Curr Pharm Des. 2008;14:1887–1899.CrossRefPubMedCentralGoogle Scholar
  54. 54.
    Krinsley JS. The severity of sepsis: yet another factor influencing glycemic control. Crit Care. 2008;12:194.CrossRefPubMedCentralGoogle Scholar
  55. 55.
    Hallman M, Slivka S, Wozniak P, Sills J. Perinatal development of myoinositol uptake into lung cells: surfactant phosphatidylglycerol and phosphatidylinositol synthesis in the rabbit. Pediatr Res. 1986;20:179–185.CrossRefPubMedCentralGoogle Scholar
  56. 56.
    Breckenridge WC, Palmer FB. Fatty acid composition of human plasma lipoprotein phosphatidylinositols. Biochim Biophys Acta. 1982;712:707–711.CrossRefPubMedCentralGoogle Scholar
  57. 57.
    Reiser R, Bryson MJ, Carr MJ, Kuiken KA. The intestinal absorption of triglycerides. J Biol Chem. 1952;194:131–138.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Foster DM, Berman M. Hydrolysis of rat chylomicron acylglycerols: a kinetic model. J Lipid Res. 1981;22:506–513.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Young SG, Zechner R. Biochemistry and pathophysiology of intravascular and intracellular lipolysis. Genes Dev. 2013;27:459–484.CrossRefPubMedCentralGoogle Scholar
  60. 60.
    Kazda A. Meeting the energy requirements in sepsis. Czech Med. 1988;11:1–9.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Clowes GH Jr, O’Donnell TF Jr, Ryan NT, Blackburn GL. Energy metabolism in sepsis: treatment based on different patterns in shock and high output stage. Ann Surg. 1974;179:684–696.CrossRefPubMedCentralGoogle Scholar
  62. 62.
    Hill GL. Implications of critical illness, injury, and sepsis on lean body mass and nutritional needs. Nutrition. 1998;14:557–558.CrossRefPubMedCentralGoogle Scholar
  63. 63.
    Chiolero R, Revelly JP, Tappy L. Energy metabolism in sepsis and injury. Nutrition. 1997;13:45S–51S.CrossRefPubMedCentralGoogle Scholar
  64. 64.
    Adhikari NK, Fowler RA, Bhagwanjee S, Rubenfeld GD. Critical care and the global burden of critical illness in adults. Lancet. 2010;376:1339–1346.CrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of Biological SciencesUniversity of AucklandAucklandNew Zealand
  2. 2.Department of SurgeryUniversity of AucklandAucklandNew Zealand

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