Acta Diabetologica

, Volume 52, Issue 2, pp 395–404 | Cite as

Endotoxemia, nutrition, and cardiometabolic disorders

  • K. A. Elisa KallioEmail author
  • Katja A. Hätönen
  • Markku Lehto
  • Veikko Salomaa
  • Satu Männistö
  • Pirkko J. Pussinen
Original Article



Circulating lipopolysaccharides (LPSs), associated with both infection and inflammation, may arise from the gastrointestinal tract microbiota, and the levels may be affected by daily nutrition. We investigated whether nutrient intake affects the association of serum LPS activity with prevalent obesity, metabolic syndrome (MetS), diabetes, and coronary heart disease (CHD) and with the risk of incident CHD events.


The nutrition cohort (n = 2,452, mean age ± SD, 52.2 ± 10.1 years) of the FINRISK 1997 Study was followed up for 10 years. Information on macronutrient intake at baseline was collected from 24-h dietary recall. Serum endotoxin activities were determined by the Limulus amebocyte lysate assay.


LPS activity was associated directly with the total energy intake and indirectly with carbohydrate intake in lean, healthy subjects. High LPS was significantly associated with prevalent obesity, MetS, diabetes, and CHD events, independently of established risk factors, CRP, and total energy or nutrient intake. The ORs (95 % CI) were 1.49 (1.21–1.85, p < 0.001, Q2–4 vs. Q1) for obesity, 2.56 (1.97–3.32, p < 0.001, Q2–4 vs. Q1) for MetS, 1.94 (1.06–3.52, p = 0.031, Q2–4 vs. Q1) for CHD, and 1.01 (1.00–1.01, p = 0.032, LPS unit) for diabetes. In the follow-up, high LPS was significantly associated with the risk of CHD events with a hazard ratio of 1.88 (1.13–3.12, p = 0.013, Q2–4 vs. Q1). This association was independent of baseline established risk factors, diet, obesity, MetS, and diabetes.


A high serum LPS activity is strongly associated with cardiometabolic disorders, which supports the role of bacterial infections and immune response in their etiology.


Lipopolysaccharide Obesity Metabolic syndrome Diabetes Cardiovascular disease 



This work was supported by the grants from the Academy of Finland (1266053 to P.J.P., 136895 and 263836 to S.M.), the Sigrid Juselius Foundation (P.J.P), the Aarne Koskelo Foundation (K.A.E.K), Folkhälsan Institute of Genetics (M.L.), the Finnish Dental Society Apollonia (K.A.E.K), and the Finnish Foundation for Cardiovascular Research (V.S.).

Conflict of interest

Elisa Kallio, Katja Hätönen, Markku Lehto, Veikko Salomaa, Satu Männistö, and Pirkko Pussinen declare that they have no conflict of interest.

Human and animal rights disclosure

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975.

Informed consent disclosure

Informed consent was obtained from all patients for being included in the study.

Supplementary material

592_2014_662_MOESM1_ESM.pdf (20 kb)
Supplementary material 1 (PDF 19 kb)


  1. 1.
    Neves AL, Coelho J, Couto L, Leite-Moreira A, Roncon-Albuquerque R Jr (2013) Metabolic endotoxemia: a molecular link between obesity and cardiovascular risk. J Mol Endocrinol 51:R51–R64CrossRefPubMedGoogle Scholar
  2. 2.
    Erridge C, Attina T, Spickett CM, Webb DJ (2007) A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr 86:1286–1292PubMedGoogle Scholar
  3. 3.
    Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56:1761–1772CrossRefPubMedGoogle Scholar
  4. 4.
    Pussinen PJ, Tuomisto K, Jousilahti P, Havulinna AS, Sundvall J, Salomaa V (2007) Endotoxemia, immune response to periodontal pathogens, and systemic inflammation associate with incident cardiovascular disease events. Arterioscler Thromb Vasc Biol 27:1433–1439CrossRefPubMedGoogle Scholar
  5. 5.
    Wiedermann CJ, Kiechl S, Dunzendorfer S, Schratzberger P, Egger G, Oberhollenzer F, Willeit J (1999) Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study. J Am Coll Cardiol 34:1975–1981CrossRefPubMedGoogle Scholar
  6. 6.
    Pussinen PJ, Havulinna AS, Lehto M, Sundvall J, Salomaa V (2011) Endotoxemia is associated with an increased risk of incident diabetes. Diabetes Care 34:392–397CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Lassenius MI, Pietilainen KH, Kaartinen K, Pussinen PJ, Syrjanen J, Forsblom C, Porsti I, Rissanen A, Kaprio J, Mustonen J, Groop PH, Lehto M, FinnDiane Study Group (2011) Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation. Diabetes Care 34:1809–1815CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI (2005) Host-bacterial mutualism in the human intestine. Science 307:1915–1920CrossRefPubMedGoogle Scholar
  9. 9.
    Kelly CJ, Colgan SP, Frank DN (2012) Of microbes and meals: the health consequences of dietary endotoxemia. Nutr Clin Pract 27:215–225CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Ghoshal S, Witta J, Zhong J, de Villiers W, Eckhardt E (2009) Chylomicrons promote intestinal absorption of lipopolysaccharides. J Lipid Res 50:90–97CrossRefPubMedGoogle Scholar
  11. 11.
    Hathaway LJ, Kraehenbuhl JP (2000) The role of M cells in mucosal immunity. Cell Mol Life Sci 57:323–332CrossRefPubMedGoogle Scholar
  12. 12.
    Hooper LV, Gordon JI (2001) Commensal host-bacterial relationships in the gut. Science 292:1115–1118CrossRefPubMedGoogle Scholar
  13. 13.
    Amar J, Burcelin R, Ruidavets JB, Cani PD, Fauvel J, Alessi MC, Chamontin B, Ferrieres J (2008) Energy intake is associated with endotoxemia in apparently healthy men. Am J Clin Nutr 87:1219–1223PubMedGoogle Scholar
  14. 14.
    Ghanim H, Abuaysheh S, Sia CL, Korzeniewski K, Chaudhuri A, Fernandez-Real JM, Dandona P (2009) Increase in plasma endotoxin concentrations and the expression of Toll-like receptors and suppressor of cytokine signaling-3 in mononuclear cells after a high-fat, high-carbohydrate meal: implications for insulin resistance. Diabetes Care 32:2281–2287CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Harte AL, Varma MC, Tripathi G, McGee KC, Al-Daghri NM, Al-Attas OS, Sabico S, O’Hare JP, Ceriello A, Saravanan P, Kumar S, McTernan PG (2012) High fat intake leads to acute postprandial exposure to circulating endotoxin in type 2 diabetic subjects. Diabetes Care 35:375–382CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Clemente-Postigo M, Queipo-Ortuno MI, Murri M, Boto-Ordonez M, Perez-Martinez P, Andres-Lacueva C, Cardona F, Tinahones FJ (2012) Endotoxin increase after fat overload is related to postprandial hypertriglyceridemia in morbidly obese patients. J Lipid Res 53:973–978CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Vartiainen E, Laatikainen T, Peltonen M, Juolevi A, Mannisto S, Sundvall J, Jousilahti P, Salomaa V, Valsta L, Puska P (2010) Thirty-five-year trends in cardiovascular risk factors in Finland. Int J Epidemiol 39:504–518CrossRefPubMedGoogle Scholar
  18. 18.
    WHO (1988) The World Health Organization MONICA Project (monitoring trends and determinants in cardiovascular disease): a major international collaboration. WHO MONICA Project Principal Investigators. J Clin Epidemiol 41:105–114CrossRefGoogle Scholar
  19. 19.
    World Health Organization 2 (2004) Obesity: prevention and managing the global epidemic. Report of a WHO Consultation. WHO Technical Report Series no. 894. WHO, GenevaGoogle Scholar
  20. 20.
    Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr, International Diabetes Federation Task Force on Epidemiology and Prevention, National Heart, Lung, and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society, International Association for the Study of Obesity (2009) Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120:1640–1645Google Scholar
  21. 21.
    Pajunen P, Koukkunen H, Ketonen M, Jerkkola T, Immonen-Raiha P, Karja-Koskenkari P, Mahonen M, Niemela M, Kuulasmaa K, Palomaki P, Mustonen J, Lehtonen A, Arstila M, Vuorenmaa T, Lehto S, Miettinen H, Torppa J, Tuomilehto J, Kesaniemi YA, Pyorala K, Salomaa V (2005) The validity of the finnish hospital discharge register and causes of death register data on coronary heart disease. Eur J Cardiovasc Prev Rehabil 12:132–137PubMedGoogle Scholar
  22. 22.
    Perloff D, Grim C, Flack J, Frohlich ED, Hill M, McDonald M, Morgenstern BZ (1993) Human blood pressure determination by sphygmomanometry. Circulation 88:2460–2470CrossRefPubMedGoogle Scholar
  23. 23.
    Pietinen P, Hartman AM, Haapa E, Rasanen L, Haapakoski J, Palmgren J, Albanes D, Virtamo J, Huttunen JK (1988) Reproducibility and validity of dietary assessment instruments. I. A self-administered food use questionnaire with a portion size picture booklet. Am J Epidemiol 128:655–666PubMedGoogle Scholar
  24. 24.
    Reinivuo H, Hirvonen T, Ovaskainen ML, Korhonen T, Valsta LM (2010) Dietary survey methodology of FINDIET 2007 with a risk assessment perspective. Public Health Nutr 13:915–919CrossRefPubMedGoogle Scholar
  25. 25.
    Missmer SA, Smith-Warner SA, Spiegelman D, Yaun SS, Adami HO, Beeson WL, van den Brandt PA, Fraser GE, Freudenheim JL, Goldbohm RA, Graham S, Kushi LH, Miller AB, Potter JD, Rohan TE, Speizer FE, Toniolo P, Willett WC, Wolk A, Zeleniuch-Jacquotte A, Hunter DJ (2002) Meat and dairy food consumption and breast cancer: a pooled analysis of cohort studies. Int J Epidemiol 31:78–85CrossRefPubMedGoogle Scholar
  26. 26.
    Musso G, Gambino R, Cassader M (2011) Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes. Annu Rev Med 62:361–380CrossRefPubMedGoogle Scholar
  27. 27.
    Deopurkar R, Ghanim H, Friedman J, Abuaysheh S, Sia CL, Mohanty P, Viswanathan P, Chaudhuri A, Dandona P (2010) Differential effects of cream, glucose, and orange juice on inflammation, endotoxin, and the expression of Toll-like receptor-4 and suppressor of cytokine signaling-3. Diabetes Care 33:991–997CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Ghanim H, Sia CL, Upadhyay M, Korzeniewski K, Viswanathan P, Abuaysheh S, Mohanty P, Dandona P (2010) Orange juice neutralizes the proinflammatory effect of a high-fat, high-carbohydrate meal and prevents endotoxin increase and toll-like receptor expression. Am J Clin Nutr 91:940–949CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Pendyala S, Walker JM, Holt PR (2012) A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology 142(1100–1101):e2PubMedGoogle Scholar
  30. 30.
    Lassenius MI, Makinen VP, Fogarty CL, Peraneva L, Jauhiainen M, Pussinen PJ, Taskinen MR, Kirveskari J, Vaarala O, Nieminen JK, Horkko S, Kangas AJ, Soininen P, Ala-Korpela M, Gordin D, Ahola AJ, Forsblom C, Groop PH, Lehto M (2014) Patients with type 1 diabetes show signs of vascular dysfunction in response to multiple high-fat meals. Nutr Metab (Lond) 11:28-7075-11-28. eCollection 2014Google Scholar
  31. 31.
    Pradhan-Palikhe P, Vikatmaa P, Lajunen T, Palikhe A, Lepantalo M, Tervahartiala T, Salo T, Saikku P, Leinonen M, Pussinen PJ, Sorsa T (2010) Elevated MMP-8 and decreased myeloperoxidase concentrations associate significantly with the risk for peripheral atherosclerosis disease and abdominal aortic aneurysm. Scand J Immunol 72:150–157CrossRefPubMedGoogle Scholar
  32. 32.
    Goto T, Eden S, Nordenstam G, Sundh V, Svanborg-Eden C, Mattsby-Baltzer I (1994) Endotoxin levels in sera of elderly individuals. Clin Diagn Lab Immunol 1:684–688PubMedCentralPubMedGoogle Scholar
  33. 33.
    Pearson FC, Dubczak J, Weary M, Bruszer G, Donohue G (1985) Detection of endotoxin in the plasma of patients with gram-negative bacterial sepsis by the Limulus amoebocyte lysate assay. J Clin Microbiol 21:865–868PubMedCentralPubMedGoogle Scholar
  34. 34.
    Wachtel RE, Tsuji K (1977) Comparison of limulus amebocyte lysates and correlation with the United States Pharmacopeial pyrogen test. Appl Environ Microbiol 33:1265–1269PubMedCentralPubMedGoogle Scholar
  35. 35.
    Kinane DF, Riggio MP, Walker KF, MacKenzie D, Shearer B (2005) Bacteraemia following periodontal procedures. J Clin Periodontol 32:708–713CrossRefPubMedGoogle Scholar
  36. 36.
    Lappin DF, Sherrabeh S, Erridge C (2011) Stimulants of Toll-like receptors 2 and 4 are elevated in saliva of periodontitis patients compared with healthy subjects. J Clin Periodontol 38:318–325CrossRefPubMedGoogle Scholar
  37. 37.
    DeStefano F, Anda RF, Kahn HS, Williamson DF, Russell CM (1993) Dental disease and risk of coronary heart disease and mortality. BMJ 306:688–691CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Demmer RT, Jacobs DR Jr, Desvarieux M (2008) Periodontal disease and incident type 2 diabetes: results from the First National Health and Nutrition Examination Survey and its epidemiologic follow-up study. Diabetes Care 31:1373–1379CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Italia 2014

Authors and Affiliations

  • K. A. Elisa Kallio
    • 1
    Email author
  • Katja A. Hätönen
    • 2
  • Markku Lehto
    • 3
    • 4
  • Veikko Salomaa
    • 2
  • Satu Männistö
    • 2
  • Pirkko J. Pussinen
    • 1
  1. 1.Institute of DentistryUniversity of HelsinkiHelsinkiFinland
  2. 2.Department of Chronic Disease PreventionNational Institute for Health and WelfareHelsinkiFinland
  3. 3.Folkhälsan Research CenterFolkhälsan Institute of GeneticsHelsinkiFinland
  4. 4.Division of Nephrology, Department of MedicineHelsinki University Central HospitalHelsinkiFinland

Personalised recommendations