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Nutrition, Intestinal Permeability, and Blood Ethanol Levels Are Altered in Patients with Nonalcoholic Fatty Liver Disease (NAFLD)

Digestive Diseases and Sciences volume 57, pages 1932–1941 (2012)Cite this article

Abstract

Background

A role of an altered dietary pattern (e.g., a diet rich in sugar) but also alterations at the level of the intestinal barrier have repeatedly been discussed to be involved in the development and progression of nonalcoholic fatty liver disease (NAFLD).

Aims

To determine if the nutritional intake, intestinal flora, and permeability and the development of NAFLD are related in humans.

Methods

Ten controls and 20 patients with NAFLD ranging from simple steatosis to steatohepatitis were included in the study. Bacterial overgrowth, orocecal transit time, and intestinal permeability were assessed. Alcohol, endotoxin, and plasminogen activator inhibitor (PAI-) 1 concentration were determined in plasma. Nutritional intake was assessed using a dietary history.

Results

Despite no differences in the prevalence of bacterial overgrowth and in the orocecal transit time, intestinal permeability, alcohol, and endotoxin levels in plasma were significantly higher in patients with NAFLD than in controls. Similar results were also found for PAI-1 plasma concentrations. Patients with NAFLD had a significantly higher intake of protein, total carbohydrates, and mono- as well as disaccharides than controls. PAI-1, endotoxin, and ALT plasma levels were positively related to total protein and carbohydrate intake.

Conclusions

Taken together, our results indicate that intestinal permeability, endogenous alcohol synthesis, and nutritional intake are markedly altered in patients with NAFLD.

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Abbreviations

ADH:

Alcohol dehydrogenase

ALT:

Alanine-aminotransferase

AST:

Aspartate-aminotransferase

BMI:

Body mass index

DBP:

Diastolic blood pressure

γ-GT:

γ-Glutamyl transpeptidase

HPAE-PAD:

High-performance-anion-exchange chromatography with pulsed amperometric detection

LBP:

Lipopolysaccharide binding protein

MUFA:

Monounsaturated fatty acids

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

OCTT:

Orocecal transit time

PAI-1:

Plasminogen activator inhibitor 1

PUFA:

Polyunsaturated fatty acids

SBP:

Systolic blood pressure

SD:

Standard deviation

SEM:

Standard error of mean

SFA:

Saturated fatty acids

SIBO:

Small intestinal bacterial overgrowth

TLR-4:

Toll-like receptor 4

TNF-α:

Tumor necrosis factor alpha

References

  1. Yang L, Bataller R, Dulyx J, et al. Attenuated hepatic inflammation and fibrosis in angiotensin type 1a receptor deficient mice. J Hepatol. 2005;43:317–323.

    PubMed  Article  CAS  Google Scholar 

  2. Adams LA, Lymp JF, St SJ, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129:113–121.

    PubMed  Article  Google Scholar 

  3. Bode C, Kugler V, Bode JC. Endotoxemia in patients with alcoholic and nonalcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess. J Hepatol. 1987;4:8–14.

    PubMed  Article  CAS  Google Scholar 

  4. Purohit V, Bode JC, Bode C, et al. Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: summary of a symposium. Alcohol. 2008;42:349–361.

    PubMed  Article  CAS  Google Scholar 

  5. Wigg AJ, Roberts-Thomson IC, Dymock RB, McCarhy PJ, Grose RH, Cummins AG. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of nonalcoholic steatohepatitis. Gut. 2001;48:206–211.

    PubMed  Article  CAS  Google Scholar 

  6. Thuy S, Ladurner R, Volynets V, et al. Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. J Nutr. 2008;138:1452–1455.

    PubMed  CAS  Google Scholar 

  7. Soza A, Riquelme A, Gonzalez R, et al. Increased orocecal transit time in patients with nonalcoholic fatty liver disease. Dig Dis Sci. 2005;50:1136–1140.

    PubMed  Article  Google Scholar 

  8. Harte AL, da Silva NF, Creely SJ, et al. Elevated endotoxin levels in nonalcoholic fatty liver disease. J Inflamm. 2010;7:15.

    Article  Google Scholar 

  9. Farhadi A, Gundlapalli S, Shaikh M, et al. Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in nonalcoholic steatohepatitis. Liver Int. 2008;28:1026–1033.

    PubMed  Article  Google Scholar 

  10. Ruiz AG, Casafont F, Crespo J, et al. Lipopolysaccharide-binding protein plasma levels and liver TNF-alpha gene expression in obese patients: evidence for the potential role of endotoxin in the pathogenesis of nonalcoholic steatohepatitis. Obes Surg. 2007;17:1374–1380.

    PubMed  Article  Google Scholar 

  11. Nair S, Cope K, Risby TH, Diehl AM. Obesity and female gender increase breath ethanol concentration: potential implications for the pathogenesis of nonalcoholic steatohepatitis. Am J Gastroenterol. 2001;96:1200–1204.

    PubMed  Article  CAS  Google Scholar 

  12. Assy N, Nasser G, Kamayse I, et al. Soft drink consumption linked with fatty liver in the absence of traditional risk factors. Can J Gastroenterol. 2008;22:811–816.

    Google Scholar 

  13. Ouyang X, Cirillo P, Sautin Y, et al. Fructose consumption as a risk factor for nonalcoholic fatty liver disease. J Hepatol. 2008;48:993–999.

    PubMed  Article  CAS  Google Scholar 

  14. Solga S, Alkhuraishe AR, Clark JM, et al. Dietary composition and nonalcoholic fatty liver disease. Dig Dis Sci. 2004;49:1578–1583.

    PubMed  Article  Google Scholar 

  15. Abdelmalek MF, Suzuki A, Guy C, et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51:1961–1971.

    PubMed  Article  CAS  Google Scholar 

  16. Bergheim I, Weber S, Vos M, et al. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J Hepatol. 2008;48:983–992.

    PubMed  Article  CAS  Google Scholar 

  17. Taylor KJ, Riely CA, Hammers L, et al. Quantitative US attenuation in normal liver and in patients with diffuse liver disease: importance of fat. Radiology. 1986;160:65–71.

    PubMed  CAS  Google Scholar 

  18. Joseph AE, Dewbury KC, McGuire PG. Ultrasound in the detection of chronic liver disease (the “bright liver”). Br J Radiol. 1979;52:184–188.

    PubMed  Article  CAS  Google Scholar 

  19. Joseph AE, Saverymuttu SH, al-Sam S, Cook MG, Maxwell JD. Comparison of liver histology with ultrasonography in assessing diffuse parenchymal liver disease. Clin Radiol. 1991;43:26–31.

    PubMed  Article  CAS  Google Scholar 

  20. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321.

    PubMed  Article  Google Scholar 

  21. Landig J, Erhardt JG, Bode JC, Bode C. Validation and comparison of two computerized methods of obtaining a diet history. Clin Nutr. 1998;17:113–117.

    PubMed  Article  CAS  Google Scholar 

  22. Erhardt JG, Meisner C, Bode JC, Bode C. Lycopene, beta-carotene, and colorectal adenomas 23. Am J Clin Nutr. 2003;78:1219–1224.

    PubMed  CAS  Google Scholar 

  23. Generoso M, De RM, De RR, et al. Cellobiose and lactulose coupled with mannitol and determined using ion-exchange chromatography with pulsed amperometric detection, are reliable probes for investigation of intestinal permeability. J Chromatogr B Analyt Technol Biomed Life Sci. 2003;783:349–357.

    PubMed  Article  CAS  Google Scholar 

  24. Fleming SC, Kapembwa MS, Laker MF, Levin GE, Griffin GE. Rapid and simultaneous determination of lactulose and mannitol in urine, by HPLC with pulsed amperometric detection, for use in studies of intestinal permeability. Clin Chem. 1990;36:797–799.

    PubMed  CAS  Google Scholar 

  25. Pascual S, Such J, Esteban A, et al. Intestinal permeability is increased in patients with advanced cirrhosis. Hepatogastroenterology. 2003;50:1482–1486.

    PubMed  Google Scholar 

  26. Parrilli G, Cuomo R, Nardone G, Maio G, Izzo CM, Budillon G. Investigation of intestine function during acute viral hepatitis using combined sugar oral loads. Gut. 1987;28:1439–1444.

    PubMed  Article  CAS  Google Scholar 

  27. Liu H, Zhang S, Yu A, et al. Studies on intestinal permeability of cirrhotic patients by analysis lactulose and mannitol in urine with HPLC/RID/MS. Bioorg Med Chem Lett. 2004;14:2339–2344.

    PubMed  Article  CAS  Google Scholar 

  28. Cariello R, Federico A, Sapone A, et al. Intestinal permeability in patients with chronic liver diseases: Its relationship with the aetiology and the entity of liver damage. Dig Liver Dis. 2010;42:200–204.

    PubMed  Article  Google Scholar 

  29. Bonnichsen RK, Theorell H. An enzymatic method for the microdetermination of ethanol. Scand J Clin Lab Invest. 1951;3:58–62.

    PubMed  Article  CAS  Google Scholar 

  30. Parlesak A, Klein B, Schecher K, Bode JC. bode C. Prevalence of small bowel bacterial overgrowth and its association with nutrition intake in nonhospitalized older adults. J Am Geriatr Soc. 2003;51:768–773.

    PubMed  Article  Google Scholar 

  31. Miele L, Valenza V, La TG, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009;49:1877–1887.

    PubMed  Article  CAS  Google Scholar 

  32. La Brooy SJ, Male PJ, Beavis AK, Misiewicz JJ. Assessment of the reproducibility of the lactulose H2 breath test as a measure of mouth to caecum transit time. Gut. 1983;24:893–896.

    PubMed  Article  Google Scholar 

  33. Toshimitsu K, Matsuura B, Ohkubo I, et al. Dietary habits and nutrient intake in nonalcoholic steatohepatitis. Nutrition. 2007;23:46–52.

    PubMed  Article  Google Scholar 

  34. Gill HK, Wu GY. Nonalcoholic fatty liver disease and the metabolic syndrome: effects of weight loss and a review of popular diets. Are low carbohydrate diets the answer? World J Gastroenterol. 2006;12:345–353.

    PubMed  CAS  Google Scholar 

  35. Zelber-Sagi S, Nitzan-Kaluski D, Goldsmith R, et al. Long term nutritional intake and the risk for nonalcoholic fatty liver disease (NAFLD): a population based study. J Hepatol. 2007;47:711–717.

    PubMed  Article  CAS  Google Scholar 

  36. Kang H, Greenson JK, Omo JT, et al. Metabolic syndrome is associated with greater histologic severity, higher carbohydrate, and lower fat diet in patients with NAFLD. Am J Gastroenterol. 2006;101:2247–2253.

    PubMed  Article  CAS  Google Scholar 

  37. Yamamoto M, Iwasa M, Iwata K, et al. Restriction of dietary calories, fat and iron improves nonalcoholic fatty liver disease. J Gastroenterol Hepatol. 2007;22:498–503.

    PubMed  Article  CAS  Google Scholar 

  38. Ibrahim W, Lee US, Yeh CC, Szabo J, Bruckner G, Chow CK. Oxidative stress and antioxidant status in mouse liver: effects of dietary lipid, vitamin E and iron. 1656. J Nutr. 1997;127:1401–1406.

    PubMed  CAS  Google Scholar 

  39. Cope K, Risby T, Diehl AM. Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology. 2000;119:1340–1347.

    PubMed  Article  CAS  Google Scholar 

  40. Logan BK, Jones AW. Endogenous ethanol production in a child with short gut syndrome. J Pediatr Gastroenterol Nutr. 2003;36:419–420.

    PubMed  Article  CAS  Google Scholar 

  41. McManus IR, Contag AO, Olson RE. Characterization of endogenous ethanol in the mammal. Science. 1960;131:102–103.

    PubMed  Article  CAS  Google Scholar 

  42. Baraona E, Julkunen R, Tannenbaum L, Lieber CS. Role of intestinal bacterial overgrowth in ethanol production and metabolism in rats. Gastroenterology. 1986;90:103–110.

    PubMed  CAS  Google Scholar 

  43. Hanover LM, White JS. Manufacturing, composition, and applications of fructose. Am J Clin Nutr. 1993;58:724S–732S.

    Google Scholar 

  44. Mezey E, Imbembo AL, Potter JJ, Rent KC, Lombardo R, Holt RP. Endogenous ethanol production and hepatic disease following jejunoileal bypass for morbid obesity. Am J Clin Nutr. 1975;28:1277–1283.

    PubMed  CAS  Google Scholar 

  45. Hunnisett A, Howard J, Davies S. Gut fermentation (or auto-brewery) syndrome. A new clinical test with initial observations and discussion of clinical and biological implications. J Nutr Med. 1990;1:33–38.

    Article  Google Scholar 

  46. Rhodes JM, Middleton P, Jewell DP. The lactulose hydrogen breath test as a diagnostic test for small-bowel bacterial overgrowth. Scand J Gastroent. 1979;14:333–336.

    PubMed  Article  CAS  Google Scholar 

  47. Alessi MC, Bastelica D, Mavri A, et al. Plasma PAI-1 levels are more strongly related to liver steatosis than to adipose tissue accumulation. Arterioscler Thromb Vasc Biol. 2003;23:1262–1268.

    PubMed  Article  CAS  Google Scholar 

  48. Le KA, Bortolotti M. Role of dietary carbohydrates and macronutrients in the pathogenesis of nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metab Care. 2008;11:477–482.

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

We would like to thank Prof. Dr. J.C. Bode and Prof. Dr. K.-P. Maier for their advice and the accompanying evaluation of the liver status of patients and controls included in the study. We further would like to thank Drs. C. Schäfer and K. Dirks for their assistance with the recruitment of patients for the study. We also would like to thank Prof. Dr. A. Heyar for his technical support with the determination of lactulose and mannitol concentrations in urine samples. This study was supported by a grant from the Center of Nutritional Medicine Hohenheim/Tübingen (PIs: AK and IB).

Conflict of interest

None.

Author information

Affiliations

  1. Department of Nutritional Medicine (180a), University of Hohenheim, Fruwirthstraße 12, 70599, Stuttgart, Germany

    Valentina Volynets, Ina B. Maier, Astrid Spruss, Sabine Wagnerberger, Stephan C. Bischoff & Ina Bergheim

  2. Department of General, Visceral and Transplant Surgery, Tuebingen University Hospital, Hoppe-Seyler-Straße 3, 72076, Tuebingen, Germany

    Markus A. Küper & Alfred Königsrainer

  3. Liver Center, City Hospital Esslingen, Hirschlandstraße 97, 73730, Esslingen, Germany

    Stefan Strahl

Authors
  1. Valentina Volynets
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  2. Markus A. Küper
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  4. Ina B. Maier
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  9. Ina Bergheim
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Correspondence to Ina Bergheim.

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Volynets, V., Küper, M.A., Strahl, S. et al. Nutrition, Intestinal Permeability, and Blood Ethanol Levels Are Altered in Patients with Nonalcoholic Fatty Liver Disease (NAFLD). Dig Dis Sci 57, 1932–1941 (2012). https://doi.org/10.1007/s10620-012-2112-9

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  • DOI: https://doi.org/10.1007/s10620-012-2112-9

Keywords

  • Intestinal barrier
  • PAI-1
  • Carbohydrate
  • Protein
  • Ethanol
  • Endotoxin