Elevated Endotoxin Levels in Non-alcoholic Fatty Liver Disease

Overview

Journal J Inflamm (Lond)

Publisher Biomed Central

Date 2010 Apr 1

PMID 20353583

Citations 191

Authors

Alison L Harte

Nancy F da Silva

Steven J Creely

Kirsty C McGee

Thomas Billyard

Elham M Youssef-Elabd

Gyanendra Tripathi

Esmat Ashour

Mohga S Abdalla

Hayat M Sharada

Ashraf I Amin

Alastair D Burt

Sudhesh Kumar

Christopher P Day

Philip G McTernan

Affiliations

Soon will be listed here.

Abstract

Background: Emerging data indicate that gut-derived endotoxin may contribute to low-grade systemic inflammation in insulin resistant states. This study aimed to examine the importance of serum endotoxin and inflammatory markers in non-alcoholic fatty liver disease (NAFLD) patients, with and without type 2 diabetes mellitus (T2DM), and to explore the effect of treatment with a lipase inhibitor, Orlistat, on their inflammatory status.

Methods: Fasted serum from 155 patients with biopsy proven NAFLD and 23 control subjects were analysed for endotoxin, soluble CD14 (sCD14), soluble tumour necrosis factor receptor II (sTNFRII) and various metabolic parameters. A subgroup of NAFLD patients were re-assessed 6 and 12 months after treatment with diet alone (n = 6) or diet plus Orlistat (n = 8).

Results: Endotoxin levels were significantly higher in patients with NAFLD compared with controls (NAFLD: 10.6(7.8, 14.8) EU/mL; controls: 3.9(3.2, 5.2) EU/mL, p < 0.001); NAFLD alone produced comparable endotoxin levels to T2DM (NAFLD: T2DM: 10.6(5.6, 14.2) EU/mL; non-diabetic: 10.6(8.5, 15.2) EU/mL), whilst a significant correlation between insulin resistance and serum endotoxin was observed (r = 0.27, p = 0.008). Both sCD14 (p < 0.01) and sTNFRII (p < 0.001) increased with severity of fibrosis. A positive correlation was also noted between sTNFRII and sCD14 in the NAFLD subjects (r = 0.29, p = 0.004).Sub-cohort treatment with Orlistat in patients with NAFLD showed significant decreases in ALT (p = 0.006), weight (p = 0.005) and endotoxin (p = 0.004) compared with the NAFLD, non-Orlistat treated control cohort at 6 and 12 months post therapy, respectively.

Conclusions: Endotoxin levels were considerably increased in NAFLD patients, with marked increases noted in early stage fibrosis compared with controls. These results suggest elevated endotoxin may serve as an early indicator of potential liver damage, perhaps negating the need for invasive liver biopsy. As endotoxin may promote insulin resistance and inflammation, interventions aimed at reducing endotoxin levels in NAFLD patients may prove beneficial in reducing inflammatory burden.

Citing Articles

Water-Soluble Cellulose Acetate Changes the Intestinal Microbiota in Mice with Non-Alcoholic Steatohepatitis.

Iida A, Takahashi E, Kuranuki S, Shimamoto S, Nakamura T, Kitagaki H Nutrients. 2025; 17(3).

PMID: 39940357 PMC: 11820315. DOI: 10.3390/nu17030500.

Immunology and treatments of fatty liver disease.

Tang S, Wu S, Zhang W, Ma L, Zuo L, Wang H Arch Toxicol. 2024; 99(1):127-152.

PMID: 39692857 DOI: 10.1007/s00204-024-03920-1.

The Effects of Rice Bran on Neuroinflammation and Gut Microbiota in Ovariectomized Mice Fed a Drink with Fructose.

Chao Y, Tung Y, Yang S, Shirakawa H, Su L, Loe P Nutrients. 2024; 16(17).

PMID: 39275295 PMC: 11397027. DOI: 10.3390/nu16172980.

HDAC6 inhibitor ACY-1215 protects from nonalcoholic fatty liver disease via inhibiting CD14/TLR4/MyD88/MAPK/NFκB signal pathway.

Fu S, Xu M, Li J, Yu M, Wang S, Han L Heliyon. 2024; 10(13):e33740.

PMID: 39055804 PMC: 11269855. DOI: 10.1016/j.heliyon.2024.e33740.

Role of liver sinusoidal endothelial cell in metabolic dysfunction-associated fatty liver disease.

He Q, He W, Dong H, Guo Y, Yuan G, Shi X Cell Commun Signal. 2024; 22(1):346.

PMID: 38943171 PMC: 11214243. DOI: 10.1186/s12964-024-01720-9.

References

Ghoshal S, Witta J, Zhong J, de Villiers W, Eckhardt E . Chylomicrons promote intestinal absorption of lipopolysaccharides. J Lipid Res. 2008; 50(1):90-7. DOI: 10.1194/jlr.M800156-JLR200. View

Brun P, Castagliuolo I, Di Leo V, Buda A, Pinzani M, Palu G . Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 2006; 292(2):G518-25. DOI: 10.1152/ajpgi.00024.2006. View

Muzio M, Polentarutti N, Bosisio D, Manoj Kumar P, Mantovani A . Toll-like receptor family and signalling pathway. Biochem Soc Trans. 2000; 28(5):563-6. DOI: 10.1042/bst0280563. View

Tapping R, Tobias P . Cellular binding of soluble CD14 requires lipopolysaccharide (LPS) and LPS-binding protein. J Biol Chem. 1997; 272(37):23157-64. DOI: 10.1074/jbc.272.37.23157. View

Xu H, Barnes G, Yang Q, Tan G, Yang D, Chou C . Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003; 112(12):1821-30. PMC: 296998. DOI: 10.1172/JCI19451. View

Lloyd-Jones K, Kelly M, Kubes P . Varying importance of soluble and membrane CD14 in endothelial detection of lipopolysaccharide. J Immunol. 2008; 181(2):1446-53. DOI: 10.4049/jimmunol.181.2.1446. View

Wigg A, Roberts-Thomson I, Dymock R, McCarthy P, Grose R, Cummins A . The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut. 2001; 48(2):206-11. PMC: 1728215. DOI: 10.1136/gut.48.2.206. View

Baker A, Harte A, Howell N, Pritlove D, Ranasinghe A, da Silva N . Epicardial adipose tissue as a source of nuclear factor-kappaB and c-Jun N-terminal kinase mediated inflammation in patients with coronary artery disease. J Clin Endocrinol Metab. 2008; 94(1):261-7. DOI: 10.1210/jc.2007-2579. View

Creely S, McTernan P, Kusminski C, Fisher F, da Silva N, Khanolkar M . Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab. 2006; 292(3):E740-7. DOI: 10.1152/ajpendo.00302.2006. View

10.

Hsieh C, Wang P, Liu R, Tung S, Chien W, Chen J . Orlistat for obesity: benefits beyond weight loss. Diabetes Res Clin Pract. 2004; 67(1):78-83. DOI: 10.1016/j.diabres.2004.05.012. View

11.

Brun P, Castagliuolo I, Floreani A, Buda A, Blasone L, Palu G . Increased risk of NASH in patients carrying the C(-159)T polymorphism in the CD14 gene promoter region. Gut. 2006; 55(8):1212. PMC: 1856285. DOI: 10.1136/gut.2006.093336. View

12.

Schroder J, Stuber F, Gallati H, Schade F, Kremer B . Pattern of soluble TNF receptors I and II in sepsis. Infection. 1995; 23(3):143-8. DOI: 10.1007/BF01793854. View

13.

Turnbaugh P, Ley R, Mahowald M, Magrini V, Mardis E, Gordon J . An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006; 444(7122):1027-31. DOI: 10.1038/nature05414. View

14.

Farhadi A, Gundlapalli S, Shaikh M, Frantzides C, Harrell L, Kwasny M . Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis. Liver Int. 2008; 28(7):1026-33. PMC: 4303249. DOI: 10.1111/j.1478-3231.2008.01723.x. View

15.

Kaisho T, Akira S . Toll-like receptors as adjuvant receptors. Biochim Biophys Acta. 2002; 1589(1):1-13. DOI: 10.1016/s0167-4889(01)00182-3. View

16.

Ley R, Turnbaugh P, Klein S, Gordon J . Microbial ecology: human gut microbes associated with obesity. Nature. 2006; 444(7122):1022-3. DOI: 10.1038/4441022a. View

17.

Erridge C, Attina T, Spickett C, Webb D . A high-fat meal induces low-grade endotoxemia: evidence of a novel mechanism of postprandial inflammation. Am J Clin Nutr. 2007; 86(5):1286-92. DOI: 10.1093/ajcn/86.5.1286. View

18.

Moreno C, Merino J, Ramirez N, Echeverria A, Pastor F, Sanchez-Ibarrola A . Lipopolysaccharide needs soluble CD14 to interact with TLR4 in human monocytes depleted of membrane CD14. Microbes Infect. 2004; 6(11):990-5. DOI: 10.1016/j.micinf.2004.05.010. View

19.

Porteu F, Nathan C . Shedding of tumor necrosis factor receptors by activated human neutrophils. J Exp Med. 1990; 172(2):599-607. PMC: 2188336. DOI: 10.1084/jem.172.2.599. View

20.

Brunt E, Janney C, Di Bisceglie A, Neuschwander-Tetri B, Bacon B . Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999; 94(9):2467-74. DOI: 10.1111/j.1572-0241.1999.01377.x. View