Correlation between intestinal permeability markers and nonalcoholic fatty liver disease

Abstract

Abstract: Objective To investigate the relationship between nonalcoholic fatty liver disease(NAFLD) and intestinal permeability markers.Methods A rat NASH model was successfully established to observe intestinal pathological changes, and serum markers, along with the expression levels of ZO-1 and Occludin, were analyzed. Additioinally, 94 NAFLD patients were enrolled, divided into two groups based on liver enzyme status: 58 patients with normal liver enzymes and 36 with abnormal liver enzymes. A control group consisting of 39 healthy individuals with normal physical examinations was also included. General baseline data, liver enzyme levels, blood lipids, blood glucose, and changes in ZO-1 and Occludin expression were compared between groups. Correlation analyses were performed to explore potential associations.Results Compared with the control group, the mucosal fold structure of the experimental group was largely intact, with mild epithelial cell detachment observed in the mucosal layer. The intestinal glands in the Lamina propria were atrophied, and their numbers were reduced. Infiltration of inflammatory cells of varying degrees and fat vacuoles of different sizes were observed in both the Lamina propria and muscularis mucosa. Serological markers, including ALT, GGT, LDL, TG, TC, GLU, INS, HOMA-IR, were significantly higher in the experimental group compared to the control group(P<0.05). Moreover, levels of ZO-1 and Occludin were significantly lower in the experimental group(P<0.05). There were significantly differences between the three groups regarding gender, age, weight, BMI, SBP, and DBP (P<0.05). BMI and DBP were higher in both the normal and abnormal liver enzyme groups compared to the control group, with the abnormal liver enzyme group showing higher values than the normal liver enzyme group (P<0.05). Serum AST, ALP, and GGT levels were significantly higher in the abnormal liver enzyme group compared to the normal liver enzyme and control groups (P<0.05); ALT levels were higher in both the normal and abnormal liver enzyme groups than in the control group (P<0.05); TBil was elevated in both the normal and abnormal liver enzyme groups relative to the control group (P<0.05). TG and TC levels were also higher in the normal and abnormal liver enzyme groups compared to the control group (P<0.05). HDL-C levels were lower in the abnormal liver enzyme group compared to both the normal liver enzyme and control groups (P<0.05), while LDL-C was higher in the normal liver enzyme group compared to the control group (P<0.05). GLU levels were higher in the abnormal liver enzyme group than in the control group (P<0.05). Both ZO-1 and Occludin expression levels were lower in the normal and abnormal liver enzyme groups compared to the control group, with the abnormal liver enzyme group showing the lowest leves (P<0.05). ZO-1 was negatively correlated with BMI, AST, ALT, GGT, and TBil (P<0.05), with the strongest correlation observed with ALT. HDL-C was positively correlated with ZO-1. Occludin was negatively correlated with BMI, AST, ALT, GGT, and GLU (P<0.05), with the strongest correlation observed with GGT, HDL-C was positively correlated with Occludin. Multivariate logistic regression analysis identified BMI and TC as risk factors for NAFLD, while ZO-1and Occludin were found to reduce the risk of NAFLD. In the analysis of NAFLD disease progression, BMI remained a risk factor, while ZO-1 and Occludincan continued to reduce the risk of disease progression.Conclusion Increased intestinal permeability is associated with the onset and progression of NAFLD.

Key words: High fat diet, Non-alcoholic fatty liver disease, Non-alcoholic steatohepatitis, Intestinal permeability

GUO Tao, DAI Guang-rong. Correlation between intestinal permeability markers and nonalcoholic fatty liver disease[J]. Chinese Hepatolgy, 2024, 29(12): 1545-1552.

References

[1] Pouwels S, Sakran N, Graham Y, et al. Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss[J]. BMC Endocr Disord, 2022,22(1):63.
[2] Younossi Z M, Blissett D, Blissett R, et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe[J]. Hepatology, 2016,64(5):1577-1586.
[3] Mittal S, El-Serag H B, Sada Y H, et al. Hepatocellular Carcinoma in the Absence of Cirrhosis in United States Veterans is Associated With Nonalcoholic Fatty Liver Disease[J]. Clin Gastroenterol Hepatol, 2016,14(1):124-131.
[4] 韦璐莹, 卢清华, 张扬武, 等. 基于“肠-肝轴”理论对非酒精性脂肪性肝病影响的研究进展[J]. 大众科技, 2022,24(05):88-91.
[5] Kolodziejczyk A A, Zheng D, Shibolet O, et al. The role of the microbiome in NAFLD and NASH[J]. EMBO Mol Med, 2019,11(2).
[6] Montalto M, Maggiano N, Ricci R, et al. Lactobacillus acidophilus protects tight junctions from aspirin damage in HT-29 cells[J]. Digestion, 2004,69(4):225-228.
[7] Furuse M, Fujimoto K, Sato N, et al. Overexpression of occludin, a tight junction-associated integral membrane protein, induces the formation of intracellular multilamellar bodies bearing tight junction-like structures[J]. J Cell Sci, 1996,109( Pt 2):429-435.
[8] 秦百君, 唐曦平, 杨昕, 等. 清解化攻方调节重症急性胰腺炎模型大鼠肠道菌群及对肠黏膜屏障的影响[J]. 中国药房, 2022,33(15):1825-1832.
[9] Sanches S C, Ramalho L N, Augusto M J, et al. Nonalcoholic Steatohepatitis: A Search for Factual Animal Models[J]. Biomed Res Int, 2015,2015:574832.
[10] Miele L, Valenza V, La Torre G, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease[J]. Hepatology, 2009,49(6):1877-1887.
[11] 李寰舟, 王娟红, 牛聪聪, 等. 复方银杏叶制剂对非酒精性脂肪肝的干预作用及机制[J]. 中国中药杂志, 2015,40(8):1580-1584.
[12] Bedossa P. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease[J]. Hepatology, 2014,60(2):565-575.
[13] Del B M, Polimeni L, Brancorsini M, et al. Non-alcoholic fatty liver disease, metabolic syndrome and patatin-like phospholipase domain-containing protein3 gene variants[J]. Eur J Intern Med, 2014,25(6):566-570.
[14] Cordeiro A, Costa R, Andrade N, et al. Does adipose tissue inflammation drive the development of non-alcoholic fatty liver disease in obesity[J]? Clin Res Hepatol Gastroenterol, 2020,44(4):394-402.
[15] Zhou F, Zhou J, Wang W, et al. Unexpected Rapid Increase in the Burden of NAFLD in China From 2008 to 2018: A Systematic Review and Meta-Analysis[J]. Hepatology, 2019,70(4):1119-1133.
[16] Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis[J]. Gastroenterology, 2015,149(2):367-378,quiz e14- quiz e15.
[17] Pal M, Febbraio M A, Lancaster G I. The roles of c-Jun NH2-terminal kinases (JNKs) in obesity and insulin resistance[J]. J Physiol, 2016,594(2):267-279.
[18] Powell E E, Wong V W, Rinella M. Non-alcoholic fatty liver disease[J]. Lancet, 2021,397(10290):2212-2224.
[19] Mofrad P, Contos M J, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values[J]. Hepatology, 2003,37(6):1286-1292.
[20] 尹慧君, 李晓利, 徐成, 等. 北京某地区老年人群非酒精性脂肪性肝病的临床特征及影响因素[J]. 中华老年多器官疾病杂志, 2022,21(9):651-654.
[21] Chen T P, Lai M, Lin W Y, et al. Metabolic profiles and fibrosis of nonalcoholic fatty liver disease in the elderly: A community-based study[J]. J Gastroenterol Hepatol, 2020,35(9):1636-1643.
[22] Muzica C M, Sfarti C, Trifan A, et al. Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: A Bidirectional Relationship[J]. Can J Gastroenterol Hepatol, 2020,2020:6638306.