Objective  To explore the therapeutic effect of different immunonutrients on nonalcoholic fatty liver disease (NAFLD), and to evaluate and compare the corresponding effects through a network Meta-analysis.

Methods  The relevant literature about immunonutrients in the treatment of NAFLD was searched in Embase, the Cochrane Library, PubMed, Web of Science, Scopus, CNKI, WanFang Data, VIP and CBM from the establishment of databases to March 17, 2024. Stata 15.0 and Review Manager 5.3 softwares were used to perform a network Meta-analysis.

Results  24 randomized controlled trials were included, involving 1 796 patients. The results of network Meta-analysis showed that probiotics [MD=-9.43, 95%CI(-13.10, -5.77)] and vitamin E [MD=-8.14, 95%CI(-15.31, -0.98)] were more effective in lowering alanine aminotransferase (ALT) than that of the control group (P<0.05). Probiotics [MD=-6.18, 95%CI(-8.84, -3.52)] and vitamin E [MD=-8.78, 95%CI(-14.15, -3.40)] were more effective in lowering aspartate transferase (AST) than that of the control group (P<0.05). The effect of probiotics on reducing body mass index (BMI) was better than that of the control group [MD=-6.18, 95%CI(-8.84, -3.52), P<0.05]. The effect of vitamin D on lowering homeostatic model assessment for insulin resistance (HOMA-IR) was better than that of the control group [MD=-0.79, 95%CI(-1.56, -0.01)]. According to the sequencing results, conjugated linoleic acid had the best effect on reducing ALT level. In terms of reducing AST, vitamin E was the best choice. Synbiotics had the best effect on reducing BMI. Vitamin D had the best effect on reducing HOMA-IR.

Conclusion  Current evidence showed that conjugated linoleic acid, vitamin E, synbiotics and vitamin D may have better intervention effects on patients with NAFLD, which requires more high-quality studies to verify in the future.

1.范建高, 徐小元, 南月敏, 等. 代谢相关(非酒精性)脂肪性肝病防治指南(2024年版)[J]. 实用肝脏病杂志, 2024, 27(4): 494-510. [Fan JG, Xu XY, Nan YM, et al. Guidelines for the prevention and treatment of metabolic dysfunction-associated (non-alcoholic) fatty liver disease (version 2024)[J]. Journal of Practical Hepatology, 2024, 27(4): 494-510.] DOI: 10.3760/cma.j.cn501113-20240327-00163.

2.Younossi ZM, Golabi P, Paik JM, et al. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review[J]. Hepatology, 2023, 77(4): 1335-1347. DOI: 10.1097/HEP.0000000000000004.

3.Li J, Zou B, Yeo YH, et al. Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: a systematic review and Meta-analysis[J]. Lancet Gastroenterol Hepatol, 2019, 4(5): 389-398. DOI: 10.1016/S2468-1253(19)30039-1.

4.中华医学会肝病学分会脂肪肝和酒精性肝病学组, 中国医师协会脂肪性肝病专家委员会. 非酒精性脂肪性肝病防治指南(2018年更新版)[J]. 临床肝胆病杂志, 2018, 34(5): 947-957. [National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology, Chinese Medical Association, Fatty Liver Expert Committee, Chinese Medical Doctor Association. Guidelines of prevention and treatment for nonalcoholic fatty liver disease: a 2018 update[J]. Journal of Clinical Hepatology, 2018, 34(5): 947-957.] DOI: 10.3969/j.issn.1001-5256.2018.05.007.

5.Musso G, Gambino R, Cassader M, et al. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease[J]. Hepatology, 2010, 52(1): 79-104. DOI: 10.1002/hep.23623.

6.Volynets V, Machann J, Küper MA, et al. A moderate weight reduction through dietary intervention decreases hepatic fat content in patients with non-alcoholic fatty liver disease (NAFLD): a pilot study[J]. Eur J Nutr, 2013, 52(2): 527-535. DOI: 10.1007/s00394-012-0355-z.

7.Zhang Q, Jia Y, Zhang Y, et al. The effects of medicinal and food homologous substances on blood lipid and blood glucose levels and liver function in patients with nonalcoholic fatty liver disease: a systematic review of randomized controlled trials[J]. Lipids Health Dis, 2023, 22(1): 137. DOI: 10.1186/s12944-023-01900-5.

8.傅昌芳, 朱翠红, 沈爱宗, 等. 免疫营养素抗恶性肿瘤作用及其临床应用[J]. 中国病原生物学杂志, 2019, 14(6): 735-738. [Fu CF, Zhu CH, Shen AZ, et al. The effect of immune-modulating nutrients on malignant tumors and their clinical use[J]. Journal of Parasitic Biology, 2019, 14(6): 735-738.] DOI: 10.13350/j.cjpb.190626.

9.中国健康管理协会临床营养与健康分会, 国家老年疾病临床医学研究中心(解放军总医院), 中国老年医学学会, 等. 免疫营养素临床应用专家共识[J]. 中华老年多器官疾病杂志, 2023, 22(11): 801-815. [Clinical Nutrition and Health Branch, Chinese Health Association, National Clinical Research Center for Geriatric Diseases (Chinese PLA General Hospital), Chinese Geriatrics Society, et al. Expert consensus on clinical application of immunonutrients[J]. Chinese Journal of Multiple Organ Diseases in the Elderly, 2023, 22(11): 801-815.] DOI: 10.11915/j.issn.1671-5403.2023.11.171.

10.Yao N, Yang Y, Li X, et al. Effects of dietary nutrients on fatty liver disease associated with metabolic dysfunction (MAFLD): based on the intestinal-hepatic axis[J]. Front Nutr, 2022, 9: 906511. DOI: 10.3389/fnut.2022.906511.

11.The Cochrane Collaboration. Cochrane handbook for systematic reviews of interventions, Version 5.1.0[M]. London: Wiley, 2018: 178-218. https://handbook-5-1.cochrane.org/

12.张天嵩. Stata软件network组命令在网状Meta分析中的应用 [J]. 中国循证医学杂志, 2015, 15(11): 1352-1356. [Zhang  TS. A suite of network commands in Stata for network Meta-analysis[J]. Chinese Journal of Evidence-Based Medicine, 2015, 15(11): 1352-1356.] DOI: 10.7507/1672-2531.20150221.

13.胡中伟, 柯娥, 黄春明, 等. 海狗油治疗非酒精性脂肪肝的研究[J]. 广州医科大学学报, 2015, 43(4): 31-33, 44. [Hu ZW, Ke E, Huang CM, et al. Therapeutic effect of seal oil on non-alcoholic fatty liver disease[J]. Academic Journal of Guangzhou Medical College, 2015, 43(4): 31-33, 44.] DOI: 10.3969/j.issn.2095-9664.2015.04.009.

14.朱国英, 黄东平, 黄建伟, 等. ω-3多不饱和脂肪酸联合膳食营养对非酒精性脂肪性肝病患者的影响[J]. 同济大学学报(医学版), 2017, 38(2): 79-83. [Zhu GY, Huang DP, Huang JW, et al. Effectiveness of combined omega-3 polyunsaturated fatty acids with dietary nutrition in patients with non-alcoholic fatty liver disease[J]. Journal of Tongji University (Medical Science), 2017, 38(2): 79-83.] DOI: 10.16118/j.1008-0392.2017.02.016.

15.Parker HM, Cohn JS, O'Connor HT, et al. Effect of fish oil supplementation on hepatic and visceral fat in overweight men: a randomized controlled trial[J]. Nutrients, 2019, 11(2): 475. DOI: 10.3390/nu11020475.

16.Šmíd V, Dvořák K, Šedivý P, et al. Effect of omega-3 polyunsaturated fatty acids on lipid metabolism in patients with metabolic syndrome and NAFLD[J]. Hepatol Commun, 2022, 6(6): 1336-1349. DOI: 10.1002/hep4.1906.

17.Spadaro L, Magliocco O, Spampinato D, et al. Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease[J]. Dig Liver Dis, 2008, 40(3): 194-199. DOI: 10.1016/j.dld.2007.10.003.

18.Abedi R, Aref-Hosseini SR, Khoshbaten M, et al. The effect of conjugated linoleic acid (CLA) on inflammatory factors in non-alcoholic fatty liver disease (NAFLD): a randomized controlled clinical trial[J]. Progress in Nutrition, 2018, 20: 173-181. DOI: 10.23751/pn.v20i2-S.5593.

19.韩源平, 徐思雅, 蒋希乐. 补充维生素D对非酒精性脂肪肝病患者肠道菌群的影响[J]. 华南理工大学学报(自然科学版), 2022, 50(11): 62-73. [Han YP, Xu SY, Jiang XL. Effects of vitamin D supplement on gut microbiota in nonalcoholic fatty liver disease patients[J]. Journal of South China University of Technology (Natural Science Edition), 2022, 50(11): 62-73.] DOI: 10.12141/j.issn.1000-565X.210715.

20.陆勇文. 补充维生素D对非酒精性脂肪肝胰岛素抵抗的影响[J]. 中外医学研究, 2019, 17(9): 39-41. [Lu YW. Effect of vitamin D supplementation on insulin resistance in nonalcoholic fatty liver[J]. Chinese and Foreign Medical Research, 2019, 17(9): 39-41.] DOI: 10.14033/j.cnki.cfmr.2019.09.017.

21.Alarfaj SJ, Bahaa MM, Yassin HA, et al. A randomized placebo-controlled, double-blind study to investigate the effect of a high oral loading dose ofcholecalciferol in non-alcoholic fatty liver disease patients, new insights on serum STAT-3 and hepassocin[J]. Eur Rev Med Pharmacol Sci, 2023, 27(16): 7607-7619. DOI: 10.26355/eurrev_202308_33413.

22.Dabbaghmanesh MH, Danafar F, Eshraghian A, et al. Vitamin D supplementation for the treatment of non-alcoholic fatty liver disease: a randomized double blind placebo controlled trial[J]. Diabetes Metab Syndr, 2018, 12(4): 513-517. DOI: 10.1016/j.dsx.2018.03.006.

23.谢双林. 多烯磷脂酰胆碱联合维生素E治疗非酒精性脂肪肝的疗效及安全性评价[J]. 中国临床药理学杂志, 2015, 31(9): 712-714. [Xie SL. Clinical study of polyene phosphatidylcholine combined with vitamn E in the treatment of non-alcoholic fatty liver disease[J]. The Chinese Journal of Clinical Pharmacology, 2015, 31(9): 712-714.] DOI: 10.13699/j.cnki.1001-6821.2015.09.010.

24.Ekhlasi G, Zarrati M, Agah S, et al. Effects of symbiotic and vitamin E supplementation on blood pressure, nitric oxide and inflammatory factors in non-alcoholic fatty liver disease[J]. EXCLI J, 2017, 16: 278-290. DOI: 10.17179/excli2016-846.

25.Pervez MA, Khan DA, Ijaz A, et al. Effects of delta-tocotrienol supplementation on liver enzymes, inflammation, oxidative stress and hepatic steatosis in patients with nonalcoholic fatty liver disease[J]. Turk J Gastroenterol, 2018, 29(2): 170-176. DOI: 10.5152/tjg.2018.17297.

26.Talari HR, Molaqanbari MR, Mokfi M, et al. The effects of vitamin B12 supplementation on metabolic profile of patients with non-alcoholic fatty liver disease: a randomized controlled trial[J]. Sci Rep, 2022, 12(1): 14047. DOI: 10.1038/s41598-022-18195-8.

27.Rezaei SMA, Mohammadi F, Eftekhari MH, et al. The effects of zinc supplementation on the metabolic factors in patients with non-alcoholic fatty liver disease: a randomized, double-blinded, placebo-controlled clinical trial[J]. BMC Nutr, 2023, 9(1): 138. DOI: 10.1186/s40795-023-00776-z.

28.陈怡文, 王磊, 唐斯伟, 等. 益生菌辅助治疗对非酒精性脂肪性肝病患者脂质过氧化损伤的保护作用[J]. 广东医学, 2021, 42(11): 1360-1363. [Chen YW, Wang L, Tang SW, et al. Protective effect of probiotic adjuvant therapy on lipid peroxidation injury in patients with non-alcoholic fatty liver disease[J]. Guangdong Medical Journal, 2021, 42(11): 1360-1363.] DOI: 10.13820/j.cnki.gdyx.20210859.

29.何周桃, 徐灿霞, 韩向阳, 等. 益生菌对非酒精性脂肪性肝病患者细胞因子表达及肠道菌群的影响[J]. 中国老年学杂志, 2017, 37(23): 5878-5880. [He ZT, Xu CX, Han XY, et al. Effects of probiotics on cytokine expression and intestinal flora in patients with non-alcoholic fatty liver disease[J]. Chinese Journal of Gerontology, 2017, 37(23): 5878-5880.] DOI: 10.3969/j.issn.1005-9202.2017.23.060.

30.杜君义, 梅璐, 于泳. 益生菌对非酒精性脂肪性肝病的治疗及对肠功能的影响[J]. 中国微生态学杂志, 2023, 35(7): 821-825. [Du JY, Mei L, Yu Y. Effect of probiotics for treatment of non-alcoholic fatty liver disease and on intestinal function[J]. Chinese Journal of Microecology, 2023, 35(7): 821-825.] DOI: 10.13381/j.cnki.cjm.202307014.

31.姚惠香, 陈维雄, 陈玮, 等. 益生菌治疗非酒精性脂肪性肝病的临床研究[J]. 胃肠病学和肝病学杂志, 2013, 22(3): 221-223. [Yao HX, Chen WX, Chen W, et al. Clinical study of probiotics in treatment of non-alcoholic fatty liver disease[J]. Chinese Journal of Gastroenterology and Hepatology, 2013, 22(3): 221-223.] DOI: 10.3969/j.issn.1006-5709.2013.03.009.

32.郑丹, 吴江, 甘洪颖, 等. 双歧杆菌三联活菌胶囊治疗非酒精性脂肪肝的临床观察[J]. 临床消化病杂志, 2018, 30(4): 240-243. [Zheng D, Wu J, Gan HY, et al. Clinical study of probiotics for non-alcoholic fatty liver disease[J]. Chinese Journal of Clinical Gastroenterology, 2018, 30(4): 240-243.] DOI: 10.3870/lcxh.j.issn.1005-541X.2018.04.09.

33.于文畅, 鲍晓蕾. 肠道益生菌联合多烯磷脂酰胆碱治疗老年非酒精性脂肪性肝病疗效[J]. 中国老年学杂志, 2016, 36(9): 2195-2197. [Yu WC, Bao XL. Efficacy of intestinal probiotics combined with polyene phosphatidylcholine in the treatment of elderly non-alcoholic fatty liver disease[J]. Chinese Journal of Gerontology, 2016, 36(9): 2195-2197.] DOI: 10.3969/j.issn.1005-9202.2016.09.068.

34.Cai GS, Su H, Zhang J. Protective effect of probiotics in patients with non-alcoholic fatty liver disease[J]. Medicine (Baltimore), 2020, 99(32): e21464. DOI: 10.1097/MD.0000000000021464.

35.袁丽, 梅璐, 于泳, 等. 益生菌干预合并糖调节受损的非酒精性脂肪肝病的疗效分析[J].中国微生态学杂志, 2017, 29(12): 1424-1427. [Yuan L, Mei L, Yu Y, et al. Efficacy of probiotics on non-alcoholic fatty liver disease and impaired glucose regulation[J]. Chinese Journal of Microecology, 2017, 29(12): 1424-1427.] DOI: 10.13381/j.cnki.cjm.201712014.

36.Abhari K, Saadati S, Yari Z, et al. The effects of Bacillus coagulans supplementation in patients with non-alcoholic fatty liver disease: a randomized,placebo-controlled, clinical trial[J]. Clin Nutr ESPEN, 2020, 39: 53-60. DOI: 10.1016/j.clnesp.2020.06.020.

37.Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver disease: pathophysiological basis for therapy[J]. J Hepatol, 2020, 72(3): 558-577. DOI: 10.1016/j.jhep.2019.10.003.

38.Shokryazdan P, Rajion MA, Meng GY, et al. Conjugated linoleic acid: a potent fatty acid linked to animal and human health[J]. Crit Rev Food Sci Nutr, 2017, 57(13): 2737-2748. DOI: 10.1080/ 10408398.2015.1060190.

39.Uchiyama K, Naito Y, Takagi T. Intestinal microbiome as a novel therapeutic target for local and systemic inflammation[J]. Pharmacol Ther, 2019, 199: 164-172. DOI: 10.1016/j.pharmthera. 2019.03.006.

40.Mehal WZ. The Inflammasome in liver injury and non-alcoholic fatty liver disease[J]. Dig Dis, 2014, 32(5): 507-515. DOI: 10.1159/000360495.

41.He J, Zhang F, Han Y. Effect of probiotics on lipid profiles and blood pressure in patients with type 2 diabetes: a Meta-analysis of RCTs[J]. Medicine (Baltimore), 2017, 96(51): e9166. DOI: 10.1097/MD.0000000000009166.

42.Takaki A, Kawai D, Yamamoto K. Multiple hits, including oxidative stress, as pathogenesis and treatment target in non-alcoholic steatohepatitis (NASH)[J]. Int J Mol Sci, 2013, 14(10): 20704-20728. DOI: 10.3390/ijms141020704.

43.König J, Wells J, Cani PD, et al. Human Intestinal barrier function in health and disease[J]. Clin Transl Gastroenterol, 2016, 7(10): e196. DOI: 10.1038/ctg.2016.54.

44.Phung N, Pera N, Farrell G, et al. Pro-oxidant-mediated hepatic fibrosis and effects of antioxidant intervention in murine dietary steatohepatitis[J]. Int J Mol Med, 2009, 24(2): 171-180. DOI: 10.3892/ijmm_00000220.

45.Cantorna MT, Rogers CJ, Arora J. Aligning the paradoxical role of vitamin D in gastrointestinal immunity[J]. Trends Endocrinol Metab, 2019, 30(7): 459-466. DOI: 10.1016/j.tem.2019.04.005.