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Open Access 01-12-2022 | Epigenetics | Research

Modulation of hepatic stellate cells by Mutaflor^® probiotic in non-alcoholic fatty liver disease management

Authors: Noha M. Hany, Sanaa Eissa, Manal Basyouni, Amany H. Hasanin, Yasmin M. Aboul-Ela, Nagwa M. Abo Elmagd, Iman F. Montasser, Mahmoud A. Ali, Paul J. Skipp, Marwa Matboli

Published in: Journal of Translational Medicine | Issue 1/2022

Abstract

Background

NAFLD and NASH are emerging as primary causes of chronic liver disease, indicating a need for an effective treatment. Mutaflor® probiotic, a microbial treatment of interest, was effective in sustaining remission in ulcerative colitis patients.

Objective

To construct a genetic-epigenetic network linked to HSC signaling as a modulator of NAFLD/NASH pathogenesis, then assess the effects of Mutaflor^® on this network.

Methods

First, in silico analysis was used to construct a genetic-epigenetic network linked to HSC signaling. Second, an investigation using rats, including HFHSD induced NASH and Mutaflor^® treated animals, was designed. Experimental procedures included biochemical and histopathologic analysis of rat blood and liver samples. At the molecular level, the expression of genetic (FOXA2, TEAD2, and LATS2 mRNAs) and epigenetic (miR-650, RPARP AS-1 LncRNA) network was measured by real-time PCR. PCR results were validated with immunohistochemistry (α-SMA and LATS2). Target effector proteins, IL-6 and TGF-β, were estimated by ELISA.

Results

Mutaflor^® administration minimized biochemical and histopathologic alterations caused by NAFLD/NASH. HSC activation and expression of profibrogenic IL-6 and TGF-β effector proteins were reduced via inhibition of hedgehog and hippo pathways. Pathways may have been inhibited through upregulation of RPARP AS-1 LncRNA which in turn downregulated the expression of miR-650, FOXA2 mRNA and TEAD2 mRNA and upregulated LATS2 mRNA expression.

Conclusion

Mutaflor^® may slow the progression of NAFLD/NASH by modulating a genetic-epigenetic network linked to HSC signaling. The probiotic may be a useful modality for the prevention and treatment of NAFLD/NASH.

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Pydyn N, Miękus K, Jura J, Kotlinowski J. New therapeutic strategies in nonalcoholic fatty liver disease: a focus on promising drugs for nonalcoholic steatohepatitis. Pharmacol Rep. 2020;72(1):1–12. https://doi.org/10.1007/s43440-019-00020-1 (Epub 2020 Jan 8).CrossRefPubMed

Perumpail BJ, Khan MA, Yoo ER, Cholankeril G, Kim D, Ahmed A. Clinical epidemiology and disease burden of nonalcoholic fatty liver disease. World J Gastroenterol. 2017;23(47):8263–76. https://doi.org/10.3748/wjg.v23.i47.8263.CrossRefPubMedPubMedCentral

Negro F. Natural history of NASH and HCC. Liver Int. 2020;40(Suppl 1):72–6. https://doi.org/10.1111/liv.14362.CrossRefPubMed

Burra P, Becchetti C, Germani G. NAFLD and liver transplantation: disease burden, current management and future challenges. JHEP Rep. 2020;2(6): 100192. https://doi.org/10.1016/j.jhepr.2020.100192.CrossRefPubMedPubMedCentral

Fang YL, Chen H, Wang CL, Liang L. Pathogenesis of non-alcoholic fatty liver disease in children and adolescence: from “two hit theory” to “multiple hit model.” World J Gastroenterol. 2018;24(27):2974–83. https://doi.org/10.3748/wjg.v24.i27.2974.CrossRefPubMedPubMedCentral

Li X, Zhu L, Wang B, Yuan M, Zhu R. Drugs and targets in fibrosis. Front Pharmacol. 2017;23(8):855. https://doi.org/10.3389/fphar.2017.00855.CrossRef

Zisser A, Ipsen DH, Tveden-Nyborg P. Hepatic stellate cell activation and inactivation in NASH-fibrosis-roles as putative treatment targets? Biomedicines. 2021;9(4):365. https://doi.org/10.3390/biomedicines9040365.CrossRefPubMedPubMedCentral

Schwabe RF, Tabas I, Pajvani UB. Mechanisms of fibrosis development in nonalcoholic steatohepatitis. Gastroenterology. 2020;158(7):1913–28. https://doi.org/10.1053/j.gastro.2019.11.311 (Epub 2020 Feb 8).CrossRefPubMed

Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med. 2018;24(7):908–22. https://doi.org/10.1038/s41591-018-0104-9 (Epub 2018 Jul 2).CrossRefPubMedPubMedCentral

10.

Dewidar B, Meyer C, Dooley S, Meindl-Beinker AN. TGF-β in hepatic stellate cell activation and liver fibrogenesis—updated 2019. Cells. 2019;8(11):1419. https://doi.org/10.3390/cells8111419.CrossRefPubMedCentral

11.

Marcher AB, Bendixen SM, Terkelsen MK, Hohmann SS, Hansen MH, Larsen BD, Mandrup S, Dimke H, Detlefsen S, Ravnskjaer K. Transcriptional regulation of hepatic stellate cell activation in NASH. Sci Rep. 2019;9(1):2324. https://doi.org/10.1038/s41598-019-39112-6.CrossRefPubMedPubMedCentral

12.

Heyens LJM, Busschots D, Koek GH, Robaeys G, Francque S. Liver fibrosis in non-alcoholic fatty liver disease: from liver biopsy to non-invasive biomarkers in diagnosis and treatment. Front Med. 2021;14(8): 615978. https://doi.org/10.3389/fmed.2021.615978.CrossRef

13.

Kiagiadaki F, Kampa M, Voumvouraki A, Castanas E, Kouroumalis E, Notas G. Activin-A causes hepatic stellate cell activation via the induction of TNFα and TGFβ in Kupffer cells. Biochim Biophys Acta Mol Basis Dis. 2018;1864(3):891–9. https://doi.org/10.1016/j.bbadis.2017.12.031 (Epub 2017 Dec 26).CrossRefPubMed

14.

Chan YT, Wang N, Tan HY, Li S, Feng Y. Targeting hepatic stellate cells for the treatment of liver fibrosis by natural products: is it the dawning of a new era? Front Pharmacol. 2020;30(11):548. https://doi.org/10.3389/fphar.2020.00548.CrossRef

15.

Hou W, Syn WK. Role of metabolism in hepatic stellate cell activation and fibrogenesis. Front Cell Dev Biol. 2018;12(6):150. https://doi.org/10.3389/fcell.2018.00150.CrossRef

16.

Gao L, Zhang Z, Zhang P, Yu M, Yang T. Role of canonical Hedgehog signaling pathway in liver. Int J Biol Sci. 2018;14(12):1636–44. https://doi.org/10.7150/ijbs.28089.CrossRefPubMedPubMedCentral

17.

Mu T, Xu L, Zhong Y, Liu X, Zhao Z, Huang C, Lan X, Lufei C, Zhou Y, Su Y, Xu L, Jiang M, Zhou H, Lin X, Wu L, Peng S, Liu S, Brix S, Dean M, Dunn NR, Zaret KS, Fu XY, Hou Y. Embryonic liver developmental trajectory revealed by single-cell RNA sequencing in the Foxa2eGFP mouse. Commun Biol. 2020;3(1):642. https://doi.org/10.1038/s42003-020-01364-8.CrossRefPubMedPubMedCentral

18.

Manmadhan S, Ehmer U. Hippo signaling in the liver—a long and ever-expanding story. Front Cell Dev Biol. 2019;12(7):33. https://doi.org/10.3389/fcell.2019.00033.CrossRef

19.

Yi J, Lu L, Yanger K, Wang W, Sohn BH, Stanger BZ, Zhang M, Martin JF, Ajani JA, Chen J, Lee JS, Song S, Johnson RL. Large tumor suppressor homologs 1 and 2 regulate mouse liver progenitor cell proliferation and maturation through antagonism of the coactivators YAP and TAZ. Hepatology. 2016;64(5):1757–72. https://doi.org/10.1002/hep.28768.CrossRefPubMed

20.

Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14(7):397–411. https://doi.org/10.1038/nrgastro.2017.38 (Epub 2017 May 10).CrossRefPubMed

21.

Naseem S, Hussain T, Manzoor S. Interleukin-6: a promising cytokine to support liver regeneration and adaptive immunity in liver pathologies. Cytokine Growth Factor Rev. 2018;39:36–45. https://doi.org/10.1016/j.cytogfr.2018.01.002 (Epub 2018 Jan 12).CrossRefPubMed

22.

Ashraf NU, Altaf M. Epigenetics: an emerging field in the pathogenesis of nonalcoholic fatty liver disease. Mutat Res. 2018;778:1–12. https://doi.org/10.1016/j.mrrev.2018.07.002 (Epub 2018 Aug 8).CrossRef

23.

Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J Hepatol. 2018;68(2):268–79. https://doi.org/10.1016/j.jhep.2017.09.003 (Epub 2017 Nov 6).CrossRefPubMed

24.

Finotti A, Fabbri E, Lampronti I, Gasparello J, Borgatti M, Gambari R. MicroRNAs and long non-coding RNAs in genetic diseases. Mol Diagn Ther. 2019;23(2):155–71. https://doi.org/10.1007/s40291-018-0380-6.CrossRefPubMedPubMedCentral

25.

Lin HY, Yang YL, Wang PW, Wang FS, Huang YH. The emerging role of microRNAs in NAFLD: highlight of microRNA-29a in modulating oxidative stress, inflammation, and beyond. Cells. 2020;9(4):1041. https://doi.org/10.3390/cells9041041.CrossRefPubMedCentral

26.

Hanson A, Wilhelmsen D, DiStefano JK. The role of long non-coding RNAs (lncRNAs) in the development and progression of fibrosis associated with nonalcoholic fatty liver disease (NAFLD). Noncoding RNA. 2018;4(3):18. https://doi.org/10.3390/ncrna4030018.CrossRefPubMedCentral

27.

Iacono A, Raso GM, Canani RB, Calignano A, Meli R. Probiotics as an emerging therapeutic strategy to treat NAFLD: focus on molecular and biochemical mechanisms. J Nutr Biochem. 2011;22(8):699–711. https://doi.org/10.1016/j.jnutbio.2010.10.002 (Epub 2011 Feb 2).CrossRefPubMed

28.

Perumpail BJ, Li AA, John N, Sallam S, Shah ND, Kwong W, Cholankeril G, Kim D, Ahmed A. The therapeutic implications of the gut microbiome and probiotics in patients with NAFLD. Diseases. 2019;7(1):27. https://doi.org/10.3390/diseases7010027.CrossRefPubMedCentral

29.

Meroni M, Longo M, Dongiovanni P. The role of probiotics in nonalcoholic fatty liver disease: a new insight into therapeutic strategies. Nutrients. 2019;11(11):2642. https://doi.org/10.3390/nu11112642.CrossRefPubMedCentral

30.

Duseja A, Acharya SK, Mehta M, Chhabra S, Rana S, Das A, Dattagupta S, Dhiman RK, Chawla YK. High potency multistrain probiotic improves liver histology in non-alcoholic fatty liver disease (NAFLD): a randomised, double-blind, proof of concept study. BMJ Open Gastroenterol. 2019;6(1):e000315. https://doi.org/10.1136/bmjgast-2019-000315.CrossRefPubMedPubMedCentral

31.

Scaldaferri F, Gerardi V, Mangiola F, Lopetuso LR, Pizzoferrato M, Petito V, Papa A, Stojanovic J, Poscia A, Cammarota G, Gasbarrini A. Role and mechanisms of action of Escherichia coli Nissle 1917 in the maintenance of remission in ulcerative colitis patients: an update. World J Gastroenterol. 2016;22(24):5505–11. https://doi.org/10.3748/wjg.v22.i24.5505.CrossRefPubMedPubMedCentral

32.

Wassenaar TM. Insights from 100 years of research with probiotic E. coli. Eur J Microbiol Immunol. 2016;6(3):147–61. https://doi.org/10.1556/1886.2016.00029.CrossRef

33.

Hungin AP, Mulligan C, Pot B, Whorwell P, Agréus L, Fracasso P, Lionis C, Mendive J, de Foy JMP, Rubin G, Winchester C, de Wit N. Systematic review: probiotics in the management of lower gastrointestinal symptoms in clinical practice—an evidence-based international guide. Aliment Pharmacol Ther. 2013;38(8):864–86. https://doi.org/10.1111/apt.12460 (Epub 2013 Aug 27).CrossRefPubMedPubMedCentral

34.

Praveschotinunt P, Duraj-Thatte AM, Gelfat I, Bahl F, Chou DB, Joshi NS. Engineered E. coli Nissle 1917 for the delivery of matrix-tethered therapeutic domains to the gut. Nat Commun. 2019;10(1):5580. https://doi.org/10.1038/s41467-019-13336-6 (Epub 2013 Aug 27).CrossRefPubMedPubMedCentral

35.

Reynolds J, Farinha M. Counting bacteria. Biology 2420 laboratory manual: microbiology. Richland College, Dallas, USA. 2005;1–10.

36.

Kosakova D, Scheer P, Lata J, Doubek J. Influence of the Escherichia coli Nissle 1917 strain on complications of the chronic experimental liver damage. Vet Med. 2007;52(3):121–9.CrossRef

37.

Arribas B, Rodríguez-Cabezas ME, Camuesco D, Comalada M, Bailón E, Utrilla P, Nieto A, Concha A, Zarzuelo A, Gálvez J. A probiotic strain of Escherichia coli, Nissle 1917, given orally exerts local and systemic anti-inflammatory effects in lipopolysaccharide-induced sepsis in mice. Br J Pharmacol. 2009;157(6):1024–33. https://doi.org/10.1111/j.1476-5381.2009.00270.x (Epub 2009 May 26).CrossRefPubMedPubMedCentral

38.

Briskey D, Heritage M, Jaskowski LA, Peake J, Gobe G, Subramaniam VN, Crawford D, Campbell C, Vitetta L. Probiotics modify tight-junction proteins in an animal model of nonalcoholic fatty liver disease. Therap Adv Gastroenterol. 2016;9(4):463–72. https://doi.org/10.1177/1756283X16645055 (Epub 2016 May 1).CrossRefPubMedPubMedCentral

39.

Sha S, Xu B, Kong X, Wei N, Liu J, Wu K. Preventive effects of Escherichia coli strain Nissle 1917 with different courses and different doses on intestinal inflammation in murine model of colitis. Inflamm Res. 2014;63(10):873–83. https://doi.org/10.1007/s00011-014-0761-1 (Epub 2014 Aug 14).CrossRefPubMed

40.

Guo JH, Han DW, Li XQ, Zhang Y, Zhao YC. The impact of small doses of LPS on NASH in high sucrose and high fat diet induced rats. Eur Rev Med Pharmacol Sci. 2014;18(18):2742–7.PubMed

41.

Khatun S, Fujimoto J, Toyoki H, Tamaya T. Clinical implications of expression of ETS-1 in relation to angiogenesis in ovarian cancers. Cancer Sci. 2003;94(9):769–73. https://doi.org/10.1111/j.1349-7006.2003.tb01517.x. CrossRefPubMed

42.

Takahashi Y, Fukusato T. Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2014;20(42):15539–48. https://doi.org/10.3748/wjg.v20.i42.15539. CrossRefPubMedPubMedCentral

43.

Paul J. Recent advances in non-invasive diagnosis and medical management of non-alcoholic fatty liver disease in adult. Egypt Liver J. 2020;10:37. https://doi.org/10.1186/s43066-020-00043-x.CrossRef

44.

Wong VW, Singal AK. Emerging medical therapies for non-alcoholic fatty liver disease and for alcoholic hepatitis. Transl Gastroenterol Hepatol. 2019;19(4):53. https://doi.org/10.21037/tgh.2019.06.06.CrossRef

45.

Kaufmann B, Reca A, Wang B, Friess H, Feldstein AE, Hartmann D. Mechanisms of nonalcoholic fatty liver disease and implications for surgery. Langenbecks Arch Surg. 2021;406(1):1–17. https://doi.org/10.1007/s00423-020-01965-1 (Epub 2020 Aug 24).CrossRefPubMed

46.

Higashi T, Friedman SL, Hoshida Y. Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev. 2017;121:27–42. https://doi.org/10.1016/j.addr.2017.05.007 (Epub 2017 May 12).CrossRefPubMedPubMedCentral

47.

Della Corte CM, Viscardi G, Papaccio F, Esposito G, Martini G, Ciardiello D, Martinelli E, Ciardiello F, Morgillo F. Implication of the Hedgehog pathway in hepatocellular carcinoma. World J Gastroenterol. 2017;23(24):4330–40. https://doi.org/10.3748/wjg.v23.i24.4330.CrossRefPubMedPubMedCentral

48.

Mouse (GRCm39) Ensembl release 103—February 2021 © EMBL-EBI: ENSMUSG00000037025. http://www.ensembl.org/Mus_musculus/Info/Index?db=core;g=ENSMUSG00000037025;r=2:147884797-147888889. Accessed July 2021.

49.

Human (GRCh38) Ensembl release 103 - February 2021 © EMBL-EBI: ENSG00000125798. http://www.ensembl.org/Homo_sapiens/Info/Index?db=core;g=ENSG00000125798;r=20:22580998-22585455. Accessed July 2021.

50.

Golson ML, Kaestner KH. Fox transcription factors: from development to disease. Development. 2016;143(24):4558–70. https://doi.org/10.1242/dev.112672.CrossRefPubMedPubMedCentral

51.

Bernardo GM, Keri RA. FOXA1: a transcription factor with parallel functions in development and cancer. Biosci Rep. 2012;32(2):113–30. https://doi.org/10.1042/BSR20110046.CrossRefPubMed

52.

Omenetti A, Choi S, Michelotti G, Diehl AM. Hedgehog signaling in the liver. J Hepatol. 2011;54(2):366–73. https://doi.org/10.1016/j.jhep.2010.10.003.CrossRefPubMed

53.

Wang DH, Tiwari A, Kim ME, Clemons NJ, Regmi NL, Hodges WA, Berman DM, Montgomery EA, Watkins DN, Zhang X, Zhang Q, Jie C, Spechler SJ, Souza RF. Hedgehog signaling regulates FOXA2 in esophageal embryogenesis and Barrett’s metaplasia. J Clin Investig. 2014;124(9):3767–80. https://doi.org/10.1172/JCI66603.CrossRefPubMedPubMedCentral

54.

Wang W, Yao LJ, Shen W, Ding K, Shi PM, Chen F, He J, Ding J, Zhang X, Xie WF. FOXA2 alleviates CCl4-induced liver fibrosis by protecting hepatocytes in mice. Sci Rep. 2017;7(1):15532. https://doi.org/10.1038/s41598-017-15831-6.CrossRefPubMedPubMedCentral

55.

Wilhelm A, Aldridge V, Haldar D, Naylor AJ, Weston CJ, Hedegaard D, Garg A, Fear J, Reynolds GM, Croft AP, Henderson NC, Buckley CD, Newsome PN. CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism. Gut. 2016;65(7):1175–85. https://doi.org/10.1136/gutjnl-2014-308325 (Epub 2015 Jun 15).CrossRefPubMed

56.

Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, Pellicoro A, Raschperger E, Betsholtz C, Ruminski PG, Griggs DW, Prinsen MJ, Maher JJ, Iredale JP, Lacy-Hulbert A, Adams RH, Sheppard D. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med. 2013;19(12):1617–24. https://doi.org/10.1038/nm.3282 (Epub 2013 Nov 10).CrossRefPubMed

57.

Chen L, Li J, Zhang J, Dai C, Liu X, Wang J, Gao Z, Guo H, Wang R, Lu S, Wang F, Zhang H, Chen H, Fan X, Wang S, Qin Z. S100A4 promotes liver fibrosis via activation of hepatic stellate cells. J Hepatol. 2015;62(1):156–64. https://doi.org/10.1016/j.jhep.2014.07.035 (Epub 2014 Aug 9).CrossRefPubMed

58.

Human (GRCh38/hg38) Ensembl release 103—February 2021 © EMBL-EBI: ENSG00000074219. http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000074219;r=19:49340595-49362457. Accessed July 2021.

59.

Zhao Z, Meng J, Su R, Zhang J, Chen J, Ma X, Xia Q. Epitranscriptomics in liver disease: basic concepts and therapeutic potential. J Hepatol. 2020;73(3):664–79. https://doi.org/10.1016/j.jhep.2020.04.009 (Epub 2020 Apr 21).CrossRefPubMed

60.

Rong ZX, Li Z, He JJ, Liu LY, Ren XX, Gao J, Mu Y, Guan YD, Duan YM, Zhang XP, Zhang DX, Li N, Deng YZ, Sun LQ. Downregulation of fat mass and obesity associated (FTO) promotes the progression of intrahepatic cholangiocarcinoma. Front Oncol. 2019;9(9):369. https://doi.org/10.3389/fonc.2019.00369.CrossRefPubMedPubMedCentral

61.

Joo JS, Cho SY, Rou WS, Kim JS, Kang SH, Lee ES, Moon HS, Kim SH, Sung JK, Kwon IS, Eun HS, Lee BS. TEAD2 as a novel prognostic factor for hepatocellular carcinoma. Oncol Rep. 2020;43(6):1785–96. https://doi.org/10.3892/or.2020.7578 (Epub 2020 Apr 6).CrossRefPubMedPubMedCentral

62.

Shu Y, Liu X, Huang H, Wen Q, Shu J. Research progress of natural compounds in anti-liver fibrosis by affecting autophagy of hepatic stellate cells. Mol Biol Rep. 2021;48(2):1915–24. https://doi.org/10.1007/s11033-021-06171-w (Epub 2021 Feb 20).CrossRefPubMedPubMedCentral

63.

Lee DH, Park JO, Kim TS, Kim SK, Kim TH, Kim MC, Park GS, Kim JH, Kuninaka S, Olson EN, Saya H, Kim SY, Lee H, Lim DS. LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development. Nat Commun. 2016;30(7):11961. https://doi.org/10.1038/ncomms11961.CrossRef

64.

Aylon Y, Gershoni A, Rotkopf R, Biton IE, Porat Z, Koh AP, Sun X, Lee Y, Fiel MI, Hoshida Y, Friedman SL, Johnson RL, Oren M. The LATS2 tumor suppressor inhibits SREBP and suppresses hepatic cholesterol accumulation. Genes Dev. 2016;30(7):786–97. https://doi.org/10.1101/gad.274167.115 (Epub 2016 Mar 24).CrossRefPubMedPubMedCentral

65.

Furth N, Aylon Y. The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway. Cell Death Differ. 2017;24(9):1488–501. https://doi.org/10.1038/cdd.2017.99 (Epub 2017 Jun 23).CrossRefPubMedPubMedCentral

66.

Ye J, Li TS, Xu G, Zhao YM, Zhang NP, Fan J, Wu J. JCAD promotes progression of nonalcoholic steatohepatitis to liver cancer by inhibiting LATS2 kinase activity. Cancer Res. 2017;77(19):5287–300. https://doi.org/10.1158/0008-5472.CAN-17-0229 (Epub 2017 Aug 3).CrossRefPubMed

67.

Schmidt-Arras D, Rose-John S. IL-6 pathway in the liver: From physiopathology to therapy. J Hepatol. 2016;64(6):1403–15. https://doi.org/10.1016/j.jhep.2016.02.004 (Epub 2016 Feb 8).CrossRefPubMed

68.

Fazel Modares N, Polz R, Haghighi F, Lamertz L, Behnke K, Zhuang Y, Kordes C, Häussinger D, Sorg UR, Pfeffer K, Floss DM, Moll JM, Piekorz RP, Ahmadian MR, Lang PA, Scheller J. IL-6 trans-signaling controls liver regeneration after partial hepatectomy. Hepatology. 2019;70(6):2075–91. https://doi.org/10.1002/hep.30774 (Epub 2019 Jul 8).CrossRefPubMed

69.

Xiang DM, Sun W, Ning BF, Zhou TF, Li XF, Zhong W, Cheng Z, Xia MY, Wang X, Deng X, Wang W, Li HY, Cui XL, Li SC, Wu B, Xie WF, Wang HY, Ding J. The HLF/IL-6/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis. Gut. 2018;67(9):1704–15. https://doi.org/10.1136/gutjnl-2016-313392 (Epub 2017 Jul 28).CrossRefPubMed

70.

Wang H, Lafdil F, Kong X, Gao B. Signal transducer and activator of transcription 3 in liver diseases: a novel therapeutic target. Int J Biol Sci. 2011;7(5):536–50. https://doi.org/10.7150/ijbs.7.536.CrossRefPubMedPubMedCentral

71.

Kong X, Horiguchi N, Mori M, Gao B. Cytokines and STATs in liver fibrosis. Front Physiol. 2012;3(3):69. https://doi.org/10.3389/fphys.2012.00069.CrossRefPubMedPubMedCentral

72.

Granzow M, Schierwagen R, Klein S, Kowallick B, Huss S, Linhart M, Mazar IG, Görtzen J, Vogt A, Schildberg FA, Gonzalez-Carmona MA, Wojtalla A, Krämer B, Nattermann J, Siegmund SV, Werner N, Fürst DO, Laleman W, Knolle P, Shah VH, Sauerbruch T, Trebicka J. Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis. Hepatology. 2014;60(1):334–48. https://doi.org/10.1002/hep.27117.CrossRefPubMed

73.

Lakner AM, Moore CC, Gulledge AA, Schrum LW. Daily genetic profiling indicates JAK/STAT signaling promotes early hepatic stellate cell transdifferentiation. World J Gastroenterol. 2010;16(40):5047–56. https://doi.org/10.3748/wjg.v16.i40.5047.CrossRefPubMedPubMedCentral

74.

Fabregat I, Caballero-Díaz D. Transforming growth factor-β-induced cell plasticity in liver fibrosis and hepatocarcinogenesis. Front Oncol. 2018;10(8):357. https://doi.org/10.3389/fonc.2018.00357.CrossRef

75.

Liu J, Kong D, Qiu J, Xie Y, Lu Z, Zhou C, Liu X, Zhang R, Wang Y. Praziquantel ameliorates CCl4-induced liver fibrosis in mice by inhibiting TGF-β/Smad signalling via up-regulating Smad7 in hepatic stellate cells. Br J Pharmacol. 2019;176(24):4666–80. https://doi.org/10.1111/bph.14831.CrossRefPubMedPubMedCentral

76.

Rajasekaran S, Rajaguru P, Sudhakar Gandhi PS. MicroRNAs as potential targets for progressive pulmonary fibrosis. Front Pharmacol. 2015;5(6):254. https://doi.org/10.3389/fphar.2015.00254.CrossRef

77.

Estep M, Armistead D, Hossain N, Elarainy H, Goodman Z, Baranova A, Chandhoke V, Younossi ZM. Differential expression of miRNAs in the visceral adipose tissue of patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2010;32(3):487–97. https://doi.org/10.1111/j.1365-2036.2010.04366.x (Epub 2010 May 22).CrossRefPubMed

78.

Fisher K, Lin J. MicroRNA in inflammatory bowel disease: translational research and clinical implication. World J Gastroenterol. 2015;21(43):12274–82. https://doi.org/10.3748/wjg.v21.i43.12274.CrossRefPubMedPubMedCentral

79.

Han LL, Yin XR, Zhang SQ. miR-650 promotes the metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by directly inhibiting LATS2 expression. Cell Physiol Biochem. 2018;51(3):1179–92. https://doi.org/10.1159/000495495 (Epub 2018 Nov 27).CrossRefPubMed

80.

Zhou C, York SR, Chen JY, Pondick JV, Motola DL, Chung RT, Mullen AC. Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins. Genome Med. 2016;8(1):31. https://doi.org/10.1186/s13073-016-0285-0.CrossRefPubMedPubMedCentral

81.

Human (GRCh38.p13) Ensembl release 103—February 2021 © EMBL-EBI: ENSG00000269609. http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000269609;r=10:102449816-102461106#.

82.

Ren Y, Zhao C, He Y, Min X, Xu H, Hu X. RPARP-AS1/miR125a-5p axis promotes cell proliferation, migration and invasion in colon cancer. Onco Targets Ther. 2021;12(14):5035–43. https://doi.org/10.2147/OTT.S304494.CrossRef

83.

Khomich O, Ivanov AV, Bartosch B. Metabolic hallmarks of hepatic stellate cells in liver fibrosis. Cells. 2019;9(1):24. https://doi.org/10.3390/cells9010024.CrossRefPubMedCentral

84.

Li H, Huang MH, Jiang JD, Peng ZG. Hepatitis C: from inflammatory pathogenesis to anti-inflammatory/hepatoprotective therapy. World J Gastroenterol. 2018;24(47):5297–311. https://doi.org/10.3748/wjg.v24.i47.5297.CrossRefPubMedPubMedCentral

85.

Li J, Zhao YR, Tian Z. Roles of hepatic stellate cells in acute liver failure: from the perspective of inflammation and fibrosis. World J Hepatol. 2019;11(5):412–20. https://doi.org/10.4254/wjh.v11.i5.412.CrossRefPubMedPubMedCentral

86.

Van Herck MA, Vonghia L, Francque SM. Animal models of nonalcoholic fatty liver disease—a starter’s guide. Nutrients. 2017;9(10):1072. https://doi.org/10.3390/nu9101072.CrossRefPubMedCentral

Title: Modulation of hepatic stellate cells by Mutaflor® probiotic in non-alcoholic fatty liver disease management
Authors: Noha M. Hany
Sanaa Eissa
Manal Basyouni
Amany H. Hasanin
Yasmin M. Aboul-Ela
Nagwa M. Abo Elmagd
Iman F. Montasser
Mahmoud A. Ali
Paul J. Skipp
Marwa Matboli
Publication date: 01-12-2022
Publisher: BioMed Central
Keyword: Epigenetics
Published in: Journal of Translational Medicine / Issue 1/2022
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-022-03543-z

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