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World Journal of Pediatrics
Published in: World Journal of Pediatrics 5/2023

Open Access 27-09-2022 | Review Article

Biliatresone: progress in biliary atresia study

Authors: Jia-Jie Zhu, Yi-Fan Yang, Rui Dong, Shan Zheng

Published in: World Journal of Pediatrics | Issue 5/2023

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Abstract

Background

Biliary atresia (BA) is one of the main causes of neonatal end-stage liver disease. Without timely diagnosis and treatment, most children with BA will develop irreversible liver fibrosis within the first two months. While current theorized causes of BA include viral infection, immune disorders, and genetic defects, the comprehensive etiology is still largely unknown. Recently, biliatresone attracted much interest for its ability to induce BA in both zebrafish and mice, so we summarized the latest progress of biliatresone research in BA and tried to answer the question of whether it could provide further clues to the etiology of human BA.

Data sources

We conducted a PubMed search for any published articles related to the topic using search terms including “biliary atresia”, “biliatresone”, “GSH”, and “HSP90”. Relevant data were extracted from the original text or supplementary materials of the corresponding articles.

Results

Biliatresone had shown its unique toxicity in multiple species such as zebrafish and mice, and pathogenic factors involved included glutathione (GSH), heat shock protein 90 (HSP90) and the related pathways. In combination with epidemiological evidence and recent studies on the intestinal flora in biliary atresia, a new pathogenic hypothesis that the occurrence of biliary atresia is partly due to biliatresone or its structure-like compounds depositing in human body via vegetables or/and the altered intestinal flora structure can be tentatively established.

Conclusions

Based on the existing evidence, we emphasized that GSH and HSP90 are involved in the development of BA, and the maternal diet, especially higher vegetable intake of Asian women of childbearing age, accompanied by the altered intestinal flora structure, may contribute to the occurrence of biliary atresia and the higher incidence in the Asia group. However, the evidence from large sample epidemiological research is necessary.
Appendix
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Literature
1.
Harpavat S, Garcia-Prats JA, Anaya C, Brandt ML, Lupo PJ, Finegold MJ, et al. Diagnostic yield of newborn screening for biliary atresia using direct or conjugated bilirubin measurements. JAMA. 2020;323:1141–50.PubMedPubMedCentralCrossRef
2.
3.
4.
Chardot C, Carton M, Spire-Bendelac N, Le Pommelet C, Golmard JL, Auvert B. Epidemiology of biliary atresia in France: a national study 1986–96. J Hepatol. 1999;31:1006–13.PubMedCrossRef
5.
Hsiao CH, Chang MH, Chen HL, Lee HC, Wu TC, Lin CC, et al. Universal screening for biliary atresia using an infant stool color card in Taiwan. Hepatology. 2008;47:1233–40.PubMedCrossRef
6.
7.
Yang L, Mizuochi T, Shivakumar P, Mourya R, Luo Z, Gutta S, et al. Regulation of epithelial injury and bile duct obstruction by NLRP3, IL-1R1 in experimental biliary atresia. J Hepatol. 2018;69:1136–44.PubMedPubMedCentralCrossRef
8.
Hays DM, Woolley MM, Snyder WH, Reed GB, Gwinn JL, Landing BH. Diagnosis of biliary atresia: relative accuracy of percutaneous liver biopsy, open liver biopsy, and operative cholangiography. J Pediatr. 1967;71:598–607.PubMedCrossRef
9.
Letter AG. Cytomegalovirus and biliary atresia. Lancet. 1973;2:1206.
10.
Tyler KL, Sokol RJ, Oberhaus SM, Le M, Karrer FM, Narkewicz MR, et al. Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts. Hepatology. 1998;27:1475–82.PubMedCrossRef
11.
Shivakumar P, Campbell KM, Sabla GE, Miethke A, Tiao G, McNeal MM, et al. Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-gamma in experimental biliary atresia. J Clin Invest. 2004;114:322–9.PubMedPubMedCentralCrossRef
12.
Wang J, Xu Y, Chen Z, Liang J, Lin Z, Liang H, et al. Liver immune profiling reveals pathogenesis and therapeutics for biliary atresia. Cell. 2020;183:1867–83.e26.PubMedCrossRef
13.
Wen J, Zhou Y, Wang J, Chen J, Yan W, Wu J, et al. Retraction note: interactions between Th1 cells and Tregs affect regulation of hepatic fibrosis in biliary atresia through the IFN-gamma/STAT1 pathway. Cell Death Differ. 2020;27:2295.PubMedCrossRef
14.
Tucker RM, Feldman AG, Fenner EK, Mack CL. Regulatory T cells inhibit Th1 cell-mediated bile duct injury in murine biliary atresia. J Hepatol. 2013;59:790–6.PubMedCrossRef
15.
Bai MR, Niu WB, Zhou Y, Gong YM, Lu YJ, Yu XX, et al. Association of common variation in ADD3 and GPC1 with biliary atresia susceptibility. Aging (Albany NY). 2020;12:7163–82.PubMedCrossRef
16.
Smith K. Biliary tract: GPC1 genetic risk further links Hedgehog signalling with pathogenesis of biliary atresia. Nat Rev Gastroenterol Hepatol. 2013;10:127.PubMedCrossRef
17.
18.
Patman G. Biliary tract: newly identified biliatresone causes biliary atresia. Nat Rev Gastroenterol Hepatol. 2015;12:369.PubMedCrossRef
19.
Joest E. Handbook of special pathological anatomy of domestic animals. 3rd ed. Paul Parey; 1949.
20.
Harper P, Plant JW, Unger DB. Congenital biliary atresia and jaundice in lambs and calves. Aust Vet J. 1990;67:18–22.PubMedCrossRef
21.
Lemaigre FP. Development of the intrahepatic and extrahepatic biliary tract: a framework for understanding congenital diseases. Ann Rev Pathol. 2020;15:1–22.CrossRef
22.
Lorent K, Gong W, Koo KA, Waisbourd-Zinman O, Karjoo S, Zhao X, et al. Identification of a plant isoflavonoid that causes biliary atresia. Sci Transl Med. 2015;7:286.CrossRef
23.
Koo KA, Lorent K, Gong W, Windsor P, Whittaker SJ, Pack M, et al. Biliatresone, a reactive natural toxin from Dysphania glomulifera and D. littoralis: discovery of the toxic moiety 1,2-diaryl-2-propenone. Chem Res Toxicol. 2015;28:1519–21.PubMedPubMedCentralCrossRef
24.
Koo KA, Waisbourd-Zinman O, Wells RG, Pack M, Porter JR. Reactivity of biliatresone, a natural biliary toxin, with glutathione, histamine, and amino acids. Chem Res Toxicol. 2016;29:142–9.PubMedPubMedCentralCrossRef
25.
Estrada MA, Zhao X, Lorent K, Kriegermeier A, Nagao SA, Berritt S, et al. Synthesis and structure-activity relationship study of biliatresone, a plant isoflavonoid that causes biliary atresia. ACS Med Chem Lett. 2017;9:61–4.PubMedPubMedCentralCrossRef
26.
Yang Y, Dong R, Jia L, Qiang L, Shan Z. Synthesis study of biliatresone, a plant isoflavonoid that causes biliary atresia in zebrafish. Chin J Exp Surg. 2019;36:3 (in Chinese).
27.
28.
Zhao X, Lorent K, Escobar-Zarate D, Rajagopalan R, Loomes KM, Gillespie K, et al. Impaired redox and protein homeostasis as risk factors and therapeutic targets in toxin-induced biliary atresia. Gastroenterology. 2020;159:1068–84.e2.PubMedCrossRef
29.
Yang Y, Wang J, Zhan Y, Chen G, Shen Z, Zheng S, et al. The synthetic toxin biliatresone causes biliary atresia in mice. Lab Invest. 2020;100:1425–35.PubMedCrossRef
30.
Thomas H. Biliary tract: MMP7–a diagnostic biomarker for biliary atresia. Nat Rev Gastroenterol Hepatol. 2018;15:68.PubMedCrossRef
31.
Iwanami N, Hess I, Schorpp M, Boehm T. Studying the adaptive immune system in zebrafish by transplantation of hematopoietic precursor cells. Methods Cell Biol. 2017;138:151–61.PubMedCrossRef
32.
Cao P, Sun J, Sullivan MA, Huang X, Wang H, Zhang Y, et al. Angelica sinensis polysaccharide protects against acetaminophen-induced acute liver injury and cell death by suppressing oxidative stress and hepatic apoptosis in vivo and in vitro. Int J Biol Macromol. 2018;111:1133–9.PubMedCrossRef
33.
Ali FEM, Bakr AG, Abo-Youssef AM, Azouz AA, Hemeida RAM. Targeting Keap-1/Nrf-2 pathway and cytoglobin as a potential protective mechanism of diosmin and pentoxifylline against cholestatic liver cirrhosis. Life Sci. 2018;207:50–60.PubMedCrossRef
34.
Luo Z, Shivakumar P, Mourya R, Gutta S, Bezerra JA. Gene expression signatures associated with survival times of pediatric patients with biliary atresia identify potential therapeutic agents. Gastroenterology. 2019;157:1138–52.e14.PubMedCrossRef
35.
Wang J, Xu J, Xia M, Yang Y, Shen Z, Chen G, et al. Correlation between hepatic oxidative damage and clinical severity and mitochondrial gene sequencing results in biliary atresia. Hepatol Res. 2019;49:695–704.PubMedCrossRef
36.
Zhao X, Lorent K, Wilkins BJ, Marchione DM, Gillespie K, Waisbourd-Zinman O, et al. Glutathione antioxidant pathway activity and reserve determine toxicity and specificity of the biliary toxin biliatresone in zebrafish. Hepatology. 2016;64:894–907.PubMedCrossRef
37.
Merino-Azpitarte M, Lozano E, Perugorria MJ, Esparza-Baquer A, Erice O, Santos-Laso A, et al. SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma. J Hepatol. 2017;67:72–83.PubMedPubMedCentralCrossRef
38.
Bock C, Boutros M, Camp JG, Clarke L, Clevers H, Knoblich JA, et al. The organoid cell atlas. Nat Biotechnol. 2021;39:13–7.PubMedCrossRef
39.
Waisbourd-Zinman O, Koh H, Tsai S, Lavrut PM, Dang C, Zhao X, et al. The toxin biliatresone causes mouse extrahepatic cholangiocyte damage and fibrosis through decreased glutathione and SOX17. Hepatology. 2016;64:880–93.PubMedCrossRef
40.
Krneta-Stankic V, Corkins ME, Paulucci-Holthauzen A, Kloc M, Gladden AB, Miller RK. The Wnt/PCP formin Daam1 drives cell-cell adhesion during nephron development. Cell Rep. 2021;36:109340.PubMedPubMedCentralCrossRef
41.
Wang DP, Tang XZ, Liang QK, Zeng XJ, Yang JB, Xu J. MicroRNA-599 promotes apoptosis and represses proliferation and epithelial-mesenchymal transition of papillary thyroid carcinoma cells via downregulation of Hey2-depentent Notch signaling pathway. J Cell Physiol. 2020;235:2492–505.PubMedCrossRef
42.
Fried S, Gilboa D, Har-Zahav A, Lavrut PM, Du Y, Karjoo S, et al. Extrahepatic cholangiocyte obstruction is mediated by decreased glutathione, Wnt and Notch signaling pathways in a toxic model of biliary atresia. Sci Rep. 2020;10:7599.PubMedPubMedCentralCrossRef
43.
Schopf FH, Biebl MM, Buchner J. The HSP90 chaperone machinery. Nat Rev Mol Cell Biol. 2017;18:345–60.PubMedCrossRef
44.
Moran Luengo T, Mayer MP, Rudiger SGD. The Hsp70-Hsp90 chaperone cascade in protein folding. Trends Cell Biol. 2019;29:164–77.PubMedCrossRef
45.
Rajagopalan R, Tsai EA, Grochowski CM, Kelly SM, Loomes KM, Spinner NB, et al. Exome sequencing in individuals with isolated biliary atresia. Sci Rep. 2020;10:2709.PubMedPubMedCentralCrossRef
46.
Dong R, Deng P, Huang Y, Shen C, Xue P, Zheng S. Identification of HSP90 as potential biomarker of biliary atresia using two-dimensional electrophoresis and mass spectrometry. PLoS One. 2013;8:e68602.PubMedPubMedCentralCrossRef
47.
Elliger CA, Halloin JM. Phenolics induced in beta vulgaris by Rhizoctonia solani infection. Phytochemistry. 1994;37:691–3.PubMedCrossRef
48.
Geigert J, Stermitz FR, Johnson G, Maag DD, Johnson DK. Two phytoalexins from sugarbeet (Beta vulgaris) leaves. Tetrahedron. 1973;29:2703–6.CrossRef
49.
Hur HG, Beger RD, Heinze TM, Lay JO Jr, Freeman JP, Dore J, et al. Isolation of an anaerobic intestinal bacterium capable of cleaving the C-ring of the isoflavonoid daidzein. Arch Microbiol. 2002;178:8–12.PubMedCrossRef
50.
Tripathi A, Debelius J, Brenner DA, Karin M, Loomba R, Schnabl B, et al. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol. 2018;15:397–411.PubMedPubMedCentralCrossRef
51.
Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver disease: pathophysiological basis for therapy. J Hepatol. 2020;72:558–77.PubMedCrossRef
52.
Song W, Sun LY, Zhu ZJ, Wei L, Qu W, Zeng ZG, et al. Association of gut microbiota and metabolites with disease progression in children with biliary atresia. Front Immunol. 2021;12:698900.PubMedPubMedCentralCrossRef
53.
Yang T, Yang S, Zhao J, Wang P, Li S, Jin Y, et al. Comprehensive analysis of gut microbiota and fecal bile acid profiles in children with biliary atresia. Front Cell Infect Microbiol. 2022;12:914247.PubMedPubMedCentralCrossRef
54.
van Wessel D, Nomden M, Bruggink J, de Kleine R, Kurilshikov A, Verkade H, et al. Gut microbiota composition of biliary atresia patients before Kasai portoenterostomy associates with long-term outcome. J Pediatr Gastroenterol Nutr. 2021;73:485–90.PubMedPubMedCentralCrossRef
55.
Wang J, Qian T, Jiang J, Yang Y, Shen Z, Huang Y, et al. Gut microbial profile in biliary atresia: a case-control study. J Gastroenterol Hepatol. 2020;35:334–42.PubMedCrossRef
56.
Jee JJ, Yang L, Shivakumar P, Xu PP, Mourya R, Thanekar U, et al. Maternal regulation of biliary disease in neonates via gut microbial metabolites. Nat Commun. 2022;13:18.PubMedPubMedCentralCrossRef
57.
Chung PHY, Zheng S, Tam PKH. Biliary atresia: east versus west. Semin Pediatr Surg. 2020;29:150950.PubMedCrossRef
58.
Hopkins PC, Yazigi N, Nylund CM. Incidence of biliary atresia and timing of hepatoportoenterostomy in the United States. J Pediatr. 2017;187:253–7.PubMedCrossRef
59.
GBD 2017 Diet Collaborators. Health effects of dietary risks in 195 countries, 1990–2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2019;393:1958–72.CrossRef
60.
Lock K, Pomerleau J, Causer L, Altmann DR, McKee M. The global burden of disease attributable to low consumption of fruit and vegetables: implications for the global strategy on diet. Bull World Health Organ. 2005;83:100–8.PubMedPubMedCentral
61.
The NS, Honein MA, Caton AR, Moore CA, Siega-Riz AM, Druschel CM, et al. Risk factors for isolated biliary atresia, national birth defects prevention study, 1997–2002. Am J Med Genet A. 2007;143A:2274–84.PubMedCrossRef
62.
Zhao D, Gong X, Li Y, Sun X, Chen Y, Deng Z, et al. Effects of cytomegalovirus infection on the differential diagnosis between biliary atresia and intrahepatic cholestasis in a Chinese large cohort study. Ann Hepatol. 2021;23:100286.PubMedCrossRef
63.
64.
Shen O, Sela HY, Nagar H, Rabinowitz R, Jacobovich E, Chen D, et al. Prenatal diagnosis of biliary atresia: a case series. Early Hum Dev. 2017;111:16–9.PubMedCrossRef
65.
Chen L, He F, Zeng K, Wang B, Li J, Zhao D, et al. Differentiation of cystic biliary atresia and choledochal cysts using prenatal ultrasonography. Ultrasonography. 2022;41:140–9.PubMedCrossRef
66.
Harpavat S, Finegold MJ, Karpen SJ. Patients with biliary atresia have elevated direct/conjugated bilirubin levels shortly after birth. Pediatrics. 2011;128:e1428–33.PubMedPubMedCentralCrossRef
Metadata
Title
Biliatresone: progress in biliary atresia study
Authors
Jia-Jie Zhu
Yi-Fan Yang
Rui Dong
Shan Zheng
Publication date
27-09-2022
Publisher
Springer Nature Singapore
Published in
World Journal of Pediatrics / Issue 5/2023
Print ISSN: 1708-8569
Electronic ISSN: 1867-0687
DOI
https://doi.org/10.1007/s12519-022-00619-0

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