BACKGROUND AND AIMS: Schistosoma mansoni infection is one of the worldwide leading causes of liver fibrosis and portal hypertension. The objective of this study was to evaluate whether polyhydroxylated bile acids (BAs), known to protect mice from the development of acquired cholestatic liver injury, counteract S. mansoni-induced inflammation and fibrosis. METHODS: Adult FVB/N wild type (WT) and Abcb11/Bsep-/- mice were infected with either 25 or 50 S. mansoni cercariae. Eight weeks post infection, effects on liver histology, serum biochemistry, gene expression profile of proinflammatory cytokines and fibrotic markers, hepatic hydroxyproline content and FACS analysis were performed. RESULTS: Bsep-/- mice infected with S. mansoni showed significantly less hepatic inflammation and tendentially less fibrosis compared to infected WT mice. Despite elevated alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels in infected Bsep-/- mice, inflammatory cells such as M2 macrophages and Mac-2/galectin-3+ cells were reduced in these animals. Accordingly, mRNA-expression levels of anti-inflammatory cytokines (IL-4 and IL-13) were increased in Bsep-/- mice upon infection. Furthermore, infected Bsep-/- mice exhibited decreased hepatic egg load and parasite fecundity, consequently affecting the worm reproduction rate. This outcome could arise from elevated serum BA levels and lower blood pH in Bsep-/- mice. CONCLUSIONS: The loss of Bsep and the resulting changes in bile acid composition and blood pH are associated with the reduction of parasite fecundity, thus attenuating the development of S. mansoni-induced hepatic inflammation and fibrosis.

Clinical Institute of Medical and Chemical Laboratory Diagnostics Medical University of Graz Graz Austria

Clinical Institute of Medical and Chemical Laboratory Diagnostics University Hospital Graz Graz Austria

Department Life Light and Matter University of Rostock Rostock Germany

Department of Parasitology Faculty of Science Charles University Prague Czechia

Division of Tropical Medicine and Infectious Diseases Center of Internal Medicine 2 Rostock University Medical Center Rostock Germany

Hans Popper Laboratory of Molecular Hepatology Division of Gastroenterology and Hepatology Department of Internal Medicine 3 Medical University of Vienna Vienna Austria

Medical Biology and Electron Microscopy Center University Medical Center Rostock Rostock Germany

Zobrazit více v PubMed

Gryseels B, Polman K, Clerinx J, Kestens L. Human schistosomiasis. Lancet. 2006;368(9541):1106‐1118. doi: 10.1016/S0140-6736(06)69440-3 PubMed DOI

McManus DP, Dunne DW, Sacko M, Utzinger J, Vennervald BJ, Zhou X‐N. Schistosomiasis. Nat Rev Dis Prim. 2018;4(1):13. doi: 10.1038/s41572-018-0013-8 PubMed DOI

Garcia‐Palmieri MR, Marcial‐Rojas RA. Portal hypertension due to schistosomiasis mansoni. Am J Med. 1959;27(5):811‐816. doi: 10.1016/0002-9343(59)90197-4 PubMed DOI

Costain AH, Phythian‐Adams AT, Colombo SAP, et al. Dynamics of host immune response development during PubMed DOI PMC

Rutitzky LI, Hernandez HJ, Stadecker MJ. Th1‐polarizing immunization with egg antigens correlates with severe exacerbation of immunopathology and death in schistosome infection. Proc Natl Acad Sci. 2001;98(23):13243‐13248. doi: 10.1073/pnas.231258498 PubMed DOI PMC

Reeves HL. Activation of hepatic stellate cells—a key issue in liver fibrosis. Front Biosci. 2002;7(1–3):d808. doi: 10.2741/reeves PubMed DOI

Kaviratne M, Hesse M, Leusink M, et al. IL‐13 activates a mechanism of tissue fibrosis that is completely TGF‐β independent. J Immunol. 2004;173(6):4020‐4029. doi: 10.4049/jimmunol.173.6.4020 PubMed DOI

Kamdem SD, Moyou‐Somo R, Brombacher F, Nono JK. Host regulators of liver fibrosis during human schistosomiasis. Front Immunol. 2018;9:2781. doi: 10.3389/fimmu.2018.02781 PubMed DOI PMC

Melman SD, Steinauer ML, Cunningham C, et al. Reduced susceptibility to praziquantel among naturally occurring Kenyan isolates of PubMed DOI PMC

Doenhoff MJ, Cioli D, Utzinger J. Praziquantel: mechanisms of action, resistance and new derivatives for schistosomiasis. Curr Opin Infect Dis. 2008;21(6):659‐667. doi: 10.1097/QCO.0b013e328318978f PubMed DOI

Traussnigg S, Schattenberg JM, Demir M, et al. Norursodeoxycholic acid versus placebo in the treatment of non‐alcoholic fatty liver disease: a double‐blind, randomised, placebo‐controlled, phase 2 dose‐finding trial. Lancet Gastroenterol Hepatol. 2019;4(10):781‐793. doi: 10.1016/S2468-1253(19)30184-0 PubMed DOI

Fickert P, Hirschfield GM, Denk G, et al. norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. J Hepatol. 2017;67(3):549‐558. doi: 10.1016/j.jhep.2017.05.009 PubMed DOI

Sombetzki M, Fuchs CD, Fickert P, et al. 24‐nor‐ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic schistosomiasis. J Hepatol. 2015;62(4):871‐878. doi: 10.1016/j.jhep.2014.11.020 PubMed DOI PMC

Fuchs CD, Paumgartner G, Wahlström A, et al. Metabolic preconditioning protects PubMed DOI

Fuchs CD, Dixon ED, Hendrikx T, et al. Tetrahydroxylated bile acids improve cholestatic liver and bile duct injury in the PubMed DOI PMC

Wang R, Salem M, Yousef IM, et al. Targeted inactivation of sister of P‐glycoprotein gene ( PubMed DOI PMC

Koslowski N, Sombetzki M, Loebermann M, et al. Single‐sex infection with female PubMed DOI PMC

Winkelmann F, Gesell Salazar M, Hentschker C, et al. Comparative proteome analysis of the tegument of male and female adult PubMed DOI PMC

Fuchs CD, Krivanec S, Steinacher D, et al. Absence of Bsep/Abcb11 attenuates MCD diet‐induced hepatic steatosis but aggravates inflammation in mice. Liver Int. 2020;40(6):1366‐1377. doi: 10.1111/liv.14423 PubMed DOI PMC

Tucker MS, Karunaratne LB, Lewis FA, Freitas TC, Liang Y. Schistosomiasis. Curr Protoc Immunol. 2013;103(1):19.1.1‐19.1.58. doi: 10.1002/0471142735.im1901s103 PubMed DOI

El Ridi R, Ozaki T, Inaba T, Ito M, Kamiya H. PubMed DOI

Winkelmann F, Frank M, Rabes A, et al. Human serum activates the tegument of female schistosomes and supports recovery from Praziquantel. Parasitol Res. 2021;120(1):209‐221. doi: 10.1007/s00436-020-06968-x PubMed DOI PMC

Remetic J, Ghallab A, Hobloss Z, et al. Loss of bile salt export pump aggravates lipopolysaccharide‐induced liver injury in mice due to impaired hepatic endotoxin clearance. Hepatology. 2022;75(5):1095‐1109. doi: 10.1002/hep.32289 PubMed DOI PMC

Newlaczyl AU, Yu L‐G. Galectin‐3—a jack‐of‐all‐trades in cancer. Cancer Lett. 2011;313(2):123‐128. doi: 10.1016/j.canlet.2011.09.003 PubMed DOI

de Oliveira FL, Gatto M, Bassi N, et al. Galectin‐3 in autoimmunity and autoimmune diseases. Exp Biol Med. 2015;240(8):1019‐1028. doi: 10.1177/1535370215593826 PubMed DOI PMC

Rockey DC, Weymouth N, Shi Z. Smooth muscle α Actin ( PubMed DOI PMC

Shen J, Lai DH, Wilson RA, et al. Nitric oxide blocks the development of the human parasite PubMed DOI PMC

Caffrey CR, McKerrow JH, Salter JP, Sajid M. Blood ‘n’ guts: an update on schistosome digestive peptidases. Trends Parasitol. 2004;20(5):241‐248. doi: 10.1016/j.pt.2004.03.004 PubMed DOI

Skelly PJ, Nation CS, Da'Dara AA. PubMed DOI PMC

Macháček T, Šmídová B, Pankrác J, Majer M, Bulantová J, Horák P. Nitric oxide debilitates the neuropathogenic schistosome PubMed DOI PMC

Wilson RA, Jones MK. Fifty years of the schistosome tegument: discoveries, controversies, and outstanding questions. Int J Parasitol. 2021;51(13–14):1213‐1232. doi: 10.1016/j.ijpara.2021.11.002 PubMed DOI

LoVerde PT, Andrade LF, Oliveira G. Signal transduction regulates schistosome reproductive biology. Curr Opin Microbiol. 2009;12(4):422‐428. doi: 10.1016/j.mib.2009.06.005 PubMed DOI PMC

Badr SGE, Pica‐Mattoccia L, Moroni R, Angelico M, Cioli D. Effect of bile salts on oviposition in vitro by PubMed DOI

Fioravanti CF, MacInnis AJ. Metabolic indices for evaluating the in vitro maintenance of PubMed DOI

Kawamoto F, Fujioka H, Kumada N, Kojima K. PubMed DOI

Sukhdeo MV, Keith S, Mettrick DF. The effects of bile on the locomotory cycle of PubMed DOI

Gerisch B, Rottiers V, Li D, et al. A bile acid‐like steroid modulates PubMed DOI PMC

Li S, Kim TI, Yoo WG, Cho PY, Kim T‐S, Hong S‐J. Bile components and amino acids affect survival of the newly excysted juvenile PubMed DOI

Zhi X, Zhou XE, Melcher K, et al. Structural conservation of ligand binding reveals a bile acid‐like signaling pathway in nematodes. J Biol Chem. 2012;287(7):4894‐4903. doi: 10.1074/jbc.M111.315242 PubMed DOI PMC

Magner DB, Wollam J, Shen Y, et al. The NHR‐8 nuclear receptor regulates cholesterol and bile acid homeostasis in PubMed DOI PMC

Li S, Yoo WG, Song J‐H, Kim TI, Hong S‐J. Bile acids drive chemotaxis of PubMed DOI PMC

Surgan MH, Roberts LS. Effect of bile salts on the absorption of glucose and oleic acid by the cestodes, PubMed DOI

Rothman AH. Role of bile salts in the biology of tapeworms. I. Effects on the metabolism of PubMed DOI

Tkachuck RD, MacInnis AJ. The effect of bile salts on the carbohydrate metabolism of two species of hymenolepidid cestodes. Comp Biochem Physiol Part B Comp Biochem. 1971;40(4):993‐1003. doi: 10.1016/0305-0491(71)90044-7 DOI

Hamali B, Pichler S, Wischnitzki E, et al. Identification and characterization of the PubMed DOI PMC

Dai F, Yoo WG, Lu Y, et al. Sodium‐bile acid co‐transporter is crucial for survival of a carcinogenic liver fluke PubMed DOI PMC

Wangwiwatsin A, Protasio AV, Wilson S, et al. Transcriptome of the parasitic flatworm PubMed DOI PMC

Spangenberg T. Alternatives to praziquantel for the prevention and control of schistosomiasis. ACS Infect Dis. 2021;7(5):939‐942. doi: 10.1021/acsinfecdis.0c00542 PubMed DOI

Driciru E, Koopman JPR, Cose S, et al. Immunological considerations for PubMed DOI PMC

Wang W, Wang L, Liang Y‐S. Susceptibility or resistance of praziquantel in human schistosomiasis: a review. Parasitol Res. 2012;111(5):1871‐1877. doi: 10.1007/s00436-012-3151-z PubMed DOI

The avian schistosome Trichobilharzia franki in mice: Migration, pathogenicity, and the host immune response