Comparative assessment of intestinal microbiota in autoimmune and non-autoimmune liver diseases in children

   The influence of the gut microbiota on the development of various diseases is of great interest to researchers. The conducted studies showed that in patients with chronic liver diseases, the dominant taxa of the gut microbiota were Bifidobacterium longum, Bifidobacterium adolescentis, Blautia massiliensis, and in healthy children — Neisseria flavescens. There is no comparative analysis of data on the taxonomic diversity of the intestinal microbiota in autoimmune and non-autoimmune liver diseases in children.

   Purpose. To investigate differences in the taxonomic diversity of fecal microbiota in patients with autoimmune and non-autoimmune liver diseases, as well as to evaluate potential biomarkers of 16S rRNA gene amplicons in these diseases by comparing the taxonomic composition.

   Material and methods. A metagenomic analysis of the intestinal microbiota of 24 children with chronic liver diseases (mean age 10,3 ± 4,7 years) was carried out with the isolation of the 16S rRNA gene region. The group included 18 children with autoimmune liver diseases and 6 children with non-autoimmune liver diseases.

   Results. The conducted study revealed 684 types of microorganisms in the studied samples of patients’ feces. The analysis of the conducted studies showed that no dominant taxa were found in the fecal samples of children with autoimmune liver diseases, while Veillonella dispar, Veillonella parvula, Cloacibacillus porcorum, Prevotella histicola and Bacteroides eggerthii were the dominant taxa in patients with non-autoimmune liver diseases.

   Conclusion. Studies have shown differences in the composition of the gut microbiota in children with autoimmune and non-autoimmune liver diseases.

1. He Y., Wu W., Zheng H.M., Li P., McDonald D., Sheng H.F. et al. Regional variation limits applications of healthy gut microbiome reference ranges and disease models. Nat Med 2018; 24(10): 1532–1535. DOI: 10.1038/s41591–018–0164-x

2. Huttenhower C., Gevers D., Knight R., Abubucker S., Badger J.H., Chinwalla A.T. et al. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 2012; 486(7402): 207–214. DOI: 10.1038/nature11234

3. David L.A., Maurice C.F., Carmody R.N., Gootenberg D.B., Button J.E., Wolfe B.E. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014; 505(7484): 559–563. DOI: 10.1038/nature12820

4. Sonnenburg E.D., Smits S.A., Tikhonov M., Higginbottom S.K., Wingreen N.S., Sonnenburg J.L. Diet-induced extinctions in the gut microbiota compound over generations. Nature 2016; 529(7585): 212–215. DOI: 10.1038/nature16504

5. Modi S.R., Collins J.J., Relman D.A. Antibiotics and the gut microbiota. Clin Invest 2014; 124(10): 4212–4218. DOI: 10.1172/JCI72333

6. Maurice C.F., Haiser H.J., Turnbaugh P.J. Xenobiotics shape the physiology and gene expression of the active human gut microbiome. Cell 2013; 152(1–2): 39–50. DOI: 10.1016/j.cell.2012.10.052

7. Sonnenburg J.L., Backhed F. Diet-microbiota interactions as moderators of human metabolism. Nature 2016; 535(7610): 56–64. DOI: 10.1038/nature18846

8. Jones R.M., Neish A.S. Gut Microbiota in Intestinal and Liver Disease. Annu Rev Pathol 2021; 16: 251–275. DOI: 10.1146/annurev-pathol-030320–095722

9. Xu X.R., Liu C.Q., Feng B.S., Liu Z.J. Dysregulation of mucosal immune response in pathogenesis of inflammatory bowel disease. World J Gastroenterol 2014; 20(12): 3255–3264. DOI: 10.3748/wjg.v20.i12.3255

10. Carrière J., Darfeuille-Michaud A., Nguyen H.T. Infectious etiopathogenesis of Crohn’s disease. World J Gastroenterol 2014; 20(34): 12102–12117. DOI: 10.3748/wjg.v20.i34.12102

11. Abraham C., Cho J.H. Inflammatory bowel disease. N Engl J Med 2009; 361(21): 2066–2078. DOI: 10.1056/NEJMra0804647

12. Kaser A., Zeissig S., Blumberg R.S. Inflammatory bowel disease. Annu Rev Immunol 2010; 28: 573–621. DOI: 10.1146/annurev-immunol-030409–101225

13. Adolph T.E., Grander C., Moschen A.R., Tilg H. Liver-Microbiome Axis in Health and Disease. Trends Immunol 2018; 39(9): 712–723. DOI: 10.1016/j.it.2018.05.002

14. Kummen M., Holm K., Anmarkrud J.A., Nygård S., Vesterhus M., Høivik M.L. et al. The gut microbial profile in patients with primary sclerosing cholangitis is distinct from patients with ulcerative colitis without biliary disease and healthy controls. Gut 2017; 66(4): 611–619. DOI: 10.1136/gutjnl-2015–310500

15. Sabino J., Vieira-Silva S., Machiels K., Joossens M., Falony G., Ballet V. et al. Primary sclerosing cholangitis is characterised by intestinal dysbiosis independent from IBD. Gut 2016; 65(10): 1681–1689. DOI: 10.1136/gutjnl-2015–311004

16. Tang R., Wei Y., Li Y., Chen W., Chen H., Wang Q. et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut 2018; 67(3): 534–541. DOI: 10.1136/gutjnl-2016–313332

17. Tripathi A., Debelius J., Brenner D.A., Karin M., Loomba R., Schnabl B. et al. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol 2018; 15(7): 397–411. DOI: 10.1038/s41575–018–0011-z

18. Manfredo Vieira S., Hiltensperger M., Kumar V., Zegarra-Ruiz D., Dehner C., Khan N. et al. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science 2018; 359(6380): 1156–1161. DOI: 10.1126/science.aar7201

19. Yuksel M., Wang Y., Tai N., Peng J., Guo J., Beland K. et al. A novel «humanized mouse» model for autoimmune hepatitis and the association of gut microbiota with liver inflammation. Hepatology 2015; 62(5): 1536–1550. DOI: 10.1002/hep.27998

20. Klaassen C.D., Cui J.Y. Review: mechanisms of how the intestinal microbiota alters the effects of drugs and bile acids. Drug Metab Dispos 2015; 43(10): 1505–1521. DOI: 10.1124/dmd.115.065698

21. Dawson P.A., Karpen S.J. Intestinal transport and metabolism of bile acids. J Lipid Res 2015; 56(6): 1085–1099. DOI: 10.1194/jlr.R054114

22. Sayin S.I., Wahlström A., Felin J., Jäntti S., Marschall H.U., Bamberg K. et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 2013; 17(2): 225–235. DOI: 10.1016/j.cmet.2013.01.003

23. Jia W., Xie G., Jia W. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat Rev Gastroenterol Hepatol 2018; 15(2): 111–128. DOI: 10.1038/nrgastro.2017.119

24. Wahlström A., Sayin S.I., Marschall H.U., Bäckhed F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab 2016; 24(1): 41–50. DOI: 10.1016/j.cmet.2016.05.005

25. Spadoni I., Zagato E., Bertocchi A., Paolinelli R., Hot E., Di Sabatino A. et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science 2015; 350(6262): 830–834. DOI: 10.1126/science.aad0135

26. Balmer M.L., Slack E., de Gottardi A., Lawson M.A., Hapfelmeier S., Miele L. et al. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota. Sci Transl Med 2014; 6(237): 237ra66. DOI: 10.1126/scitranslmed.3008618

27. Chen F., Stappenbeck T.S. Microbiome control of innate reactivity. Curr Opin Immunol 2019; 56: 107–113. DOI: 10.1016/j.coi.2018.12.003

28. Callahan B.J., McMurdie P.J., Rosen M.J., Han A.W., Johnson A.J., Holmes S.P. DADA2: High-resolution sample inference from Illumina amplicon data. Nat Methods 2016; 13(7): 581–583. DOI:10.1038/nmeth.3869

29. Wang E.T., Moyzis R.K. Genetic evidence for ongoing balanced selection at human DNA repair genes ERCC8, FANCC, and RAD51C. Mutat Res 2007; 616(1–2): 165–174. DOI: 10.1016/j.mrfmmm.2006.11.030

30. Quast C., Pruesse E., Yilmaz P., Gerken J., Schweer T., Yarza P. et al. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res 2013; 41(Database issue): D590–D596. DOI: 10.1093/nar/gks1219

31. Blander J.M., Longman R.S., Iliev I.D., Sonnenberg G.F., Artis D. Regulation of inflammation by microbiota interactions with the host. Nat Immunol 2017; 18(8): 851–860. DOI: 10.1038/ni.3780

32. Clemente J.C., Manasson J., Scher J.U. The role of the gut microbiome in systemic inflammatory disease. BMJ 2018; 360: j5145. DOI: 10.1136/bmj.j5145

33. Gevers D., Kugathasan S., Denson L.A., Vázquez-Baeza Y., Van Treuren W., Ren B. et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe 2014; 15(3): 382–392. DOI: 10.1016/j.chom.2014.02.005

34. Kummen M., Hov J.R. The gut microbial influence on cholestatic liver disease. Liver Int 2019; 39(7): 1186–1196. DOI: 10.1111/liv.14153

35. Nakamoto N., Sasaki N., Aoki R., Miyamoto K., Suda W., Teratani T. et al. Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis. Nat Microbiol 2019; 4(3): 492–503. DOI: 10.1038/s41564–018–0333–1

36. Liao L., Schneider K.M., Galvez E.J.C., Frissen M., Marschall H.U., Su H. et al. Intestinal dysbiosis augments liver disease progression via NLRP3 in a murine model of primary sclerosing cholangitis. Gut 2019; 68(8): 1477–1492. DOI: 10.1136/gutjnl-2018–316670

37. Zhao S., Gong Z., Zhou J., Tian C., Gao Y., Xu C. et al. Deoxycholic Acid Triggers NLRP3 Inflammasome Activation and Aggravates DSS-Induced Colitis in Mice. Front Immunol 2016; 7: 536. DOI: 10.3389/fimmu.2016.00536

38. Deng X., Li Z., Li G., Li B., Jin X., Lyu G. Comparison of Microbiota in Patients Treated by Surgery or Chemotherapy by 16S rRNA Sequencing Reveals Potential Biomarkers for Colorectal Cancer Therapy. Front Microbiol 2018; 9: 1607. DOI: 10.3389/fmicb.2018.01607

39. Kasai C., Sugimoto K., Moritani I., Tanaka J., Oya Y., Inoue H. et al. Comparison of human gut microbiota in control subjects and patients with colorectal carcinoma in adenoma: Terminal restriction fragment length polymorphism and next-generation sequencing analyses. Oncol Rep 2016; 35(1): 325–33. DOI: 10.3892/or.2015.4398

40. Matera G., Muto V., Vinci M., Zicca E., Abdollahi-Roodsaz S., van de Veerdonk F.L. et al. Receptor recognition of and immune intracellular pathways for Veillonella parvula lipopoly-saccharide. Clin Vaccine Immunol 2009; 16(12): 1804–1809. DOI: 10.1128/CVI.00310–09

41. De Cruz P., Kang S., Wagner J., Buckley M., Sim WH., Prideaux L. et al. Association between specific mucosa-associated microbiota in Crohn’s disease at the time of resection and subsequent disease recurrence: a pilot study. J Gastroenterol Hepatol 2015; 30(2): 268–278. DOI: 10.1111/jgh.12694

42. Bongaerts G.P., Schreurs B.W., Lunel F.V., Lemmens J.A., Pruszczynski M., Merkx M.A. Was isolation of Veillonella from spinal osteomyelitis possible due to poor tissue perfusion? Med Hypotheses 2004; 63(4): 659–661. DOI: 10.1016/j.mehy.2004.02.052

43. Rovery C., Etienne A., Foucault C., Berger P., Brouqui P. Veillonella montpellierensis endocarditis. Emerg Infect Dis 2005; 11(7): 1112–1114. DOI: 10.3201/eid1107.041361

44. Wei Y., Li Y., Yan L., Sun C., Miao Q., Wang Q. et al. Alterations of gut microbiome in autoimmune hepatitis. Gut 2020; 69(3): 569–577. DOI: 10.1136/gutjnl-2018–317836

45. Downes J., Hooper S.J., Wilson M.J., Wade W.G. Prevotella histicola sp. nov., isolated from the human oral cavity. Int J Syst Evol Microbiol 2008; 58(Pt 8): 1788–1791. DOI: 10.1099/ijs.0.65656–0

46. Balakrishnan B., Luckey D., Bodhke R., Chen J., Marietta E., Jeraldo P. et al. Prevotella histicola Protects From Arthritis by Expansion of Allobaculum and Augmenting Butyrate Production in Humanized Mice. Front Immunol 2021; 12: 609644. DOI: 10.3389/fimmu.2021.609644

47. Mangalam A.K., Murray J. Microbial monotherapy with Prevotella histicola for patients with multiple sclerosis. Expert Rev Neurother 2019; 19(1): 45–53. DOI: 10.1080/14737175.2019.1555473

48. Shahi S.K., Jensen S.N., Murra A.C., Tang N., Guo H., Gibson-Corley K.N. et al. Human Commensal Prevotella histicola Ameliorates Disease as Effectively as Interferon-Beta in the Experimental Autoimmune Encephalomyelitis. Front Immunol 2020; 11: 578648. DOI: 10.3389/fimmu.2020.578648

49. Liu C.Y., Su W.B., Guo L.B., Zhang Y.W. Cloning, expression, and characterization of a novel heparinase I from Bacteroides eggerthii. Prep Biochem Biotechnol 2020; 50(5): 477–485. DOI: 10.1080/10826068.2019.1709977

50. Kmezik C., Krska D., Mazurkewich S., Larsbrink J. Characterization of a novel multidomain CE15–GH8 enzyme encoded by a polysaccharide utilization locus in the human gut bacterium Bacteroides eggerthii. Sci Rep 2021; 11(1): 17662. DOI: 10.1038/s41598–021–96659-z

51. Petersen A.B., Christensen I.A., Rønne M.E., Stender E.G.P., Teze D., Svensson B. et al. 1H, 13C, 15N resonance assignment of the enzyme KdgF from Bacteroides eggerthii. Biomol NMR Assign 2022; 16(2): 343–347. DOI: 10.1007/s12104–022–10102–6

52. Domingo M.C., Yansouni C., Gaudreau C., Lamothe F., Lévesque S., Tremblay C. et al. Cloacibacillus sp., a Potential Human Pathogen Associated with Bacteremia in Quebec and New Brunswick. Clin Microbiol 2015; 53(10): 3380–3. DOI: 10.1128/JCM.01137–15

53. Puón-Peláez X.D., McEwan N.R., Gómez-Soto J.G., Álvarez-Martínez R.C., Olvera-Ramírez A.M. Metataxonomic and Histopathological Study of Rabbit Epizootic Enteropathy in Mexico. Animals (Basel) 2020; 10(6): 936. DOI: 10.3390/ani10060936