Gut microbiota in autoimmune and non-autoimmune liver diseases in children

Relevance. 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 of the study. 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. Scope and methods of research. 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 identification of the V3-V4 region of the 16S rRNA gene. The group included 18 children with autoimmune liver diseases and 6 children with non-autoimmune liver diseases. Research results. The conducted study revealed 684 types of microorganisms in the studied samples of patients’ faeces. The analysis of the conducted studies showed that no dominant taxa were found in the faecal 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.

gut microbiota, children, autoimmune liver diseases, 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 JH., Chinwalla AT. et al. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature. 2012; 486(7402): 207-14. doi: 10.1038/nature11234.

3. David L.A., Maurice C. F., Carmody R. N. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014; 505(7484): 559-63. 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): 212-5. doi: 10.1038/nature16504.

5. Modi S.R., Collins J. J., Relman D. A. Antibiotics and the gut microbiota. Clin Invest. 2014; 124(10): 4212-8. 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): 3255-64. doi: 10.3748/wjg.v20.i12.3255.

10. Carrière J., Darfeuille-Michaud A., Nguyen HT. Infectious etiopathogenesis of Crohn’s disease. World J Gastroenterol. 2014; 20(34): 12102-17. doi: 10.3748/wjg.v20.i34.12102.

11. Abraham C., Cho J. H. Inflammatory bowel disease. N Engl J Med. 2009; 361(21): 2066-78. 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): 1681-9. 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): 1536-50. 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): 1505-21. 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): 1085-99. 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): 225-35. 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): 830-4. 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): 165-74. 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. Volynets G.V., Nikitin A. V., Skvortsova T. A., Potapov A. S., Dudurich V. V., Danilov L. G. Gut microbiota in chronic liver disease in children.Russian Bulletin of Perinatology and Pediatrics. 2023; 68(2): 69-73. (in Russ.) doi: 10.21508/1027-4065-2023-68-2-69-73.@@ Волынец Г. В., Никитин А. В., Скворцова Т. А., Потапов А. С., Дудурич В. В., Данилов Л. Г. Кишечная микробиота при хронических заболеваниях печени у детей. Российский вестник перинатологии и педиатрии. 2023; 68(2): 69-73. doi: 10.21508/1027-4065-2023-68-2-69-73.

36. 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.

37. 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.

38. 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.

39. 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.

40. 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.

41. 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 lipopolysaccharide. Clin Vaccine Immunol. 2009; 16(12): 1804-9. doi: 10.1128/CVI.00310-09.

42. 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): 268-78. doi: 10.1111/jgh.12694.

43. 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): 659-61. doi: 10.1016/j.mehy.2004.02.052.

44. Rovery C., Etienne A., Foucault C., Berger P., Brouqui P. Veillonella montpellierensis endocarditis. Emerg Infect Dis. 2005; 11(7): 1112-4. doi: 10.3201/eid1107.041361.

45. 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.

46. 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): 1788-91. doi: 10.1099/ijs.0.65656-0.

47. 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.

48. 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.

49. 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.

50. 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.

51. 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.

52. 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.

53. 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.

54. 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.