Зонулин и его роль в возникновении младенческих колик: механизмы взаимосвязи

Цель. На основании изучения научных источников выявить механизмы связи между воздействием белка зонулина на кишечную стенку и возникновением младенческих колик. Материалы и методы. Произведен поиск научных статей в базах данных PubMed, Scopus, Web of Science, F1000Research. Отобрано 96 источников, опубликованных в период с 1991 по 2023 год. Результаты. Представлены сведения об истории открытия белка зонулина, а также современный взгляд на строение плотных межклеточных соединений эпителия кишечника, описаны процессы, посредством которых осуществляется эффект зонулина в отношении изменения проницаемости кишечного барьера. Приведены данные нескольких исследований, в которых было обнаружено повышение уровня зонулина в группах детей с коликами и с дисфункцией ЖКТ. Произведен обзор работ, в которых отмечена связь зонулина с внекишечной патологией - психическими расстройствами, эндокринными, аутоиммунными, сердечно-легочными, аллергическими, инфекционными заболеваниями. Зонулин является перспективной фармакологической мишенью - на сегодняшний день существует специфическая молекула-ингибитор зонулина, показывающая эффективность в лечении целиакии и мультисистемного воспалительного синдрома у детей. Заключение. Анализ научных публикаций свидетельствует о несомненной актуальности изучения зонулина, как фактора, влияющего на проницаемость кишечной стенки и ряд других процессов. Его роль в формировании кишечных колик требует более детального изучения, поскольку открытия в этой области могут быть активно интегрированы в клиническую практику.

зонулин, проницаемость кишечника, кишечный барьер

1. Zeevenhooven J., Browne P. D., L’Hoir M.P., de Weerth C., Benninga M. A. Infant colic: mechanisms and management. Nature reviews Gastroenterology & hepatology. 2018 Aug;15(8):479-96. doi: 10.1038/s41575-018-0008-7.

2. Hjern A. et al. A systematic review of prevention and treatment of infantile colic. Acta Paediatrica. 2020;109(9):1733-1744. doi: 10.1111/apa.15247.

3. Banks J.B., Rouster A. S., Chee J. Colic. [Updated 2022 Aug 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. PMID: 33760546.

4. Anna Pärtty, Marko Kalliomäki, Seppo Salminen, Erika Isolauri. Infantile Colic Is Associated With Low-grade Systemic Inflammation. J Pediatr Gastroenterol Nutr. 2017 May;64(5):691-695. doi: 10.1097/MPG.0000000000001340.

5. Rhoads J. M. et al. Infant colic represents gut inflammation and dysbiosis. The Journal of pediatrics. 2018;203:55-61. e3. doi: 10.1016/j.jpeds.2018.07.042.

6. Serek P., Oleksy-Wawrzyniak M. The effect of bacterial infections, probiotics and zonulin on intestinal barrier integrity.International Journal of Molecular Sciences. 2021;22(21):11359. doi: 10.3390/ijms222111359.

7. Fasano A. All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Research. 2020;9. doi: 10.12688/f1000research.20510.1

8. Tajik N. et al. Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis. Nature communications. 2020;11(1):1995. doi: 10.1038/s41467-020-15831-7.

9. Caviglia G. P. et al. Physiopathology of intestinal barrier and the role of zonulin. Minerva Biotecnologica. 2019;31(3)83-92. doi:10.23736/S1120-4826.19.02554-0.

10. Fasano A. et al. Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro. The Journal of clinical investigation. 1995;96(2):710-720. doi: 10.1172/JCI118114.

11. Fasano A. et al. Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro The Journal of clinical investigation. 1995;96(2):710-720. doi: 10.1172/JCI118114.

12. Craig Sturgeon, Alessio Fasano. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers. 2016 Oct 21;4(4): e1251384. doi: 10.1080/21688370.2016.1251384.

13. Fasano A. et al. The enterotoxic effect of zonula occludens toxin on rabbit small intestine involves the paracellular pathway. Gastroenterology. 1997;112(3):839-846. doi: 10.1053/gast.1997.v112.pm9041245.

14. Fasano A., Baudry B., Pumplin D. W., Wasserman S. S., Tall B. D., Ketley J. M., Kaper J. B. Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5242-6. doi: 10.1073/pnas.88.12.5242.

15. Fasano A. et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. The Lancet. 2000;355(9214):1518-1519. doi: 10.1016/S0140-6736(00)02169-3.

16. Edyta Szymanska, Aldona Wierzbicka et.al. Fecal Zonulin as a Noninvasive Biomarker of Intestinal Permeability in Pediatric Patients with Inflammatory Bowel Diseases-Correlation with Disease Activity and Fecal Calprotectin. J Clin Med. 2021 Aug 30;10(17):3905. doi: 10.3390/jcm10173905.

17. Wang W. et al. Human zonulin, a potential modulator of intestinal tight junctions. Journal of cell science. - 2000;113(24. - С. 4435-4440.]. doi: 10.1242/jcs.113.24.4435

18. Tripathi A. et al. Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2. Proceedings of the National Academy of Sciences. 2009;106(39):16799-16804. doi: 10.1073/pnas.0906773106.

19. Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiological reviews. 2011. doi: 10.1152/physrev.00003.2008

20. Lee B. et al. Tight junction in the intestinal epithelium: its association with diseases and regulation by phytochemicals. Journal of immunology research. 2018;2018.][6c Salvo Romero E. et al. The intestinal barrier function and its involvement in digestive disease. Rev Esp Enferm Dig. 2015;107(11):686-96.] doi: 10.1155/2018/2645465.

21. Spadoni I. et al. A gut-vascular barrier controls the systemic dissemination of bacteria. Science. 2015;350(6262):830-834. doi: 10.1126/science.aad0135.

22. Ramena Yathish and Ramena Grace. Cell-Cell Junctions and Epithelial Differentiation. Journal of Morphology and Anatomy. 2018, (2):1.

23. Adil M. S., Narayanan S. P., Somanath P. R. Cell-cell junctions: structure and regulation in physiology and pathology. Tissue Barriers. 2021;9(1):1848212. doi: 10.1080/21688370.2020.1848212.

24. Stevenson B. R. et al. Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. The Journal of cell biology. 1986;103(3):755-766. doi: 10.1083/jcb.103.3.755.

25. Kuo W. T. et al. Tight junction proteins occludin and ZO-1 as regulators of epithelial proliferation and survival. Annals of the New York Academy of Sciences. 2022;1514(1):21-33. doi: 10.1111/nyas.14798.

26. Stephan C. Bischoff, Giovanni Barbara et.al.Intestinal permeability - a new target for disease prevention and therapy. BMC Gastroenterol. 2014 Nov 18;14:189. doi: 10.1186/s12876-014-0189-7.

27. Furuse M. et al. Occludin: a novel integral membrane protein localizing at tight junctions. The Journal of cell biology. 1993;123(6):1777-1788. doi: 10.1083/jcb.123.6.1777.

28. Heinemann U., Schuetz A. Structural features of tight-junction proteins.International journal of molecular sciences. 2019;20(23):6020. doi: 10.3390/ijms20236020.

29. Martìn-Padura I. et al. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. The Journal of cell biology. 1998;142(1):117-127. doi: 10.1083/jcb.142.1.117.

30. Ikenouchi J. et al. Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. The Journal of cell biology. 2005;171(6):939-945. doi: 10.1083/jcb.200510043.

31. Higashi T. et al. Analysis of the ‘angulin’proteins LSR, ILDR1 and ILDR2-tricellulin recruitment, epithelial barrier function and implication in deafness pathogenesis. Journal of cell science. 2013;126(4):966-977. doi: 10.1242/jcs.116442.

32. Beata Łoniewska, Dagmara Węgrzyn et.al. The Influence of Maternal-Foetal Parameters on Concentrations of Zonulin and Calprotectin in the Blood and Stool of Healthy Newborns during the First Seven Days of Life. An Observational Prospective Cohort Study. J Clin Med. 2019 Apr 7;8(4):473. doi: 10.3390/jcm8040473.

33. Khavkin A. I., Bogdanova N. M., Novikova V. P. Biological role of zonulin: a biomarker of increased intestinal permeability syndrome. Rossiyskiy Vestnik Perinatologii i Pediatrii. 2021;66(1):31-38. (in Russ.) doi: 10.21508/1027-4065-2021-66-1-31-38.@@ Хавкин А. И., Богданова Н. М., Новикова В. П. Биологическая роль зонулина и эффективность его использования в качестве биомаркера синдрома повышенной кишечной проницаемости. Российский вестник перинатологии и педиатрии. 2021;66(1):31-38. doi: 10.21508/1027-4065-2021-66-1-31-38.

34. Goldblum S.E., Rai U., Tripathi A., Thakar M., De Leo L., Di Toro N., Not T., Ramachandran R., Puche A. C., Hollenberg M. D., Fasano A. The active Zot domain (aa 288-293) increases ZO-1 and myosin 1C serine/threonine phosphorylation, alters interaction between ZO-1 and its binding partners, and induces tight junction disassembly through proteinase activated receptor 2 activation. The FASEB journal. 2011 Jan;25(1):144. doi: 10.1096/fj.10-158972.

35. McNeil E., Capaldo C. T., Macara I. G. Zonula occludens-1 function in the assembly of tight junctions in Madin-Darby canine kidney epithelial cells. Molecular biology of the cell. 2006 Apr;17(4):1922-32. doi: 10.1091/mbc.e05-07-0650.

36. Ohlsson B., Orho-Melander M., Nilsson P. M. Higher Levels of Serum Zonulin May Rather Be Associated with Increased Risk of Obesity and Hyperlipidemia, Than with Gastroin testinal Symptoms or Disease Manifestations.Int J Mol Sci. 2017; 18(3): E582. doi: 10.3390/ijms18030582.

37. Krakowiak O., Nowak R. Mikroflora przewodu pokarmowe go człowieka-znaczenie, rozwój, modyfikacje. Post Fitoter. 2015; 3: 193-200.

38. Clemente M.G., De Virgiliis S., Kang J. S. et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut. 2003 Feb;52(2):218. doi: 10.1136/gut.52.2.218.

39. Thomas K.E., Sapone A., Fasano A., Vogel S. N. Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease. The Journal of Immunology. 2006 Feb 15;176(4):2512-21. doi: 10.4049/jimmunol.176.4.2512.

40. Zybina N.N., Nikonov E. L., Gershtein E. S. et al. Zonulin is a marker of epithelial and endothelial barrier functions in non-communicable diseases (narrative review).Russian Journal of Evidence-Based Gastroenterology. 2022;11(1):28 44. (in Russ.) doi: 10.17116/dokgastro20221101128.@@ Зыбина Н. Н., Никонов Е. Л. и другие. Зонулин как маркер проницаемости клеточных контактов при соматических и онкологических заболеваниях. Доказательная гастроэнтерология. 2022;11(1):28 44. doi: 10.17116/dokgastro20221101128.

41. Lammers K.M., Lu R., Brownley J. et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. 2008 Jul 1;135(1):194-204. doi: 10.1053/j.gastro.2008.03.023.

42. Maria Raffaella Barbaro, Cesare Cremon et.al. Serum zonulin and its diagnostic performance in non-coeliac gluten sensitivity. Gut. 2020 Nov;69(11):1966-1974. doi: 10.1136/gutjnl-2019-319281.

43. Dudašova Petrovičova O., Stanković I., Ðordević B., Dopsaj V., Milinković N., Dopsaj M. How Supplementation with SOD-Rich Plant Extract, Combined with Gliadin, Can Affect Oxidative Stress Markers and Zonulin Levels in Exercise-Induced Oxidative Stress. Metabolites. 2023 Dec 17;13(12):1200. doi: 10.3390/metabo13121200.

44. El Asmar R., Panigrahi P., Bamford P., Berti I., Not T., Coppa G. V., Catassi C., Fasano A. Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure. Gastroenterology. 2002 Nov 1;123(5):1607-15. doi: 10.1053/gast.2002.36578.

45. Anna Tarko, Anna Suchojad et.al. Zonulin: A Potential Marker of Intestine Injury in Newborns. Epub 2017 Jul. doi: 10.1155/2017/2413437.

46. Xiao Wang, Ashfaque A Memon et al. The association of zonulin-related proteins with prevalent and incident inflammatory bowel disease. BMC Gastroenterol. 2022 Jan 3;22(1):3. doi: 10.1186/s12876-021-02075-y.

47. Naydenov NG, Feygin A, Wang D, et al.: Nonmuscle Myosin IIA Regulates Intestinal Epithelial Barrier in vivo and Plays a Protective Role During Experimental Colitis. Sci Rep. 2016;6:24161. doi: 10.1038/srep24161.

48. Su L. et al. Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis. Gastroenterology. 2009;136(2):551-563. doi: 10.1053/j.gastro.2008.10.081.

49. Laukoetter M. G. et al. JAM-A regulates permeability and inflammation in the intestine in vivo. The Journal of experimental medicine. 2007;204(13):3067-3076. doi: 10.1084/jem.20071416.

50. Sturgeon C., Lan J., Fasano A. Zonulin transgenic mice show altered gut permeability and increased morbidity/mortality in the DSS colitis model. Ann N Y Acad Sci. 2017;1397(1): 130-42. doi: 10.1111/nyas.13343.

51. Paweł Serek, Monika Oleksy-Wawrzyniak. The Effect of Bacterial Infections, Probiotics and Zonulin on Intestinal Barrier Integrity.Int J Mol Sci. 2021 Oct 21;22(21):11359. doi: 10.3390/ijms222111359.

52. Rita Nocerino, Francesca De Filippis et al. The therapeutic efficacy of Bifidobacterium animalis subsp. lactis BB-12® in infant colic: A randomised, double blind, placebo-controlled trial. Aliment Pharmacol Ther. 2020 Jan;51(1):110-120. doi: 10.1111/apt.15561.

53. Amirhossein Ramezani Ahmadi, Mehdi Sadeghian et al. The Effects of Probiotic/Synbiotic on Serum Level of Zonulin as a Biomarker of Intestinal Permeability: A Systematic Review and Meta-Analysis. Iran J Public Health. 2020 Jul; 49(7). doi: 10.18502/ijph.v49i7.3575.

54. Wilms E., Gerritsen J. Effects of Supplementation of the Synbiotic Ecologic® 825/FOS P6 on Intestinal Barrier Function in Healthy Humans: A Randomized Controlled Trial. PLoS One, 2016; 11(12). doi: 10.1371/journal.pone.0167775.

55. Lidia Sánchez-Alcoholado, Rafael Ordóñez. Gut Microbiota-Mediated Inflammation and Gut Permeability in Patients with Obesity and Colorectal Cancer.Int J Mol Sci. 2020 Sep 16;21(18):6782. doi: 10.3390/ijms21186782.

56. Sonnal Lohia, Antonia Vlahou, Jerome Zoidakis. Microbiome in Chronic Kidney Disease (CKD): An Omics Perspective. Toxins (Basel). 2022 Feb 26;14(3):176. doi: 10.3390/toxins14030176.

57. Apor Veres-Székely, Csenge Szász et al. Zonulin as a Potential Therapeutic Target in Microbiota-Gut-Brain Axis Disorders: Encouraging Results and Emerging Questions.Int. J. Mol. Sci. 2023, 24(8), 7548. doi: 10.3390/ijms24087548.

58. Mariusz Kaczmarczyk, Ulrike Löber et al. The gut microbiota is associated with the small intestinal paracellular permeability and the development of the immune system in healthy children during the first two years of life. J Transl Med, 2021 Apr 28;19(1):177. doi: 10.1186/s12967-021-02839-w.

59. Christian Milani, Sabrina Duranti et al. The First Microbial Colonizers of the Human Gut: Composition, Activities, and Health Implications of the Infant Gut Microbiota. Microbiol Mol Biol Rev. 2017 Nov 8;81. doi: 10.1128/mmbr.00036-17.

60. Beata Łoniewska, Karolina Adamek et.al. Analysis of Faecal Zonulin and Calprotectin Concentrations in Healthy Children During the First Two Years of Life. An Observational Prospective Cohort Study. J Clin Med. 2020 Mar 12;9(3):777. doi: 10.3390/jcm9030777.

61. Karin Malíčková, Irena Francová et al. Fecal zonulin is elevated in Crohn’s disease and in cigarette smokers. Pract Lab Med. 2017 Sep 23;9:39-44. doi: 10.1016/j.plabm.2017.09.001.

62. Łoniewska B., Adamek K., Węgrzyn D., Kaczmarczyk M. et al. Analysis of faecal zonulin and calprotectin concentrations in healthy children during the first two years of life. An observational prospective cohort study. Journal of Clinical Medicine. 2020 Mar 12;9(3):777. doi: 10.3390/jcm9030777.

63. Kolyva S., Triga M., Kritikou D., Chrysis D. The effect of feeding patterns on serum zonulin levels in infants at 3-4 months of age. European Journal of Pediatrics. 2021 Nov;180(11):3273-8. doi: 10.1007/s00431-021-04102-2.

64. Dr Rachel Reed. The Human Microbiome: considerations for pregnancy, birth and early mothering. April 13, 2016

65. Vanuytsel T., Vermeire S., Cleynen I. The role of Haptoglobin and its related protein, Zonulin, in inflammatory bowel disease. Tissue barriers. 2013;1(5): e27321. doi: 10.4161/tisb.27321.

66. Birna Asbjornsdottir, Heiddis Snorradottir et al. Zonulin-Dependent Intestinal Permeability in Children Diagnosed with Mental Disorders: A Systematic Review and Meta-Analysis. Nutrients. 2020 Jul 3;12(7):1982. doi: 10.3390/nu12071982.

67. Esnafoglu E. et al. Increased serum zonulin levels as an intestinal permeability marker in autistic subjects. The Journal of pediatrics. 2017;188):240-244. doi: 10.1016/j.jpeds.2017.04.004.

68. Özyurt G. et al. Increased zonulin is associated with hyperactivity and social dysfunctions in children with attention deficit hyperactivity disorder.Comprehensive psychiatry. 2018;87):138-142. doi: 10.1016/j.comppsych.2018.10.006.

69. Maget A. et al. Sex differences in zonulin in affective disorders and associations with current mood symptoms. Journal of Affective Disorders. 2021;294):441-446. doi: 10.1016/j.jad.2021.07.021.

70. Bruce R. Stevens, Ruby Goel et al. Increased human intestinal barrier permeability plasma biomarkers zonulin and FABP2 correlated with plasma LPS and altered gut microbiome in anxiety or depression. Gut. 2018 Aug;67(8):1555-1557. doi: 10.1136/gutjnl-2017-314759.

71. Nouri M., Bredberg A., Weström B., Lavasani S.Intestinal barrier dysfunction develops at the onset of experimental autoimmune encephalomyelitis, and can be induced by adoptive transfer of auto-reactive T cells. PloS one. 2014 Sep 3;9(9): e106335 doi: 10.1371/journal.pone.0106335.

72. Moreno-Navarrete J.M., Sabater M., Ortega F., Ricart W., Fernandez-Real J. M. Circulating zonulin, a marker of intestinal permeability, is increased in association with obesity-associated insulin resistance. PloS one. 2012 May 18;7(5): e37160. doi: 10.1371/journal.pone.0037160.

73. Żak-Gołąb A., Kocełak P., Aptekorz M. et al. Gut microbiota, microinflammation, metabolic profile, and zonulin concentration in obese and normal weight subjects.International journal of endocrinology. 2013 Oct;2013 doi: 10.1155/2013/674106.

74. Zhang D., Zhang L., Zheng Y., Yue F., Russell R. D., Zeng Y. Circulating zonulin levels in newly diagnosed Chinese type 2 diabetes patients. Diabetes research and clinical practice. 2014 Nov 1;106(2):312-8. doi: 10.1016/j.diabres.2014.08.017.

75. Jayashree B., Bibin Y. S., Prabhu D., Shanthirani C. S., Gokulakrishnan K., Lakshmi B. S., Mohan V., Balasubramanyam M. Increased circulatory levels of lipopolysaccharide (LPS) and zonulin signify novel biomarkers of proinflammation in patients with type 2 diabetes. Molecular and cellular biochemistry. 2014 Mar;388:203-10. doi: 10.1007/s11010-013-1911-4.

76. Pacifico L., Bonci E., Marandola L., Romaggioli S., Bascetta S., Chiesa C. Increased circulating zonulin in children with biopsy-proven nonalcoholic fatty liver disease. World Journal of Gastroenterology: WJG. 2014 Dec 12;20(45):17107. doi: 10.3748/wjg.v20.i45.17107.

77. Klaus D.A., Motal M. C., Burger-Klepp U. et al. Increased plasma zonulin in patients with sepsis. Biochemia medica. 2013 Feb 15;23(1):107-11. doi: 10.11613/BM.2013.013.

78. Skardelly M., Armbruster F. P., Meixensberger J., Hilbig H. Expression of zonulin, c-kit, and glial fibrillary acidic protein in human gliomas. Translational oncology. 2009 Sep 1;2(3):117-20. doi: 10.1593/tlo.09115.

79. Serrano-Villar S., Sainz T., Ma Z. M. et al. Effects of combined CCR5/integrase inhibitors-based regimen on mucosal immunity in HIV-infected patients naïve to antiretroviral therapy: a pilot randomized trial. PLoS pathogens. 2016 Jan 21;12(1): e1005381. doi: 10.1371/journal.ppat.1005381.

80. Zachary M. Slifer, B Radha Krishnan et al. Larazotide acetate: a pharmacological peptide approach to tight junction regulation. Am J Physiol Gastrointest Liver Physiol. 2021 Jun 1;320(6): G983-G989. doi: 10.1152/ajpgi.00386.2020.

81. Meters Biopharma, Inc. Larazotide. Orally-administered, gut-restricted tight-junction regulator for celiac disease. Pipeline (Online), 2020, https://9meters.com/pipeline https://ichgcp.net/clinical-trials-registry/NCT03569007

82. Slifer Z.M., Krishnan B. R., Madan J., Blikslager A. T. Larazotide acetate: A pharmacological peptide approach to tight junction regulation. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2021 Jun 1;320(6): G983-9. doi: 10.1152/ajpgi.00386.2020.

83. Paterson B.M., Lammers K. M. et al. The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study. Aliment Pharmacol Ther. 2007 Sep 1;26(5):757-66. doi: 10.1111/j.1365-2036.2007.03413.x.

84. Shobha Gopalakrishnan et al. Larazotide acetate regulates epithelial tight junctions in vitro and in vivo. Peptides. 2012 May;35(1):86-94. doi: 10.1016/j.peptides.2012.02.015.

85. Daniel A Leffler, Ciaran P Kellym et.al. Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial. Gastroenterology. 2015 Jun;148(7). doi: 10.1053/j.gastro.2015.02.008.

86. Lael M. Yonker, Zoe Swank et al. Zonulin Antagonist, Larazotide (AT1001), As an Adjuvant Treatment for Multisystem Inflammatory Syndrome in Children: A Case Series. Crit Care Explor. 2022 Feb 18;10(2): e0641. doi: 10.1097/CCE.0000000000000641.

87. Di Micco S., Musella S., Sala M. et al. Peptide Derivatives of the Zonulin Inhibitor Larazotide (AT1001) as Potential AntiSARS-CoV-2: Molecular Modelling, Synthesis and Bioactivity Evaluation.International Journal of Molecular Sciences. 2021; doi: 10.3390/ijms22179427.

88. Jeremy D. Johnson, Katherine Cocker, Elisabeth Chang. Infantile Colic: Recognition and Treatment. Am Fam Physician. 2015 Oct 1;92(7):577-82. PMID: 26447441.

89. Amy A. Gelfand Infant Colic. Semin Pediatr Neurol. 2016 Feb;23(1):79-82. doi: 10.1016/j.spen.2015.08.003.

90. Valerie Sung. Infantile colic. Aust Prescr. 2018 Aug;41(4):105-110. doi: 10.18773/austprescr.2018.033.

91. Banks J.B., Rouster A. S., Chee J. Colic. [Updated 2022 Aug 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. PMID: 33760546.

92. Anna Pärtty, Marko Kalliomäki, Seppo Salminen, Erika Isolauri. Infantile Colic Is Associated With Low-grade Systemic Inflammation. J Pediatr Gastroenterol Nutr. 2017 May;64(5):691-695. doi: 10.1097/MPG.0000000000001340.

93. Khasanova S. S., Kamilova A. T. Dynamics of fecal zonulin values in premature children of the first two weeks of life. Rossiyskiy Vestnik Perinatolo gii i Pediatrii. 2019;64(2):52-56. (in Russ.) doi: 10.21508/1027-4065-2019-64-2-52-56.@@ Хасанова С. С., Камилова А. Т. Динамика значений фекального зонулина у недоношенных детей первых двух недель жизни. Российский вестник перинатологии и педиатрии. 2019;64(2):52-56. doi: 10.21508/1027-4065-2019-64-2-52-56.

94. Gurova М. М. Infantile colic from the perspective of evidence-based medicine: prevalence, principles of differential diagnosis and diet therapy algorithm. Meditsinskiy sovet = Medical Council. 2019;(17):147-155. (In Russ.) doi: 10.21518/2079-701X-2019-17-147-155.@@ Гурова М. М. Младенческая колика с позиций доказательной медицины: распространенность, принципы дифференциальной диагностики, алгоритм выбора диетотерапии. Медицинский Совет. 2019;(17):147-155. doi: 10.21518/2079-701X-2019-17-147-155.

95. Siel Daelemans, Linde Peeters et al. Recent advances in understanding and managing infantile colic. F1000Res. 2018 Sep 7;7: F1000 Faculty Rev-1426. doi: 10.12688/f1000research.14940.1.

96. Lucas Scheffler, Alyce Crane et al. Widely Used Commercial ELISA Does Not Detect Precursor of Haptoglobin2, but Recognizes Properdin as a Potential Second Member of the Zonulin Family. Front Endocrinol (Lausanne). 2018 Feb 5;9:22. doi: 10.3389/fendo.2018.00022.