The reasons for the formation of tolerance to food antigens

• Lilia K. Dobrodeeva
• Vyacheslav A. Shtaborov

Abstract

One of the main issues of the peculiarities of the immune reactions of the gastrointestinal tract is the mechanisms of ensuring tolerance to food antigens. Concentrations of antibodies to food antigens actually reflect the state of the intestinal mucosa barrier function, and the degree of penetration of antigens into the blood determines the level of immune response to them.

The aim of the study was to determine the risk criteria for violation of tolerance to food antigens.

Material and methods. The study included the results of a survey and examination of 1334 adults living in the north of the European part of the Russian Federation, including 1100 born in the North, of which 970 were women and 364 were men. The average age of the respondents was 45.5±1.0 years. The comparison group consisted of 344 patients with pathology of the gastrointestinal tract who applied to the medical company “Biocor”. The content of immunoglobulins (Ig) G to food antigens, total IgA, cytokines (tumor necrosis factor α, interleukin-6, interleukin-4) in blood serum were determined by enzyme immunoassay.

Results. Rural residents often (more than 28%) have elevated concentrations of IgG to potato, river fish, wheat and rye antigens. Urban residents have the most pronounced decrease in tolerance to food antigens of chicken, cod, beef and pork. In healthy individuals, elevated (>100 ME/ml) concentrations of antibodies to meat products are recorded in the range of 11.3–13.9%, to dairy antigens – 11.5–14.1%, cereals – 11.9–13.4%. Slightly less frequently, elevated concentrations of antibodies to fish antigens (7.5–10.1%), vegetables (3.8–7.0%) and fruits (4.9–6.5%) are detected. In inflammatory and oncological diseases of the gastrointestinal tract, the content of antibodies to food antigens increases sharply. On average, the frequency of impaired tolerance to food antigens in patients is 2.7–6.1 times higher than in healthy individuals.

Conclusion. Violation of tolerance to food antigens is associated with an increase in blood pro-inflammatory cytokines, mainly interleukin-6. In practically healthy individuals, a decrease in tolerance to food antigens is associated with a deficiency of blood IgA. The risk criteria for violation of the diet or consumption of low-quality foods may be an increase in the frequency of detection of elevated concentrations of antibodies to meat products in 14.6±3.0%, fish – 10.7±2.3%, cereals – 13.7±1.6%, dairy products – 14.8±1.5%, vegetables – 7.8±2.4% and fruits – 6.9±5.8%.

Keywords:food antigens; tolerance to food antigens; IgG; interleukin-6; cytokines

References

1. Birulina J.G., Ivanov V.V., Buyko E.E., Bykov V.V., Smagliy l.V., Nosarev A.V., et al. High-fat, high-carbohydrate diet-induced experimental model of metabolic syndrome in rats. Byulleten’ sibirskoy meditsiny [Bulletin of Siberian Medicine]. 2020; 19 (4): 14–20. DOI: https://doi.org/10.20538/1682-0363-2020-4-14-20 (in Russian)

2. Shepeleva O.A. Degteva G.N., Novikova Yu.A. Food security of the Arctic and near-Arctic territories of the European North of Russia. Ekologiya cheloveka [Human Ecology]. 2019; (10): 24–32. DOI: https://doi.org/10.33396/1728-0869-2019-10-24-32 (in Russian)

3. Nikiforova N.A., Karapetyan T.A., Dorshakova N.V. Peculiarities of nutrition of the inhabitants of the North. Ekologiya cheloveka [Human Ecology]. 2018; (11): 20–2. DOI: https://doi.org/10.33396/1728-0869-2018-11-20-25 (in Russian)

4. Abd-Elhakim Y.M., Hashem M.M.M., Abo-El-Sooud K., Ali H.A., Anwar A., El-Metwally A.E., et al. Involvement of tumor necrosis factor-α, interferon gamma-γ, and interleukins 1β, 6, and 10 in immunosuppression due to long-term exposure to five common food preservatives in rats. Gene. 2020; 742: 144590. DOI: https://doi.org/10.1016/j.gene.2020.144590

5. Maier E., Kurz K., Jenny M., Schennach H., Ueberall F., Fuchs D. Food preservatives sodium benzoate and propionic acid and colorant curcumin suppress Th1-type immune response in vitro. Food Chem Toxicol. 2010; 48 (7): 1950–6. DOI: https://doi.org/10.1016/j.fct.2010.04.042

6. Weström B., Arévalo Sureda E., Pierzynowska K., Pierzynowski S.G., Pérez-Cano F.J. The immature gut barrier and its importance in establishing immunity in newborn mammals. Front Immunol. 2020; 9 (11): 1153. DOI: https://doi.org/10.3389/fimmu.2020.01153

7. Maher S., Geoghegan C., Brayden D.J. Intestinal permeation enhancers to improve oral bioavailability of macromolecules: Reasons for low efficacy in humans. Expert Opin Drug Deliv 2021; 18 (2): 273–300. DOI: https://doi.org/10.1080/17425247.2021.1825375

8. Suzuki T. Regulation of the intestinal barrier by nutrients: The role of tight junctions. Anim Sci J. 2020; 91 (1): e13357. DOI: https://doi.org/10.1111/asj.13357

9. Shukla P.K., Meena A.S., Dalal K., Canelas C., Samak G., Pierre J.F., et al. Chronic stress and corticosterone exacerbate alcohol-induced tissue injury in the gut-liver-brain axis. Sci Rep. 2021; 11 (1): 826. DOI: https://doi.org/10.1038/s41598-020-80637-y

10. Labanski A., Langhorst J., Engler H., Elsenbruch S. Stress and the brain-gut axis in functional and chronic-inflammatory gastrointestinal diseases: A transdisciplinary challenge. Psychoneuroendocrinology. 2020; 111: 104501. DOI: https://doi.org/10.1016/j.psyneuen.2019.104501

11. Spalinger M.R., Sayoc-Becerra A., Santos A.N., Shawki A., Canale V., Krishnan M., et al. PTPN2 regulates interactions between macrophages and intestinal epithelial cells to promote intestinal barrier function. Gastroenterology. 2020; 159 (5): 1763–77.e14. DOI: https://doi.org/10.1053/j.gastro.2020.07.004

12. Saito Y., Shimizu M., Iwatsuki K., Hanyu H., Tadaishi M., Sugita-Konishi Y., et al. Effect of short-time treatment with TNF-α on stem cell activity and barrier function in enteroids. Cytotechnology. 2021; 73 (4): 669–82. DOI: https://doi.org/10.1007/s10616-021-00487-y

13. Chen Z., Luo J., Li J., Kim G., Stewart A., Urban J.F. Jr, et al. Interleukin-33 promotes serotonin release from enterochromaffin cells for intestinal homeostasis. Immunity. 2021; 54 (1): 151–63.e6. DOI: https://doi.org/10.1016/j.immuni.2020.10.014

14. Kyritsi K., Kennedy L., Meadows V., Hargrove L., Demieville J., Pham L., et al. Mast cells induce ductular reaction mimicking liver injury in mice through mast cell-derived transforming growth factor beta 1 signaling. Hepatology. 2021; 73 (6): 2397–410. DOI: https://doi.org/10.1002/hep.31497

15. Paray B.A., Albeshr M.F., Jan A.T., Rather I.A. Leaky gut and autoimmunity: An intricate balance in individuals health and the diseased state. Int J Mol Sci. 2020; 21 (24): 9770. DOI: https://doi.org/10.3390/ijms21249770

16. Mohebali N., Ekat K., Kreikemeyer B., Breitrück A. Barrier protection and recovery effects of gut commensal bacteria on differentiated intestinal epithelial cells in vitro. Nutrients. 2020; 12 (8): 2251. DOI: https://doi.org/10.3390/nu12082251

17. Kim C.H. Control of lymphocyte functions by gut microbiota-derived short-chain fatty acids. Cell Mol Immunol. 2021; 18 (5): 1161–71. DOI: https://doi.org/10.1038/s41423-020-00625-0

18. Ornelas A., Dowdell A.S., Lee J.S., Colgan S.P. Microbial metabolite regulation of epithelial cell-cell interactions and barrier function. Cells. 2022; 11 (6): 944. DOI: https://doi.org/10.3390/cells11060944

19. Vojdani A. Molecular mimicry as a mechanism for food immune reactivities and autoimmunity. Altern Ther Health Med. 2015; 21 (1): 34–45.

20. Bischoff S.C., Barbara G., Buurman W., Ockhuizen T., Schulzke J.D., Serino M., et al. Intestinal permeability – a new target for disease prevention and therapy. BMC Gastroenterol. 2014; 14: 189. DOI: https://doi.org/10.1186/s12876-014-0189-7

21. Mu Q., Kirby J., Reilly C.M., Luo X.M. Leaky gut as a danger signal for autoimmune diseases. Front Immunol. 2017; 8: 598. DOI: https://doi.org/10.3389/fimmu.2017.00598

22. Shamriz O., Mizrahi H., Werbner M., Shoenfeld Y., Avni O., Koren O. Microbiota at the crossroads of autoimmunity. Autoimmun Rev. 2016; 15 (9): 859–69. DOI: https://doi.org/10.1016/j.autrev.2016.07.012

23. Rinninella E., Cintoni M., Raoul P., Gasbarrini A., Mele M.C. Food additives, gut microbiota, and irritable bowel syndrome: A hidden track. Int J Environ Res Public Health. 2020; 17 (23): 8816. DOI: https://doi.org/10.3390/ijerph17238816

Среди 582 практически здоровых людей без патологии ЖКТ сочетанное повышение ФНОα и ИЛ-6 наблюдали у 24 обследуемых, одновременное повышение содержания в крови ФНОα и ИЛ-4 - у 8 человек. Увеличение содержания в крови цитокинов, дефицит IgA, в том числе с повышенными уровнями IgE, снижает толерантность к пищевым антигенам (табл. 3).

Среди изучаемых факторов влияния на снижение толерантности к пищевым антигенам у практически здоровых людей заметно выделяются повышение в крови содержания провоспалительных цитокинов и дефицит содержания в периферической крови IgA.

Заключение

Таким образом, нарушение толерантности к пищевым антигенам ассоциировано с повышением в крови провоспалительных цитокинов, преимущественно ИЛ-6. Наиболее вероятным механизмом влияния цитокинов на нарушение толерантности к пищевым продуктам является повышение парацеллюлярной проницаемости кишечной стенки для пищевых продуктов. При воспалительных и онкологических заболеваниях ЖКТ резко увеличивается содержание антител к пищевым антигенам. У практически здоровых лиц снижение толерантности к пищевым антигенам ассоциировано с дефицитом в крови IgA.

Сравнительный анализ частоты регистрации повышенных концентраций IgG к пищевым антигенам у практически здоровых лиц и пациентов с различными заболеваниями ЖКТ позволил установить уровни риска нарушения толерантности к пищевым антигенам в пределах M±1,5σ. Критериями риска нарушения пищевого рациона или потребления пищевых продуктов низкого качества могут быть увеличение частоты выявления повышенных концентраций антител к мясным продуктам более чем в 14,6±3,0%, рыбе - 10,7±2,3%, зерновым - 13,7±1,6%, молочным продуктам - 14,8±1,5%, овощам - 7,8±2,4% и фруктам - 6,9±5,8%. Такие критерии могут быть использованы для оценки качества питания отдельных контингентов людей, оценки эффективности лечебного питания, а также для ретроспективного контроля качества пищевых продуктов.

Литература

1. Бирулина Ю.Г., Иванов В.В., Буйко Е.Е., Быков В.В., Смаглий Л.В., Носарев А.В., и др. Экспериментальная модель метаболического синдрома у крыс на основе высокожировой и высокоуглеводной диеты // Бюллетень сибирской медицины. 2020. Т. 19, № 4. С. 14-20. DOI: https://doi.org/10.20538/1682-0363-2020-4-14-20

2. Шепелева О.А., Дегтева Г.Н., Новикова Ю.А. Продовольственная безопасность арктических и приарктических территорий Европейского Севера России // Экология человека. 2019. № 10. С. 24-32. DOI: https://doi.org/10.33396/1728-0869-2019-10-24-32

3. Никифорова Н.А., Карапетян Т.А., Доршакова Н.В. Особенности питания жителей Севера (обзор литературы) // Экология человека. 2018. № 11. С. 20-22. DOI: https://doi.org/10.33396/1728-0869-2018-11-20-25

4. Abd-Elhakim Y.M., Hashem M.M.M., Abo-El-Sooud K., Ali H.A., Anwar A., El-Metwally A.E. et al. Involvement of tumor necrosis factor-α, interferon gamma-γ, and interleukins 1β, 6, and 10 in immunosuppression due to long-term exposure to five common food preservatives in rats // Gene. 2020. Vol. 742. Article ID 144590. DOI: https://doi.org/10.1016/j.gene.2020.144590

5. Maier E., Kurz K., Jenny M., Schennach H., Ueberall F., Fuchs D. Food preservatives sodium benzoate and propionic acid and colorant curcumin suppress Th1-type immune response in vitro // Food Chem. Toxicol. 2010. Vol. 48, N 7. P. 1950-1956. DOI: https://doi.org/10.1016/j.fct.2010.04.042

6. Weström B., Arévalo Sureda E., Pierzynowska K., Pierzynowski S.G., Pérez-Cano F.J. The immature gut barrier and its importance in establishing immunity in newborn mammals // Front. Immunol. 2020. Vol. 9, N 11. P. 1153. DOI: https://doi.org/10.3389/fimmu.2020.01153

7. Maher S., Geoghegan C., Brayden D.J. Intestinal permeation enhancers to improve oral bioavailability of macromolecules: Reasons for low efficacy in humans // Expert Opin. Drug Deliv. 2021. Vol. 18, N 2. P. 273-300. DOI: https://doi.org/10.1080/17425247.2021.1825375

8. Suzuki T. Regulation of the intestinal barrier by nutrients: The role of tight junctions // Anim. Sci. J. 2020. Vol. 91, N 1. Article ID e13357. DOI: https://doi.org/10.1111/asj.13357

9. Shukla P.K., Meena A.S., Dalal K., Canelas C., Samak G., Pierre J.F. et al. Chronic stress and corticosterone exacerbate alcohol-induced tissue injury in the gut-liver-brain axis // Sci. Rep. 2021. Vol. 11, N 1. P. 826. DOI: https://doi.org/10.1038/s41598-020-80637-y

10. Labanski A., Langhorst J., Engler H., Elsenbruch S. Stress and the brain-gut axis in functional and chronic-inflammatory gastrointestinal diseases: A transdisciplinary challenge // Psychoneuroendocrinology. 2020. Vol. 111. Article ID 104501. DOI: https://doi.org/10.1016/j.psyneuen.2019.104501

11. Spalinger M.R., Sayoc-Becerra A., Santos A.N., Shawki A., Canale V., Krishnan M. et al. PTPN2 regulates interactions between macrophages and intestinal epithelial cells to promote intestinal barrier function // Gastroenterology. 2020. Vol. 159, N 5. P. 1763-1777.e14. DOI: https://doi.org/10.1053/j.gastro.2020.07.004

12. Saito Y., Shimizu M., Iwatsuki K., Hanyu H., Tadaishi M., Sugita-Konishi Y. et al. Effect of short-time treatment with TNF-α on stem cell activity and barrier function in enteroids // Cytotechnology. 2021. Vol. 73, N 4. P. 669-682. DOI: https://doi.org/10.1007/s10616-021-00487-y

13. Chen Z., Luo J., Li J., Kim G., Stewart A., Urban J.F. Jr et al. Interleukin-33 promotes serotonin release from enterochromaffin cells for intestinal homeostasis // Immunity. 2021. Vol. 54, N 1. P. 151-163.e6. DOI: https://doi.org/10.1016/j.immuni.2020.10.014

14. Kyritsi K., Kennedy L., Meadows V., Hargrove L., Demieville J., Pham L. et al. Mast cells induce ductular reaction mimicking liver injury in mice through mast cell-derived transforming growth factor beta 1 signaling // Hepatology. 2021. Vol. 73, N 6. P. 2397-2410. DOI: https://doi.org/10.1002/hep.31497

15. Paray B.A., Albeshr M.F., Jan A.T., Rather I.A. Leaky gut and autoimmunity: An intricate balance in individuals health and the diseased state // Int. J. Mol. Sci. 2020. Vol. 21, N 24. P. 9770. DOI: https://doi.org/10.3390/ijms21249770

16. Mohebali N., Ekat K., Kreikemeyer B., Breitrück A. Barrier protection and recovery effects of gut commensal bacteria on differentiated intestinal epithelial cells in vitro // Nutrients. 2020. Vol. 12, N 8. P. 2251. DOI: https://doi.org/10.3390/nu12082251

17. Kim C.H. Control of lymphocyte functions by gut microbiota-derived short-chain fatty acids // Cell. Mol. Immunol. 2021. Vol. 18, N 5. P. 1161-1171. DOI: https://doi.org/10.1038/s41423-020-00625-0

18. Ornelas A., Dowdell A.S., Lee J.S., Colgan S.P. Microbial metabolite regulation of epithelial cell-cell interactions and barrier function // Cells. 2022. Vol. 11, N 6. P. 944. DOI: https://doi.org/10.3390/cells11060944

19. Vojdani A. Molecular mimicry as a mechanism for food immune reactivities and autoimmunity // Altern. Ther. Health Med. 2015. Vol. 21, N 1. P. 34-45.

20. Bischoff S.C., Barbara G., Buurman W., Ockhuizen T., Schulzke J.D., Serino M. et al. Intestinal permeability - a new target for disease prevention and therapy // BMC Gastroenterol. 2014. Vol. 14. P. 189. DOI: https://doi.org/10.1186/s12876-014-0189-7

21. Mu Q., Kirby J., Reilly C.M., Luo X.M. Leaky gut as a danger signal for autoimmune diseases // Front. Immunol. 2017. Vol. 8. P. 598. DOI: https://doi.org/10.3389/fimmu.2017.00598

22. Shamriz O., Mizrahi H., Werbner M., Shoenfeld Y., Avni O., Koren O. Microbiota at the crossroads of autoimmunity // Autoimmun. Rev. 2016. Vol. 15, N 9. P. 859-869. DOI: https://doi.org/10.1016/j.autrev.2016.07.012

23. Rinninella E., Cintoni M., Raoul P., Gasbarrini A., Mele M.C. Food additives, gut microbiota, and irritable bowel syndrome: A hidden track // Int. J. Environ. Res. Public Health. 2020. Vol. 17, N 23. P. 8816. DOI: https://doi.org/10.3390/ijerph17238816

All articles in our journal are distributed under the CC BY-NC-ND 4.0 (Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International)

© GEOTAR-Media Publishing Group. The use of textual and illustrative content from this publication for the training of any artificial intelligence systems - including machine learning models and neural networks - is strictly prohibited without the prior written consent of the copyright holder.