Immune Cytokines IFN-γ, TGF-β, TNF-α, and IL-1β  Modulate the Pathophysiological Markers in Idiopathic Parkinson’s Disease

Osama Abdel-Hameed Majeed ^1*, Makarim Qassim Al-Lami ¹, Gheyath AlGawwam ²

This study showed the biochemical and immunological links between Parkinson's Disease and gastrointestinal disorders, highlighting shared pathophysiological markers.

Abstract

Background: Parkinson's disease (PD) is a neurodegenerative aging disease, with idiopathic PD being most common. Gastrointestinal tract disorders (GITD) and microbiota changes may trigger idiopathic PD. Neurotoxins from microbiota can travel from the gut to the brain via the brain-gut axis (BGA), leading to α-syn protein misfolding and dopaminergic neuron death. Methods: The aim of the current study was to investigate the link between PD and GITD by measuring several biochemical and immunological markers in 142 patients. The biochemical markers measured were vitamins B6, B12, and D, calcium, serotonin, ghrelin, dopamine, and α-syn protein. The immunological markers included transforming growth factor-beta (TGF-β), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interferon-gamma (IFN-γ). All markers were measured using the Enzyme-Linked Immunosorbent Assay (ELISA) technique. Results: PD patients were significantly older (63.76±12.29 years) compared to GITD and control groups (41.00±15.54 and 41.25±18.30 years, respectively). Males predominated in the PD group (74.5%), while females were more common in the GITD and control groups. PD and GITD patients showed significantly lower levels of vitamins and neurotransmitters but higher calcium and α-synuclein compared to controls. Immunological markers were elevated in PD and GITD groups, with significant differences between them (P-value < 0.001). Conclusion: The study concluded that certain biochemical and immunological markers provide strong evidence of the brain-gut axis's involvement in the initiation of idiopathic Parkinson's disease.

Keywords: Brain-Gut axis, Dopamine, Vagus nerve, Microbiota, Parkinson's Disease (PD), Gastrointestinal Disorders (GITD), Alpha-synuclein, Neuroinflammation, Biochemical markers

References

Alam, M. R., Raj, K., & Singh, S. (2022). The roles of calcium ions in Parkinson’s disease: Calcium channel inhibitors as a novel agents? Journal of Molecular Pathology, 3(4), 243-261.

Al-Kuraishy, H. M., Al-Gareeb, A. I., Elewa, Y. H. A., Zahran, M. H., Alexiou, A., Papadakis, M., & Batiha, G. E.-S. (2023). Parkinson’s disease risk and hyperhomocysteinemia: the possible link. Cellular and Molecular Neurobiology, 43(6), 2743-2759.

Badanjak, K., Fixemer, S., Smajic, S., Skupin, A., & Grünewald, A. (2021). The contribution of microglia to neuroinflammation in Parkinson’s disease. International Journal of Molecular Sciences, 22(9), 4676.

Barichella, M., Garrì, F., Caronni, S., Bolliri, C., Zocchi, L., Macchione, M. C., Ferri, V., Calandrella, D., & Pezzoli, G. (2022). Vitamin D status and Parkinson’s disease. Brain Sciences, 12(6), 790.

Bayliss, J. A., & Andrews, Z. B. (2013). Ghrelin is neuroprotective in Parkinson’s disease: molecular mechanisms of metabolic neuroprotection. Therapeutic advances in endocrinology and metabolism, 4(1), 25-36.

Bloem, B. R., Okun, M. S., & Klein, C. (2021). Parkinson's disease. The Lancet, 397(10291), 2284-2303.

Brudek, T. (2019). Inflammatory bowel diseases and Parkinson’s disease. Journal of Parkinson's disease, 9(s2), S331-S344.

Cerri, S., Mus, L., & Blandini, F. (2019). Parkinson’s disease in women and men: what’s the difference? Journal of Parkinson's disease, 9(3), 501-515.

Chan, L., Chung, C.-C., Yu, R.-C., & Hong, C.-T. (2023). Cytokine profiles of plasma extracellular vesicles as progression biomarkers in Parkinson’s disease. Aging (Albany NY), 15(5), 1603.

DeMaagd, G., & Philip, A. (2015). Parkinson’s disease and its management: part 1: disease entity, risk factors, pathophysiology, clinical presentation, and diagnosis. Pharmacy and therapeutics, 40(8), 504.

Dumic, I., Nordin, T., Jecmenica, M., Stojkovic Lalosevic, M., Milosavljevic, T., & Milovanovic, T. (2019). Gastrointestinal tract disorders in older age. Canadian Journal of Gastroenterology and Hepatology, 2019.

Goodwin, J., & Pountney, D. L. (2014). Interactions between Calcium and Alpha-Synuclein in Neurodegeneration. Biomolecules (2218-273X), 4(3).

Greco, D. S. (2012). Endocrine causes of calcium disorders. Topics in companion animal medicine, 27(4), 150-155.

Guo, T., & Chen, L. (2022). Gut microbiota and inflammation in Parkinson’s disease: Pathogenetic and therapeutic insights. European Journal of Inflammation, 20, 1721727X221083763.

Guzel, T., & Mirowska-Guzel, D. (2022). The role of serotonin neurotransmission in gastrointestinal tract and pharmacotherapy. Molecules, 27(5), 1680.

Hassan, R. M., Kamal, Z. B., Al Marzook, T. J., & Hussein, W. A. (2010). Open Access Esophagogastroduodenoscopy. Journal of the Faculty of Medicine Baghdad, 52(3), 269-273.

Hazaa, H. F., & Lami, F. H. (2018). Irritable bowel syndrome among high school students, Bagdad, Iraq, 2017-2018. Journal of the Faculty of Medicine Baghdad, 60(2), 113-118.

Jamil, L., Alobaidi, F., & Lami, F. (2017). Risk Factors for Gastrointestinal Disorders Among Iraqi Americans in Southeast Michigan, United States. Scientific Pages Gastroenterol, 1(1), 1-8.

Kashima, R., & Hata, A. (2018). The role of TGF-β superfamily signaling in neurological disorders. Acta biochimica et biophysica Sinica, 50(1), 106-120.

Korytny, A., Klein, A., Marcusohn, E., Freund, Y., Neuberger, A., Raz, A., Miller, A., & Epstein, D. (2021). Hypocalcemia is associated with adverse clinical course in patients with upper gastrointestinal bleeding. Internal and Emergency Medicine, 1-10.

Liu, T., Liu, J., Wang, C., Zou, D., Wang, C., Xu, T., Ci, Y., Guo, X., & Qi, X. (2023). Prevalence of gastrointestinal symptoms and their association with psychological problems in youths. Annals of Palliative Medicine, 12(2), 31123-31323.

Magnusen, A. F., Hatton, S. L., Rani, R., & Pandey, M. K. (2021). Genetic defects and pro-inflammatory cytokines in Parkinson's disease. Frontiers in neurology, 12, 636139.

Masri, O. A., Chalhoub, J. M., & Sharara, A. I. (2015). Role of vitamins in gastrointestinal diseases. World Journal of Gastroenterology: WJG, 21(17), 5191.

Masule, M. V., Rathod, S., Agrawal, Y., Patil, C. R., Nakhate, K. T., Ojha, S., Goyal, S. N., & Mahajan, U. B. (2022). Ghrelin mediated regulation of neurosynaptic transmitters in depressive disorders. Current Research in Pharmacology and Drug Discovery, 3, 100113.

Meade, R. M., Fairlie, D. P., & Mason, J. M. (2019). Alpha-synuclein structure and Parkinson’s disease–lessons and emerging principles. Molecular neurodegeneration, 14, 1-14.

Miquel-Rio, L., Sarriés-Serrano, U., Pavia-Collado, R., Meana, J. J., & Bortolozzi, A. (2023). The Role of α-Synuclein in the Regulation of Serotonin System: Physiological and Pathological Features. Biomedicines, 11(2), 541.

Mizuno, Y., Shimoda, S., & Origasa, H. (2018). Long-term treatment of Parkinson’s disease with levodopa and other adjunctive drugs. Journal of Neural Transmission, 125, 35-43.

Narayanan, S. P., Anderson, B., & Bharucha, A. E. (2021). Sex-and gender-related differences in common functional gastroenterologic disorders. Mayo Clinic Proceedings,

Nobis, L., Maio, M. R., Saleh, Y., Manohar, S., Kienast, A., McGann, E., & Husain, M. (2023). Role of serotonin in modulation of decision-making in Parkinson’s disease. Journal of Psychopharmacology, 37(4), 420-431.

Pang, S. Y.-Y., Ho, P. W.-L., Liu, H.-F., Leung, C.-T., Li, L., Chang, E. E. S., Ramsden, D. B., & Ho, S.-L. (2019). The interplay of aging, genetics and environmental factors in the pathogenesis of Parkinson’s disease. Translational Neurodegeneration, 8, 1-11.

Perez, A., Guan, L., Sutherland, K., & Cao, C. (2016). Immune system and Parkinson’s disease. Arch Med, 8(2), 1-6.

Rietdijk, C. D., Perez-Pardo, P., Garssen, J., Van Wezel, R. J., & Kraneveld, A. D. (2017). Exploring Braak’s hypothesis of Parkinson’s disease. Frontiers in neurology, 8, 232637.

Schaeffer, E., Kluge, A., Böttner, M., Zunke, F., Cossais, F., Berg, D., & Arnold, P. (2020). Alpha synuclein connects the gut-brain axis in Parkinson’s disease patients–a view on clinical aspects, cellular pathology and analytical methodology. Frontiers in cell and developmental biology, 8, 573696.

Shen, L. (2015). Associations between B vitamins and Parkinson’s disease. Nutrients, 7(9), 7197-7208.

Shihab, S. S., Jawad, F. H. M., Nasir, Z. M., & Jasim, E. M. (2022). Use of dietary supplements in a sample of Iraqis. Journal of the Faculty of Medicine, 64(1).

Sokolovska, H., Zhang, Y., Fathi, A., & Lee, Y. (2022). Dietary vitamin B1, B2, and B6 intake influence the microbial composition and functional potential of the gut microbiome in Parkinson’s disease. Undergraduate Journal of Experimental Microbiology and Immunology, 8.

Surmeier, D. J., Halliday, G. M., & Simuni, T. (2017). Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease. Experimental neurology, 298, 202-209.

Tehrani, S. S., Sarfi, M., Yousefi, T., Ahangar, A. A., Gholinia, H., Ahangar, R. M., Maniati, M., & Saadat, P. (2020). Comparison of the calcium-related factors in Parkinson’s disease patients with healthy individuals. Caspian Journal of Internal Medicine, 11(1), 28.

Virameteekul, S., Phokaewvarangkul, O., & Bhidayasiri, R. (2021). Profiling the most elderly parkinson’s disease patients: Does age or disease duration matter? PloS one, 16(12), e0261302.

Vivarelli, M., Montalti, R., & Risaliti, A. (2013). Multimodal treatment of hepatocellular carcinoma on cirrhosis: an update. World Journal of Gastroenterology: WJG, 19(42), 7316.

Wang, J., Wu, S., Zhang, Y., Yang, J., & Hu, Z. (2022). Gut microbiota and calcium balance. Frontiers in Microbiology, 13, 1033933.

Wang, W., Jiang, S., Xu, C., Tang, L., Liang, Y., Zhao, Y., & Zhu, G. (2022). Interactions between gut microbiota and Parkinson's disease: The role of microbiota-derived amino acid metabolism. Frontiers in Aging Neuroscience, 14, 976316.

Yan, J., Fu, Q., Cheng, L., Zhai, M., Wu, W., Huang, L., & Du, G. (2014). Inflammatory response in Parkinson's disease. Molecular medicine reports, 10(5), 2223-2233.

Yang, X., Lou, J., Shan, W., Ding, J., Jin, Z., Hu, Y., Du, Q., Liao, Q., Xie, R., & Xu, J. (2021). Pathophysiologic role of neurotransmitters in digestive diseases. Frontiers in physiology, 12, 567650.

Yin, J., Valin, K. L., Dixon, M. L., & Leavenworth, J. W. (2017). The role of microglia and macrophages in CNS homeostasis, autoimmunity, and cancer. Journal of immunology research, 2017.

Yohn, C. N., Gergues, M. M., & Samuels, B. A. (2017). The role of 5-HT receptors in depression. Molecular brain, 10, 1-12.

Zeng, J., Wang, X., Pan, F., & Mao, Z. (2022). The relationship between Parkinson’s disease and gastrointestinal diseases. Frontiers in Aging Neuroscience, 14, 955919.

Zhou, Z. D., Yi, L. X., Wang, D. Q., Lim, T. M., & Tan, E. K. (2023). Role of dopamine in the pathophysiology of Parkinson’s disease. Translational Neurodegeneration, 12(1), 44.

Zimmermann, M., & Brockmann, K. (2022). Blood and cerebrospinal fluid biomarkers of inflammation in Parkinson’s disease. Journal of Parkinson's disease, 12(s1), S183-S200.