Synergic Trio of Metabolic Regulators Supporting the Vicious Circle of Pathological Processes in Post-Traumatic Stress Disorder

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Abstract

Post-traumatic stress disorder (PTSD) is a maladaptive response to exposure of extreme intensity stressor. The body of animals and humans reacts at the systemic and cellular levels, as with any response to external challenges. Disorder of the collective work of stress-realizing and stress-limiting systems causes transformation of behavior, cognitive abilities and other functions of the central nervous system in stress-sensitive individuals. Currently, it has been proven that in the pathogenesis of PTSD, an important place is occupied by changes in the number and composition of the intestinal microbiota. In this regard, methods of improving the microflora are being considered. Analyzing data of Russian and foreign researchers, the authors came to the conclusion, that metabolic, somatic and mental health largely depends on the coordinated functioning of the main interdependent components of metabolism: hepatobiliary system, intestinal microbiota and, according to the authors, on the state of mast cells. A close study of the interaction of these components will allow us to identify new therapeutic targets and the most effective methods of treating PTSD.

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About the authors

M. V. Kondashevskaya

Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution "Petrovsky National Research Centre of Surgery"

Author for correspondence.
Email: marivladiko@mail.ru
Russian Federation, Moscow

K. A. Artemyeva

Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution "Petrovsky National Research Centre of Surgery"

Email: marivladiko@mail.ru
Russian Federation, Moscow

L. M. Mikhaleva

Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution "Petrovsky National Research Centre of Surgery"

Email: marivladiko@mail.ru
Russian Federation, Moscow

References

  1. Lapshin MS, Kondashevskaya MV, Epishev VV, Patochkina NA (2023) Pathogenesis of Post-Traumatic Stress Disorder and Therapeutic Targets. Neurosci Behav Physiol 53(6): 1072–1083. https://doi.org/ 10.1007/s11055–023–01501-w
  2. Speer KE, Semple S, McKune AJ (2020) Acute Physiological Responses Following a Bout of Vigorous Exercise in Military Soldiers and First Responders with PTSD: An Exploratory Pilot Study. Behav Sci (Basel) 10(2): 59. https://doi.org/ 10.3390/bs10020059
  3. Liu B, Yuan ML, Hu Y, Ge FF, Wang JY, Zhang W (2021) A Review of Research Progress in the Pathophysiological Mechanism of Stress-related Mental Disorders. Sichuan Da Xue Xue Bao Yi Xue Ban 52(1): 22–27. https://doi.org/ 10.12182/20210160101
  4. Sugama S, Kakinuma Y (2020) Stress and brain immunity: Microglial homeostasis through hypothalamus-pitu itary-adrenal gland axis and sympathetic nervous system. Brain Behav Immun Health 7: 100111. https://doi.org/ 10.1016/j.bbih.2020.100111
  5. Patas K, Baker DG, Chrousos GP, Agorastos A (2024) Inflammation in Posttraumatic Stress Disorder: Dysregulation or Recalibration? Curr Neuropharmacol 22(4): 524–542. https://doi.org/ 10.2174/1570159X21666230807152051
  6. Speer K, Upton D, Semple S, McKune A (2018) Systemic low-grade inflammation in post-traumatic stress disorder: a systematic review. J Inflamm Res 11: 111–121. https://doi.org/ 10.2147/JIR.S155903
  7. Naviaux RK (2014) Metabolic features of the cell danger response. Mitochondrion 16: 7–17. https://doi.org/ 10.1016/j.mito.2013.08.006
  8. Kondashevskaya MV, Mikhaleva LM, Artem'yeva KA, Aleksankina VV, Areshidze DA, Kozlova MA, Pashkov AA, Manukhina EB, Downey HF, Tseilikman OB, Yegorov ON, Zhukov MS, Fedotova JO, Karpenko MN, Tseilikman VE (2023) Unveiling the Link: Exploring Mitochondrial Dysfunction as a Probable Mechanism of Hepatic Damage in Post-Traumatic Stress Syndrome. Int J Mol Sci 24: 13012. https://doi.org/10.3390/ijms241613012
  9. Sun J, Ince MN, Abraham C, Barrett T, Brenner LA, Cong Y, Dashti R, Dudeja PK, Elliott D, Griffith TS, Heeger PS, Hoisington A, Irani K, Kim TK, Kapur N, Leventhal J, Mohamadzadeh M, Mutlu E, Newberry R, Peled JU, Rubinstein I, Sengsayadeth S, Tan CS, Tan XD, Tkaczyk E, Wertheim J, Zhang ZJ (2023) Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans: report of an expert meeting. Gut Microbes 15(2): 2267180. https://doi.org/ 10.1080/19490976.2023.2267180
  10. Pearson-Leary J, Zhao C, Bittinger K, Eacret D, Luz S, Vigderman AS, Dayanim G, Bhatnagar S (2020) The gut microbiome regulates the increases in depressive-type behaviors and in inflammatory processes in the ventral hippocampus of stress vulnerable rats. Mol Psychiatry 25: 1068–1079. https://doi.org/ 10.1038/s41380–019–0380-x
  11. Кондашевская МВ (2019) Экосистема тучных клеток – ключевой полифункциональный компонент организма животных и человека. Группа МДВ. Москва. [Kondashevskaya MV (2019) The mast cell ecosystem is a key multifunctional component of animals and humans. MDV Group. Moscow. (In Russ)].
  12. Zass LJ, Hart SA, Seedat S, Hemmings SM, Malan-Müller S (2017) Neuroinflammatory genes associated with post-traumatic stress disorder: implications for comorbidity. Psychiatr Genet 27(1): 1–16. https://doi.org/ 10.1097/YPG.0000000000000143
  13. Traina G (2021) The role of mast cells in the gut and brain. J Integr Neurosci 20: 185–196. https://doi.org/ 10.31083/j.jin.2021.01.313
  14. Кондашевская МВ (2023) Гепарин-адаптоген, секретируемый тучными клетками, горизонты гепаринотерапии. Группа МДВ. Москва. [Kondashevskaya MV (2023) Heparin-adaptogen secreted by mast cells, Horizons of heparin therapy. MDV Group. Moscow. (In Russ)].
  15. Perković MN, Milković L, Uzun S, Mimica N, Pivac N, Waeg G, Žarković N (2021) Association of Lipid Peroxidation Product 4-Hydroxynonenal with Post-Traumatic Stress Disorder. Biomolecules 11(9): 1365. https://doi.org/10.3390/biom11091365
  16. Петухов ВА (2003) Липидный дистресс-синдром. М. ВЕДИ. [Petukhov VA (2003) Lipid distress syndrome. M. VEDI. (In Russ)].
  17. Петухов ВА, Магомедов МС (2007) Липидный дистресс-синдром Савельева: 20 лет спустя. Поликлиника 2: 90–94. [Petukhov VA, Magomedov MS (2007) Saveliev's lipid distress syndrome: 20 years later. Poliklinika 2: 90–94. (In Russ)].
  18. Савельев ВС, Петухов ВА, Каралкин АВ, Фомин ДК (2002) Внепеченочные билиарные дисфункции при липидном дистресс-синдроме: этиопатогенез, диагностика и принципы лечения. Русск мед журн 2: 62. [Savelyev VS, Petukhov VA, Karalkin AV, Fomin DK (2002) Extrahepatic biliary dysfunction in10.1002/hep.32028 lipid distress syndrome: etiopathogenesis, diagnosis and principles of treatment. Russ Med J 2: 62. (In Russ)].
  19. Du J, Zhu M, Bao H, Li B, Dong Y, Xiao C, Zhang GY, Henter I, Rudorfer M, Vitiello B (2016) The Role of Nutrients in Protecting Mitochondrial Function and Neurotransmitter Signaling: Implications for the Treatment of Depression, PTSD, and Suicidal Behaviors. Crit Rev Food Sci Nutr 56(15): 2560–2578. https://doi.org/ 10.1080/10408398.2013.876960
  20. Wang Y, Yutuc E, Griffiths WJ (2021) Cholesterol metabolism pathways – are the intermediates more important than the products? FEBS J 288(12): 3727–3745. https://doi.org/ 10.1111/febs.15727
  21. Wang Y, Pandak WM, Hylemon PB, Min HK, Min J, Fuchs M, Sanyal AJ, Ren S (2023) Cholestenoic Acid as Endogenous Epigenetic Regulator Decreases Hepatocyte Lipid Accumulation in Vitro and in Vivo. Am J Physiol Gastrointest Liver Physiol 326(2): G147–G162. https://doi.org/ 10.1152/ajpgi.00184.2023
  22. Peng Z, Duggan MR, Dark HE, Daya GN, An Y, Davatzikos C, Erus G, Lewis A, Moghekar AR, Walker KA (2022) Association of liver disease with brain volume loss, cognitive decline, and plasma neurodegenerative disease biomarkers. Neurobiol Aging 120: 34–42. https://doi.org/10.1016/j.neurobiolaging.2022.08.004
  23. Bharti V, Bhardwaj A, Elias DA, Metcalfe AWS, Kim JS (2022) A Systematic Review and Meta-Analysis of Lipid Signatures in Post-traumatic Stress Disorder. Front Psychiatry 13: 847310. https://doi.org/10.3389/fpsyt.2022.847310
  24. Bell AS, Wagner J, Rosoff DB, Lohoff FW (2023) Proprotein convertase subtilisin/kexin type 9 (PCSK9) in the central nervous system. Neurosci Biobehav Rev 149: 105155. https://doi.org/10.1016/j.neubiorev.2023.105155
  25. Barale C, Melchionda E, Morotti A, Russo I (2021) PCSK9 Biology and Its Role in Atherothrombosis. Int J Mol Sci 22(11): 5880. https://doi.org/ 10.3390/ijms22115880
  26. Jaafar AK, Techer R, Chemello K, Lambert G, Bourane S (2023) PCSK9 and the nervous system: a no-brainer? J Lipid Res 64(9): 100426. https://doi.org/ 10.1016/j.jlr.2023.100426
  27. Agnello F, Mauro MS, Rochira C, Landolina D, Finocchiaro S, Greco A, Ammirabile N, Raffo C, Mazzone PM, Spagnolo M, Occhipinti G, Imbesi A, Giacoppo D, Capodanno D (2023) PCSK9 inhibitors: current status and emerging frontiers in lipid control. Expert Rev Cardiovasc Ther 23: 1–18. https://doi.org/ 10.1080/14779072.2023.2288169
  28. Vilella A, Bodria M, Papotti B, Zanotti I, Zimetti F, Remaggi G, Elviri L, Potì F, Ferri N, Lupo MG, Panighel G, Daini E, Vandini E, Zoli M, Giuliani D, Bernini F (2023) PCSK9 ablation attenuates Aβ pathology, neuroinflammation and cognitive dysfunctions in 5XFAD mice. Brain Behav Immun 115: 517–534. https://doi.org/ 10.1016/j.bbi.2023.11.008
  29. Cai J, Rimal B, Jiang C, Chiang JYL, Patterson AD (2022) Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther 237: 108238. https://doi.org/10.1016/j.pharmthera.2022.108238
  30. Kriaa A, Bourgin M, Potiron A, Mkaouar H, Jablaoui A, Gérard P, Maguin E, Rhimi M (2019) Microbial impact on cholesterol and bile acid metabolism: current status and future prospects. J Lipid Res 60(2): 323–332. https://doi.org/ 10.1194/jlr.R088989
  31. Simbrunner B, Trauner M, Reiberger T (2021) Review article: therapeutic aspects of bile acid signalling in the gut-liver axis. Aliment Pharmacol Ther 54(10): 1243–1262. https://doi.org/ 10.1111/apt.16602
  32. Teratani T, Mikami Y, Nakamoto N, Suzuki T, Harada Y, Okabayashi K, Hagihara Y, Taniki N, Kohno K, Shibata S, Miyamoto K, Ishigame H, Chu PS, Sujino T, Suda W, Hattori M, Matsui M, Okada T, Okano H, Inoue M, Yada T, Kitagawa Y, Yoshimura A, Tanida M, Tsuda M, Iwasaki Y, Kanai T (2020) The liver-brain-gut neural arc maintains the Treg cell niche in the gut. Nature 585(7826): 591–596. https://doi.org/ 10.1038/s41586–020–2425–3
  33. Lin H, Wang L, Liu Z, Long K, Kong M, Ye D, Chen X, Wang K, Wu KK, Fan M, Song E, Wang C, Hoo RL, Hui X, Hallenborg P, Piao H, Xu A, Cheng KK (2022) Hepatic MDM2 Causes Metabolic Associated Fatty Liver Disease by Blocking Triglyceride-VLDL Secretion via ApoB Degradation. Adv Sci (Weinh) 9(20): e2200742. https://doi.org/ 10.1002/advs.202200742
  34. Ke S, Hartmann J, Ressler KJ, Liu YY, Koenen KC (2023) The emerging role of the gut microbiome in posttraumatic stress disorder. Brain Behav Immun 114: 360–370. https://doi.org/10.1016/j.bbi.2023.09.005
  35. Bajaj JS, Sikaroodi M, Fagan A, Heuman D, Gilles H, Gavis EA, Fuchs M, Gonzalez-Maeso J, Nizam S, Gillevet PM, Wade JB (2019) Posttraumatic stress disorder is associated with altered gut microbiota that modulates cognitive performance in veterans with cirrhosis. Am J Physiol Gastrointest Liver Physiol 317: G661–G669. https://doi.org/10.1152/ajpgi.00194.2019
  36. Bastiaanssen TFS, Cowan CSM, Claesson MJ, Dinan TG, Cryan JF (2019) Making Sense of the Microbiome in Psychiatry. Int J Neuropsychopharmacol 22(1): 37–52. https://doi.org/ 10.1093/ijnp/pyy067
  37. Xiao L, Liu S, Wu Y, Huang Y, Tao S, Liu Y, Tang Y, Xie M, Ma Q, Yin Y, Dai M, Zhang M, Llamocca E, Gui H, Wang Q (2023) The interactions between host genome and gut microbiome increase the risk of psychiatric disorders: Mendelian randomization and biological annotation. Brain Behav Immun 113: 389–400. https://doi.org/ 10.1016/j.bbi.2023.08.003
  38. Montiel-Castro AJ, González-Cervantes RM, Bravo-Ruiseco G, Pacheco-López G (2013) The microbiota-gut-brain axis: neurobehavioral correlates, health and sociality. Front Integr Neurosci 7: 70. https://doi.org/ 10.3389/fnint.2013.00070
  39. Douglas-Escobar M, Elliott E, Neu J (2013) Effect of intestinal microbial ecology on the developing brain. JAMA Pediatr 167(4): 374–379. https://doi.org/ 10.1001/jamapediatrics.2013.497
  40. Xiao L, Liu S, Wu Y, Huang Y, Tao S, Liu Y, Tang Y, Xie M, Ma Q, Yin Y, Dai M, Zhang M, Llamocca E, Gui H, Wang Q (2023) The interactions between host genome and gut microbiome increase the risk of psychiatric disorders: Mendelian randomization and biological annotation. Brain Behav Immun 113: 389–400. https://doi.org/ 10.1016/j.bbi.2023.08.003
  41. Molina-Torres G, Rodriguez-Arrastia M, Roman P, Sanchez-Labraca N, Cardona D (2019) Stress and the gut microbiota-brain axis. Behav Pharmacol 30 (2 and 3-Spec Issue): 187–200. https://doi.org/ 10.1097/FBP.0000000000000478
  42. Gao F, Guo R, Ma Q, Li Y, Wang W, Fan Y, Ju Y, Zhao B, Gao Y, Qian L, Yang Z, He X, Jin X, Liu Y, Peng Y, Chen C, Chen Y, Gao C, Zhu F, Ma X (2022) Stressful events induce long-term gut microbiota dysbiosis and associated post-traumatic stress symptoms in healthcare workers fighting against COVID-19. J Affect Disord 303: 187–195. https://doi.org/10.1016/j.jad.2022.02.024
  43. Malan-Müller S, Valles-Colomer M, Palomo T, Leza JC (2023) The gut-microbiota-brain axis in a Spanish population in the aftermath of the COVID-19 pandemic: microbiota composition linked to anxiety, trauma, and depression profiles. Gut Microbes 15: 2162306. https://doi.org/10.1080/19490976.2022.2162306
  44. Pearson-Leary J, Zhao C, Bittinger K, Eacret D, Luz S, Vigderman AS, Dayanim G, Bhatnagar S (2020) The gut microbiome regulates the increases in depressive-type behaviors and in inflammatory processes in the ventral hippocampus of stress vulnerable rats. Mol Psychiatry 25: 1068–1079. https://doi.org/ 10.1038/s41380–019–0380-x
  45. Клёсов РА, Каркищенко НН, Степанова ОИ, Матвеенко ЕЛ (2020) Лекарственное поражение гастроинтестинальной системы и пути ее коррекции (обзор). Биомедицина 16(3): 14–34. [Klesov RA, Karkischenko NN, Stepanova OI, Matveyenko EL (2020) Drug-Induced Injury of the Gastrointestinal System and Methods for Its Correction (A Review). J Biomed 16(3): 14–34. (In Russ)]. https://doi.org/ 10.33647/2074–5982–16–3–14–34
  46. Alagiakrishnan K, Halverson T (2021) Microbial Therapeutics in Neurocognitive and Psychiatric Disorders. J Clin Med Res 13: 439–459. https://doi.org/10.14740/jocmr4575
  47. Halverson T, Alagiakrishnan K (2020) Gut microbes in neurocognitive and mental health disorders. Ann Med 52(8): 423–443. https://doi.org/10.1080/07853890.2020.1808239
  48. Снегирева НА, [Сидорова ЕВ], Дьяков ИН, Гаврилова МВ, Чернышова ИН, Пашков ЕП, Свитич ОА (2021) IgM- и IgA-ответ перитонеальных B1-клеток на Т-независимый антиген второго рода в присутствии γδT-клеток in vitro. Мед иммунол 23(2): 245–256. [Snegireva NA, [Sidorova EV], Dyakov IN, Gavrilova MV, Chernishova IN, Pashkov EP, Svitich OA (2021) IgM- and IgA-response of peritoneal B1 cells to the TI-2 antigen with in vitro presence of yôTcells". Med Immunol 23(2): 245–256. (In Russ)]. https://doi.org/ 10.15789/1563–0625-IAI-2157
  49. Renga G, Moretti S, Oikonomou V, Borghi M, Zelante T, Paolicelli G, Costantini C, De Zuani M, Villella VR, Raia V, Del Sordo R, Bartoli A, Baldoni M, Renauld JC, Sidoni A, Garaci E, Maiuri L, Pucillo C, Romani L (2018) IL-9 and Mast Cells Are Key Players of Candida albicans Commensalism and Pathogenesis in the Gut. Cell Rep 23: 1767–1778. https://doi.org/10.1016/j.celrep.2018.04.034
  50. Girolamo F, Coppola C, Ribatti D (2017) Immunoregulatory effect of mast cells influenced by microbes in neurodegenerative diseases. Brain Behav Immun 65: 68–89. https://doi.org/ 10.1016/j.bbi.2017.06.017
  51. Yang G, Yang L, Zhou X (2023) Inhibition of bacterial swimming by heparin binding of flagellin FliC from Escherichia coli strain Nissle 1917. Arch Microbiol 205(8): 286. https://doi.org/ 10.1007/s00203–023–03622–9
  52. Meadows V, Kennedy L, Ekser B, Kyritsi K, Kundu D, Zhou T, Chen L, Pham L, Wu N, Demieville J, Hargrove L, Glaser S, Alpini G, Francis H (2021) Mast Cells Regulate Ductular Reaction and Intestinal Inflammation in Cholestasis Through Farnesoid X Receptor Signaling. Hepatology 74(5): 2684–2698. https://doi.org/10.1002/hep.32028
  53. Theoharides TC (2020) The impact of psychological stress on mast cells. Ann Allergy Asthma Immunol 125(4): 388–392. https://doi.org/ 10.1016/j.anai.2020.07.007
  54. Woźniak E, Owczarczyk-Saczonek A, Placek W (2021) Psychological Stress, Mast Cells, and Psoriasis-Is There Any Relationship? Int J Mol Sci 22: 13252. https://doi.org/10.3390/ijms222413252
  55. Theoharides TC (2017) Neuroendocrinology of mast cells: Challenges and controversies. Exp Dermatol 26(9): 751–759. https://doi.org/ 10.1111/exd.13288
  56. Traina G, Cocchi M (2020) Mast cells, astrocytes, arachidonic acid: do they play a role in depression? Appl Sci 10: 3455. https://doi.org/10.3390/app10103455
  57. Jones MK, Nair A, Gupta M (2019) Mast cells in neurodegenerative disease. Front Cell Neurosci 13: 171. https://doi.org/ 0.3389/fncel.2019.00171
  58. Kempuraj D, Selvakumar GP, Ahmed ME, Raikwar SP, Thangavel R, Khan A, Zaheer SA, Iyer SS, Burton C, James D, Zaheer A (2020) COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation. Neuroscientist 26: 402–414. https://doi.org/ 10.1177/1073858420941476
  59. Afrin LB, Weinstock LB, Molderings GJ (2020) Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome. Int J Infect Dis 100: 327–332. https://doi.org/10.1016/j.ijid.2020.09.016
  60. Afrin LB, Self S, Menk J, Lazarchick J (2017) Characterization of mast cell activation syndrome. Am J Med Sci 353: 207–215. https://doi.org/ 10.1016/j.amjms.2016.12.013
  61. Altmüller J, Haenisch B, Kawalia A, Menzen M, Nöthen MM, Fier H, Molderings GJ (2017) Mutational profiling in the peripheral blood leukocytes of patients with systemic mast cell activation syndrome using next generation sequencing. Immunogenetics 69: 359–369. https://doi.org/ 10.1007/s00251–017–0981-y
  62. Afrin LB, Self S, Menk J, Lazarchick J (2017) Characterization of mast cell activation syndrome. Am J Med Sci 353: 207–215. https://doi.org/ 10.1016/j.amjms.2016.12.013
  63. Afrin LB, Weinstock LB, Molderings GJ (2020) Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome. Int J Infect Dis 100: 327–332. https://doi.org/10.1016/j.ijid.2020.09.016

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2. Fig. 1. The biological role of cholesterol.

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3. Fig. 2. Enterohepatic bile circulation and microbial processing of bile acids. The big green arrow is the passive absorption and active transport of bile from the intestine to the liver. Small solid green arrows reflect the direction of the flow of bile. The dotted arrows represent the effects of the microbiota. BA+Glyc+Taur – bile contains bile acids, glycine and taurine.

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4. Fig. 3. The path of development of liver diseases and other diseases in hypercholesterolemia. TG – triglycerides, LDL – low-density lipoproteins, CV – cardiovascular diseases.

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5. Fig. 4. Functions of the normal intestinal microflora. CNS is the central nervous system.

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6. Fig. 5. The functions of intestinal mast cells are normal.

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