Immunological Mechanisms of the Gut–brain–cardiovascular Axis in Coronary Heart Disease with Comorbid Anxiety and Depression
Abstract
Coronary heart disease (CHD) is frequently accompanied by anxiety and depression, conditions that markedly worsen cardiovascular outcomes. Increasing evidence indicates that immune dysregulation, driven by gut microbiota alterations, plays a central role in linking psychological disorders with cardiovascular pathology through the gut–brain–cardiovascular axis. This narrative review systematically summarizes recent advances in the immunological mechanisms underlying CHD complicated by anxiety and depression. We focus on gut microbiota–immune interactions, inflammatory signaling pathways, immune-related microbial metabolites, and neuroimmune communication that collectively shape cardiovascular and mental health. Relevant studies addressing immune biomarkers, cytokine profiles, intestinal barrier dysfunction, and immune-modulating therapeutic strategies were critically analyzed. Gut microbiota dysbiosis contributes to intestinal barrier impairment and translocation of microbial products, leading to activation of innate and adaptive immune responses. Elevated pro-inflammatory cytokines, including interleukin 6 and tumor necrosis factor α, serve as key mediators linking systemic inflammation with atherosclerosis and neuropsychiatric symptoms. Microbial metabolites, such as trimethylamine N-oxide, exacerbate immune-driven vascular inflammation, whereas short-chain fatty acids exert immunoregulatory and anti-inflammatory effects. Neuroimmune mechanisms, including hypothalamic–pituitary–adrenal (HPA) axis activation and immune modulation of autonomic function, further integrate psychological stress with cardiovascular immune injury. Immune dysregulation represents a unifying mechanism connecting gut microbiota imbalance, neuropsychiatric disorders, and coronary heart disease. Targeting immune–microbiota interactions within the gut–brain–cardiovascular axis may offer novel diagnostic biomarkers and immunomodulatory therapeutic strategies for CHD patients with comorbid anxiety and depression. This immunological perspective provides a translational framework for future research and integrated clinical management.
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2. Gambaro E, Gramaglia C, Baldon G, Chirico E, Martelli M, Renolfi A, et al. "Gut-brain axis": Review of the role of the probiotics in anxiety and depressive disorders. Brain Behav. 2020;10(10):e01803.
3. Vallianou NG, Kounatidis D, Panagopoulos F, Evangelopoulos A, Stamatopoulos V, Papagiorgos A, et al. Gut Microbiota and Its Role in the Brain-Gut-Kidney Axis in Hypertension. Curr Hypertens Rep. 2023;25(11):367-76.
4. Sherman MP, Zaghouani H, Niklas V. Gut microbiota, the immune system, and diet influence the neonatal gut-brain axis. Pediatr Res. 2015;77(1-2):127-35.
5. Liang J, Zhao Y, Xi Y, Xiang C, Yong C, Huo J, et al. Association between Depression, Anxiety Symptoms and Gut Microbiota in Chinese Elderly with Functional Constipation. Nutrients. 2022;14(23)
6. Yao Y, Qi X, Jia Y, Ye J, Chu X, Wen Y, et al. Evaluating the interactive effects of dietary habits and human gut microbiome on the risks of depression and anxiety. Psychol Med. 2023;53(7):3047-55.
7. Bear T, Dalziel J, Coad J, Roy N, Butts C, Gopal P. The Microbiome-Gut-Brain Axis and Resilience to Developing Anxiety or Depression under Stress. Microorganisms. 2021;9(4)
8. Wang Y, Lv M, Wang T, Sun J, Wang Y, Xia M, et al. Research on mechanism of charred hawthorn on digestive through modulating "brain-gut" axis and gut flora. J Ethnopharmacol. 2019;245:112166.
9. You X, Gao B. Association between Intestinal Flora Metabolites and Coronary Artery Vulnerable Plaque Characteristics in Coronary Heart Disease. Brit J Hosp Med. 2025;86(3):1-13.
10. Zhang H, Jing L, Zhai C, Xiang Q, Tian H, Hu H. Intestinal Flora Metabolite Trimethylamine Oxide Is Inextricably Linked to Coronary Heart Disease. J Cardiovasc Pharm. 2023;81(3):175-82.
11. Wen Y, Sun Z, Xie S, Hu Z, Lan Q, Sun Y, et al. Intestinal Flora Derived Metabolites Affect the Occurrence and Development of Cardiovascular Disease. J Multidiscip Health. 2022;15:2591-603.
12. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57-63.
13. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19(5):576-85.
14. Amrein M, Li XS, Walter J, Wang Z, Zimmermann T, Strebel I, et al. Gut microbiota-dependent metabolite trimethylamine N-oxide (TMAO) and cardiovascular risk in patients with suspected functionally relevant coronary artery disease (fCAD). Clin Res Cardiol. 2022;111(6):692-704.
15. Ottosson F, Brunkwall L, Smith E, Orho-Melander M, Nilsson PM, Fernandez C, et al. The gut microbiota-related metabolite phenylacetylglutamine associates with increased risk of incident coronary artery disease. J Hypertens. 2020;38(12):2427-34.
16. Xiang X, Jiang Q, Yang H, Zhou X, Chen Y, Chen H, et al. A review on shellfish polysaccharides: Extraction, characterization and amelioration of metabolic syndrome. Front Nutr. 2022;9:974860.
17. Yafarova AA, Dementeva EV, Zlobovskaya OA, Sheptulina AF, Lopatukhina EV, Timofeev YS, et al. Gut Microbiota and Metabolic Alterations Associated with Heart Failure and Coronary Artery Disease. Int J Mol Sci. 2024;25(20)
18. Sun L, Jia H, Li J, Yu M, Yang Y, Tian D, et al. Cecal Gut Microbiota and Metabolites Might Contribute to the Severity of Acute Myocardial Ischemia by Impacting the Intestinal Permeability, Oxidative Stress, and Energy Metabolism. Front Microbiol. 2019;10:1745.
19. Tang WH, Kitai T, Hazen SL. Gut Microbiota in Cardiovascular Health and Disease. Circ Res. 2017;120(7):1183-96.
20. Li W, Li H, Wang S, Han K, Liu Y, An Z, et al. Regional pattern and signatures of gut microbiota in rural residents with coronary heart disease: A metagenomic analysis. Front Cell Infect Mi. 2022;12:1007161.
21. Dicks L. Cardiovascular Disease May Be Triggered by Gut Microbiota, Microbial Metabolites, Gut Wall Reactions, and Inflammation. Int J Mol Sci. 2024;25(19)
22. Jin M, Qian Z, Yin J, Xu W, Zhou X. The role of intestinal microbiota in cardiovascular disease. J Cell Mol Med. 2019;23(4):2343-50.
23. Zou Y, Song X, Liu N, Sun W, Liu B. Intestinal Flora: A Potential New Regulator of Cardiovascular Disease. Aging Dis. 2022;13(3):753-72.
24. Serra D, Almeida LM, Dinis T. The Impact of Chronic Intestinal Inflammation on Brain Disorders: the Microbiota-Gut-Brain Axis. Mol Neurobiol. 2019;56(10):6941-51.
25. Bartolomaeus H, McParland V, Wilck N. [Gut-heart axis: How gut bacteria influence cardiovascular diseases]. Herz. 2020;45(2):134-41.
26. Fung TC. The microbiota-immune axis as a central mediator of gut-brain communication. Neurobiol Dis. 2020;136:104714.
27. Valenza G, Matic Z, Catrambone V. The brain-heart axis: integrative cooperation of neural, mechanical and biochemical pathways. Nat Rev Cardiol. 2025;22(8):537-50.
28. Khalil M, Lau HC, Thackeray JT, Mikail N, Gebhard C, Quyyumi AA, et al. Heart-brain axis: Pushing the boundaries of cardiovascular molecular imaging. J Nucl Cardiol. 2024;36:101870.
29. Perrotta S, Carnevale L, Perrotta M, Pallante F, Mikolajczyk TP, Fardella V, et al. A heart-brain-spleen axis controls cardiac remodeling to hypertensive stress. Immunity. 2025;58(3):648-65.
30. Soda T, Pasqua T, De Sarro G, Moccia F. Cognitive Impairment and Synaptic Dysfunction in Cardiovascular Disorders: The New Frontiers of the Heart-Brain Axis. Biomedicines. 2024;12(10)
31. Seligowski AV, Webber TK, Marvar PJ, Ressler KJ, Philip NS. Involvement of the brain-heart axis in the link between PTSD and cardiovascular disease. Depress Anxiety. 2022;39(10-11):663-74.
32. Huang F, Duan J, Liu W, Yang C, Yang L. BDNF mediates the heart-brain axis: implications for cardiovascular diseases and mental disorders. Eur Arch Psy Clin N. 2025;
33. Wang D, Dai F, Liu W, Ge L, Qi X, Ma G. Longitudinal change and prognostic value of anxiety and depression in coronary heart disease patients. Irish J Med Sci. 2021;190(1):107-16.
34. Bai B, Yin H, Guo L, Ma H, Wang H, Liu F, et al. Comorbidity of depression and anxiety leads to a poor prognosis following angina pectoris patients: a prospective study. Bmc Psychiatry. 2021;21(1):202.
35. Sara J, Ahmad A, Toya T, Suarez PL, Lerman LO, Lerman A. Anxiety Disorders Are Associated With Coronary Endothelial Dysfunction in Women With Chest Pain and Nonobstructive Coronary Artery Disease. J Am Heart Assoc. 2021;10(17):e021722.
36. Watkins LL, Koch GG, Sherwood A, Blumenthal JA, Davidson JR, O'Connor C, et al. Association of anxiety and depression with all-cause mortality in individuals with coronary heart disease. J Am Heart Assoc. 2013;2(2):e000068.
37. Nemeroff CB, Goldschmidt-Clermont PJ. Heartache and heartbreak--the link between depression and cardiovascular disease. Nat Rev Cardiol. 2012;9(9):526-39.
38. Sonoda K, Khoo CP. Psychological Interventions for Depression and Anxiety in Patients With Coronary Heart Disease or Heart Failure. Am Fam Physician. 2024;110(6):575-6.
39. Simpson CA, Diaz-Arteche C, Eliby D, Schwartz OS, Simmons JG, Cowan C. The gut microbiota in anxiety and depression - A systematic review. Clin Psychol Rev. 2021;83:101943.
40. Cao Y, Cheng Y, Pan W, Diao J, Sun L, Meng M. Gut microbiota variations in depression and anxiety: a systematic review. Bmc Psychiatry. 2025;25(1):443.
41. Peirce JM, Alvina K. The role of inflammation and the gut microbiome in depression and anxiety. J Neurosci Res. 2019;97(10):1223-41.
42. Zhu Y, Luo J, Yang Z, Miao Y. High-throughput sequencing analysis of differences in intestinal microflora between ulcerative colitis patients with different glucocorticoid response types. Genes Genom. 2020;42(10):1197-206.
43. Yu HJ, Jing C, Xiao N, Zang XM, Zhang CY, Zhang X, et al. Structural difference analysis of adult's intestinal flora basing on the 16S rDNA gene sequencing technology. Eur Rev Med Pharmaco. 2020;24(24):12983-92.
44. Simats A, Sager HB, Liesz A. Heart-brain axis in health and disease: role of innate and adaptive immunity. Cardiovasc Res. 2025;120(18):2325-35.
45. Hu JR, Abdullah A, Nanna MG, Soufer R. The Brain-Heart Axis: Neuroinflammatory Interactions in Cardiovascular Disease. Curr Cardiol Rep. 2023;25(12):1745-58.
46. Lauinger AR, Sepe JJ. Vascularization, Innervation, and Inflammation: Pathways Connecting the Heart-Brain Axis and Implications in a Clinical Setting. Biomedicines. 2025;13(1)
47. Huang X, Zhang J, Liang J, Duan Y, Xie W, Zheng F. Association of Cardiovascular Health With Risk of Incident Depression and Anxiety. Am J Geriat Psychiat. 2024;32(5):539-49.
48. van Sloten TT, Valentin E, Climie RE, Jouven X, Lemogne C, Goldberg M, et al. Association of Cardiovascular Health With Risk of Clinically Relevant Depressive Symptoms. Jama Psychiat. 2023;80(4):342-9.
49. Dhana A, DeCarli CS, Dhana K, Desai P, Ng T, Evans DA, et al. Cardiovascular Health and Biomarkers of Neurodegenerative Disease in Older Adults. Jama Netw Open. 2025;8(3):e250527.
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| Issue | Articles in Press | |
| Section | Review Article(s) | |
| Keywords | ||
| Anxiety Atherosclerosis Brain-gut axis Comorbidity Coronary disease Cytokines Depressive disorder Gastrointestinal microbiome Inflammation Neuroimmunomodulation | ||
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How to Cite
1.
Xu Y, Chen X. Immunological Mechanisms of the Gut–brain–cardiovascular Axis in Coronary Heart Disease with Comorbid Anxiety and Depression. Iran J Allergy Asthma Immunol. 2026;:1-12.
