The Interplay of Cross-Organ Immune Regulation in Inflammation and Cancer

Abstract

Organs dynamically interact with each other through immunomodulation to create a systemic immune response and influence disease progression. While traditional studies have tended to focus on single-organ immunity, recent studies have placed greater emphasis on reciprocal immune interactions between organs, such as those between the gut, liver, and brain. However, the precise mechanisms underlying these interorgan immune interactions remain unclear. Here, we synthesize the molecular and cellular bases of cross-organ immune regulation in the context of inflammation and neoplasia. Specifically, we describe the immune coordination between the gut, liver, and brain and how they immunomodulate other organs (including the thyroid, lung, cardiovascular system, kidney, bone, and skin). In addition, we explore clinical therapies that target these cross-organ immune modulations, the limitations of the treatments, and the potential benefits for patients. We also conclude by highlighting innovative technologies such as multiomics analysis, machine learning, and organ-on-a-chip platforms, which are providing unprecedented insights into interorgan immunity. Elucidating these mechanisms will advance precision medicine and enable the development of targeted therapies for diseases caused by cross-organ immunity.

Keywords

cancer / cross-organ immune regulation / gut–liver–brain axis / immune crosstalk / inflammation / systemic immunity

References

[1] R. J. Landovitz, H. Scott, and S. G. Deeks, “Prevention, Treatment and Cure of HIV Infection,” Nature Reviews Microbiology 21 (2023): 657-670.

[2] M. Gluud, E. M. H. Pallesen, T. B. Buus, et al., “Malignant T Cells Induce Skin Barrier Defects Through Cytokine-Mediated JAK/STAT Signaling in Cutaneous T-Cell Lymphoma,” Blood 141 (2023): 180-193.

[3] M. Aliyu, F. T. Zohora, A. U. Anka, et al., “Interleukin-6 Cytokine: An Overview of the Immune Regulation, Immune Dysregulation, and Therapeutic Approach,” International Immunopharmacology 111 (2022): 109130.

[4] L. Maiorino, J. Daßler-Plenker, L. Sun, and M. Egeblad, “Innate Immunity and Cancer Pathophysiology,” Annual Review of Pathology 17 (2022): 425-457.

[5] C. Michaudel and H. Sokol, “The Gut Microbiota at the Service of Immunometabolism,” Cell Metabolism 32 (2020): 514-523.

[6] J. K. Nicholson, E. Holmes, J. Kinross, et al., “Host-Gut Microbiota Metabolic Interactions,” Science 336 (2012): 1262-1267.

[7] Q. Wang, Q. Lu, S. Jia, and M. Zhao, “Gut Immune Microenvironment and Autoimmunity,” International Immunopharmacology 124 (2023): 110842.

[8] A. M. Mowat and W. W. Agace, “Regional Specialization Within the Intestinal Immune System,” Nature Reviews Immunology 14 (2014): 667-685.

[9] S. Schulte, D. Decker, B. Nowduri, et al., “Improving Morphological and Functional Properties of Enteric Neuronal Networks in Vitro Using a Novel Upside-Down Culture Approach,” American Journal of Physiology Gastrointestinal and Liver Physiology 326 (2024): G567-G582.

[10] A. Zhou, L. Tang, S. Zeng, Y. Lei, S. Yang, and B. Tang, “Gut Microbiota: A New Piece in Understanding Hepatocarcinogenesis,” Cancer Letters 474 (2020): 15-22.

[11] A. Albillos, A. de Gottardi, and M. Rescigno, “The Gut-Liver Axis in Liver Disease: Pathophysiological Basis for Therapy,” Journal of Hepatology 72 (2020): 558-577.

[12] M. Kim, C. Galan, A. A. Hill, et al., “Critical Role for the Microbiota in CX(3)CR1(+) Intestinal Mononuclear Phagocyte Regulation of Intestinal T Cell Responses,” Immunity 49 (2018): 151-163.e155.

[13] P. Barooah, S. Saikia, M. J. Kalita, et al., “IL-10 Polymorphisms and Haplotypes Predict Susceptibility to Hepatocellular Carcinoma Occurrence in Patients With Hepatitis C Virus Infection From Northeast India,” Viral Immunology 33 (2020): 457-467.

[14] P. Luo, F. Wang, N. Wong, et al., “Divergent Roles of Kupffer Cell TLR2/3 Signaling in Alcoholic Liver Disease and the Protective Role of EGCG,” Cellular and Molecular Gastroenterology and Hepatology 9 (2020): 145-160.

[15] Y. Hsueh, H. Chen, B. Syu, et al., “Endogenous IL-10 Maintains Immune Tolerance but IL-10 Gene Transfer Exacerbates Autoimmune Cholangitis,” Journal of Autoimmunity 95 (2018): 159-170.

[16] A. Yang, T. Inamine, K. Hochrath, et al., “Intestinal Fungi Contribute to Development of Alcoholic Liver Disease,” Journal of Clinical Investigation 127 (2017): 2829-2841.

[17] X. Zhang, X. Ji, Q. Wang, and J. Z. Li, “New Insight Into Inter-Organ Crosstalk Contributing to the Pathogenesis of Non-Alcoholic Fatty Liver Disease (NAFLD),” Protein Cell 9 (2018): 164-177.

[18] P. J. Trivedi, G. M. Hirschfield, D. H. Adams, and J. M. Vierling, “Immunopathogenesis of Primary Biliary Cholangitis, Primary Sclerosing Cholangitis and Autoimmune Hepatitis: Themes and Concepts,” Gastroenterology 166 (2024): 995-1019.

[19] R. Roy and S. K. Singh, “The Microbiome Modulates the Immune System to Influence Cancer Therapy,” Cancers (Basel) 16, no. 4 (2024): 779.

[20] P. Muscolino, B. Granata, F. Omero, et al., “Potential Predictive Role of Gut Microbiota to Immunotherapy in HCC Patients: A Brief Review,” Frontiers in Oncology 13 (2023): 1247614.

[21] H. Gupta, G. S. Youn, M. J. Shin, and K. T. Suk, “Role of Gut Microbiota in Hepatocarcinogenesis,” Microorganisms 7, no. 5 (2019): 121.

[22] Q. Li, L. Ma, S. Shen, et al., “Intestinal Dysbacteriosis-Induced IL-25 Promotes Development of HCC via Alternative Activation of Macrophages in Tumor Microenvironment,” Journal of Experimental & Clinical Cancer Research 38 (2019): 303.

[23] S. Leclercq, S. Matamoros, P. D. Cani, et al., “Intestinal Permeability, Gut-Bacterial Dysbiosis, and Behavioral Markers of Alcohol-Dependence Severity,” PNAS 111 (2014): E4485-4493.

[24] P. Portincasa, L. Bonfrate, M. Khalil, et al., “Intestinal Barrier and Permeability in Health, Obesity and NAFLD,” Biomedicines 10, no. 1 (2021): 83.

[25] P. D. Cani, A. Everard, and T. Duparc, “Gut Microbiota, Enteroendocrine Functions and Metabolism,” Current Opinion in Pharmacology 13 (2013): 935-940.

[26] J. F. Cryan, K. J. O'Riordan, C. S. M. Cowan, et al., “The Microbiota-Gut-Brain Axis,” Physiological Reviews 99 (2019): 1877-2013.

[27] Y. Zhang, N. Tang, H. Zhou, and Y. Zhu, “The Role of Microbial Metabolites in Endocrine Tumorigenesis: From the Mechanistic Insights to Potential Therapeutic Biomarkers,” Biomedicine & Pharmacotherapy 172 (2024): 116218.

[28] D. Erny, A. L. Hrabě de Angelis, D. Jaitin, et al., “Host Microbiota Constantly Control Maturation and Function of Microglia in the CNS,” Nature Neuroscience 18 (2015): 965-977.

[29] A. Parker, S. Fonseca, and S. R. Carding, “Gut Microbes and Metabolites as Modulators of Blood-Brain Barrier Integrity and Brain Health,” Gut Microbes 11 (2020): 135-157.

[30] K. V. Sandhu, E. Sherwin, H. Schellekens, C. Stanton, T. G. Dinan, and J. F. Cryan, “Feeding the Microbiota-Gut-Brain Axis: Diet, Microbiome, and Neuropsychiatry,” Translational Research 179 (2017): 223-244.

[31] L. Desbonnet, L. Garrett, G. Clarke, J. Bienenstock, and T. G. Dinan, “The Probiotic Bifidobacteria Infantis: An Assessment of Potential Antidepressant Properties in the Rat,” Journal of Psychiatric Research 43 (2008): 164-174.

[32] X. Xie, L. Wang, S. Dong, S. Ge, and T. Zhu, “Immune Regulation of the Gut-Brain Axis and Lung-Brain Axis Involved in Ischemic Stroke,” Neural Regeneration Research 19 (2024): 519-528.

[33] S. El Aidy, T. G. Dinan, and J. F. Cryan, “Immune Modulation of the Brain-Gut-Microbe Axis,” Frontiers in Microbiology 5 (2014): 146.

[34] J. A. Bravo, P. Forsythe, M. V. Chew, et al., “Ingestion of Lactobacillus Strain Regulates Emotional Behavior and Central GABA Receptor Expression in a Mouse via the Vagus Nerve,” PNAS 108 (2011): 16050-16055.

[35] S. F. Maier, L. E. Goehler, M. Fleshner, and L. R. Watkins, “The Role of the Vagus Nerve in Cytokine-to-Brain Communication,” Annals of the New York Academy of Sciences 840 (1998): 289-300.

[36] V. A. Pavlov and K. J. Tracey, “Neural Circuitry and Immunity,” Immunologic Research 63 (2015): 38-57.

[37] R. M. Al-Sadi and T. Y. Ma, “IL-1beta Causes an Increase in Intestinal Epithelial Tight Junction Permeability,” Journal of Immunology 178 (2007): 4641-4649.

[38] C. T. Capaldo and A. Nusrat, “Cytokine Regulation of Tight Junctions,” Biochimica Et Biophysica Acta 1788 (2009): 864-871.

[39] G. Clarke, E. M. Quigley, J. F. Cryan, and T. G. Dinan, “Irritable Bowel Syndrome: Towards Biomarker Identification,” Trends in Molecular Medicine 15 (2009): 478-489.

[40] L. A. Graff, J. R. Walker, and C. N. Bernstein, “Depression and Anxiety in Inflammatory Bowel Disease: A Review of Comorbidity and Management,” Inflammatory Bowel Diseases 15 (2009): 1105-1118.

[41] M. Ek, M. Kurosawa, T. Lundeberg, and A. Ericsson, “Activation of Vagal Afferents After Intravenous Injection of Interleukin-1beta: Role of Endogenous Prostaglandins,” Journal of Neuroscience 18 (1998): 9471-9479.

[42] L. E. Goehler, C. R. Busch, N. Tartaglia, et al., “Blockade of Cytokine Induced Conditioned Taste Aversion by Subdiaphragmatic Vagotomy: Further Evidence for Vagal Mediation of Immune-Brain Communication,” Neuroscience Letters 185 (1995): 163-166.

[43] H. Zhu, C. Cao, Z. Wu, et al., “The Probiotic L. Casei Zhang Slows the Progression of Acute and Chronic Kidney Disease,” Cell Metabolism 33 (2021): 1926-1942.e1928.

[44] Y. Sui, R. Jiang, M. Niimi, et al., “Gut Bacteria Exacerbates TNBS-Induced Colitis and Kidney Injury Through Oxidative Stress,” Redox Biology 72 (2024): 103140.

[45] B. A. Peters, Q. Qi, M. Usyk, et al., “Association of the Gut Microbiome With Kidney Function and Damage in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL),” Gut Microbes 15 (2023): 2186685.

[46] H. Wang, A. Ainiwaer, Y. Song, et al., “Perturbed Gut Microbiome and Fecal and Serum Metabolomes Are Associated With Chronic Kidney Disease Severity,” Microbiome 11 (2023): 3.

[47] M. R. Denburg, K. Koepsell, J. Lee, J. Gerber, K. Bittinger, and G. E. Tasian, “Perturbations of the Gut Microbiome and Metabolome in Children With Calcium Oxalate Kidney Stone Disease,” Journal of the American Society of Nephrology 31 (2020): 1358-1369.

[48] S. Gupta and S. Singh Kanwar, “The Influence of Dysbiosis on Kidney Stones That Risk up Renal Cell Carcinoma (RCC),” Seminars in Cancer Biology 70 (2021): 134-138.

[49] J. C. Swarte, T. J. Knobbe, J. R. Björk, et al., “Health-Related Quality of Life Is Linked to the Gut Microbiome in Kidney Transplant Recipients,” Nature Communications 14 (2023): 7968.

[50] X. Zhu, X. Fu, X. Meng, et al., “Gut Microbiome and Metabolites Mediate the Benefits of Caloric Restriction in Mice After Acute Kidney Injury,” Redox Biology 77 (2024): 103373.

[51] L. Pan, H. Yu, J. Fu, et al., “Berberine Ameliorates Chronic Kidney Disease Through Inhibiting the Production of Gut-Derived Uremic Toxins in the Gut Microbiota,” Acta Pharmaceutica Sinica B 13 (2023): 1537-1553.

[52] Y. W. Zhang, Y. Wu, X. F. Liu, X. Chen, and J. C. Su, “Targeting the Gut Microbiota-Related Metabolites for Osteoporosis: The Inextricable Connection of Gut-Bone Axis,” Ageing Research Reviews 94 (2024): 102196.

[53] Z. Lyu, Y. Hu, Y. Guo, and D. Liu, “Modulation of Bone Remodeling by the Gut Microbiota: A New Therapy for Osteoporosis,” Bone Research 11 (2023): 31.

[54] X. Q. Zheng, D. B. Wang, Y. R. Jiang, and C. L. Song, “Gut Microbiota and Microbial Metabolites for Osteoporosis,” Gut Microbes 17 (2025): 2437247.

[55] D. Wang, J. Cai, Q. Pei, et al., “Gut Microbial Alterations in Arginine Metabolism Determine Bone Mechanical Adaptation,” Cell Metabolism 36 (2024): 1252-1268.e1258.

[56] L. Zhu, X. Jian, B. Zhou, et al., “Gut Microbiota Facilitate Chronic Spontaneous Urticaria,” Nature Communications 15 (2024): 112.

[57] Z. Fang, T. Pan, L. Li, et al., “Bifidobacterium Longum Mediated Tryptophan Metabolism to Improve Atopic Dermatitis via the Gut-Skin Axis,” Gut Microbes 14 (2022): 2044723.

[58] J. Lou, S. Cui, J. Li, G. Jin, Y. Fan, and N. Huang, “Causal Relationship Between the Gut Microbiome and Basal Cell Carcinoma, Melanoma Skin Cancer, Ease of Skin Tanning: Evidence From Three Two-Sample Mendelian Randomisation Studies,” Frontiers in Immunology 15 (2024): 1279680.

[59] D. Davar, A. K. Dzutsev, J. A. McCulloch, et al., “Fecal Microbiota Transplant Overcomes Resistance to Anti-PD-1 Therapy in Melanoma Patients,” Science 371 (2021): 595-602.

[60] J. Zhao, Q. Zhang, W. Cheng, et al., “Heart-Gut Microbiota Communication Determines the Severity of Cardiac Injury After Myocardial Ischaemia/Reperfusion,” Cardiovascular Research 119 (2023): 1390-1402.

[61] K. A. Romano, I. Nemet, P. Prasad Saha, et al., “Gut Microbiota-Generated Phenylacetylglutamine and Heart Failure,” Circulation: Heart Failure 16 (2023): e009972.

[62] J. Zhen, Z. Zhou, M. He, et al., “The Gut Microbial Metabolite Trimethylamine N-Oxide and Cardiovascular Diseases,” Frontiers in Endocrinology (Lausanne) 14 (2023): 1085041.

[63] A. Luqman, A. Hassan, M. Ullah, et al., “Role of the Intestinal Microbiome and Its Therapeutic Intervention in Cardiovascular Disorder,” Frontiers in Immunology 15 (2024): 1321395.

[64] R. Wang, R. Tang, B. Li, X. Ma, B. Schnabl, and H. Tilg, “Gut Microbiome, Liver Immunology, and Liver Diseases,” Cellular & Molecular Immunology 18 (2021): 4-17.

[65] S. March, N. Nerurkar, A. Jain, et al., “Autonomous Circadian Rhythms in the Human Hepatocyte Regulate Hepatic Drug Metabolism and Inflammatory Responses,” Science Advances 10 (2024): eadm9281.

[66] D. G. Doherty, “Immunity, Tolerance and Autoimmunity in the Liver: A Comprehensive Review,” Journal of Autoimmunity 66 (2016): 60-75.

[67] A. Guillot and F. Tacke, “Liver Macrophages: Old Dogmas and New Insights,” Hepatology Communications 3 (2019): 730-743.

[68] K. Berding, K. Vlckova, W. Marx, et al., “Diet and the Microbiota-Gut-Brain Axis: Sowing the Seeds of Good Mental Health,” Advances in Nutrition 12 (2021): 1239-1285.

[69] A. Chakrabarti, L. Geurts, L. Hoyles, et al., “The Microbiota-Gut-Brain Axis: Pathways to Better Brain Health. Perspectives on What We Know, What We Need to Investigate and How to Put Knowledge Into Practice,” Cellular and Molecular Life Sciences 79 (2022): 80.

[70] A. Farzi, E. E. Fröhlich, and P. Holzer, “Gut Microbiota and the Neuroendocrine System,” Neurotherapeutics 15 (2018): 5-22.

[71] M. Yan, S. Man, B. Sun, et al., “Gut Liver Brain Axis in Diseases: The Implications for Therapeutic Interventions,” Signal Transduction and Targeted Therapy 8 (2023): 443.

[72] A. Chen, Z. Fang, X. Chen, et al., “Microglia-Derived TNF-alpha Mediates Endothelial Necroptosis Aggravating Blood Brain-Barrier Disruption After Ischemic Stroke,” Cell Death & Disease 10 (2019): 487.

[73] B. N. Gantner, K. M. LaFond, and M. G. Bonini, “Nitric Oxide in Cellular Adaptation and Disease,” Redox Biology 34 (2020): 101550.

[74] J. Wang, Q. Sun, J. Zhang, H. Wang, and H. Liu, “Classical Signaling and Trans-Signaling Pathways Stimulated by Megalobrama Amblycephala IL-6 and IL-6R,” International Journal of Molecular Sciences 23, no. 4 (2022): 2019.

[75] S. Rose-John, “Local and Systemic Effects of Interleukin-6 (IL-6) in Inflammation and Cancer,” FEBS Letters 596 (2022): 557-566.

[76] M. D. Sweeney, Z. Zhao, A. Montagne, A. R. Nelson, and B. V. Zlokovic, “Blood-Brain Barrier: From Physiology to Disease and Back,” Physiological Reviews 99 (2019): 21-78.

[77] G. C. Terstappen, A. H. Meyer, R. D. Bell, and W. Zhang, “Strategies for Delivering Therapeutics Across the Blood-Brain Barrier,” Nat Rev Drug Discovery 20 (2021): 362-383.

[78] S. Y. Cheon and J. Song, “The Association Between Hepatic Encephalopathy and Diabetic Encephalopathy: The Brain-Liver Axis,” International Journal of Molecular Sciences 22, no. 1 (2021): 463.

[79] P. Izquierdo-Altarejos, A. Cabrera-Pastor, H. Gonzalez-King, C. Montoliu, and V. Felipo, “Extracellular Vesicles From Hyperammonemic Rats Induce Neuroinflammation and Motor Incoordination in Control Rats,” Cells 9, no. 3 (2020): 572.

[80] J. Albrecht and M. D. Norenberg, “Glutamine: A Trojan Horse in Ammonia Neurotoxicity,” Hepatology 44 (2006): 788-794.

[81] P. Ott and F. S. Larsen, “Blood-Brain Barrier Permeability to Ammonia in Liver Failure: A Critical Reappraisal,” Neurochemistry International 44 (2004): 185-198.

[82] B. Görg, H. J. Bidmon, V. Keitel, et al., “Inflammatory Cytokines Induce Protein Tyrosine Nitration in Rat Astrocytes,” Archives of Biochemistry and Biophysics 449 (2006): 104-114.

[83] B. Görg, A. Morwinsky, V. Keitel, N. Qvartskhava, K. Schrör, and D. Häussinger, “Ammonia Triggers Exocytotic Release of L-Glutamate From Cultured Rat Astrocytes,” Glia 58 (2010): 691-705.

[84] R. Reinehr, B. Görg, S. Becker, et al., “Hypoosmotic Swelling and Ammonia Increase Oxidative Stress by NADPH Oxidase in Cultured Astrocytes and Vital Brain Slices,” Glia 55 (2007): 758-771.

[85] D. Haussinger and F. Schliess, “Pathogenetic Mechanisms of Hepatic Encephalopathy,” Gut 57 (2008): 1156-1165.

[86] A. R. Jayakumar, K. S. Panickar, C. R. K. Murthy, and M. D. Norenberg, “Oxidative Stress and Mitogen-Activated Protein Kinase Phosphorylation Mediate Ammonia-Induced Cell Swelling and Glutamate Uptake Inhibition in Cultured Astrocytes,” Journal of Neuroscience 26 (2006): 4774-4784.

[87] M. J. Hurley, R. Bates, J. Macnaughtan, and A. H. V. Schapira, “Bile Acids and Neurological Disease,” Pharmacology & Therapeutics 240 (2022): 108311.

[88] W. J. Ray and V. Buggia-Prevot, “Novel Targets for Alzheimer's Disease: A View Beyond Amyloid,” Annual Review of Medicine 72 (2021): 15-28.

[89] Y. Cheng, C. He, D. Tian, et al., “Physiological Beta-Amyloid Clearance by the Liver and Its Therapeutic Potential for Alzheimer's Disease,” Acta Neuropathologica 145 (2023): 717-731.

[90] C. Luongo, M. Dentice, and D. Salvatore, “Deiodinases and Their Intricate Role in Thyroid Hormone Homeostasis,” Nature reviews Endocrinology 15 (2019): 479-488.

[91] Y. Shen, X. Wang, J. Xie, et al., “Thyroid Disturbance in Patients With Chronic Hepatitis C Infection: A Systematic Review and Meta-Analysis,” Journal of Gastrointestinal and Liver Diseases 25 (2016): 227-234.

[92] J. T. Blackard, L. Kong, A. K. Huber, and Y. Tomer, “Hepatitis C Virus Infection of a Thyroid Cell Line: Implications for Pathogenesis of Hepatitis C Virus and Thyroiditis,” Thyroid: Official Journal of the American Thyroid Association 23 (2013): 863-870.

[93] N. Akeno, J. T. Blackard, and Y. Tomer, “HCV E2 Protein Binds Directly to Thyroid Cells and Induces IL-8 Production: A New Mechanism for HCV Induced Thyroid Autoimmunity,” Journal of Autoimmunity 31 (2008): 339-344.

[94] A. L. Zignego, C. Giannini, and L. Gragnani, “HCV and Lymphoproliferation,” Clinical & Developmental Immunology 2012 (2012): 980942.

[95] E. Piantanida, S. Ippolito, D. Gallo, et al., “The Interplay Between Thyroid and Liver: Implications for Clinical Practice,” Journal of Endocrinological Investigation 43 (2020): 885-899.

[96] Y. Wang, W. Liu, X. Liu, et al., “Role of Liver in Modulating the Release of Inflammatory Cytokines Involved in Lung and Multiple Organ Dysfunction in Severe Acute Pancreatitis,” Cell Biochemistry and Biophysics 71 (2015): 765-776.

[97] C. Y. Wang, C. S. Calfee, D. W. Paul, et al., “One-Year Mortality and Predictors of Death Among Hospital Survivors of Acute Respiratory Distress Syndrome,” Intensive Care Medicine 40 (2014): 388-396.

[98] P. Yang, P. Formanek, S. Scaglione, and M. Afshar, “Risk Factors and Outcomes of Acute Respiratory Distress Syndrome in Critically Ill Patients With Cirrhosis,” Hepatology Research 49 (2019): 335-343.

[99] G. Bellani, J. G. Laffey, T. Pham, et al., “Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries,” Jama 315 (2016): 788-800.

[100] M. A. Matthay and R. L. Zemans, “The Acute Respiratory Distress Syndrome: Pathogenesis and Treatment,” Annual Review of Pathology 6 (2011): 147-163.

[101] A. Gacouin, M. Locufier, F. Uhel, et al., “Liver Cirrhosis Is Independently Associated With 90-Day Mortality in ARDS Patients,” Shock (Augusta, Ga.) 45 (2016): 16-21.

[102] M. B. Fallon and J. Zhang, “The Lung in Liver Disease: Old Problem, New Concepts,” Transactions of the American Clinical and Climatological Association 124 (2013): 250-262.

[103] R. Herrero, G. Sánchez, I. Asensio, et al., “Liver-Lung Interactions in Acute Respiratory Distress Syndrome,” Intensive Care Medicine Experimental 8 (2020): 48.

[104] M. Bilzer, F. Roggel, and A. L. Gerbes, “Role of Kupffer Cells in Host Defense and Liver Disease,” Liver International 26 (2006): 1175-1186.

[105] D. Torre, C. Zeroli, M. Giola, et al., “Serum Levels of Interleukin-1 Alpha, Interleukin-1 Beta, Interleukin-6, and Tumor Necrosis Factor in Patients With Acute Viral Hepatitis,” Clinical Infectious Diseases 18 (1994): 194-198.

[106] C. Gabay and I. Kushner, “Acute-Phase Proteins and Other Systemic Responses to Inflammation,” New England Journal of Medicine 340 (1999): 448-454.

[107] G. A. Roth, G. A. Mensah, C. O. Johnson, et al., “Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study,” Journal of the American College of Cardiology 76 (2020): 2982-3021.

[108] W. de Haan, W. Dheedene, K. Apelt, et al., “Endothelial Zeb2 Preserves the Hepatic Angioarchitecture and Protects Against Liver Fibrosis,” Cardiovascular Research 118 (2022): 1262-1275.

[109] G. Targher, C. D. Byrne, and H. Tilg, “NAFLD and Increased Risk of Cardiovascular Disease: Clinical Associations, Pathophysiological Mechanisms and Pharmacological Implications,” Gut 69 (2020): 1691-1705.

[110] X. Liu, Y. Shao, L. Han, R. Zhang, and J. Chen, “Emerging Evidence Linking the Liver to the Cardiovascular System: Liver-Derived Secretory Factors,” Journal of Clinical and Translational Hepatology 11 (2023): 1246-1255.

[111] F. Jiang, Q. Chen, W. Wang, Y. Ling, Y. Yan, and P. Xia, “Hepatocyte-Derived Extracellular Vesicles Promote Endothelial Inflammation and Atherogenesis via microRNA-1,” Journal of Hepatology 72 (2020): 156-166.

[112] F. Royo, L. Moreno, J. Mleczko, et al., “Hepatocyte-Secreted Extracellular Vesicles Modify Blood Metabolome and Endothelial Function by an Arginase-Dependent Mechanism,” Scientific Reports 7 (2017): 42798.

[113] Y. Wang, P. Jin, J. Liu, and X. Xie, “Exosomal microRNA-122 Mediates Obesity-Related Cardiomyopathy Through Suppressing Mitochondrial ADP-Ribosylation Factor-Like 2,” Clinical Science (London, England: 1979) 133 (2019): 1871-1881.

[114] Z. Wang, E. Klipfell, B. J. Bennett, et al., “Gut Flora Metabolism of Phosphatidylcholine Promotes Cardiovascular Disease,” Nature 472 (2011): 57-63.

[115] R. A. Koeth, Z. Wang, B. S. Levison, et al., “Intestinal Microbiota Metabolism of L-Carnitine, a Nutrient in Red Meat, Promotes Atherosclerosis,” Nature Medicine 19 (2013): 576-585.

[116] W. Zhu, J. C. Gregory, E. Org, et al., “Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk,” Cell 165 (2016): 111-124.

[117] X. S. Li, S. Obeid, R. Klingenberg, et al., “Gut Microbiota-Dependent Trimethylamine N-Oxide in Acute Coronary Syndromes: A Prognostic Marker for Incident Cardiovascular Events Beyond Traditional Risk Factors,” European Heart Journal 38, no. 11 (2017): 814-824.

[118] W. W. Tang, Z. Wang, B. S. Levison, et al., “Intestinal Microbial Metabolism of Phosphatidylcholine and Cardiovascular Risk,” New England Journal of Medicine 368 (2013): 1575-1584.

[119] W. W. Tang, Z. Wang, Y. Fan, et al., “Prognostic Value of Elevated Levels of Intestinal Microbe-Generated Metabolite Trimethylamine-N-Oxide in Patients With Heart Failure: Refining the Gut Hypothesis,” Journal of the American College of Cardiology 64 (2014): 1908-1914.

[120] K. Zhu, Y. Wang, P. Shu, et al., “Increased Serum Levels of Fetuin B in Patients With Coronary Artery Disease,” Endocrine 58 (2017): 97-105.

[121] A. Lother, O. Bondareva, A. R. Saadatmand, et al., “Diabetes Changes Gene Expression but Not DNA Methylation in Cardiac Cells,” Journal of Molecular and Cellular Cardiology 151 (2021): 74-87.

[122] R. K. Mailer, C. Rangaswamy, S. Konrath, J. Emsley, and T. Renné, “An Update on Factor XII-Driven Vascular Inflammation,” Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1869 (2022): 119166.

[123] R. Dantzer, “Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa,” Physiological Reviews 98 (2018): 477-504.

[124] X. Zhang, B. Lei, Y. Yuan, et al., “Brain Control of Humoral Immune Responses Amenable to Behavioural Modulation,” Nature 581 (2020): 204-208.

[125] M. Rosas-Ballina, M. Ochani, W. R. Parrish, et al., “Splenic Nerve Is Required for Cholinergic Antiinflammatory Pathway Control of TNF in Endotoxemia,” PNAS 105 (2008): 11008-11013.

[126] J. Zhang, L. Chang, Y. Pu, and K. Hashimoto, “Abnormal Expression of Colony Stimulating Factor 1 Receptor (CSF1R) and Transcription Factor PU.1 (SPI1) in the Spleen From Patients With Major Psychiatric Disorders: A Role of Brain-Spleen Axis,” Journal of Affective Disorders 272 (2020): 110-115.

[127] C. Xu, S. K. Lee, D. Zhang, and P. S. Frenette, “The Gut Microbiome Regulates Psychological-Stress-Induced Inflammation,” Immunity 53 (2020): 417-428.e414.

[128] M. T. Bailey, S. E. Dowd, J. D. Galley, A. R. Hufnagle, R. G. Allen, and M. Lyte, “Exposure to a Social Stressor Alters the Structure of the Intestinal Microbiota: Implications for Stressor-Induced Immunomodulation,” Brain, Behavior, and Immunity 25 (2011): 397-407.

[129] I. Tsilioni, N. Dodman, A. I. Petra, et al., “Elevated Serum Neurotensin and CRH Levels in Children With Autistic Spectrum Disorders and Tail-Chasing Bull Terriers With a Phenotype Similar to Autism,” Translational Psychiatry 4 (2014): e466.

[130] Y. Taché, V. Martinez, M. Million, and L. Wang, “Stress and the Gastrointestinal Tract III. Stress-Related Alterations of Gut Motor Function: Role of Brain Corticotropin-Releasing Factor Receptors,” American Journal of Physiology Gastrointestinal and Liver Physiology 280 (2001): G173-177.

[131] G. Matteoli, P. J. Gomez-Pinilla, A. Nemethova, et al., “A Distinct Vagal Anti-Inflammatory Pathway Modulates Intestinal Muscularis Resident Macrophages Independent of the Spleen,” Gut 63 (2014): 938-948.

[132] G. Agirman, K. B. Yu, and E. Y. Hsiao, “Signaling Inflammation Across the Gut-Brain Axis,” Science 374 (2021): 1087-1092.

[133] M. Ziaka and A. Exadaktylos, “Pathophysiology of Acute Lung Injury in Patients With Acute Brain Injury: The Triple-Hit Hypothesis,” Critical Care (London, England) 28 (2024): 71.

[134] A. Koutsoukou, M. Katsiari, S. E. Orfanos, et al., “Respiratory Mechanics in Brain Injury: A Review,” World Journal of Critical Care Medicine 5 (2016): 65-73.

[135] J. Imai and H. Katagiri, “Regulation of Systemic Metabolism by the Autonomic Nervous System Consisting of Afferent and Efferent Innervation,” International Immunology 34 (2022): 67-79.

[136] N. D. Powell, E. K. Sloan, M. T. Bailey, et al., “Social Stress Up-Regulates Inflammatory Gene Expression in the Leukocyte Transcriptome via Beta-Adrenergic Induction of Myelopoiesis,” PNAS 110 (2013): 16574-16579.

[137] D. Gautam, S. Han, F. F. Hamdan, et al., “A Critical Role for Beta Cell M3 Muscarinic Acetylcholine Receptors in Regulating Insulin Release and Blood Glucose Homeostasis in Vivo,” Cell Metabolism 3 (2006): 449-461.

[138] S. Faulkner, P. Jobling, B. March, C. C. Jiang, and H. Hondermarck, “Tumor Neurobiology and the War of Nerves in Cancer,” Cancer Discovery 9 (2019): 702-710.

[139] C. Magnon, S. J. Hall, J. Lin, et al., “Autonomic Nerve Development Contributes to Prostate Cancer Progression,” Science 341 (2013): 1236361.

[140] C. Zhao, Y. Hayakawa, Y. Kodama, et al., “Denervation Suppresses Gastric Tumorigenesis,” Science Translational Medicine 6 (2014): 250ra115.

[141] Y. Yan, J. Pan, Y. Chen, et al., “Increased Dopamine and Its Receptor Dopamine Receptor D1 Promote Tumor Growth in Human Hepatocellular Carcinoma,” Cancer Communications (Lond) 40 (2020): 694-710.

[142] N. Cullin, C. Azevedo Antunes, R. Straussman, C. K. Stein-Thoeringer, and E. Elinav, “Microbiome and Cancer,” Cancer Cell 39 (2021): 1317-1341.

[143] H. Kayama, R. Okumura, and K. Takeda, “Interaction Between the Microbiota, Epithelia, and Immune Cells in the Intestine,” Annual Review of Immunology 38 (2020): 23-48.

[144] W. M. de Vos, H. Tilg, M. Van Hul, and P. D. Cani, “Gut Microbiome and Health: Mechanistic Insights,” Gut 71 (2022): 1020-1032.

[145] S. Iacob, D. G. Iacob, and L. M. Luminos, “Intestinal Microbiota as a Host Defense Mechanism to Infectious Threats,” Frontiers in Microbiology 9 (2018): 3328.

[146] K. Pant, S. K. Venugopal, M. J. Lorenzo Pisarello, and S. A. Gradilone, “The Role of Gut Microbiome-Derived Short-Chain Fatty Acid Butyrate in Hepatobiliary Diseases,” American Journal of Pathology 193 (2023): 1455-1467.

[147] P. Schnupf, V. Gaboriau-Routhiau, and N. Cerf-Bensussan, “Modulation of the Gut Microbiota to Improve Innate Resistance,” Current Opinion in Immunology 54 (2018): 137-144.

[148] V. Lazar, L. Ditu, G. G. Pircalabioru, et al., “Aspects of Gut Microbiota and Immune System Interactions in Infectious Diseases, Immunopathology, and Cancer,” Frontiers in Immunology 9 (2018): 1830.

[149] E. Chun, S. Lavoie, D. Fonseca-Pereira, et al., “Metabolite-Sensing Receptor Ffar2 Regulates Colonic Group 3 Innate Lymphoid Cells and Gut Immunity,” Immunity 51 (2019): 871-884.e876.

[150] Y. Luo and Y. Song, “Mechanism of Antimicrobial Peptides: Antimicrobial, Anti-Inflammatory and Antibiofilm Activities,” International Journal of Molecular Sciences 22, no. 21 (2021): 11401.

[151] Q. Y. Zhang, Z. B. Yan, Y. M. Meng, et al., “Antimicrobial Peptides: Mechanism of Action, Activity and Clinical Potential,” Military Medical Research 8 (2021): 48.

[152] D. Vandamme, B. Landuyt, W. Luyten, and L. Schoofs, “A Comprehensive Summary of LL-37, the Factotum Human Cathelicidin Peptide,” Cellular Immunology 280 (2012): 22-35.

[153] J. Libertucci and V. B. Young, “The Role of the Microbiota in Infectious Diseases,” Nature Microbiology 4 (2019): 35-45.

[154] H. Tilg, T. E. Adolph, and M. Trauner, “Gut-Liver Axis: Pathophysiological Concepts and Clinical Implications,” Cell Metabolism 34 (2022): 1700-1718.

[155] A. S. Meijnikman, M. Davids, H. Herrema, et al., “Microbiome-Derived Ethanol in Nonalcoholic Fatty Liver Disease,” Nature Medicine 28 (2022): 2100-2106.

[156] R. Loomba, L. Ling, D. M. Dinh, et al., “The Commensal Microbe Veillonella as a Marker for Response to an FGF19 Analog in NASH,” Hepatology 73 (2021): 126-143.

[157] J. S. Bajaj, S. C. Ng, and B. Schnabl, “Promises of Microbiome-Based Therapies,” Journal of Hepatology 76 (2022): 1379-1391.

[158] T. L. Laursen, A. Mellemkjær, H. J. Møller, H. Grønbæk, and K. Kazankov, “Spotlight on Liver Macrophages for Halting Injury and Progression in Nonalcoholic Fatty Liver Disease,” Expert Opinion on Therapeutic Targets 26 (2022): 697-705.

[159] P. N. Newsome, K. Buchholtz, K. Cusi, et al., “A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis,” New England Journal of Medicine 384 (2021): 1113-1124.

[160] Y. Liu, K. Chen, F. Li, et al., “Probiotic Lactobacillus Rhamnosus GG Prevents Liver Fibrosis Through Inhibiting Hepatic Bile Acid Synthesis and Enhancing Bile Acid Excretion in Mice,” Hepatology 71 (2020): 2050-2066.

[161] M. R. Mahmud, S. Akter, S. K. Tamanna, et al., “Impact of Gut Microbiome on Skin Health: Gut-Skin Axis Observed Through the Lenses of Therapeutics and Skin Diseases,” Gut Microbes 14 (2022): 2096995.

[162] G. R. Gibson, R. Hutkins, M. E. Sanders, et al., “Expert Consensus Document: The International Scientific Association for Probiotics and Prebiotics (ISAPP) Consensus Statement on the Definition and Scope of Prebiotics,” Nature Reviews Gastroenterology & Hepatology 14 (2017): 491-502.

[163] M. Divangahi, P. Aaby, S. A. Khader, et al., “Trained Immunity, Tolerance, Priming and Differentiation: Distinct Immunological Processes,” Nature Immunology 22 (2021): 2-6.

[164] G. D. Brown, J. Herre, D. L. Williams, J. A. Willment, A. S. J. Marshall, and S. Gordon, “Dectin-1 Mediates the Biological Effects of Beta-Glucans,” Journal of Experimental Medicine 197 (2003): 1119-1124.

[165] N. M. Sahasrabudhe, H. A. Schols, M. M. Faas, and P. de Vos, “Arabinoxylan Activates Dectin-1 and Modulates Particulate Beta-Glucan-Induced Dectin-1 Activation,” Molecular Nutrition & Food Research 60 (2016): 458-467.

[166] C. Lin, H. Chen, Y. Chen, et al., “Rice Bran Feruloylated Oligosaccharides Activate Dendritic Cells via Toll-Like Receptor 2 and 4 Signaling,” Molecules (Basel, Switzerland) 19 (2014): 5325-5347.

[167] M. Bermudez-Brito, C. Rösch, H. A. Schols, M. M. Faas, and P. de Vos, “Resistant Starches Differentially Stimulate Toll-Like Receptors and Attenuate Proinflammatory Cytokines in Dendritic Cells by Modulation of Intestinal Epithelial Cells,” Molecular Nutrition & Food Research 59 (2015): 1814-1826.

[168] C. P. Sodhi, P. Wipf, Y. Yamaguchi, et al., “The Human Milk Oligosaccharides 2'-Fucosyllactose and 6'-Sialyllactose Protect Against the Development of Necrotizing Enterocolitis by Inhibiting Toll-Like Receptor 4 Signaling,” Pediatric Research 89 (2021): 91-101.

[169] N. M. Sahasrabudhe, M. Beukema, L. Tian, et al., “Dietary Fiber Pectin Directly Blocks Toll-Like Receptor 2-1 and Prevents Doxorubicin-Induced Ileitis,” Frontiers in Immunology 9 (2018): 383.

[170] P. Panigrahi, S. Parida, N. C. Nanda, et al., “A Randomized Synbiotic Trial to Prevent Sepsis Among Infants in Rural India,” Nature 548 (2017): 407-412.

[171] F. Mangiola, G. Ianiro, F. Franceschi, S. Fagiuoli, G. Gasbarrini, and A. Gasbarrini, “Gut Microbiota in Autism and Mood Disorders,” World Journal of Gastroenterology 22 (2016): 361-368.

[172] R. E. Ooijevaar, E. M. Terveer, H. W. Verspaget, E. J. Kuijper, and J. J. Keller, “Clinical Application and Potential of Fecal Microbiota Transplantation,” Annual Review of Medicine 70 (2019): 335-351.

[173] M. M. Smits and D. H. Van Raalte, “Corrigendum: Safety of Semaglutide,” Frontiers in Endocrinology (Lausanne) 12 (2021): 786732.

[174] K. Akutko and A. Stawarski, “Probiotics, Prebiotics and Synbiotics in Inflammatory Bowel Diseases,” Journal of Clinical Medicine 10, no. 11 (2021): 2466.

[175] S. Meini, R. Laureano, L. Fani, et al., “Breakthrough Lactobacillus Rhamnosus GG Bacteremia Associated With Probiotic Use in an Adult Patient With Severe Active Ulcerative Colitis: Case Report and Review of the Literature,” Infection 43 (2015): 777-781.

[176] C. Venter, S. Eyerich, T. Sarin, and K. C. Klatt, “Nutrition and the Immune System: A Complicated Tango,” Nutrients 12, no. 3 (2020): 818.

[177] A. J. Macpherson, M. G. de Agüero, and S. C. Ganal-Vonarburg, “How Nutrition and the Maternal Microbiota Shape the Neonatal Immune System,” Nature Reviews Immunology 17 (2017): 508-517.

[178] I. J. Malesza, M. Malesza, J. Walkowiak, et al., “High-Fat, Western-Style Diet, Systemic Inflammation, and Gut Microbiota: A Narrative Review,” Cells 10, no. 11 (2021): 3164.

[179] S. Negi, D. K. Das, S. Pahari, S. Nadeem, and J. N. Agrewala, “Potential Role of Gut Microbiota in Induction and Regulation of Innate Immune Memory,” Frontiers in Immunology 10 (2019): 2441.

[180] S. P. Wiertsema, J. van Bergenhenegouwen, J. Garssen, and L. M. J. Knippels, “The Interplay Between the Gut Microbiome and the Immune System in the Context of Infectious Diseases Throughout Life and the Role of Nutrition in Optimizing Treatment Strategies,” Nutrients 13, no. 3 (2021): 886.

[181] A. J. Forgie, J. M. Fouhse, and B. P. Willing, “Diet-Microbe-Host Interactions That Affect Gut Mucosal Integrity and Infection Resistance,” Frontiers in Immunology 10 (2019): 1802.

[182] H. Sung, J. Ferlay, R. L. Siegel, et al., “Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,” CA: A Cancer Journal for Clinicians 71 (2021): 209-249.

[183] A. Forner, M. Reig, and J. Bruix, “Hepatocellular Carcinoma,” Lancet 391 (2018): 1301-1314.

[184] A. Villanueva, “Hepatocellular Carcinoma,” New England Journal of Medicine 380 (2019): 1450-1462.

[185] A. Vogel, T. Meyer, G. Sapisochin, R. Salem, and A. Saborowski, “Hepatocellular Carcinoma,” Lancet 400 (2022): 1345-1362.

[186] S. M. Akula, S. L. Abrams, L. S. Steelman, et al., “RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1 and TP53 Pathways and Regulatory miRs as Therapeutic Targets in Hepatocellular Carcinoma,” Expert Opinion on Therapeutic Targets 23 (2019): 915-929.

[187] R. K. Shrimali, Z. Yu, M. R. Theoret, D. Chinnasamy, N. P. Restifo, and S. A. Rosenberg, “Antiangiogenic Agents Can Increase Lymphocyte Infiltration Into Tumor and Enhance the Effectiveness of Adoptive Immunotherapy of Cancer,” Cancer Research 70 (2010): 6171-6180.

[188] J. Corominas, V. Sapena, M. Sanduzzi-Zamparelli, et al., “Activated Lymphocytes and Increased Risk of Dermatologic Adverse Events During Sorafenib Therapy for Hepatocellular Carcinoma,” Cancers (Basel) 13, no. 3 (2021): 426.

[189] N. M. Agostino, V. M. Chinchilli, C. J. Lynch, et al., “Effect of the Tyrosine Kinase Inhibitors (sunitinib, Sorafenib, Dasatinib, and Imatinib) on Blood Glucose Levels in Diabetic and Nondiabetic Patients in General Clinical Practice,” Journal of Oncology Pharmacy Practice: Official Publication of the International Society of Oncology Pharmacy Practitioners 17 (2011): 197-202.

[190] A. Holstein, P. Kovacs, and W. Beil, “Severe Hypoglycemia due to Possible Interaction Between Glibenclamide and Sorafenib in a Patient With Hepatocellular Carcinoma,” Current Drug Safety 8, no. 2 (2013): 148-152.

[191] W. T. Watford, B. D. Hissong, J. H. Bream, Y. Kanno, L. Muul, and J. J. O'Shea, “Signaling by IL-12 and IL-23 and the Immunoregulatory Roles of STAT4,” Immunological Reviews 202 (2004): 139-156.

[192] Q. Zeng, J. Song, D. Wang, et al., “Identification of Sorafenib as a Treatment for Type 1 Diabetes,” Frontiers in Immunology 13 (2022): 740805.

[193] P. R. Galle, F. Tovoli, F. Foerster, M. A. Wörns, A. Cucchetti, and L. Bolondi, “The Treatment of Intermediate Stage Tumours Beyond TACE: From Surgery to Systemic Therapy,” Journal of Hepatology 67 (2017): 173-183.

[194] C. Fang, Y. Chen, N. Wu, et al., “Author Correction: MiR-488 Inhibits Proliferation and Cisplatin Sensibility in Non-Small-Cell Lung Cancer (NSCLC) Cells by Activating the eIF3a-Mediated NER Signaling Pathway,” Scientific Reports 11 (2021): 22452.

[195] R. Ranasinghe, M. L. Mathai, and A. Zulli, “Cisplatin for Cancer Therapy and Overcoming Chemoresistance,” Heliyon 8 (2022): e10608.

[196] G. B. Long, C. W. Xiao, X. Y. Zhao, J. Zhang, and X. Li, “Effects of Hepatic Arterial Infusion Chemotherapy in the Treatment of Hepatocellular Carcinoma: A Meta-Analysis,” Medicine 99 (2020): e20745.

[197] B. Zhang, G. Ramesh, C. C. Norbury, and W. B. Reeves, “Cisplatin-Induced Nephrotoxicity is Mediated by Tumor Necrosis Factor-alpha Produced by Renal Parenchymal Cells,” Kidney International 72 (2007): 37-44.

[198] A. G. Casanova, M. T. Hernández-Sánchez, F. J. López-Hernández, et al., “Systematic Review and Meta-Analysis of the Efficacy of Clinically Tested Protectants of Cisplatin Nephrotoxicity,” European Journal of Clinical Pharmacology 76 (2020): 23-33.

[199] A. Haslam and V. Prasad, “Estimation of the Percentage of US Patients With Cancer Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy Drugs,” JAMA Network Open 2 (2019): e192535.

[200] R. Banchereau, A. S. Chitre, A. Scherl, et al., “Intratumoral CD103+ CD8+ T Cells Predict Response to PD-L1 Blockade,” Journal for ImmunoTherapy of Cancer 9, no. 4 (2021): e002231.

[201] D. Song, T. Powles, L. Shi, L. Zhang, M. A. Ingersoll, and Y. Lu, “Bladder Cancer, a Unique Model to Understand Cancer Immunity and Develop Immunotherapy Approaches,” Journal of Pathology 249 (2019): 151-165.

[202] M. Dougan, A. M. Luoma, S. K. Dougan, and K. W. Wucherpfennig, “Understanding and Treating the Inflammatory Adverse Events of Cancer Immunotherapy,” Cell 184 (2021): 1575-1588.

[203] S. C. Sasson, S. M. Slevin, V. T. Cheung, et al., “Interferon-Gamma-Producing CD8(+) Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor-Colitis,” Gastroenterology 161 (2021): 1229-1244.e1229.

[204] M. L. Axelrod, W. C. Meijers, E. M. Screever, et al., “T Cells Specific for Alpha-Myosin Drive Immunotherapy-Related Myocarditis,” Nature 611 (2022): 818-826.

[205] X. Bai, J. Hu, A. Betof Warner, et al., “Early Use of High-Dose Glucocorticoid for the Management of irAE Is Associated With Poorer Survival in Patients With Advanced Melanoma Treated With Anti-PD-1 Monotherapy,” Clinical Cancer Research 27 (2021): 5993-6000.

[206] GBD 2019 Hepatitis B Collaborators. Global, Regional, and National Burden of Hepatitis B, 1990-2019: A Systematic Analysis for the Global Burden of Disease Study 2019. The Lancet Gastroenterology and Hepatology 7(9), 796-829 (2022).

[207] X. Ding, Q. Zhu, S. Zhang, et al., “Precision Medicine for Hepatocellular Carcinoma: Driver Mutations and Targeted Therapy,” Oncotarget 8, no. 33 (2017): 55715-55730.

[208] J. D. Yang, P. Hainaut, G. J. Gores, A. Amadou, A. Plymoth, and L. R. Roberts, “A Global View of Hepatocellular Carcinoma: Trends, Risk, Prevention and Management,” Nature Reviews Gastroenterology & Hepatology 16 (2019): 589-604.

[209] H. L. Y. Chan, “Maintenance of High Levels of Viral Suppression and Improved Safety Profile of Tenofovir Alafenamide (TAF) Relative to Tenofovir Disoproxil Fumarate (TDF) in Chronic Hepatitis B Patients Treated for 5 Years in 2 Ongoing Phase 3 Studies,” The Liver Meeting Digital Experience^™, AASLD (2020).

[210] M. H. Nguyen, G. Wong, E. Gane, J. Kao, and G. Dusheiko, “Hepatitis B Virus: Advances in Prevention, Diagnosis, and Therapy,” Clinical Microbiology Reviews 33, no. 2 (2020): e00046-e00119.

[211] B. J. Fowler, B. D. Gelfand, Y. Kim, et al., “Nucleoside Reverse Transcriptase Inhibitors Possess Intrinsic Anti-Inflammatory Activity,” Science 346 (2014): 1000-1003.

[212] Y. Ming, G. Xin, B. Ji, et al., “Entecavir as a P2×7R Antagonist Ameliorates Platelet Activation and Thrombus Formation,” Journal of Pharmacological Sciences 144 (2020): 43-51.

[213] M. Yuen, D. Chen, G. M. Dusheiko, et al., “Hepatitis B Virus Infection,” Nature reviews Disease primers 4 (2018): 18035.

[214] H. H. Hoffmann, W. M. Schneider, and C. M. Rice, “Interferons and Viruses: An Evolutionary Arms Race of Molecular Interactions,” Trends in Immunology 36 (2015): 124-138.

[215] H. J. Anders, J. Lichtnekert, and R. Allam, “Interferon-alpha and -beta in Kidney Inflammation,” Kidney International 77 (2010): 848-854.

[216] D. P. Simmons, P. A. Wearsch, D. H. Canaday, et al., “Type I IFN Drives a Distinctive Dendritic Cell Maturation Phenotype That Allows Continued Class II MHC Synthesis and Antigen Processing,” Journal of Immunology 188 (2012): 3116-3126.

[217] D. Kishimoto, Y. Kirino, M. Tamura, et al., “Dysregulated Heme Oxygenase-1(low) M2-Like Macrophages Augment Lupus Nephritis via Bach1 Induced by Type I Interferons,” Arthritis Research & Therapy 20 (2018): 64.

[218] A. Triantafyllopoulou, C. Franzke, S. V. Seshan, et al., “Proliferative Lesions and Metalloproteinase Activity in Murine Lupus Nephritis Mediated by Type I Interferons and Macrophages,” PNAS 107 (2010): 3012-3017.

[219] L. Chen, Z. Wu, L. Yang, et al., “Nitric Oxide in Multikinase Inhibitor-Induced Hand-Foot Skin Reaction,” Translational Research 245 (2022): 82-98.

[220] M. Kudo, K. Ueshima, O. Yokosuka, et al., “Sorafenib Plus Low-Dose Cisplatin and Fluorouracil Hepatic Arterial Infusion Chemotherapy Versus Sorafenib Alone in Patients With Advanced Hepatocellular Carcinoma (SILIUS): A Randomised, Open Label, Phase 3 Trial,” The Lancet Gastroenterology and Hepatology 3 (2018): 424-432.

[221] D. B. Johnson, J. M. Balko, M. L. Compton, et al., “Fulminant Myocarditis With Combination Immune Checkpoint Blockade,” New England Journal of Medicine 375 (2016): 1749-1755.

[222] P. Caturegli, G. Di Dalmazi, M. Lombardi, et al., “Hypophysitis Secondary to Cytotoxic T-Lymphocyte-Associated Protein 4 Blockade: Insights Into Pathogenesis From an Autopsy Series,” American Journal of Pathology 186 (2016): 3225-3235.

[223] A. A. Tarhini, H. Zahoor, Y. Lin, et al., “Baseline Circulating IL-17 Predicts Toxicity While TGF-beta1 and IL-10 Are Prognostic of Relapse in Ipilimumab Neoadjuvant Therapy of Melanoma,” Journal for ImmunoTherapy of Cancer 3 (2015): 39.

[224] J. Zhou, H. Xiong, X. Chen, Z. Zhang, L. Zhu, and B. Wu, “Correlation Between Immune-Related Adverse Events and Long-Term Outcomes in Pembrolizumab-Treated Patients With Unresectable Hepatocellular Carcinoma: A Retrospective Study,” World Journal of Gastrointestinal Oncology 15 (2023): 689-699.

[225] H. Un, R. A. Ugan, D. Kose, et al., “A Novel Effect of Aprepitant: Protection for Cisplatin-Induced Nephrotoxicity and Hepatotoxicity,” European Journal of Pharmacology 880 (2020): 173168.

[226] Y. I. Chirino and J. Pedraza-Chaverri, “Role of Oxidative and Nitrosative Stress in Cisplatin-Induced Nephrotoxicity,” Experimental and Toxicologic Pathology 61 (2009): 223-242.

[227] P. A. Ott, Y. Bang, S. A. Piha-Paul, et al., “T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028 (vol 37, pg 318, 2019),” Journal of Clinical Oncology 37 (2019): 688-688.

[228] T. S. Nowicki, S. Hu-Lieskovan, and A. Ribas, “Mechanisms of Resistance to PD-1 and PD-L1 Blockade,” Cancer Journal 24 (2018): 47-53.

[229] B. Routy, E. Le Chatelier, L. Derosa, et al., “Gut Microbiome Influences Efficacy of PD-1-Based Immunotherapy Against Epithelial Tumors,” Science 359 (2018): 91-97.

[230] C. D. Mathers and D. Loncar, “Projections of Global Mortality and Burden of Disease From 2002 to 2030,” PLOS Medicine 3 (2006): e442.

[231] A. Duhoux, L. Fournier, L. Gauvin, and P. Roberge, “What Is the Association Between Quality of Treatment for Depression and Patient Outcomes? A Cohort Study of Adults Consulting in Primary Care,” Journal of Affective Disorders 151 (2013): 265-274.

[232] S. M. Stahl, “Mechanism of Action of Serotonin Selective Reuptake Inhibitors. Serotonin Receptors and Pathways Mediate Therapeutic Effects and Side Effects,” Journal of Affective Disorders 51 (1998): 215-235.

[233] P. C. Casarotto, M. Girych, S. M. Fred, et al., “Antidepressant Drugs Act by Directly Binding to TRKB Neurotrophin Receptors,” Cell 184 (2021): 1299-1313.e1219.

[234] W. Mu, G. Xu, Z. Wei, et al., “The Role of NLRP3 Inflammasome in Psychotropic Drug-Induced Hepatotoxicity,” Cell Death Discovery 8 (2022): 313.

[235] X. Chen, D. Zhang, Y. Li, W. Wang, W. Bei, and J. Guo, “NLRP3 Inflammasome and IL-1beta Pathway in Type 2 Diabetes and Atherosclerosis: Friend or Foe?,” Pharmacological Research 173 (2021): 105885.

[236] Z. Wang, G. Xu, H. Wang, et al., “Icariside II, a Main Compound in Epimedii Folium, Induces Idiosyncratic Hepatotoxicity by Enhancing NLRP3 Inflammasome Activation,” Acta Pharmaceutica Sinica B 10 (2020): 1619-1633.

[237] Y. Pan, X. Y. Chen, Q. Y. Zhang, and L. D. Kong, “Microglial NLRP3 Inflammasome Activation Mediates IL-1beta-Related Inflammation in Prefrontal Cortex of Depressive Rats,” Brain, Behavior, and Immunity 41 (2014): 90-100.

[238] A. Camargo, A. P. Dalmagro, I. A. V. Wolin, M. P. Kaster, and A. L. S. Rodrigues, “The Resilient Phenotype Elicited by Ketamine Against Inflammatory Stressors-Induced Depressive-Like Behavior Is Associated With NLRP3-Driven Signaling Pathway,” Journal of Psychiatric Research 144 (2021): 118-128.

[239] E. A. Troyer, J. N. Kohn, and S. Hong, “Are We Facing a Crashing Wave of Neuropsychiatric Sequelae of COVID-19? Neuropsychiatric Symptoms and Potential Immunologic Mechanisms,” Brain, Behavior, and Immunity 87 (2020): 34-39.

[240] M. Zimniak, L. Kirschner, H. Hilpert, et al., “The Serotonin Reuptake Inhibitor Fluoxetine Inhibits SARS-CoV-2 in Human Lung Tissue,” Scientific Reports 11 (2021): 5890.

[241] T. Oskotsky, I. Marić, A. Tang, et al., “Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants,” JAMA Network Open 4 (2021): e2133090.

[242] S. Schloer, L. Brunotte, A. Mecate-Zambrano, et al., “Drug Synergy of Combinatory Treatment With Remdesivir and the Repurposed Drugs Fluoxetine and Itraconazole Effectively Impairs SARS-CoV-2 Infection in Vitro,” British Journal of Pharmacology 178 (2021): 2339-2350.

[243] I. Lukić, D. Getselter, O. Ziv, et al., “Antidepressants Affect Gut Microbiota and Ruminococcus Flavefaciens Is Able to Abolish Their Effects on Depressive-Like Behavior,” Translational Psychiatry 9 (2019): 133.

[244] W. Zhang, W. Qu, H. Wang, and H. Yan, “Antidepressants Fluoxetine and Amitriptyline Induce Alterations in Intestinal Microbiota and Gut Microbiome Function in Rats Exposed to Chronic Unpredictable Mild Stress,” Translational Psychiatry 11 (2021): 131.

[245] L. Li, E. Yoo, X. Li, et al., “The Atypical Antipsychotic Risperidone Targets Hypothalamic Melanocortin 4 Receptors to Cause Weight Gain,” Journal of Experimental Medicine 218, no. 7 (2021): e20202484.

[246] C. Greenhill, “Deciphering the Role of Leptin in Weight Gain Associated With Anti-Psychotic Medications,” Nature Reviews Endocrinology 20 (2024): 63.

[247] M. Klünemann, S. Andrejev, S. Blasche, et al., “Bioaccumulation of Therapeutic Drugs by Human Gut Bacteria,” Nature 597 (2021): 533-538.

[248] C. S. Voican, E. Corruble, S. Naveau, and G. Perlemuter, “Antidepressant-Induced Liver Injury: A Review for Clinicians,” American Journal of Psychiatry 171 (2014): 404-415.

[249] M. V. Mitkov, R. M. Trowbridge, B. N. Lockshin, and J. P. Caplan, “Dermatologic Side Effects of Psychotropic Medications,” Psychosomatics 55 (2014): 1-20.

[250] S. A. Bliss and J. K. Warnock, “Psychiatric Medications: Adverse Cutaneous Drug Reactions,” Clinics in Dermatology 31 (2013): 101-109.

[251] B. J. Goldstein and P. J. Goodnick, “Selective Serotonin Reuptake Inhibitors in the Treatment of Affective Disorders-III. Tolerability, Safety and Pharmacoeconomics,” Journal of Psychopharmacology 12 (1998): S55-87.

[252] A. Serretti and L. Mandelli, “Antidepressants and Body Weight: A Comprehensive Review and Meta-Analysis,” Journal of Clinical Psychiatry 71 (2010): 1259-1272.

[253] K. B. Thor, “Serotonin and Norepinephrine Involvement in Efferent Pathways to the Urethral Rhabdosphincter: Implications for Treating Stress Urinary Incontinence,” Urology 62 (2003): 3-9.

[254] K. Williams and M. F. Reynolds, “Sexual Dysfunction in Major Depression,” CNS Spectrums 11 (2006): 19-23.

[255] L. De Picker, F. Van Den Eede, G. Dumont, G. Moorkens, and B. G. Sabbe, “Antidepressants and the Risk of Hyponatremia: A Class-by-Class Review of Literature,” Psychosomatics 55 (2014): 536-547.

[256] A. F. Carvalho, M. S. Sharma, A. R. Brunoni, E. Vieta, and G. A. Fava, “The Safety, Tolerability and Risks Associated With the Use of Newer Generation Antidepressant Drugs: A Critical Review of the Literature,” Psychotherapy and Psychosomatics 85 (2016): 270-288.

[257] V. C. Patel, S. Lee, M. J. McPhail, et al., “Rifaximin-alpha Reduces Gut-Derived Inflammation and Mucin Degradation in Cirrhosis and Encephalopathy: RIFSYS Randomised Controlled Trial,” Journal of Hepatology 76 (2022): 332-342.

[258] J. S. Bajaj, D. M. Heuman, A. J. Sanyal, et al., “Modulation of the Metabiome by Rifaximin in Patients With Cirrhosis and Minimal Hepatic Encephalopathy,” PLoS ONE 8 (2013): e60042.

[259] N. M. Bass, K. D. Mullen, A. Sanyal, et al., “Rifaximin Treatment in Hepatic Encephalopathy,” New England Journal of Medicine 362 (2010): 1071-1081.

[260] K. D. Mullen, A. J. Sanyal, N. M. Bass, et al., “Rifaximin Is Safe and Well Tolerated for Long-Term Maintenance of Remission From Overt Hepatic Encephalopathy,” Clinical Gastroenterology and Hepatology 12 (2014): 1390-1397.e1392.

[261] S. B. Ahn, D. W. Jun, B. Kang, J. H. Lim, S. Lim, and M. Chung, “Randomized, Double-Blind, Placebo-Controlled Study of a Multispecies Probiotic Mixture in Nonalcoholic Fatty Liver Disease,” Scientific Reports 9 (2019): 5688.

[262] M. R. Bomhof, J. A. Parnell, H. R. Ramay, et al., “Histological Improvement of Non-Alcoholic Steatohepatitis With a Prebiotic: A Pilot Clinical Trial,” European Journal of Nutrition 58 (2019): 1735-1745.

[263] M. S. Kuchay, S. Krishan, S. K. Mishra, et al., “Effect of Dulaglutide on Liver Fat in Patients With Type 2 Diabetes and NAFLD: Randomised Controlled Trial (D-LIFT Trial),” Diabetologia 63 (2020): 2434-2445.

[264] M. J. Armstrong, P. Gaunt, G. P. Aithal, et al., “Liraglutide Safety and Efficacy in Patients With Non-Alcoholic Steatohepatitis (LEAN): A Multicentre, Double-Blind, Randomised, Placebo-Controlled Phase 2 Study,” Lancet 387 (2016): 679-690.

[265] S. Chuah, J. Lee, Y. Song, et al., “Uncoupling Immune Trajectories of Response and Adverse Events From Anti-PD-1 Immunotherapy in Hepatocellular Carcinoma,” Journal of Hepatology 77 (2022): 683-694.

[266] M. Saiz-Rodríguez, C. Belmonte, M. Román, et al., “Effect of Polymorphisms on the Pharmacokinetics, Pharmacodynamics and Safety of Sertraline in Healthy Volunteers,” Basic & Clinical Pharmacology & Toxicology 122 (2018): 501-511.

[267] A. Jiang, C. Wei, W. Zhu, F. Wu, and B. Wu, “Adverse Event Profiles of Drug-Induced Liver Injury Caused by Antidepressant Drugs: A Disproportionality Analysis,” Therapeutic Advances in Drug Safety 15 (2024): 20420986241244585.

[268] S. Giatti, S. Diviccaro, L. Cioffi, and R. Cosimo Melcangi, “Post-Finasteride Syndrome and Post-Ssri Sexual Dysfunction: Two Clinical Conditions Apparently Distant, but Very Close,” Frontiers in Neuroendocrinology 72 (2024): 101114.

[269] S. Ballou, J. Iturrino, V. Rangan, et al., “Improving Medication Tolerance: A Pilot Study in Disorders of Gut-Brain Interaction Treated With Tricyclic Antidepressants,” Journal of Clinical Gastroenterology 56 (2022): 452-456.

[270] S. N. Chaudhari, J. N. Luo, D. A. Harris, et al., “A Microbial Metabolite Remodels the Gut-Liver Axis Following Bariatric Surgery,” Cell Host & Microbe 29 (2021): 408-424.e407.

[271] L. Liu, H. Wang, X. Chen, Y. Zhang, H. Zhang, and P. Xie, “Gut Microbiota and Its Metabolites in Depression: From Pathogenesis to Treatment,” EBioMedicine 90 (2023): 104527.

[272] K. J. Waller, H. Saihi, W. Li, et al., “Single-Cell Phenotypes of Peripheral Blood Immune Cells in Early and Late Stages of Non-Alcoholic Fatty Liver Disease,” Clinical and Molecular Hepatology 29 (2023): 417-432.

[273] C. D'Mello and M. G. Swain, “Liver-Brain Inflammation Axis,” American Journal of Physiology Gastrointestinal and Liver Physiology 301 (2011): G749-761.

[274] Z. Wang, M. Zeng, Z. Wang, F. Qin, J. Chen, and Z. He, “Dietary Polyphenols to Combat Nonalcoholic Fatty Liver Disease via the Gut-Brain-Liver Axis: A Review of Possible Mechanisms,” Journal of Agricultural and Food Chemistry 69 (2021): 3585-3600.

[275] S. Zhang, S. Lu, and Z. Li, “Extrahepatic Factors in Hepatic Immune Regulation,” Frontiers in Immunology 13 (2022): 941721.

[276] Y. Guo, X. Chen, P. Gong, G. Li, W. Yao, and W. Yang, “The Gut-Organ-Axis Concept: Advances the Application of Gut-on-Chip Technology,” International Journal of Molecular Sciences 24, no. 4 (2023): 4089.

[277] S. Zundler, C. Günther, A. E. Kremer, M. M. Zaiss, V. Rothhammer, and M. F. Neurath, “Gut Immune Cell Trafficking: Inter-Organ Communication and Immune-Mediated Inflammation,” Nature Reviews Gastroenterology & Hepatology 20 (2023): 50-64.

[278] Y. Huang, F. Liu, J. Lai, et al., “The Adjuvant Treatment Role of Omega-3 Fatty Acids by Regulating Gut Microbiota Positively in the Acne Vulgaris,” The Journal of Dermatological Treatment 35 (2024): 2299107.

[279] J. Shen, W. Liang, R. Zhao, et al., “Cross-Tissue Multi-Omics Analyses Reveal the Gut Microbiota's Absence Impacts Organ Morphology, Immune Homeostasis, Bile Acid and Lipid Metabolism,” Imeta 4 (2025): e272.

[280] M. Xu, C. Guo, M. Li, et al., “Brain-Gut-Liver Axis: Chronic Psychological Stress Promotes Liver Injury and Fibrosis via Gut in Rats,” Frontiers in Cellular and Infection Microbiology 12 (2022): 1040749.

[281] R. Kim and J. H. Sung, “Recent Advances in Gut- and Gut-Organ-Axis-on-a-Chip Models,” Advanced Healthcare Materials 13 (2024): e2302777.

[282] Y. Yang, Z. Bo, J. Wang, et al., “Machine Learning Based on Alcohol Drinking-Gut Microbiota-Liver Axis in Predicting the Occurrence of Early-Stage Hepatocellular Carcinoma,” BMC cancer 24 (2024): 1468.

[283] M. H. Kim, D. van Noort, J. H. Sung, and S. Park, “Organ-on-a-Chip for Studying Gut-Brain Interaction Mediated by Extracellular Vesicles in the Gut Microenvironment,” International Journal of Molecular Sciences 22, no. 24 (2021): 13513.

[284] K. C. Bauer, R. Trehan, B. Ruf, et al., The Gut Microbiome Controls Liver Tumors via the Vagus Nerve. bioRxiv (2024), https://doi.org/10.1101/2024.01.23.576951.

[285] Y. Zhang, S. M. Lu, J. J. Zhuang, and L. G. Liang, “Advances in Gut-Brain Organ Chips,” Cell Proliferation 57, no. 9 (2024): e13724.

[286] X. Wang, Y. Zhu, Z. Cheng, et al., “Emerging Microfluidic Gut-on-a-Chip Systems for Drug Development,” Acta Biomaterialia 188 (2024): 48-64.

[287] K. W. Lee, J. S. Shin, C. M. Lee, et al., “Gut-on-a-Chip for the Analysis of Bacteria-Bacteria Interactions in Gut Microbial Community: What Would Be Needed for Bacterial Co-Culture Study to Explore the Diet-Microbiota Relationship?,” Nutrients 15, no. 5 (2023): 1131.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.