Pathologic and therapeutic insights into cholestatic liver disease-associated depressive disorder

Abstract

The prevalence of depressive-like behavior is significantly higher in patients with cholestatic liver disease, leading to a notable reduction in the quality of life. This situation underscores the urgent need to investigate the mechanisms underlying the association between cholestasis and clinical depression. This review provides a comprehensive examination of how neuroendocrine disorders resulting from cholestasis influence the onset of depression through both direct and indirect mechanisms. First, how the accumulation of bile acids in the central nervous system (CNS) during cholestasis leads to damage to the blood-brain barrier, neuroinflammation, and neurodegeneration is discussed, highlighting the key roles of bile acid receptors, such as FXR and TGR5, in this process. Additionally, the gut-brain axis has been shown to be involved in the development of brain diseases in a variety of ways. Therefore, the indirect indirect effects of bile acids via the gut-brain axis, which affect the composition of the gut microbiota, the integrity of the gut barrier, and the secretion of gut hormones are summarized, thereby regulating the development of depression. However, whether bile acids can directly enter the CNS and which targets are targetable within the gut-brain axis remain pivotal questions. Addressing these issues will open new avenues for developing more effective therapeutic strategies aimed at alleviating depressive symptoms experienced by patients with cholestasis.

Keywords

cholestatic liver disease / bile acids / depression / gut microbes / gut-brain axis

References

[1] Sherlock S, Dooley J: Diseases of the Liver and Biliary System . Wiley Online Library; 2002.

[2] European Association for the Study of the Liver: EASL Clinical Practice Guidelines: Management of Cholestatic Liver Diseases. Journal of Hepatology 2009, 51: 237-267.

[3] Burt AD, Ferrell LD, Hübscher SG: MacSween’s Pathology of the Liver . Elsevier Health Sciences; 2022.

[4] Lefkowitch JH: Scheuer’s Liver Biopsy Interpretation . Elsevier Health Sciences; 2020.

[5] Wu H, Chen C, Ziani S, Nelson LJ, Ávila MA, Nevzorova YA, et al.: Fibrotic Events in the Progression of Cholestatic Liver Disease. Cells 2021, 10: 1107.

[6] Hilscher MB, Kamath PS, Eaton JE: Cholestatic Liver Diseases: A Primer for Generalists and Subspecialists. Mayo Clinic Proceedings 2020, 95: 2263-2279.

[7] Siddique A, Kowdley KV: Approach to a Patient with Elevated Serum Alkaline Phosphatase. Clinics in Liver Disease 2012, 16: 199-229.

[8] Jüngst C, Berg T, Cheng J, Green RM, Jia J, Mason AL, et al.: Intrahepatic Cholestasis in Common Chronic Liver Diseases. European Journal of Clinical Investigation 2013, 43: 1069-1083.

[9] Pollheimer MJ, Fickert P, Stieger B: Chronic Cholestatic Liver Diseases: Clues from Histopathology for Pathogenesis. Molecular Aspects of Medicine 2014, 37: 35-56.

[10] Levy C: Primary Biliary Cholangitis: Treatment Options Finally Expand. Hepatology (Baltimore, Md.) 2017, 65: 1405-1407.

[11] Glantz A, Reilly SJ, Benthin L, Lammert F, Mattsson LA, Marschall HU: Intrahepatic Cholestasis of Pregnancy: Amelioration of Pruritus by UDCA is Associated with Decreased Progesterone Disulphates in Urine. Hepatology (Baltimore, Md.) 2008, 47: 544-551.

[12] Demorrow S: Bile Acids in Hepatic Encephalopathy. Journal of Clinical and Experimental Hepatology 2019, 9: 117-124.

[13] Palmela I, Correia L, Silva RF, Sasaki H, Kim KS, Brites D, et al.: Hydrophilic Bile Acids Protect Human Blood-Brain Barrier Endothelial Cells From Disruption by Unconjugated Bilirubin: An In Vitro Study. Frontiers in Neuroscience 2015, 9: 80.

[14] Poupon RE, Chretien Y, Chazouilleres O, Poupon R, Chwalow J: Quality of Life in Patients with Primary Biliary Cirrhosis. Hepatology (Baltimore, Md.) 2004, 40: 489-494.

[15] Selmi C, Gershwin ME, Lindor KD, Worman HJ, Gold EB, Watnik M, et al.: Quality of Life and Everyday Activities in Patients with Primary Biliary Cirrhosis. Hepatology (Baltimore, Md.) 2007, 46: 1836-1843.

[16] Witt-Sullivan H, Heathcote J, Cauch K, Blendis L, Ghent C, Katz A, et al.: The Demography of Primary Biliary Cirrhosis in Ontario, Canada. Hepatology (Baltimore, Md.) 1990, 12: 98-105.

[17] Abbas G, Jorgensen RA, Lindor KD: Fatigue in Primary Biliary Cirrhosis. Nature Reviews. Gastroenterology & Hepatology 2010, 7: 313-319.

[18] Leutscher PDC, Lagging M, Buhl MR, Pedersen C, Norkrans G, Langeland N, et al.: Evaluation of Depression as a Risk Factor for Treatment Failure in Chronic Hepatitis C. Hepatology (Baltimore, Md.) 2010, 52: 430-435.

[19] Mano N, Goto T, Uchida M, Nishimura K, Ando M, Kobayashi N, et al.: Presence of Protein-Bound Unconjugated Bile Acids In the Cytoplasmic Fraction of Rat Brain. Journal of Lipid Research 2004, 45: 295-300.

[20] Reinicke M, Schroter J, Muller-Klieser D, Helmschrodt C, Ceglarek U: Free Oxysterols and Bile Acids Including Conjugates - Simultaneous Quantification in Human Plasma and Cerebrospinal Fluid by Liquid Chromatography-Tandem Mass Spectrometry. Analytica Chimica Acta 2018, 1037: 245-255.

[21] Zheng X, Chen T, Zhao A, Wang X, Xie G, Huang F, et al.: The Brain Metabolome of Male Rats across the Lifespan. Scientific Reports 2016, 6: 24125.

[22] Baloni P, Funk CC, Yan J, Yurkovich JT, Kueider-Paisley A, Nho K, et al.: Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease. Cell Reports Medicine 2020, 1: 100138.

[23] Nho K, Kueider-Paisley A, MahmoudianDehkordi S, Arnold M, Risacher SL, Louie G, et al.: Altered Bile Acid Profile in Mild Cognitive Impairment and Alzheimer’s Disease: Relationship to Neuroimaging and CSF Biomarkers. Alzheimer’s & Dementia 2019, 15: 232-244.

[24] MahmoudianDehkordi S, Arnold M, Nho K, Ahmad S, Jia W, Xie G, et al.: Altered Bile Acid Profile Associates with Cognitive Impairment in Alzheimer’s Disease-An Emerging Role for Gut Microbiome. Alzheimer’s & Dementia 2019, 15: 76-92.

[25] Ehtezazi T, Rahman K, Davies R, Leach AG: The Pathological Effects of Circulating Hydrophobic Bile Acids in Alzheimer’s Disease. Journal of Alzheimer’s Disease Reports 2023, 7: 173-211.

[26] Clifford BL, Sedgeman LR, Williams KJ, Morand P, Cheng A, Jarrett KE, et al.: FXR Activation Protects Against NAFLD Via Bile-acid-dependent Reductions in Lipid Absorption. Cell Metabolism 2021, 33: 1671-1684 e4.

[27] Hertel J, Harms AC, Heinken A, Baldini F, Thinnes CC, Glaab E, et al.: Integrated Analyses of Microbiome and Longitudinal Metabolome Data Reveal Microbial-host Interactions on Sulfur Metabolism in Parkinson’s Disease. Cell Reports 2019, 29: 1767-1777. e8.

[28] Nie K, Li Y, Zhang J, Gao Y, Qiu Y, Gan R, et al.: Distinct Bile Acid Signature in Parkinson’s Disease with Mild Cognitive Impairment. Frontiers in Neurology 2022, 13: 897867.

[29] Bron B, Waldram R, Silk DB, Williams R: Serum, Cerebrospinal Fluid, and Brain Levels of Bile Acids in Patients with Fulminant Hepatic Failure. Gut 1977, 18: 692-696.

[30] Xie G, Wang X, Jiang R, Zhao A, Yan J, Zheng X, et al.: Dysregulated Bile Acid Signaling Contributes to the Neurological Impairment in Murine Models of Acute and Chronic Liver Failure. EBioMedicine 2018, 37: 294-306.

[31] Xu E, Wang B, Lu S, Zhang C, Zhu L, Liu X, et al.: Tandem Mass Tag-based Quantitative Proteomic Analysis of the Liver Reveals Potential Protein Targets of Xiaochaihutang in CUMS Model of Depression. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences 2021, 1181: 122898.

[32] Zhao J, Jung YH, Jin Y, Kang S, Jang CG, Lee J: A Comprehensive Metabolomics Investigation of Hippocampus, Serum, and Feces Affected by Chronic Fluoxetine Treatment Using the Chronic Unpredictable Mild Stress Mouse Model of Depression. Scientific Reports 2019, 9: 7566.

[33] Huang F, Pariante CM, Borsini A: From Dried Bear Bile to Molecular Investigation: A Systematic Review of the Effect of Bile Acids on Cell Apoptosis, Oxidative Stress and Inflammation in the Brain, Across Pre-clinical Models of Neurological, Neurodegenerative and Neuropsychiatric Disorders. Brain Behavior, and Immunity 2022, 99: 132-146.

[34] Nishimura M, Yaguti H, Yoshitsugu H, Naito S, Satoh T: Tissue Distribution of mRNA Expression of Human Cytochrome P450 Isoforms Assessedby High-Sensitivity Real-time Reverse Transcription PCR. Yakugaku Zasshi 2003, 123: 369-375.

[35] Ogundare M, Theofilopoulos S, Lockhart A, Hall LJ, Arenas E, Sjövall J, et al.: Cerebrospinal Fluid Steroidomics: are Bioactive Bile Acids Present in Brain? The Journal of Biological Chemistry 2010, 285: 4666-4679.

[36] Lund EG, Guileyardo JM, Russell DW: cDNA Cloning of Cholesterol 24-hydroxylase, a Mediator of Cholesterol Homeostasis in the Brain. Proceedings of the National Academy of Sciences of the United States of America 1999, 96: 7238-7243.

[37] Russell DW, Halford RW, Ramirez DM, Shah R, Kotti T: Cholesterol 24-hydroxylase: An Enzyme of Cholesterol Turnover in the Brain. Annual Review of Biochemistry 2009, 78: 1017-1040.

[38] Lund EG, Xie C, Kotti T, Turley SD, Dietschy JM, Russell DW: Knockout of the Cholesterol 24-hydroxylase Gene in Mice Reveals a Brain-specific Mechanism of Cholesterol Turnover. The Journal of Biological Chemistry 2003, 278: 22980-22988.

[39] Kotti TJ, Ramirez DM, Pfeiffer BE, Huber KM, Russell DW: Brain Cholesterol Turnover Required for Geranylgeraniol Production and Learning in Mice. Proceedings of the National Academy of Sciences of the United States of America 2006, 103: 3869-3874.

[40] Papassotiropoulos A, Streffer JR, Tsolaki M, Schmid S, Thal D, Nicosia F, et al.: Increased Brain β-amyloid Load, Phosphorylated Tau, and Risk of Alzheimer Disease Associated with an Intronic CYP46 Polymorphism. Archives of Neurology 2003, 60: 29-35.

[41] Boussicault L, Alves S, Lamazière A, Planques A, Heck N, Moumné L, et al.: CYP46A1, the Rate-limiting Enzyme for Cholesterol Degradation, is Neuroprotective in Huntington’s Disease. Brain 2016, 139: 953-970.

[42] Han M, Wang S, Yang N, Wang X, Zhao W, Saed HS, et al.: Therapeutic Implications of Altered Cholesterol Homeostasis Mediated by Loss of CYP46A1 in Human Glioblastoma. EMBO Molecular Medicine 2020, 12: e10924.

[43] Sun L, Xie C, Wang G, Wu Y, Wu Q, Wang X, et al.: Gut Microbiota and Intestinal FXR Mediate the Clinical Benefits of Metformin. Nature Medicine 2018, 24: 1919-1929.

[44] St-Pierre MV, Kullak-Ublick GA, Hagenbuch B, Meier PJ: Transport of Bile Acids in Hepatic and Non-hepatic Tissues. The Journal of Experimental Biology 2001, 204: 1673-1686.

[45] Kaur K, Allahbadia G, Singh M: An Update on Role of Bile Acids in Neurological Functions and Neurodegenerative Diseases: A Narrative Review. Journal of Clinical and Biomedical Investigation 2023, 3: 22-39.

[46] Choudhuri S, Cherrington NJ, Li N, Klaassen CD: Constitutive Expression of Various Xenobiotic and Endobiotic Transporter mRNAs in the Choroid Plexus of Rats. Drug Metabolism and Disposition 2003, 31: 1337-1345.

[47] Ose A, Kusuhara H, Endo C, Tohyama K, Miyajima M, Kitamura S, et al.: Functional Characterization of Mouse Organic Anion Transporting Peptide 1a4 in the Uptake and Efflux of Drugs Across the Blood-brain Barrier. Drug Metabolism and Disposition 2010, 38: 168-176.

[48] Nizamutdinov D, Demorrow S, Mcmillin M, Kain J, Mukherjee S, Zeitouni S, et al.: Hepatic Alterations are Accompanied by Changes to Bile Acid Transporter-expressing Neurons in the Hypothalamus after Traumatic Brain Injury. Scientific Reports 2017, 7: 40112.

[49] Quinn M, Mcmillin M, Galindo C, Frampton G, Pae HY, DeMorrow S: Bile Acids Permeabilize the Blood Brain Barrier after Bile Duct Ligation in Rats Via Rac1-dependent Mechanisms. Digestive and Liver Disease 2014, 46: 527-534.

[50] Chen WG, Zheng JX, Xu X, Hu YM, Ma YM: Hippocampal FXR Plays a Role in the Pathogenesis of Depression: A Preliminary Study Based on Lentiviral Gene Modulation. Psychiatry Research 2018, 264: 374-379.

[51] Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ: Distribution of the Vitamin D Receptor and 1α-hydroxylase in Human Brain. Journal of Chemical Neuroanatomy 2005, 29: 21-30.

[52] Kempf A, Tews B, Arzt ME, Weinmann O, Obermair FJ, Pernet V, et al.: The Sphingolipid Receptor S1PR2 is a Receptor for Nogo-A Repressing Synaptic Plasticity. PLoS Biology 2014, 12: e1001763.

[53] Vassileva G, Golovko A, Markowitz L, Abbondanzo SJ, Zeng M, Yang S, et al.: Targeted Deletion of Gpbar1 Protects Mice from Cholesterol Gallstone Formation. The Biochemical Journal 2006, 398: 423-430.

[54] Ma K, Saha PK, Chan L, Moore DD: Farnesoid X Receptor is Essential for Normal Glucose Homeostasis. Journal of Clinical Investigation 2006, 116: 1102-1109.

[55] Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ: Targeted Disruption of the Nuclear Receptor FXR/BAR Impairs Bile Acid and Lipid Homeostasis. Cell 2000, 102: 731-744.

[56] Yan N, Yan T, Xia Y, Hao H, Wang G, Gonzalez FJ: The Pathophysiological Function of Non-gastrointestinal Farnesoid X Receptor. Pharmacology & Therapeutics 2021, 226: 107867.

[57] Chen Q, Ma H, Guo X, Liu J, Gui T, Gai Z . Farnesoid X Receptor (FXR) Aggravates Amyloid-β-triggered Apoptosis by Modulating the cAMP-response Element-binding Protein (CREB)/Brain-derived Neurotrophic Factor (BDNF) Pathway In Vitro. Medical Science Monitor 2019, 25: 9335.

[58] Huang C, Wang J, Hu W, Wang C, Lu X, Tong L, et al.: Identification of Functional Farnesoid X Receptors in Brain Neurons. FEBS Letters 2016, 590: 3233-3242.

[59] Hu W, Wu J, Ye T, Chen Z, Tao J, Tong L, et al.: Farnesoid X Receptor-mediated Cytoplasmic Translocation of CRTC2 Disrupts CREB-BDNF Signaling in Hippocampal CA1 and Leads to the Development of Depression-like Behaviors in Mice. International Journal of Neuropsychopharmacology 2020, 23: 673-686.

[60] Riazi K, Galic MA, Kentner AC, Reid AY, Sharkey KA, Pittman QJ: Microglia-dependent Alteration of Glutamatergic Synaptic Transmission and Plasticity in the Hippocampus During Peripheral Inflammation. Journal of Neuroscience 2015, 35: 4942-4952.

[61] Lu C, Wei Z, Wang Y, Li S, Tong L, Liu X, et al.: Soy Isoflavones Alleviate Lipopolysaccharide-induced Depressive-like Behavior by Suppressing Neuroinflammation, Mediating Tryptophan Metabolism and Promoting Synaptic Plasticity. Food & Function 2022, 13: 9513-9522.

[62] Brites D, Fernandes A: Neuroinflammation and Depression: Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation. Frontiers in Cellular Neuroscience 2015, 9: 476.

[63] Zheng ZH, Tu JL, Li XH, Hua Q, Liu WZ, Liu Y, et al.: Neuroinflammation Induces Anxiety- and Depressive-like Behavior by Modulating Neuronal Plasticity in the Basolateral Amygdala. Brain, Behavior, and Immunity 2021, 91: 505-518.

[64] Correia AS, Cardoso A, Vale N: Oxidative Stress in Depression: The Link with the Stress Response, Neuroinflammation, Serotonin, Neurogenesis and Synaptic Plasticity. Antioxidants 2023, 12: 470.

[65] Butterworth RF: Neurosteroids in Hepatic Encephalopathy: Novel Insights and New Therapeutic Opportunities. The Journal of Steroid Biochemistry and Molecular Biology 2016, 160: 94-97.

[66] Keitel V, Görg B, Bidmon HJ, Zemtsova I, Spomer L, Zilles K, et al.: The Bile Acid Receptor TGR5 (Gpbar-1) Acts as a Neurosteroid Receptor in Brain. Glia 2010, 58: 1794-1805.

[67] Mcmillin M, Frampton G, Tobin R, Dusio G, Smith J, Shin H, et al.: TGR5 Signaling Reduces Neuroinflammation During Hepatic Encephalopathy. Journal of Neurochemistry 2015, 135: 565-576.

[68] Li XY, Zhang SY, Hong YZ, Chen ZG, Long Y, Yuan DH, et al.: TGR5-mediated Lateral Hypothalamus-dCA3-Dorsolateral Septum Circuit Regulates Depressive-Like Behavior in Male Mice. Neuron 2024, 112: 1795-1814.e10.

[69] Pols TW, Nomura M, Harach T, Lo Sasso G, Oosterveer MH, Thomas C, et al.: TGR5 Activation Inhibits Atherosclerosis by Reducing Macrophage Inflammation and Lipid Loading. Cell Metabolism 2011, 14: 747-757.

[70] Shi Y, Su W, Zhang L, Shi C, Zhou J, Wang P, et al.: TGR5 Regulates Macrophage Inflammation in Nonalcoholic Steatohepatitis by Modulating NLRP3 Inflammasome Activation. Frontiers in Immunology 2021, 11: 609060.

[71] Yoneno K, Hisamatsu T, Shimamura K, Kamada N, Ichikawa R, Kitazume MT, et al.: TGR 5 Signalling Inhibits the Production of Pro-inflammatory Cytokines by In Vitro Differentiated Inflammatory and Intestinal Macrophages in Crohn’s Disease. Immunology 2013, 139: 19-29.

[72] Kiriyama Y, Nochi H: The Biosynthesis, Signaling, and Neurological Functions of Bile Acids. Biomolecules 2019, 9: 232.

[73] Wang H, Tan Y-Z, Mu R-H, Tang SS, Liu X, Xing SY, et al.: Takeda G Protein-Coupled Receptor 5 Modulates Depression-like Behaviors Via Hippocampal CA3 Pyramidal Neurons Afferent to Dorsolateral Septum. Biological Psychiatry 2021, 89: 1084-1095.

[74] Yanguas-Casás N, Barreda-Manso MA, Nieto-Sampedro M, Romero-Ramírez L: TUDCA: An Agonist of the Bile Acid Receptor GPBAR1/TGR5 With Anti-inflammatory Effects in Microglial Cells. Journal of Cellular Physiology 2017, 232: 2231-2245.

[75] Wu X, Lv YG, Du YF, Chen F, Reed MN, Hu M, et al.: Neuroprotective Effects of INT-777 Against Aβ1-42-induced Cognitive Impairment, Neuroinflammation, Apoptosis, and Synaptic Dysfunction in Mice. Brain, Behavior, and Immunity 2018, 73: 533-545.

[76] Lu X, Yang RR, Zhang JL, Wang P, Gong Y, Hu WF, et al.: Tauroursodeoxycholic Acid Produces Antidepressant-like Effects in a Chronic Unpredictable Stress Model of Depression Via Attenuation of Neuroinflammation, Oxido-nitrosative Stress, and Endoplasmic Reticulum Stress. Fundamental & Clinical Pharmacology 2018, 32: 363-377.

[77] Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al.: Neurotoxic Reactive Astrocytes are Induced by Activated Microglia. Nature 2017, 541: 481-487.

[78] Bhargava P, Smith MD, Mische L, Harrington E, Fitzgerald KC, Martin K, et al.: Bile Acid Metabolism is Altered in Multiple Sclerosis and Supplementation Ameliorates Neuroinflammation. Journal of Clinical Investigation 2020, 130: 3467-3482.

[79] Sun XC, Ren XF, Chen L, Gao XQ, Xie JX, Chen WF: Glucocorticoid Receptor is Involved in the Neuroprotective Effect of Ginsenoside Rg1 Against Inflammation-induced Dopaminergic Neuronal Degeneration in Substantia Nigra. Journal of Steroid Biochemistry and Molecular Biology 2016, 155: 94-103.

[80] Schweingruber N, Reichardt SD, Luhder F, Reichardt HM: Mechanisms of Glucocorticoids in the Control of Neuroinflammation. Journal of Neuroendocrinology 2012, 24: 174-182.

[81] Mcmillin M, Frampton G, Quinn M, Divan A, Grant S, Patel N, et al.: Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling. Molecular Endocrinology (Baltimore, Md.) 2015, 29: 1720-1730.

[82] Lee MH, Nuccio SP, Mohanty I, Hagey LR, Dorrestein PC, Chu H, et al.: How Bile Acids and the Microbiota Interact to Shape Host Immunity. Nature Reviews Immunology 2024, 24: 798-809.

[83] Mcguckin MA, Eri R, Simms LA, Florin TH, Radford-Smith G: Intestinal Barrier Dysfunction in Inflammatory Bowel Diseases. Inflammatory Bowel Diseases 2009, 15: 100-113.

[84] Shen L, Su L, Turner JR: Mechanisms and Functional Implications of Intestinal Barrier Defects. Digestive Diseases 2009, 27: 443-449.

[85] Linden S, Sutton P, Karlsson N, Korolik V, McGuckin MA: Mucins in the Mucosal Barrier to Infection. Mucosal Immunology 2008, 1: 183-197.

[86] Bergstrom KS, Xia L: Mucin-type O-glycans and their Roles in Intestinal Homeostasis. Glycobiology 2013, 23: 1026-1037.

[87] Tanabe S, Suzuki T, Wasano Y, Nakajima F, Kawasaki H, Tsuda T, et al.: Anti-inflammatory and Intestinal Barrier-protective Activities of Commensal Lactobacilli and Bifidobacteria in Thoroughbreds: Role of Probiotics in Diarrhea Prevention in Neonatal Thoroughbreds. Journal of Equine Science 2014, 25: 37-43.

[88] Koboziev I, Karlsson F, Grisham MB: Gut-associated Lymphoid Tissue, T Cell Trafficking, and Chronic Intestinal Inflammation. Annals of the New York Academy of Sciences 2010, 1207: E86-E93.

[89] Sun Q, Shang Y, She R, Jiang T, Wang D, Ding Y, et al.: Detection of Intestinal Intraepithelial Lymphocytes, Goblet Cells and Secretory IgA in the Intestinal Mucosa During Newcastle Disease Virus Infection. Avian Pathology 2013, 42: 541-545.

[90] Medina-Rodríguez EM, Martínez-Raga J, Sanz Y: Intestinal Barrier, Immunity and Microbiome: Partners in the Depression Crime. Pharmacological Reviews 2024, 76: 956-969.

[91] Yang B, Sun T, Chen Y, Xiang H, Xiong J, Bao S: The Role of Gut Microbiota in Mice With Bile Duct Ligation-Evoked Cholestatic Liver Disease-Related Cognitive Dysfunction. Frontiers in Microbiology 2022, 13: 909461.

[92] Goossens E, Li J, Callens C, Van Rysselberghe N, Kettunen H, Vuorenmaa J, et al.: Acute Endotoxemia-induced Respiratory and Intestinal Dysbiosis. International Journal of Molecular Sciences 2022, 23: 11602.

[93] Zhang X-P, Zhang J, Song QL, Chen HQ: Mechanism of Acute Pancreatitis Complicated with Injury of Intestinal Mucosa Barrier. Journal of Zhejiang University Science B 2007, 8: 888-895.

[94] Wei C, Jiang W, Wang R, Zhong H, He H, Gao X, et al.: Brain Endothelial GSDMD Activation Mediates Inflammatory BBB Breakdown. Nature 2024, 629: 1-8.

[95] Kelly JR, Kennedy PJ, Cryan JF, Dinan TG, Clarke G, Hyland NP: Breaking Down the Barriers: The Gut Microbiome, Intestinal Permeability and Stress-related Psychiatric Disorders. Frontiers In Cellular Neuroscience 2015, 9: 392.

[96] Ma Y, Huang Z, Li C: The Bile Acids Specifically Modulate Colonic MUC2 and Tight Junction Protein Expression in the Human Colon Cancer Cell Line. Current Developments in Nutrition 2021, 5: 33.

[97] Sorrentino G, Perino A, Yildiz E, El Alam G, Bou Sleiman M, Gioiello A, et al.: Bile Acids Signal Via TGR5 to Activate Intestinal Stem Cells and Epithelial Regeneration. Gastroenterology 2020, 159: 956-968. e8.

[98] Ji C-G, Xie XL, Yin J, Qi W, Chen L, Bai Y, et al.: Bile Acid Receptor TGR5 Overexpression is Associated with Decreased Intestinal Mucosal Injury and Epithelial Cell Proliferation in Obstructive Jaundice. Translational Research 2017, 182: 88-102.

[99] Ward JB, Mroz MS, Keely SJ: The Bile Acid Receptor, TGR 5, Regulates Basal And Cholinergic-induced Secretory Responses in Rat Colon. Neurogastroenterology & Motility 2013, 25: 708-711.

[100] Verbeke L, Farre R, Verbinnen B, Covens K, Vanuytsel T, Verhaegen J, et al.: The FXR Agonist Obeticholic Acid Prevents Gut Barrier Dysfunction and Bacterial Translocation in Cholestatic Rats. The American Journal of Pathology 2015, 185: 409-419.

[101] Volksdorf T, Heilmann J, Eming SA, Schawjinski K, Zorn-Kruppa M, Ueck C, et al.: Tight Junction Proteins Claudin-1 and Occludin are Important for Cutaneous Wound Healing. The American Journal of Pathology 2017, 187: 1301-1312.

[102] Gadaleta RM, Oldenburg B, Willemsen EC, Spit M, Murzilli S, Salvatore L, et al.: Activation of Bile Salt Nuclear Receptor FXR is Repressed by Pro-inflammatory Cytokines Activating NF-κB Signaling in the Intestine. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 2011, 1812: 851-858.

[103] Ceulemans LJ, Verbeke L, Decuypere JP, Farré R, De Hertogh G, Lenaerts K, et al.: Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats. PLoS One 2017, 12: e0169331.

[104] Speight RA, Davey T, White K, Kirby JA, Mansfield JC: PTH-066 Activation of the Bile Acid Receptor, Farnesoid-x Receptor, Maintains Gut Epithelial Cell Morphology, Possibly via Inhibition of Myosin Light Chain Kinase Expression. Gut 2015, 64: A435.

[105] Baars A, Oosting A, Knol J, Garssen J, van Bergenhenegouwen J: The Gut Microbiota as a Therapeutic Target in IBD and Metabolic Disease: A Role for the Bile Acid Receptors FXR and TGR5. Microorganisms 2015, 3: 641-666.

[106] Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS: Bile Acids and the Gut Microbiome. Current Opinion in Gastroenterology 2014, 30: 332-338.

[107] Zheng M, Zhai Y, Yu Y, Shen J, Chu S, Focaccia E, et al.: TNF Compromises Intestinal Bile-Acid Tolerance Dictating Colitis Progression and Limited Infliximab Response. Cell Metabolism 2024, 36: 2086-2103.e9.

[108] Zweers SJ, de Vries EM, Lenicek M, Tolenaars D, de Waart DR, Koelfat KV, et al.: Prolonged Fibroblast Growth Factor 19 Response in Patients with Primary Sclerosing Cholangitis After an Oral Chenodeoxycholic Acid Challenge. Hepatology International 2017, 11: 132-140.

[109] Zhang J, Li H, Zhou H, Fang L, Xu J, Yan H, et al.: Lowered Fasting Chenodeoxycholic Acid Correlated with the Decrease of Fibroblast Growth Factor 19 in Chinese Subjects with Impaired Fasting Glucose. Scientific Reports 2017, 7: 6042.

[110] Beenken A, Mohammadi M: The FGF Family: Biology, Pathophysiology and Therapy. Nature Reviews. Drug Discovery 2009, 8: 235-253.

[111] Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, et al.: Fibroblast Growth Factor 15 Functions as an Enterohepatic Signal to Regulate Bile Acid Homeostasis. Cell Metabolism 2005, 2: 217-225.

[112] Galvez-Contreras AY, Campos-Ordonez T, Lopez-Virgen V, Gomez-Plascencia J, Ramos-Zuniga R, Gonzalez-Perez O: Growth Factors as Clinical Biomarkers of Prognosis and Diagnosis in Psychiatric Disorders. Cytokine & Growth Factor Reviews 2016, 32: 85-96.

[113] Tian F, Xu W, Chen L, Chen T, Feng X, Chen J, et al.: Ginsenoside Compound K Increases Glucagon-Like Peptide-1 Release and L-cell Abundance in db/db Mice Through TGR5/YAP Signaling. International Immunopharmacology 2022, 113: 109405.

[114] Hui S, Huang L, Wang X, Zhu X, Zhou M, Chen M, et al.: Capsaicin Improves Glucose Homeostasis by Enhancing Glucagon-like Peptide-1 Secretion Through the Regulation of Bile Acid Metabolism via the Remodeling of the Gut Microbiota in Male Mice. FASEB Journal 2020, 34: 8558-8573.

[115] Kuhre RE, Wewer Albrechtsen NJ, Larsen O, Jepsen SL, Balk-Møller E, Andersen DB, et al.: Bile Acids are Important Direct and Indirect Regulators of the Secretion of Appetite- and Metabolism-regulating Hormones from the Gut and Pancreas. Molecular Metabolism 2018, 11: 84-95.

[116] Guerrero-Hreins E, Goldstone AP, Brown RM, Sumithran P: The Therapeutic Potential of GLP-1 Analogues for Stress-related Eating and Role of GLP-1 in Stress, Emotion and Mood: A Review. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2021, 110: 110303.

[117] Chen X, Zhao P, Wang W, Guo L, Pan Q: The Antidepressant Effects of GLP-1 Receptor Agonists: A Systematic Review and Meta-Analysis. The American Journal of Geriatric Psychiatry 2024, 32: 117-127.

[118] Jin M, Zhang S, Huang B, Li L, Liang H, Ni A, et al.: Dulaglutide Treatment Reverses Depression-like Behavior and Hippocampal Metabolomic Homeostasis in Mice Exposed to Chronic Mild Stress. Brain and Behavior 2024, 14: e3448.

[119] Sharma AN, Ligade SS, Sharma JN, Shukla P, Elased KM, Lucot JB: GLP-1 Receptor Agonist Liraglutide Reverses Long-term Atypical Antipsychotic Treatment Associated Behavioral Depression and Metabolic Abnormalities in Rats. Metabolic Brain Disease 2015, 30: 519-527.

[120] Weina H, Yuhu N, Christian H, Birong L, Feiyu S, Le W: Liraglutide Attenuates the Depressive- and Anxiety-like Behaviour in the Corticosterone Induced Depression Model via Improving Hippocampal Neural Plasticity. Brain Research 2018, 1694: 55-62.

[121] Çiçekli MN, Tiryaki ES, Altun A, Günaydin C: GLP-1 Agonist Liraglutide Improves Ouabain-induced Mania and Depressive State via GSK-3β Pathway. Journal of Receptor and Signal Transduction Research 2022, 42: 486-494.

[122] Yang F, Wang X, Qi J, Zhang K, Jiang Y, Feng B, et al.: Glucagon-like Peptide 1 Receptor Activation Inhibits Microglial Pyroptosis via Promoting Mitophagy to Alleviate Depression-like Behaviors in Diabetic Mice. Nutrients 2022, 15: 38.

[123] Wei W, Liu Y, Hou Y, Cao S, Chen Z, Zhang Y, et al.: Psychological Stress-Induced Microbial Metabolite Indole-3-acetate Disrupts Intestinal Cell Lineage Commitment. Cell Metabolism 2024, 36: 466-483.e7.

[124] Awoniyi M, Wang J, Ngo B, Meadows V, Tam J, Viswanathan A, et al.: Protective and Aggressive Bacterial Subsets and Metabolites Modify Hepatobiliary Inflammation and Fibrosis in a Murine Model of PSC. Gut 2023, 72: 671-685.

[125] Nikolova VL, Cleare AJ, Young AH, Stone JM: Acceptability, Tolerability, and Estimates of Putative Treatment Effects of Probiotics as Adjunctive Treatment in Patients with Depression: A Randomized Clinical Trial. JAMA Psychiatry 2023, 80: 842-847.

[126] Liu P, Liu Z, Wang J, Gao M, Zhang Y, Yang C, et al.: Immunoregulatory Role of the Gut Microbiota in Inflammatory Depression. Nature Communications 2024, 15: 3003.

[127] Liu L, Wang H, Chen X, Zhang Y, Zhang H, Xie P: Gut Microbiota and Its Metabolites in Depression: from Pathogenesis to Treatment. EBioMedicine 2023, 90: 104527.

[128] Lv WJ, Wu XL, Chen WQ, Li YF, Zhang GF, Chao LM, et al.: The Gut Microbiome Modulates the Changes in Liver Metabolism and in Inflammatory Processes in the Brain of Chronic Unpredictable Mild Stress Rats. Oxidative Medicine and Cellular Longevity 2019: 7902874.

[129] Guo C, Li Y, Wang P, Li Y, Qiu C, Li M, et al.: Alterations of Gut Microbiota in Cholestatic Infants and Their Correlation with Hepatic Function. Frontiers in Microbiology 2018, 9: 2682.

[130] Li GH, Huang SJ, Li X, Liu XS, Du QL: Response of Gut Microbiota to Serum Metabolome Changes in Intrahepatic Cholestasis of Pregnant Patients. World Journal of Gastroenterology 2020, 26: 7338.

[131] Lajczak-Mcginley NK, Porru E, Fallon CM, Smyth J, Curley C, McCarron PA, et al.: The Secondary Bile Acids, Ursodeoxycholic Acid and Lithocholic Acid, Protect Against Intestinal Inflammation by Inhibition of Epithelial Apoptosis. Physiological Reports 2020, 8: e14456.

[132] Fitzpatrick LR, Jenabzadeh P: IBD and Bile Acid Absorption: Focus on Pre-clinical and Clinical Observations. Frontiers in Physiology 2020, 11: 564.

[133] Zheng L: New Insights into the Interplay between Intestinal Flora and Bile Acids in Inflammatory Bowel Disease. World Journal of Clinical Cases 2022, 10: 10823-10839.

[134] Kurdi P, Kawanishi K, Mizutani K, Yokota A: Mechanism of Growth Inhibition by Free Bile Acids in Lactobacilli and Bifidobacteria. Journal of Bacteriology 2006, 188: 1979-1986.

[135] Foley MH, O’Flaherty S, Allen G, Rivera AJ, Stewart AK, Barrangou R, et al.: Lactobacillus Bile Salt Hydrolase Substrate Specificity Governs Bacterial Fitness and Host Colonization . Proceedings of the National Academy of Sciences of the United States of America 2021, 118: e2017709118.

[136] Islam KB, Fukiya S, Hagio M, Fujii N, Ishizuka S, Ooka T, et al.: Bile Acid is a Host Factor that Regulates the Composition of the Cecal Microbiota in Rats. Gastroenterology 2011, 141: 1773-1781.

[137] Little R, Wine E, Kamath BM, Griffiths AM, Ricciuto A: Gut Microbiome in Primary Sclerosing Cholangitis: A Review. World J Gastroenterology 2020, 26: 2768-2780.

[138] Feng P, Li Q, Liu L, Wang S, Wu Z, Tao Y, et al.: Crocetin Prolongs Recovery Period of DSS-Induced Colitis via Altering Intestinal Microbiome and Increasing Intestinal Permeability. International Journal of Molecular Sciences 2022, 23: 3832.

[139] Murakami M, Iwamoto J, Honda A, Tsuji T, Tamamushi M, Ueda H, et al.: Detection of Gut Dysbiosis Due to Reduced Clostridium Subcluster XIVa Using the Fecal or Serum Bile Acid Profile. Inflammatory Bowel Diseases 2018, 24: 1035-1044.

[140] Hang S, Paik D, Yao L, Kim E, Trinath J, Lu J, et al.: Bile Acid Metabolites Control T_H17 and T_reg Cell Differentiation . Nature 2019, 576: 143-148.

[141] Campbell C, Mckenney PT, Konstantinovsky D, Isaeva OI, Schizas M, Verter J, et al.: Bacterial Metabolism of Bile Acids Promotes Generation of Peripheral Regulatory T Cells. Nature 2020, 581: 475-479.

[142] Caspani G, Corbet Burcher G, Garralda ME, Cooper M, Pierce CM, Als LC, et al.: Inflammation and Psychopathology in Children Following PICU Admission: An Exploratory Study. Evidence-Based Mental Health 2018, 21: 139-144.

[143] Mann ER, Lam YK, Uhlig HH: Short-chain Fatty Acids: Linking Diet, the Microbiome and Immunity. Nature Reviews Immunology 2024, 24: 577-595.

[144] Agus A, Planchais J, Sokol H: Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease. Cell Host & Microbe 2018, 23: 716-724.

[145] Yano JM, Yu K, Donaldson GP, Shastri GG, Ann P, Ma L, et al.: Indigenous Bacteria from the Gut Microbiota Regulate Host Serotonin Biosynthesis. Cell 2015, 161: 264-276.

[146] Larrosa M, Luceri C, Vivoli E, Pagliuca C, Lodovici M, Moneti G, et al.: Polyphenol Metabolites from Colonic Microbiota Exert Anti-inflammatory Activity on Different Inflammation Models. Molecular Nutrition & Food Research 2009, 53: 1044-1054.

[147] Denis MC, Furtos A, Dudonne S, Montoudis A, Garofalo C, Desjardins Y, et al.: Apple Peel Polyphenols and Their Beneficial Actions on Oxidative Stress and Inflammation. PLoS One 2013, 8: e53725.

[148] Huang C, Ming D, Wang W, Wang Z, Hu Y, Ma X, et al.: Pyrroloquinoline Quinone Alleviates Jejunal Mucosal Barrier Function Damage and Regulates Colonic Microbiota in Piglets Challenged with Enterotoxigenic Escherichia coli . Frontiers in Microbiology 2020, 11: 1754.

[149] Nunes C, Teixeira N, Serra D, Freitas V, Almeida L, Laranjinha J: Red Wine Polyphenol Extract Efficiently Protects Intestinal Epithelial Cells from Inflammation via Opposite Modulation of JAK/STAT and Nrf2 Pathways. Toxicology Research, 2016, 5: 53-65.