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Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut–brain pathways

Published online by Cambridge University Press:  26 August 2015

Marta Martin-Subero ,
George Anderson ,
Buranee Kanchanatawan ,
Michael Berk  and
Michael Maes
Marta Martin-Subero*
Affiliation:
Department of Psychiatry, Hospital Universitari Germans Trias I Pujol, Badalona, Spain Department of Psychiatry, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
George Anderson
Affiliation:
Department of Psychiatry, CRC, Glasgow, UK
Buranee Kanchanatawan
Affiliation:
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Michael Berk
Affiliation:
Department of Psychiatry, University of Melbourne, Parkville, Victoria, Australia School of Medicine, Deakin University, Geelong, Victoria, Australia Orygen Youth Health Research Centre, Centre for Youth Mental Health, University of Melbourne, Parkville, Australia Barwon Health and the Geelong Clinic, Swanston Centre, Geelong, Victoria, Australia
Michael Maes
Affiliation:
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand School of Medicine, Deakin University, Geelong, Victoria, Australia Department of Psychiatry, Health Sciences Center, Londrina State University, University Hospital, Londrina, Paraná, Brazil
*
*Address for correspondence: Marta Martin-Subero, Department of Psychiatry, Hospital Universitari Germans Trias I Pujol, Badalona, Spain (Email: marta.martin.subero@gmail.com).
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Abstract

The nature of depression has recently been reconceptualized, being conceived as the clinical expression of activated immune-inflammatory, oxidative, and nitrosative stress (IO&NS) pathways, including tryptophan catabolite (TRYCAT), autoimmune, and gut–brain pathways. IO&NS pathways are similarly integral to the pathogenesis of inflammatory bowel disease (IBD). The increased depression prevalence in IBD associates with a lower quality of life and increased morbidity in IBD, highlighting the role of depression in modulating the pathophysiology of IBD.This review covers data within such a wider conceptualization that better explains the heightened co-occurrence of IBD and depression. Common IO&NS underpinning between both disorders is evidenced by increased pro-inflammatory cytokine levels, eg, interleukin-1 (IL-1) and tumor necrosis factor-α, IL-6 trans-signalling; Th-1- and Th-17-like responses; neopterin and soluble IL-2 receptor levels; positive acute phase reactants (haptoglobin and C-reactive protein); lowered levels of negative acute phase reactants (albumin, transferrin, zinc) and anti-inflammatory cytokines (IL-10 and transforming growth factor-β); increased O&NS with damage to lipids, proteinsm and DNA; increased production of nitric oxide (NO) and inducible NO synthase; lowered plasma tryptophan but increased TRYCAT levels; autoimmune responses; and increased bacterial translocation. As such, heightened IO&NS processes in depression overlap with the biological underpinnings of IBD, potentially explaining their increased co-occurrence. This supports the perspective that there is a spectrum of IO&NS disorders that includes depression, both as an emergent comorbidity and as a contributor to IO&NS processes. Such a frame of reference has treatment implications for IBD when “comorbid” with depression.

Keywords

Comorbidityhaptoglobinimmunologyinflammatory bowel diseasemajor depressionoxidative stress
Type
Review Articles
Information
CNS Spectrums , Volume 21 , Issue 2 , April 2016 , pp. 184 - 198
Copyright
© Cambridge University Press 2015 

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Footnotes

†

M.B. is supported by a NHMRC Senior Principal Research Fellowship 1059660. M.M. wants to thank the Fundación Española de Psiquiatría y Salud Mental.

References

1.Mittermaier, C, Dejaco, C, Waldhoer, T, et al. Impact of depressive mood on relapse in patients with inflammatory bowel disease: a prospective 18-month follow-up study. Psychosom Med. 2004; 66(1): 79–84.Google Scholar
2.Loftus, EV Jr. Management of extraintestinal manifestations and other complications of inflammatory bowel disease. Curr Gastroenterol Rep. 2004; 6(6): 506–513.Google Scholar
3.Podolsky, DK. Inflammatory bowel disease. N Engl J Med. 2002; 347(6): 417–429.Google Scholar
4.Scheib, P, Wirsching, M. Psychosomatic aspects of inflammatory bowel diseases. Fortschr Med. 1991; 109(12): 258–260.Google Scholar
5.Ramchandani, D, Schindler, B, Katz, J. Evolving concepts of psychopathology in inflammatory bowel disease: implications for treatment. Med Clin North Am. 1994; 78(6): 1321–1330.Google Scholar
6.Anderson, G, Maes, M. Oxidative/nitrosative stress and immuno-inflammatory pathways in depression: treatment implications. Curr Pharm Des. 2014; 20(23): 3812–3847.CrossRefGoogle ScholarPubMed
7.Andrews, H, Barczak, P, Allan, RN. Psychiatric illness in patients with inflammatory bowel disease. Gut. 1987; 28(12): 1600–1604.Google Scholar
8.Helzer, JE, Stillings, WA, Chammas, S, Norland, CC, Alpers, DH. A controlled study of the association between ulcerative colitis and psychiatric diagnoses. Dig Dis Sci. 1982; 27(6): 513–518.Google Scholar
9.Helzer, JE, Chammas, S, Norland, CC, Stillings, WA, Alpers, DH. A study of the association between Crohn’s disease and psychiatric illness. Gastroenterology. 1984; 86(2): 324–330.Google Scholar
10.Walker, EA, Gelfand, MD, Gelfand, AN, Creed, F, Katon, WJ. The relationship of current psychiatric disorder to functional disability and distress in patients with inflammatory bowel disease. Gen Hosp Psychiatry. 1996; 18(4): 220–229.Google Scholar
11.Walker, JR, Ediger, JP, Graff, LA, et al. The Manitoba IBD cohort study: a population-based study of the prevalence of lifetime and 12-month anxiety and mood disorders. Am J Gastroenterol. 2008; 103(8): 1989–1997.CrossRefGoogle ScholarPubMed
12.Leonard, B, Maes, M. Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev. 2012; 36(2): 764–785.CrossRefGoogle ScholarPubMed
13.Papp, M, Lakatos, PL, Hungarian IBD Study Group, et al. Haptoglobin polymorphisms are associated with Crohn’s disease, disease behavior, and extraintestinal manifestations in Hungarian patients. Dig Dis Sci. 2007; 52(5): 1279–1284.CrossRefGoogle ScholarPubMed
14.Addolorato, G, Capristo, E, Stefanini, GF, Gasbarrini, G. Inflammatory bowel disease: a study of the association between anxiety and depression, physical morbidity, and nutritional status. Scand J Gastroenterol. 1997; 32(10): 1013–1021.CrossRefGoogle ScholarPubMed
15.Kurina, LM, Goldacre, MJ, Yeates, D, Gill, LE. Depression and anxiety in people with inflammatory bowel disease. J Epidemiol Community Health. 2001; 55(10): 716–720.CrossRefGoogle ScholarPubMed
16.Iglesias, M, Barreiro de Acosta, M, Vázquez, I, et al. Psychological impact of Crohn’s disease on patients in remission: anxiety and depression risks. Rev Esp Enferm Dig. 2009; 101(4): 249–257.Google Scholar
17.Hlavaty, T, Krajcovicova, A, Koller, T, et al. Higher vitamin D serum concentration increases health related quality of life in patients with inflammatory bowel diseases. World J Gastroenterol. 2014; 20(42): 15787–15796.CrossRefGoogle ScholarPubMed
18.Kerr, DC, Zava, DT, Piper, WT, Saturn, SR, Frei, B, Gombart, AF. Associations between vitamin D levels and depressive symptoms in healthy young adult women. Psychiatry Res. 2015; 227(1): 46–51.Google Scholar
19.Walker, JR, Graff, LA, Dutz, JP, Bernstein, CN. Psychiatric disorders in patients with immune-mediated inflammatory diseases: prevalence, association with disease activity, and overall patient well-being. J Rheumatol Suppl. 2011; 88: 31–35.Google Scholar
20.Mayer, EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci. 2011; 12(8): 453–466.Google Scholar
21.Collins, SM, Surette, M, Bercik, P. The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol. 2012; 10(11): 735–742.CrossRefGoogle ScholarPubMed
22.Bested, AC, Logan, AC, Selhub, EM. Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: Part I—autointoxication revisited. Gut Pathog. 2013; 5(1): 5.Google Scholar
23.Di Mauro, A, Neu, J, Riezzo, G, et al. Gastrointestinal function development and microbiota. Ital J Pediatr. 2013; 39: 15.Google Scholar
24.Shen, W, Gaskins, HR, McIntosh, MK. Influence of dietary fat on intestinal microbes, inflammation, barrier function and metabolic outcomes. J Nutr Biochem. 2013; 25(3): 270–280.CrossRefGoogle ScholarPubMed
25.Ghanizadeh, A, Berk, M. Molecular hydrogen: an overview of its neurobiological effects and therapeutic potential for bipolar disorder and schizophrenia. Med Gas Res. 2013; 3(1): 11.Google Scholar
26.Guo, S, Al-Sadi, R, Said, HM, Ma, TY. Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14. Am J Pathol. 2013; 182(2): 375–387.Google Scholar
27.Fasano, A. Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications. Clin Gastroenterol Hepatol. 2012; 10(10): 1096–1100.Google Scholar
28.Wiest, R, Garcia-Tsao, G. Bacterial translocation (BT) in cirrhosis. Hepatology. 2005; 41(3): 422–433.Google Scholar
29.Anderson, G, Berk, M, Maes, M. Biological phenotypes underpin the physio-somatic symptoms of somatization, depression, and chronic fatigue syndrome. Acta Psychiatr Scand. 2014; 129(2): 83–97.Google Scholar
30.Maes, M, Bosmans, E, Suy, E, Vandervorst, C, De Jonckheere, C, Raus, J. Immune disturbances during major depression: upregulated expression of interleukin-2 receptors. Neuropsychobiology. 1990–1991; 24(3): 115–120.Google Scholar
31.Maes, M, Vandoolaeghe, E, Ranjan, R, Bosmans, E, Bergmans, R, Desnyder, R. Increased serum interleukin-1-receptor-antagonist concentrations in major depression. J Affect Disord. 1995; 36(1–2): 29–36.Google Scholar
32.Dowlati, Y, Herrmann, N, Swardfager, W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010; 67(5): 446–457.Google Scholar
33.Caraci, F, Spampinato, S, Sortino, MA, et al. Dysfunction of TGF-β1 signaling in Alzheimer’s disease: perspectives for neuroprotection. Cell Tissue Res. 2012; 347(1): 291–301.Google Scholar
34.Musil, R, Schwarz, MJ, Riedel, M, et al. Elevated macrophage migration inhibitory factor and decreased transforming growth factor-beta levels in major depression—no influence of celecoxib treatment. J Affect Disord. 2011; 134(1–3): 217–225.Google Scholar
35.Holtzman, S, Abbey, SE, Chan, C, Bargman, JM, Stewart, DE. A genetic predisposition to produce low levels of IL-10 is related to depressive symptoms: a pilot study of patients with end stage renal disease. Psychosomatics. 2012; 53(2): 155–161.CrossRefGoogle ScholarPubMed
36.Roque, S, Correia-Neves, M, Mesquita, AR, Palha, JA, Sousa, N. Interleukin-10: a key cytokine in depression? Cardiovasc Psychiatry Neurol. 2009; 2009: 187894.Google Scholar
37.Maes, M, Anderson, G, Kubera, M, Berk, M. Targeting classical IL-6 signalling or IL-6 trans-signalling in depression? Expert Opin Ther Targets. 2014; 18(5): 495–512.Google Scholar
38.Maes, M, Leonard, BE, Myint, AM, Kubera, M, Verkerk, R. The new “5-HT” hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35(3): 702–721.Google Scholar
39.Maes, M. Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35(3): 664–675.Google Scholar
40.Beurel, E, Harrington, LE, Jope, RS. Inflammatory T helper 17 cells promote depression-like behavior in mice. Biol Psychiatry. 2013; 73(7): 622–630.CrossRefGoogle ScholarPubMed
41.Wong, CK, Cao, J, Yin, YB, Lam, CWK. Interleukin-17A activation on bronchial epithelium and basophils: a novel inflammatory mechanism. Eur Respir J. 2010; 35(4): 883–893.Google Scholar
42.Maes, M, Scharpe, S, Bosmans, E, et al. Disturbances in acute phase plasma proteins during melancholia: additional evidence for the presence of an inflammatory process during that illness. Prog Neuropsychopharmacol Biol Psychiatry. 1992; 16(4): 501–515.CrossRefGoogle ScholarPubMed
43.Sluzewska, A, Rybakowski, J, Bosmans, E, et al. Indicators of immune activation in major depression. Psychiatry Res. 1996; 64(3): 161–167.Google Scholar
44.Fãnanás, L, Moral, P, Gutiérrez, B, et al. Haptoglobin phenotypes and gene frequencies in bipolar disorder: an association study in family-history subgroups. Hum Hered. 1997; 47(1): 27–32.Google Scholar
45.Maes, M, Vandoolaeghe, E, Neels, H, et al. Lower serum zinc in major depression is a sensitive marker of treatment resistance and of the immune/inflammatory response in that illness. Biol Psychiatry. 1997; 42(5): 349–358.CrossRefGoogle ScholarPubMed
46.Nowak, G, Szewczyk, B, Pilc, A. Zinc and depression: an update. Pharmacol Rep. 2005; 57(6): 713–718.Google ScholarPubMed
47.Song, C, Dinan, T, Leonard, BE. Changes in immunoglobulin, complement and acute phase protein levels in the depressed patients and normal controls. J Affect Disord. 1994; 30(4): 283–288.Google Scholar
48.Berk, M, Wadee, AA, Kuschke, RH, O’Neill-Kerr, A. Acute phase proteins in major depression. J Psychosom Res. 1997; 43(5): 529–534.CrossRefGoogle ScholarPubMed
49.Maes, M, Galecki, P, Chang, YS, Berk, M. A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35(3): 676–692.Google Scholar
50.Michel, TM, Frangou, S, Camara, S, et al. Altered glial cell line-derived neurotrophic factor (GDNF) concentrations in the brain of patients with depressive disorder: a comparative post-mortem study. Eur Psychiatry. 2008; 23(6): 413–420.Google Scholar
51.Massudi, H, Grant, R, Braidy, N, Guest, J, Farnsworth, B, Guillemin, GJ. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One. 2012; 7(7): e42357.Google Scholar
52.Rybka, J, Kędziora-Kornatowska, K, Banaś-Leżańska, P, et al. Interplay between the pro-oxidant and antioxidant systems and proinflammatory cytokine levels, in relation to iron metabolism and the erythron in depression. Free Radic Biol Med. 2013; 63: 187–194.Google Scholar
53.Phillips, AC, Robertson, T, Carroll, D, et al. Do symptoms of depression predict telomere length? Evidence from the west of Scotland twenty-07 study. Psychosom Med. 2013; 75(3): 288–296.CrossRefGoogle ScholarPubMed
54.Wolkowitz, OM, Mellon, SH, Epel, ES, et al. Leukocyte telomere length in major depression: correlations with chronicity, inflammation and oxidative stress—preliminary findings. PLoS One. 2011; 6(3): e17837.Google Scholar
55.Maes, M, Kubera, M, Mihaylova, I, et al. Increased autoimmune responses against auto-epitopes modified by oxidative and nitrosative damage in depression: implications for the pathways to chronic depression and neuroprogression. J Affect Disord. 2013; 149(1–3): 23–29.CrossRefGoogle ScholarPubMed
56.Jacka, FN, Pasco, JA, Mykletun, A, et al. Association of Western and traditional diets with depression and anxiety in women. Am J Psychiatry. 2010; 167(3): 305–311.Google Scholar
57.Deberdt, R, Van Hooren, J, Biesbrouck, M, Amery, W. Antinuclear factor-positive mental depression: a single disease entity? Biol Psychiatry. 1976; 11(1): 69–74.Google Scholar
58.Maes, M, Meltzer, H, Jacobs, J, et al. Autoimmunity in depression: increased antiphospholipid autoantibodies. Acta Psychiatr Scand. 1993; 87(3): 160–166.CrossRefGoogle ScholarPubMed
59.Maes, M, Bosmans, E, Suy, E, Vandervorst, C, DeJonckheere, C, Raus, J. Depression-related disturbances in mitogen-induced lymphocyte responses and interleukin-1 beta and soluble interleukin-2 receptor production. Acta Psychiatr Scand. 1991; 84(4): 379–386.Google Scholar
60.Lapteva, L, Nowak, M, Yarboro, CH, et al. Anti-N-methyl-D-aspartate receptor antibodies, cognitive dysfunction, and depression in systemic lupus erythematosus. Arthritis Rheum. 2006; 54(8): 2505–2514.Google Scholar
61.Karimifar, M, Sharifi, I, Shafiey, K. Anti-ribosomal P antibodies related to depression in early clinical course of systemic lupus erythematosus. J Res Med Sci. 2013; 18(10): 860–864.Google Scholar
62.Maes, M, Mihaylova, I, Kubera, M, Leunis, J-C, Geffard, M. IgM-mediated autoimmune responses directed against multiple neoepitopes in depression: new pathways that underpin the inflammatory and neuroprogressive pathophysiology. J Affect Disord. 2011; 135(1–3): 414–418.Google Scholar
63.Maes, M, Kubera, M, Leunis, JC, Berk, M, Geffard, M, Bosmans, E. In depression, bacterial translocation may drive inflammatory responses, oxidative and nitrosative stress (O&NS), and autoimmune responses directed against O&NS-damaged neoepitopes. Acta Psychiatr Scand. 2013; 127(5): 344–354.Google Scholar
64.Lapin, IP. Neurokynurenines (NEKY) as common neurochemical links of stress and anxiety. Adv Exp Med Biol. 2003; 527: 121–125.Google ScholarPubMed
65.O’Connor, JC, Lawson, MA, André, C, et al. Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry. 2009; 14(5): 511–522.Google Scholar
66.Oxenkrug, GF. Genetic and hormonal regulation of tryptophan kynurenine metabolism: implications for vascular cognitive impairment, major depressive disorder, and aging. Ann N Y Acad Sci. 2007; 1122: 35–49.Google Scholar
67.Maes, M, Bonaccorso, S, Marino, V, et al. Treatment with interferon-alpha (IFN alpha) of hepatitis C patients induces lower serum dipeptidyl peptidase IV activity, which is related to IFN alpha-induced depressive and anxiety symptoms and immune activation. Mol Psychiatry. 2001; 6(4): 475–480.Google Scholar
68.Bonaccorso, S, Puzella, A, Marino, V, et al. Immunotherapy with interferon-alpha in patients affected by chronic hepatitis C induces an intercorrelated stimulation of the cytokine network and an increase in depressive and anxiety symptoms. Psychiatry Res. 2001; 105(1–2): 45–55.Google Scholar
69.Bonaccorso, S, Marino, V, Biondi, M, Grimaldi, F, Ippoliti, F, Maes, M. Depression induced by treatment with interferon-alpha in patients affected by hepatitis C virus. J Affect Disord. 2002; 72(3): 237–241.Google Scholar
70.Maes, M, Kubera, M, Leunis, J-C. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett. 2008; 29(1): 117–124.Google Scholar
71.Yirmiya, R. Endotoxin produces a depressive-like episode in rats. Brain Res. 1996; 711(1–2): 163–174.Google Scholar
72.De La Garza, R II. Endotoxin- or pro-inflammatory cytokine-induced sickness behavior as an animal model of depression: focus on anhedonia. Neurosci Biobehav Rev. 2005; 29(4–5): 761–770.CrossRefGoogle ScholarPubMed
73.Lucas, K, Maes, M. Role of the Toll like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Mol Neurobiol. 2013; 48(1): 190–204.Google Scholar
74.Mozaffari, S, Abdollahi, M. Melatonin, a promising supplement in inflammatory bowel disease: a comprehensive review of evidences. Curr Pharm Des. 2011; 17(38): 4372–4378.Google Scholar
75.Sun, X, Shao, Y, Jin, Y, et al. Melatonin reduces bacterial translocation by preventing damage to the intestinal mucosa in an experimental severe acute pancreatitis rat model. Exp Ther Med. 2013; 6(6): 1343–1349.Google Scholar
76.Chojnacki, C, Walecka-Kapica, E, Mokwinska, M, et al. Influence of tianeptine on melatonin homeostasis and psychosomatic symptoms in patients with irritable bowel syndrome. J Physiol Pharmacol. 2013; 64(2): 177–183.Google Scholar
77.Maloy, KJ, Powrie, F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011; 474(7351): 298–306.CrossRefGoogle ScholarPubMed
78.Sarra, M, Pallone, F, Macdonald, TT, Monteleone, G. IL-23/IL-17 axis in IBD. Inflamm Bowel Dis. 2010; 16(10): 1808–1813.Google Scholar
79.Sekut, L, Connolly, K. AntiTNF-alpha agents in the treatment of inflammation. Expert Opin Investig Drugs. 1998; 7(11): 1825–1839.Google Scholar
80.Yan, SLS, Russell, J, Granger, DN. Platelet activation and platelet-leukocyte aggregation elicited in experimental colitis are mediated by interleukin-6. Inflamm Bowel Dis. 2014; 20(2): 353–362.Google Scholar
81.Zhang, SJ, Wang, L, Ming, L, et al. Blockade of IL-6 signal exacerbates acute inflammatory bowel disease via inhibiting IL-17 producing in activated CD4+ Th17 population. Eur Rev Med Pharmacol Sci. 2013; 17(24): 3291–3295.Google Scholar
82.McGeachy, MJ, et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol. 2007; 8(12): 1390–1397.Google Scholar
83.Kuboyama, S. Increased circulating levels of interleukin-1 receptor antagonist in patients with inflammatory bowel disease. Kurume Med J. 1998; 45(1): 33–37.Google Scholar
84.Cominelli, F, Pizarro, TT. Interleukin-1 and interleukin-1 receptor antagonist in inflammatory bowel disease. Aliment Pharmacol Ther. 1996; 10(Suppl 2): 49–53; discussion 54.Google Scholar
85.Kaser, A, Zeissig, S, Blumberg, RS. Inflammatory bowel disease. Annu Rev Immunol. 2010; 28: 573–621.Google Scholar
86.Jovani, M, Fiorino, G, Danese, S. Anti-IL-13 in inflammatory bowel disease: from the bench to the bedside. Curr Drug Targets. 2013; 14(12): 1444–1452.Google Scholar
87.Wolk, K, Warszawska, K, Hoeflich, C, et al. Deficiency of IL-22 contributes to a chronic inflammatory disease: pathogenetic mechanisms in acne inversa. J Immunol. 2011; 186(2): 1228–1239.Google Scholar
88.Eken, A, Singh, AK, Treuting, PM, Oukka, M. IL-23R+ innate lymphoid cells induce colitis via interleukin-22-dependent mechanism. Mucosal Immunol. 2014; 7(1): 143–154.Google Scholar
89.Maloy, KJ, Kullberg, MC. IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal Immunol. 2008; 1(5): 339–349.CrossRefGoogle ScholarPubMed
90.Song, L, Zhou, R, Huang, S, et al. High intestinal and systemic levels of interleukin-23/T-helper 17 pathway in Chinese patients with inflammatory bowel disease. Mediators Inflamm. 2013; 2013: 425915.Google Scholar
91.Troncone, E, Marafini, I, Pallone, F, Monteleone, G. Th17 cytokines in inflammatory bowel diseases: discerning the good from the bad. Int Rev Immunol. 2013; 32(5–6): 526–533.CrossRefGoogle ScholarPubMed
92.Rossi, M, Bot, A. The Th17 cell population and the immune homeostasis of the gastrointestinal tract. Int Rev Immunol. 2013; 32(5–6): 471–474.Google Scholar
93.Tao, F, Qian, C, Guo, W, Luo, Q, Xu, Q, Sun, Y. Inhibition of Th1/Th17 responses via suppression of STAT1 and STAT3 activation contributes to the amelioration of murine experimental colitis by a natural flavonoid glucoside icariin. Biochem Pharmacol. 2013; 85(6): 798–807.Google Scholar
94.He, Y, Lin, L-J, Zheng, C-Q, Jin, Y, Lin, Y. Cytokine expression and the role of Thl7 cells in mice colitis. Hepatogastroenterology. 2012; 59(118): 1809–1813.Google Scholar
95.Pak, S, Holland, N, Garnett, EA, et al. Cytokine profiles in peripheral blood of children and adults with Crohn disease. J Pediatr Gastroenterol Nutr. 2012; 54(6): 769–775.Google Scholar
96.Beltrán, CJ, Candia, E, Erranz, B, et al. Peripheral cytokine profile in Chilean patients with Crohn’s disease and ulcerative colitis. Eur Cytokine Netw. 2009; 20(1): 33–38.Google Scholar
97.Ciećko-Michalska, I, Fedak, D, Mach, T. Neopterin in assessing the activity of inflammatory bowel diseases: ulcerative colitis and Crohn’s disease. Przegl Lek. 2010; 67: 1262–1265.Google Scholar
98.Husain, N, Tokoro, K, Popov, JM, Naides, SJ, Kwasny, MJ, Buchman, AL. Neopterin concentration as an index of disease activity in Crohn’s disease and ulcerative colitis. J Clin Gastroenterol. 2013; 47(3): 246–251.Google Scholar
99.Matsuura, T, West, GA, Klein, JS, Ferraris, L, Fiocchi, C. Soluble interleukin 2 and CD8 and CD4 receptors in inflammatory bowel disease. Gastroenterology. 1992; 102(6): 2006–2014.Google Scholar
100.Van Kemseke, C, Belaiche, J, Louis, E. Frequently relapsing Crohn’s disease is characterized by persistent elevation in interleukin-6 and soluble interleukin-2 receptor serum levels during remission. Int J Colorectal Dis. 2000; 15(4): 206–210.Google Scholar
101.Dalekos, GN, Manoussakis, MN, Goussia, AC, Tsianos, EV, Moutsopoulos, HM. Soluble interleukin-2 receptors, antineutrophil cytoplasmic antibodies, and other autoantibodies in patients with ulcerative colitis. Gut. 1993; 34(5): 658–664.Google Scholar
102.Nielsen, OH, Brynskov, J. Soluble interleukin-2 receptors in ulcerative colitis. Mediators Inflamm. 1993; 2(2): 115–118.Google Scholar
103.Srivastava, MD, Rossi, TM, Lebenthal, E. Serum soluble interleukin-2 receptor, soluble CD8 and soluble intercellular adhesion molecule-1 levels in Crohn’s disease, celiac disease, and systemic lupus erythematosus. Res Commun Mol Pathol Pharmacol. 1995; 87(1): 21–26.Google Scholar
104.Kiss, LS, Szamosi, T, Molnar, T, et al. Early clinical remission and normalisation of CRP are the strongest predictors of efficacy, mucosal healing and dose escalation during the first year of adalimumab therapy in Crohn’s disease. Aliment Pharmacol Ther. 2011; 34(8): 911–922.Google Scholar
105.Kiss, LS, Papp, M, Lovasz, BD, et al. High-sensitivity C-reactive protein for identification of disease phenotype, active disease, and clinical relapses in Crohn’s disease: a marker for patient classification? Inflamm Bowel Dis. 2012; 18(9): 1647–1654.Google Scholar
106.Weeke, B, Jarnum, S. Serum concentration of 19 serum proteins in Crohn’s disease and ulcerative colitis. Gut. 1971; 12(4): 297–302.Google Scholar
107.Alkhouri, RH, Hashmi, H, Baker, RD, Gelfond, D, Baker, SS. Vitamin and mineral status in patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2013; 56(1): 89–92.Google Scholar
108.Hwang, C, Ross, V, Mahadevan, U. Micronutrient deficiencies in inflammatory bowel disease: from A to zinc. Inflamm Bowel Dis. 2012; 18(10): 1961–1981.Google Scholar
109.Biancheri, P, Giuffrida, P, Docena, GH, MacDonald, TT, Corazza, GR, Di Sabatino, A. The role of transforming growth factor (TGF)-β in modulating the immune response and fibrogenesis in the gut. Cytokine Growth Factor Rev. 2014; 25(1): 45–55.Google Scholar
110.Lv, H, Jiang, Y, Li, J, et al. Association between polymorphisms in the promoter region of interleukin-10 and susceptibility to inflammatory bowel disease. Mol Biol Rep. 2014; 41(3): 1299–1310.Google Scholar
111.Li, M, Wang, B, Zhang, M, et al. Symbiotic gut microbes modulate human metabolic phenotypes. Proc Natl Acad Sci U S A. 2008; 105(6): 2117–2122.Google Scholar
112.Izcue, A, Coombes, JL, Powrie, F. Regulatory lymphocytes and intestinal inflammation. Annu. Rev. Immunol. 2009; 27: 313–338.Google Scholar
113.Martin, FP, Rezzi, S, Philippe, D, et al. Metabolic assessment of gradual development of moderate experimental colitis in IL-10 deficient mice. J Proteome Res. 2009; 8(5): 2376–2387.Google Scholar
114.Glocker, EO, Kotlarz, D, Boztug, K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009; 361(21): 2033–2045.CrossRefGoogle ScholarPubMed
115.Zhu, H, Li, YR. Oxidative stress and redox signaling mechanisms of inflammatory bowel disease: updated experimental and clinical evidence. Exp Biol Med (Maywood). 2012; 237(5): 474–480.Google Scholar
116.Hatsugai, M, Kurokawa, MS, Kouro, T, et al. Protein profiles of peripheral blood mononuclear cells are useful for differential diagnosis of ulcerative colitis and Crohn’s disease. J Gastroenterol. 2010; 45(5): 488–500.Google Scholar
117.Rachmilewitz, D, Stamler, JS, Karmeli, F, et al. Peroxynitrite-induced rat colitis—a new model of colonic inflammation. Gastroenterology. 1993; 105(6): 1681–1688.CrossRefGoogle ScholarPubMed
118.Naito, Y, Takagi, T, Yoshikawa, T. Molecular fingerprints of neutrophil-dependent oxidative stress in inflammatory bowel disease. J Gastroenterol. 2007; 42(10): 787–798.Google Scholar
119.Kolesov, SA, Korkotashvili, LV, Yazykova, AB, Fedulova, EN, Tutina, OA, Tolkacheva, NI. S-nitrosothiols, nitric oxide and proinflammatory cytokines in children with inflammatory bowel disease. Clin Lab. 2013; 59(9–10): 953–957.Google Scholar
120.Achitei, D, Ciobica, A, Balan, G, Gologan, E, Stanciu, C, Stefanescu, G. Different profile of peripheral antioxidant enzymes and lipid peroxidation in active and non-active inflammatory bowel disease patients. Dig Dis Sci. 2013; 58(5): 1244–1249.Google Scholar
121.Alzoghaibi, MA. Concepts of oxidative stress and antioxidant defense in Crohn’s disease. World J Gastroenterol. 2013; 19(39): 6540–6547.Google Scholar
122.Nanau, RM, Neuman, MG. Metabolome and inflammasome in inflammatory bowel disease. Transl Res. 2012; 160(1): 1–28.Google Scholar
123.Martinović, Z, Perisić, K, Pejnović, N, Lukacević, S, Rabrenović, L, Petrović, M. Antiphospholipid antibodies in inflammatory bowel diseases. Vojnosanit Pregl. 1998; 55(2 Suppl): 47–49.Google Scholar
124.O’Donnell, S, O’Sullivan, M, O’Morain, CA, Ryan, BM. The clinical significance of antimicrobial serologic responses within an Irish Crohn’s disease population. Eur J Gastroenterol Hepatol. 2013; 25(12): 1464–1469.Google Scholar
125.Dotan, I. New serologic markers for inflammatory bowel disease diagnosis. Dig Dis. 2010; 28(3): 418–423.Google Scholar
126.Forrest, CM, Gould, SR, Darlington, LG, Stone, TW. Levels of purine, kynurenine and lipid peroxidation products in patients with inflammatory bowel disease. Adv Exp Med Biol. 2003; 527: 395–400.Google Scholar
127.Gupta, NK, Thaker, AI, Kanuri, N, et al. Serum analysis of tryptophan catabolism pathway: correlation with Crohn’s disease activity. Inflamm Bowel Dis. 2012; 18(7): 1214–1220.Google Scholar
128.Lin, HM, Barnett, MP, Roy, NC, et al. Metabolomic analysis identifies inflammatory and noninflammatory metabolic effects of genetic modification in a mouse model of Crohn’s disease. J Proteome Res. 2010; 9: 1965–1975.Google Scholar
129.Wolf, AM, Wolf, D, Rumpold, H, et al. Overexpression of indoleamine 2,3-dioxygenase in human inflammatory bowel disease. Clin Immunol. 2004; 113(1): 47–55.Google Scholar
130.Ciorba, MA. Indoleamine 2,3 dioxygenase in intestinal disease. Curr Opin Gastroenterol. 2013; 29(2): 146–152.Google Scholar
131.Xavier, RJ, Podolsky, DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007; 448(7152): 427–434.Google Scholar
132.Gassler, N, Rohr, C, Schneider, A, et al. Inflammatory bowel disease is associated with changes of enterocytic junctions. Am J Physiol Gastrointest Liver Physiol. 2001; 281(1): G216–G228.Google Scholar
133.Qin, X. Etiology of inflammatory bowel disease: a unified hypothesis. World J Gastroenterol. 2012; 18(15): 1708–1722.Google Scholar
134.Söderholm, JD, Peterson, KH, Olaison, G, et al. Epithelial permeability to proteins in the noninflamed ileum of Crohn’s disease? Gastroenterology. 1999; 117(1): 65–72.Google Scholar
135.Katz, KD, Hollander, D, Vadheim, CM, et al. Intestinal permeability in patients with Crohn’s disease and their healthy relatives. Gastroenterology. 1989; 97(4): 927–931.Google Scholar
136.Lepage, P, Häsler, R, Spehlmann, ME, et al. Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology. 2011; 141(1): 227–236.Google Scholar
137.Machiels, K, Joossens, M, Sabino, J, et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut. 2014; 63(8): 1275–1283.Google Scholar
138.Montrose, DC, Scherl, EJ, Bosworth, BP, et al. S1P1 localizes to the colonic vasculature in ulcerative colitis and maintains blood vessel integrity. J Lipid Res. 2013; 54(3): 843–851.CrossRefGoogle Scholar
139.Greenspon, J, Li, R, Xiao, L, et al. Sphingosine-1-phosphate regulates the expression of adherens junction protein E-cadherin and enhances intestinal epithelial cell barrier function. Dig Dis Sci. 2011; 56(5): 1342–1353.Google Scholar
140.Chen, Y, Jiang, T, Chen, P, et al. Emerging tendency towards autoimmune process in major depressive patients: a novel insight from Th17 cells. Psychiatry Res. 2011; 188(2): 224–230.Google Scholar
141.Sluzewska, A, Sobieska, M, Rybakowski, JK. Changes in acute-phase proteins during lithium potentiation of antidepressants in refractory depression. Neuropsychobiology. 1997; 35(5): 123–127.Google Scholar
142.Pasco, JA, Nicholson, GC, Williams, LJ, et al. Association of high-sensitivity C-reactive protein with de novo major depression. Br J Psychiatry. 2010; 197(5): 372–377.CrossRefGoogle ScholarPubMed
143.Hsuchou, H, Kastin, AJ, Mishra, PK, Pan, W. C-reactive protein increases BBB permeability: implications for obesity and neuroinflammation. Cell Physiol Biochem. 2012; 30(5): 1109–1119.CrossRefGoogle ScholarPubMed
144.Hannestad, J, Gallezot, JD, Schafbauer, T, et al. Endotoxin-induced systemic inflammation activates microglia: [11C]PBR28 positron emission tomography in nonhuman primates. Neuroimage. 2012; 63(1): 232–239.Google Scholar
145.Bian, Y, Zhao, X, Li, M, Zeng, S, Zhao, B. Various roles of astrocytes during recovery from repeated exposure to different doses of lipopolysaccharide. Behav Brain Res. 2013; 253: 253–261.Google Scholar
146.Seo, JS, Park, JY, Choi, J, et al. NADPH oxidase mediates depressive behavior induced by chronic stress in mice. J Neurosci. 2012; 32(28): 9690–9699.Google Scholar
147.Maes, M, Fišar, Z, Medina, M, Scapagnini, G, Nowak, G, Berk, M. New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates—Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology. 2012; 20(3): 127–150.Google Scholar
148.Gerasimidis, K, Edwards, C, Stefanowicz, F, et al. Micronutrient status in children with IBD: true deficiencies or epiphenomenon of the systemic inflammatory response. J Pediatr Gastroenterol Nutr. 2013; 56(6): e50–e51.Google Scholar
149.Grønli, O, Kvamme, JM, Friborg, O, Wynn, R. Zinc deficiency is common in several psychiatric disorders. PLoS One. 2013; 8(12): e82793.Google Scholar
150.Aggett, PJ, Harries, JT. Current status of zinc in health and disease states. Arch Dis Child. 1979; 54(12): 909–917.Google Scholar
151.Rath, E, Haller, D. Mitochondria at the interface between danger signaling and metabolism: role of unfolded protein responses in chronic inflammation. Inflamm Bowel Dis. 2012; 18(7): 1364–1377.Google Scholar
152.Shao, L, Martin, MV, Watson, SJ, et al. Mitochondrial involvement in psychiatric disorders. Ann Med. 2008; 40(4): 281–295.Google Scholar
153.Tan, DX, Manchester, LC, Liu, X, Rosales-Corral, SA, Acuna-Castroviejo, D, Reiter, RJ. Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin’s primary function and evolution in eukaryotes. J Pineal Res. 2013; 54(2): 127–138.Google Scholar
154.Post, RM, Rubinow, DR, Ballenger, JC. Conditioning and sensitisation in the longitudinal course of affective illness. Br J Psychiatry. 1986; 149(2): 191–201.Google Scholar
155.Rhee, I, Zhong, M-C, Reizis, B, Cheong, C, Veillette, A. Control of dendritic cell migration, T cell-dependent immunity and autoimmunity by protein tyrosine phosphatase PTPN12 expressed in dendritic cells. Mol Cell Biol. 2014; 34(5): 888–899.Google Scholar
156.Kubera, M, Curzytek, K, Duda, W, et al. A new animal model of (chronic) depression induced by repeated and intermittent lipopolysaccharide administration for 4 months. Brain Behav Immun. 2013; 31: 96–104.Google Scholar
157.Lawson, MA, Parrott, JM, McCusker, RH, Dantzer, R, Kelley, KW, O’Connor, JC. Intracerebroventricular administration of lipopolysaccharide induces indoleamine-2,3-dioxygenase-dependent depression-like behaviors. Journal of Neuroinflammation. 2013; 10(1): 87.Google Scholar
158.Doenlen, R, Krügel, U, Wirth, T, et al. Electrical activity in rat cortico-limbic structures after single or repeated administration of lipopolysaccharide or staphylococcal enterotoxin B. Proc Biol Sci. 2011; 278(1713): 1864–1872.Google Scholar
159.Haba, R, Shintani, N, Onaka, Y, et al. Lipopolysaccharide affects exploratory behaviors toward novel objects by impairing cognition and/or motivation in mice: possible role of activation of the central amygdala. Behav Brain Res. 2012; 228(2): 423–431.Google Scholar
160.Dobos, N, de Vries, EF, Kema, IP, et al. The role of indoleamine 2,3-dioxygenase in a mouse model of neuroinflammation-induced depression. J Alzheimers Dis. 2012; 28(4): 905–915.Google Scholar
161.Salazar, A, Gonzalez-Rivera, BL, Redus, L, Parrott, JM, O’Connor, JC. Indoleamine 2,3-dioxygenase mediates anhedonia and anxiety-like behaviors caused by peripheral lipopolysaccharide immune challenge. Horm Behav. 2012; 62(3): 202–209.Google Scholar
162.Levin, AD, van den Brink, GR. Selective inhibition of mucosal serotonin as treatment for IBD? Gut. 2014; 63(6): 866–867.Google Scholar
163.Collins, S, Verdu, E, Denou, E, Bercik, P. The role of pathogenic microbes and commensal bacteria in irritable bowel syndrome. Dig Dis. 2009; 27(Suppl 1): 85–89.Google Scholar
164.Bailey, MT, Dowd, SE, Parry, NM, Galley, JD, Schauer, DB, Lyte, M. Stressor exposure disrupts commensal microbial populations in the intestines and leads to increased colonization by Citrobacter rodentium. Infect Immun. 2010; 78(4): 1509–1519.Google Scholar
165.Ghia, JE, Blennerhassett, P, Deng, Y, Verdu, EF, Khan, WI, Collins, SM. Reactivation of inflammatory bowel disease in a mouse model of depression. Gastroenterology. 2009; 136(7): 2280–2288.Google Scholar
166.Bonaz, BL, Bernstein, CN. Brain-gut interactions in inflammatory bowel disease. Gastroenterology. 2013; 144(1): 36–49.Google Scholar
167.D'Haens, GR, Panaccione, R, Higgins, PD, et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol. 2011; 106(2): 199–212; quiz 213.Google Scholar
168.Banovic, I, Gilibert, D, Cosnes, J. Perception of improved state of health and subjective quality of life in Crohn’s disease patients treated with infliximab. J Crohns Colitis. 2009; 3(1): 25–31.Google Scholar
169.Raison, CL, Rutherford, RE, Woolwine, BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013; 70(1): 31–41.Google Scholar
170.Tyring, S, Gottlieb, A, Papp, K, et al. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet. 2006; 367(9504): 29–35.Google Scholar
171.Krügel, U, Fischer, J, Radicke, S, Sack, U, Himmerich, H. Antidepressant effects of TNF-α blockade in an animal model of depression. J Psychiatr Res. 2013; 47(5): 611–616.CrossRefGoogle ScholarPubMed
172.Sun, Z, Lasson, A, Olanders, K, Deng, X, Andersson, R. Gut barrier permeability, reticuloendothelial system function and protease inhibitor levels following intestinal ischaemia and reperfusion—effects of pretreatment with N-acetyl-L-cysteine and indomethacin. Dig Liver Dis. 2002; 34(8): 560–569.Google Scholar
173.Berk, M, Copolov, DL, Dean, O, et al. N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008; 64(6): 468–475.Google Scholar
174.Maes, M, Twisk, FN, Kubera, M, Ringel, K, Leunis, JC, Geffard, M. Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome. J Affect Disord. 2012; 136(3): 909–917.Google Scholar
175.Goodhand, JR, Greig, FI, Koodun, Y, et al. Do antidepressants influence the disease course in inflammatory bowel disease? A retrospective case-matched observational study. Inflamm Bowel Dis. 2012; 18(7): 1232–1239.Google Scholar
176.Mikocka-Walus, AA, Gordon, AL, Stewart, BJ, Andrews, JM. A magic pill? A qualitative analysis of patients’ views on the role of antidepressant therapy in inflammatory bowel disease (IBD). BMC Gastroenterol. 2012; 12: 93.Google Scholar
177.Mikocka-Walus, A, Andrews, JM. Attitudes towards antidepressants among people living with inflammatory bowel disease: an online Australia-wide survey. J Crohns Colitis. 2014; 8(4): 296–303.Google Scholar
178.Iskandar, HN, Cassell, B, Kanuri, N, et al. Tricyclic antidepressants for management of residual symptoms in inflammatory bowel disease. J Clin Gastroenterol. 2014; 48(5): 423–429.Google Scholar
179.Szigethy, E, Bujoreanu, SI, Youk, AO, et al. Randomized efficacy trial of two psychotherapies for depression in youth with inflammatory bowel disease. J Am Acad Child Adolesc Psychiatry. 2014; 53(7): 726–735.Google Scholar