Psychopharmacology of the visceral immune-brain axis

Being one of the most prevalent and severe mood disorders, major depression is deleterious to the patients` quality of life and of enormous socio-economic impact. According to the World Health Organization, depression is the second most frequent cause of disability-adjusted life years in the age category of 15 - 44 years for both genders, with the number of patients continuing to grow. A proportion of some 40 % of the patients does not satisfactorily respond to the available antidepressant drugs, which reflects the incomplete understanding of the aetiology of affective disorders. Apart from vulnerability and psychosocial factors, chronic immune challenge has emerged as a circumstance relevant to the pathogenesis of mood disorders. The cytokine hypothesis of depression holds that systemic inflammatory processes associated with elevated levels of circulating proinflammatory cytokines disturb several brain mechanisms that control anxiety, mood, stress resilience and cognition. Visceral immune activation and inflammation are associated with a variety of psychiatric abnormalities, and there is clinical evidence that constituents of the intestinal microbiome across a leaky mucosal barrier may be a factor underlying mood disorders. Preclinical evidence indicates that gastrointestinal infection and inflammation as well as intraperitoneal administration of bacterial lipopolysaccharide induce behavioural disturbances. The current research proposal sets out to specifically examine the visceral immune - brain axis in an innovative and comprehensive manner and to identify key mechanisms that are suitable for pharmacological modulation. The main hypotheses to be addressed are that factors derived from the intestinal microbiome (lipopolysaccharide, pepidoglycan) or intestinal hormones under the regulatory influence of the microbiome (glucagon-like peptide, peptide YY) have an impact on the visceral immune - brain axis; visceral immune challenge has a short- and long-term impact on affective behaviour; specific brain signalling mechanisms involving receptor-activator of nuclear factor B ligand, cyclooxygenase-2 and brain-derived neurotrophic factor play a role in the behavioural effects of peripheral immune challenge; and activation of the visceral immune - brain axis is associated with deranged activity of the hypothalamic- pituitary-adrenal axis, disturbed glucocorticoid feedback on the brain and altered neurogenesis in the limbic system.