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 microbiota 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 microbiota (lipopolysaccharide, pepidoglycan) or intestinal hormones under the regulatory influence of the microbiota (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.

Peripheral immune activation by bacterial or viral infections or by the intestinal microbiota signalling across the mucosal gut barrier can give rise to mood disorders. Microbial constituents can stimulate pattern recognition receptors (PRRs) of the innate immune system, but there is still limited information on how this immune activation is translated to disturbances of brain function and behaviour. In this regard, the FWF-funded project disclosed a number of factors that help explain the behavioural alterations due to immune activation. The results showed that several microbial PRR stimulants activating different Toll-like receptors (TLRs) are involved in causing behavioural depression (e.g., sickness, lethargy, anorexia) of different severity. Importantly, bacterial peptidoglycans synergize with bacterial lipopolysaccharide (LPS) and exaggerate the immune, neuroinflammatory and behavioural responses to LPS. On the other hand, intranasal administration of the neuroprotective neuropeptide Y (NPY) prevents behavioural depression due to LPS through a site of action in the brain that links neuroinflammation to behavioural disturbances. Stimulation of other TLRs by bacterial lipoteichoic acid or the viral mimic polyinosinic:polycytidylic acid likewise causes neuroinflammatory and behavioural disturbances, the pattern of which is distinct from those induced by LPS. Emerging evidence attributes the intestinal microbiota a role in maintaining brain function and health, because a number of neuropsychiatric disorders has been associated with a disturbance of the gut microbial community. In order to substantiate the evidence for such a gut microbiota-brain interaction, antibiotic-induced depletion of the mouse gut microbiota was found to appreciably decrease bacteria-derived metabolites in the colon, to alter the profile of metabolites in blood plasma, and to impair working memory. This cognitive deficit was associated with brain region-related changes in the expression of cognition- relevant signalling molecules such as brain-derived neurotrophic factor and the cerebral NPY system. The experiments indicate that bacteria- and host-derived metabolites contribute to the impact of a disturbed gut microbiota on brain function and behaviour. The quality of nutrition is not only an important factor in shaping the microbial community in the gut but also has an influence on mental health. Microbial alterations induced by high-fat diet (HFD) in mice were found to result in neurochemical and behavioural changes indicative of a depression-like phenotype. Further analysis showed that the gut microbiota plays an essential role in this nutrition-related behavioural disturbance, because antibiotic-induced depletion of the gut microbiota reduced not only the HFD-evoked weight gain and adiposity but also prevented HFD-induced depression-like behaviour. The most recent experiments indicate that a microbiota-dependent release of the hormone leptin from adipose tissue mediates the HFD-induced depression-like behaviour.