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.
