Accumulating evidence indicates that disruption of the gut microbial community (dysbiosis) impairs mental health. Causality in gut microbiota-brain relationships has been probed by the use of germ-free mice and antibiotic-induced gut dysbiosis. However, both models have limitations, as the blood-brain barrier is impaired and brain ultrastructure and neurochemistry are altered in germ-free mice, while antibiotics may directly interfere with brain function. To address the concerns related to antibiotic-induced gut dysbiosis, the effect of intragastric treatment of adult mice with multiple antibiotics on gut microbial community structure, metabolite profile in the colon, circulating metabolites, expression of neuronal signalling molecules in distinct brain areas and cognitive behaviour was investigated. 16S rDNA sequencing confirmed antibiotic-induced microbial community disruption, and metabolomics disclosed that gut dysbiosis was accompanied by depletion of bacteria-derived metabolites in the colon and alterations of lipid species and converted microbe-derived molecules in the plasma. Novel object recognition, but not spatial, memory was impaired in antibiotic-treated mice. This cognitive decline was associated with brain region-specific changes in the expression of brain-derived neurotrophic factor, N-methyl-D-aspartate receptor subunit 2B, serotonin transporter and neuropeptide Y system. Pharmacokinetic analyses ruled out that these molecular and behavioural alterations were due to a direct effect of the antibiotics (ampicillin, bacitracin, meropenem, neomycin, vancomycin) on the brain. Circulating metabolites and the cerebral neuropeptide Y system thus appear to play a role in the cognitive impairment and dysregulation of cerebral signalling molecules due to antibiotic-induced gut dysbiosis. The structure and function of the gut microbiota is also governed by environmental factors such as the quality of nutrition, and clinical studies suggest that a high-fat diet enhances the risk of depression. Experimental studies in rodents have shown that a high-fat diet can affect emotional and cognitive behaviour. To address a possible role of the intestinal microbiota in nutrition-brain relationships, mice were fed with a high-fat diet (60 kJ%) for 8 weeks. The high-fat diet caused the mice to gain significantly more weight than control animals although the food consumption did not increase. The high-fat diet also led to a pronounced disruption of the intestinal microbial community as revealed by 16S rDNA sequencing. When subjected to a battery of tests assessing locomotor, exploratory, social, anxiety-related, depression-related and cognitive behaviour, mice fed with the high-fat diet displayed a depression-like behavioural phenotype. These results indicate that high-fat diet-treated mice represent an animal model of diet-induced depression in which diet-induced alterations of intestinal microbiota and metabolic status may play a role and await to be characterized.