Integrated multi-omics profiling highlights the diet-gut-brain axis in low-calorie diets promoted novelty-seeking behavior

The foods that we eat are closely linked to the development and function of neurophysiology, affecting mood, cognition, and mental health. Yet, it is not known whether and how dietary patterns affect brain function and mood. Here, we explored the impact of various diets on the behavior of mice. Low-calorie (LC) diet-fed mice exhibited increased novel exploratory behaviors, including novelty to new foods, objects, and environments. The host transcriptome sequencing showed an increase of Areg in the cerebral cortex of mice fed with LC, and IMPC showed that Areg knock-out mice exhibited significantly decreased exploration of novel environments. According to the metagenomic sequencing results, a significant increase in the levels of s_Schaedlerella and s_1XD8-76 was observed after LC feeding. Integrated analysis of microbiota metabolites and host transcriptomics suggested that 68 differential metabolites in LC-fed mice were associated with upregulation of Areg expression. This study demonstrates the powerful impact of LC feeding on the restoration of gut microbiota and the improvement of novelty-seeking behavior. In addition, this study supports the idea that microbiota-associated metabolites can modulate host gene transcription, which provides a link between dietary patterns and their impact on the emotional and cognitive centers of the brain. • Low-calorie (LC) diet-fed mice exhibited increased novel exploratory behaviors. • Amphiregulin (AREG) was up-regulated in LC-fed mice. • Areg knock-out mice showed reduced novelty-seeking behavior.