Microbiota-host crosstalk: the role of short-term dietary restriction in neurological and metabolic dysregulation

Excessive dieting (ED), a common weight-control strategy, often causes neurological and emotional disturbances, yet its gut-brain interaction mechanisms remain unclear. Employing a short-term dietary (SDR) adult male rabbit model, we found that SDR can induced cerebral cortex up-regulation of the immune-related genes (e.g., C1QC, SAA3) enriched in NF-kappa B signaling pathways, contrasted with down-regulation of sex hormone-related genes (e.g., PRLR, SPA17) implicated in metabolic homeostasis. Furthermore, dysregulated expression of metabolic genes (e.g., PPM1J, GALNT18) in the cecum of the SDR group interacted to impair the immune protection pathways related to intestinal mucosa. Then, SDR significantly increased the cecal Firmicutes/Bacteroidetes ratio (from 3.38 to 5.57) and reduced microbial diversity. Specifically, beneficial bacteria involved in tryptophan metabolism and neurotransmitter synthesis (e.g., Bacteroidales_bacterium, Alistipes_indistinctus) decreased, whereas bile acid-metabolizing bacteria (e.g., Clostridium_sp._CAG:710, Ruminococcus_sp._Marseille-P6503) linked to increase energy metabolism. The top 20 genes from the brain-gut axis analysis (e.g., ITPR1, CAMK4, CDK5R1) were enriched in critical neural pathways like axon guidance, GABAergic synapse, and long-term potentiation. Notably, key neurodevelopmental genes (e.g., GPR37, GPX3) correlated with these microbial shifts, implicating oxidative stress, synaptic plasticity, and mitochondrial function in microbiota-host crosstalk. This study highlights a "microbial-metabolism-neural" axis in SDR, providing novel targets for future obesity intervention strategies.