Oral supplementation of sodium butyrate prevents lipid metabolism disorders and intestinal injury by modulating immunity, intestinal barrier functions, and gut microbiota in a corticosterone-induced chronic stress model in mice

In intensive livestock and poultry farming, chronic stress poses a significant threat to animal health, primarily through its impact on butyric acid levels and intestinal microbiota balance. In our previous study, we found that the intestinal butyric acid level was significantly reduced in chronic stress models, suggesting that butyrate supplementation should be an effective anti-chronic stress strategy. Therefore, in this study, we aimed to investigate whether sodium butyrate (NaBu) prevents chronic stress-induced lipid metabolism disorders and intestinal injury by reducing intestinal damage and remodeling the microbiota. In vitro models, IEC-6 cells, a small intestinal epithelial cell line, were divided into three groups, including control (CON), corticosterone (CORT, 400 μM) and CORT + NaBu (400 μM CORT + 1 mM NaBu). In vivo models, sixty mice were divided into CON, CORT (intraperitoneal injection of 20 mg/kg CORT) and CORT + NaBu (intraperitoneal injection of 20 mg/kg CORT + intragastric gavage with 200 mg/kg NaBu). The results showed that NaBu effectively reversed CORT-induced IEC-6 migration inhibition, inhibited apoptosis, and restored barrier function, which was associated with downregulated IL-12 and upregulated LRP5 expression. In addition, NaBu administration prevented anorexia, promoted body weight gain, and improved lipid metabolism in a corticosterone-induced chronic stress model in mice, as evidenced by a significant reduction of serum alkaline phosphatase (AKP) and Low-density lipoprotein cholesterol (LDL-C). Histopathological staining and scanning electron microscopy analyses revealed that NaBu treatment restored the normal villi morphology of the small intestinal villi and mitigated epithelial cell damage caused by CORT. 16S rRNA sequencing demonstrated that NaBu facilitated intestinal microbiota remodeling, marked by significant increases in Desulfobacterota and Bacillus abundance and decreases in Proteobacteria and Enterorhabdus abundances. Furthermore, analysis suggests that CORT-induced chronic stress may disrupt the cecal microbiota-metabolite axis and lead to intestinal injury and metabolic abnormalitiesbased on previous metabolic evidence and current results of microbial imbalance and downstream metabolic/intestinal abnormalities. These findings indicate that NaBu exerts a protective role in the prevention of chronic stress-related disorders, providing a potential prophylactic strategy for animals at high risk of stress exposure.