Sodium butyrate protects broiler chickens against lethal Salmonella Enteritidis infection by remodelling the gut microbiota and preserving immune homeostasis.

Salmonella Enteritidis (SE) is a zoonotic pathogen of major public health concern, and poultry operations are a key reservoir for human infection. Although sodium butyrate (NaB) has documented immunomodulatory and anti-inflammatory properties, whether it can enhance resistance against SE infection in chickens and by what mechanisms remain unclear. Here we evaluated the effects of early dietary NaB supplementation on SE susceptibility in broiler chickens. Newly hatched chicks were randomly assigned to one of three groups-an uninfected negative control (Ctrl), an SE-challenged positive control (SE), and a group receiving 300 mg/kg dietary NaB before SE challenge (NaB+SE). Dietary NaB increased the survival rate of SE-challenged chicks from 5.26% to 52.63% (P < 0.05) and attenuated SE-induced villus damage and excessive pro-inflammatory responses. Flow cytometry showed that NaB prevented the SE-associated depletion of splenic B cells and macrophages. Cecal 16S rRNA gene sequencing revealed that NaB altered cecal microbiota structure, reducing potential pathogens and enriching beneficial bacteria, including Blautia species. These results indicate that sodium butyrate enhances resistance to SE infection through modulation of immune homeostasis and restructuring of the gut microbial community, and may represent a non-antibiotic intervention to reduce SE transmission in commercial poultry production.