Gut Microbiota-Derived Butyrate Strengthens Blood-Brain Barrier Integrity and Attenuates Streptococcus suis SC19-Induced Meningitis: Involvement of the Gut-Brain Axis.

Streptococcus suis serotype 2 (SS2) is a major zoonotic pathogen that causes severe meningitis and high mortality in both humans and swine. Growing evidence shows that metabolites generated along the gut-brain axis regulate neuroinflammation. In this study, we demonstrate that oral administration of sodium butyrate (NaB) (300 or 600 mg/kg/day) for 28 days lowered mortality and lessened neuropathological signs in mice infected with SS2 (SC19 strain). Butyrate prophylaxis was associated with lower bacterial loads in the blood and brain tissue, preserved expression of tight junction proteins (ZO-1, Claudin-5, and Occludin) in the brain, and maintained blood-brain barrier (BBB) integrity and permeability. 16S rRNA sequencing analysis revealed that SC19 infection significantly diminished the diversity and richness of the gut microbiota, notably depleting key short-chain fatty acid (SCFA)-producing bacterial taxa. Butyrate intervention restored microbial homeostasis and enriched SCFA-producing communities. Mechanistically, butyrate was associated with upregulated expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant effectors (heme oxygenase 1 [HO-1] and NQO1), while inhibiting phosphorylation of NF-κB p65 and the secretion of proinflammatory cytokines (interleukin-1β [IL-1β], interleukin-6 [IL-6], and tumor necrosis factor-α [TNF-α]) in human cortical microvessels endothelial cells/D3 (hCMEC/D3) cells. Critically, these protective effects were abrogated upon pharmacological inhibition of Nrf2, indicating the critical role of Nrf2 in butyrate-mediated attenuation of neuroinflammation and oxidative stress. Our findings highlight the prophylactic potential of modulating the gut-brain axis as a novel strategy to mitigate central nervous system (CNS) infections associated with foodborne pathogens.