Nicotinamide produced by Bifidobacterium longum A127 ameliorates heat stress-induced brain damage by inhibiting the p38 MAPK pathway

Background Heat stress (HS) is a significant threat to mental health, and the gut microbiota forms a key biological barrier that protects the host against extreme environments. This study isolated the unique strain Bifidobacterium longum A127 from long-lived individuals in Hainan and investigated its protective mechanism against HS-induced brain injury in detail. Results Animal experiments revealed that HS induced microglial overactivation, neuronal apoptosis, and anxiety-like behaviors in mice. Supplementation with Bifidobacterium longum A127 significantly increased gut barrier integrity, reduced brain lipopolysaccharide (LPS) levels, alleviated neuroinflammation and oxidative stress, and restored HS-induced gut microbiota dysbiosis. Mechanistically, the key metabolite nicotinamide (NAM) was identified as central to its neuroprotective effect. NAM supplementation effectively improved behavioral deficits, reduced inflammatory and oxidative stress markers, and increased brain Nicotinamide adenine dinucleotide (NAD ⁺ ) levels and glutathione (GSH) redox activity in HS group mice. NAM provided protection by inhibiting HS-induced overactivation of the p38 MAPK pathway. Conclusion Bifidobacterium longum A127 and its metabolite NAM effectively mitigate HS-induced brain injury by reducing brain LPS, inflammation, and oxidative stress, and suppressing p38 MAPK overactivation.