The neuroprotective effect of short-chain fatty acids against hypoxia-reperfusion injury

Gut microbe-derived short-chain fatty acids (SCFAs) are known to have a profound impact on various brain functions, including cognition, mood, and overall neurological health. However, their role, if any, in protecting against hypoxic injury and ischemic stroke has not been extensively studied. In this study, we investigated the effects of two major SCFAs abundant in the gut, propionate (P) and butyrate (B), on hypoxia-reperfusion injury using a neuronal cell line and a zebrafish model. Neuro 2a (N2a) cells treated with P and B exhibited reduced levels of mitochondrial and cytosolic reactive oxygen species (ROS), diminished loss of mitochondrial membrane potential, suppressed caspase activation, and lower rates of cell death when exposed to CoCl₂, a chemical commonly used to simulate hypoxia. Furthermore, adult zebrafish fed SCFA-supplemented feeds showed less susceptibility to hypoxic conditions compared to the control group, as indicated by multiple behavioral measures. Histological analysis of 2,3,5-Triphenyltetrazolium chloride (TTC) stained brain sections revealed less damage in the SCFA-fed group. We also found that Fatty Acid Binding Protein 7 (FABP7), also known as Brain Lipid Binding Protein (BLBP), a neuroprotective fatty acid binding protein, was upregulated in the brains of the SCFA-fed group. Additionally, when FABP7 was overexpressed in N2a cells, it protected the cells from injury caused by CoCl₂ treatment. Overall, our data provide evidence for a neuroprotective role of P and B against hypoxic brain injury and suggest the potential of dietary supplementation with SCFAs to mitigate stroke-induced brain damage.