The Neuroprotective Effect of Short-chain Fatty Acids Against Hypoxia-reperfusion Injury

Abstract

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-induced hypoxia, compared to the control group. Furthermore, adult zebrafish fed with SCFAs-supplemented feeds showed less susceptibility to hypoxic conditions compared to the control group, as indicated by multiple behavioral measures. Histological analysis of TTC-stained brain sections revealed lesser damage in the SCFAs-fed group. We also found that FABP7 (also known as BLBP), a neuroprotective fatty acid binding protein, was upregulated in the brains of the SCFAs-fed group. Additionally, when FABP7 was overexpressed in N2a cells, it protected the cells from hypoxia-reperfusion injury. Overall, our data clearly demonstrates a neuroprotective role of P and B against hypoxic brain injury and suggests the potential of dietary supplementation with SCFAs to mitigate stroke-induced brain damage. HighlightsO_LIShort-chain fatty acid (SCFA) Propionate (P) and Butyrate (B) protect N2a cells from hypoxia-reperfusion. C_LIO_LIZebrafish, when fed an SCFA-supplemented diet, are more resilient to hypoxia-reperfusion. C_LIO_LISCFAs in the diet boost brain expression of FABP7 (fatty acid binding protein). C_LIO_LIFABP7 overexpression in N2a cells provides protection against hypoxia-reperfusion. C_LIO_LISCFAs reduce reactive oxygen species (ROS) levels and increase FABP7, contributing to neuroprotection. C_LI