Sodium Butyrate(SB) mediates Histone Crotonylation and Alleviated Neonatal Rats Hypoxic -Ischemic Brain Injury Through Gut-Brain Axis [ChIP-seq]

Neonatal hypoxic-ischemic encephalopathy (HIE) refers to nervous system damage caused by perinatal hypoxia, which is the major cause of long-term neuro-developmental disorders in surviving infants. However, the mechanisms still require further investigation. In this study, we found that the butanoate metabolism pathway exhibited significantly decreased and short chain fatty acid (SCFAs)-producing bacteria, especially butyrate-producing bacteria, were significantly decreased in fecal of neonatal hypoxic-ischemic brain damage (HIBD) rats. Surprisingly, Sodium butyrate (SB) treatment could ameliorate pathological damage both in the cerebral cortex and hippocampus and facilitate recovery of SCFAs-producing bacteria related to metabolic pathways in neonatal HIBD rats. Moreover, we found that in samples from SB treatment neonatal HIBD rats cortex with high levels of butyrate acid along with aberrant key crotonyl-CoA-producing enzymes ACADS levels was observed compared HIBD rats. We also demonstrated that a decrease in histone 3-lysine 9-crotonylation (H3K9cr) downregulated expression of the HIE-related neurotrophic genes Bdnf, Gdnf, Cdnf, and Manf in HIBD rats. Furthermore, SB restored H3K9cr binding to HIE-related neurotrophic genes. Collectively, our results indicate that SB contributes to ameliorate pathological of HIBD by altering gut microbiota and brain SCFAs levels subsequently affecting histone crotonylation-mediated neurotrophic-related genes expression. This may be a novel microbiological approach for preventing and treating HIE.新生儿缺氧缺血性脑病（Neonatal hypoxic-ischemic encephalopathy, HIE）是指围产期缺氧引发的神经系统损伤，是存活婴儿长期神经发育障碍的主要诱因。然而，其具体致病机制仍有待进一步研究。本研究发现，新生儿缺氧缺血性脑损伤（neonatal hypoxic-ischemic brain damage, HIBD）模型大鼠的粪便样本中，丁酸代谢通路活性显著下调，产短链脂肪酸（short chain fatty acid, SCFAs）菌群的丰度显著降低，其中产丁酸菌的变化尤为显著。令人意外的是，丁酸钠（Sodium butyrate, SB）干预可改善新生儿HIBD模型大鼠的大脑皮层与海马体病理损伤，并促进与短链脂肪酸生成相关代谢通路的菌群恢复。此外，与HIBD模型大鼠相比，经SB干预的HIBD大鼠皮层样本中丁酸水平升高，且关键巴豆酰辅酶A生成酶ACADS的表达水平异常。本研究还证实，HIBD模型大鼠体内组蛋白3赖氨酸9巴豆酰化（histone 3-lysine 9-crotonylation, H3K9cr）水平下调，可抑制HIE相关神经营养基因Bdnf、Gdnf、Cdnf及Manf的表达。此外，丁酸钠可恢复H3K9cr与上述HIE相关神经营养基因的结合活性。综上，本研究结果表明，丁酸钠可通过调控肠道菌群与脑内短链脂肪酸水平，进而影响组蛋白巴豆酰化介导的神经营养相关基因表达，从而改善HIBD的病理损伤。这一发现或为HIE的防治提供一种全新的微生物学干预策略。