Sodium butyrate mediates histone crotonylation and alleviated neonatal rats hypoxic–ischemic brain injury through gut–brain axis

Abstract

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 were 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 pathology 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.

Gut microbiota and central nervous system: a bidirectional two-sample Mendelian randomized analysis

“…Reversely, the decreased abundance of Lachnospiraceae family is negatively associated with severity in other CNS diseases, such as depression and Parkinson [30,31]. Meanwhile, previous studies of hypoxic or ischemic-hypoxic brain injury have shown a decrease in the proportion of Firmicutes [5]. It's di cult to conclude they are protective or risk factor, because of Lachnospiraceae family and Butyricoccus genus as a member of the Firmicutes.…”

“…Anoxic brain injury (ABI), such as traumatic brain injury [1], stroke [2], cardiac arrest [3], asphyxia [4] and neonatal ischemic hypoxic encephalopathy [5], is a common clinical cause of central nervous system (CNS) injury. It can occur in various age groups with poor prognosis.…”

“…Seki, et al found Klebsiella may as an outstanding predictor indicator of brain injury in preterm infants [12]. Animal study have shown that the prognosis of ABI in rats can be improved by intervening gut microbiota (such as butyrate-producing bacteria) [5,13]. However, the causal relationship still unclear.…”

Folate-deficiency induced acyl-CoA synthetase short-chain family member 2 increases lysine crotonylome involved in neural tube defects

“…Data obtained from Mass spectrometry in different samples were chromatographic peaks and the peak areas were integrated on all chromatographic peaks. The peak areas denotes the relevant metabolites (He et al, 2022).…”

Treatment of preterm brain injury via gut‐microbiota–metabolite–brain axis

“…Mice experiments found that high dietary fiber intake improved cognitive and social behavioral deficits in the offspring of obese maternal mice by modulating the composition of the offspring's Clostridiales and Bacteroidales and SCFAs 125 . Moreover, sodium butyrate promoted the recovery of SCFA‐producing bacteria in neonatal rats with hypoxic–ischemic brain damage, facilitating the recovery of cerebral cortex and hippocampus 126 . However, not all fibers are beneficial; unfermented fibers may elicit the production of pro‐inflammatory factors by immune cells, activating the NLRP3 and TLR2 pathways and exacerbating inflammation in Inflammatory bowel disease (IBD) 127 .…”