The Benefits of Butyrate Include a Reduction in Microglial Inflammation in the Brain
Butyrate is produced by microbial species in the gut microbiome in response to dietary fiber intake. It can also be delivered as a supplement, although it has an unpleasant scent and taste. A broad range of research indicates that butyrate is a useful, beneficial metabolite. For example, it upregulates BDNF expression, which in turn upregulates neurogenesis. BDNF has other beneficial roles, such as in ensuring mitochondrial quality in skeletal muscle. Further, animal studies indicate that increased BDNF can raise dopamine levels and reduce the presence of inflammatory microglia in the brain, and even slow metabolic aging.
Unfortunately the gut microbiome changes with age, pro-inflammatory microbes increasing in number at the expense of populations that produce beneficial metabolites such as butyrate. Both levels of butyrate and expression of BDNF decline with age. Further, aging is characterized by a range of detrimental changes, such as reduced neurogenesis, that are influenced by butyrate and BDNF. Obviously, loss of butyrate production is just one factor among many accounting for reduced BDNF expression, and in turn reduced BDNF expression is only one contributing cause of issues such as loss of neurogenesis. Nonetheless, the situation can be improved to some degree by restoring a more youthful gut microbiome and its production of butyrate.
Sympathetic activation is a hallmark of heart failure and the underlying mechanism remains elusive. Butyrate is generated by gut microbiota and influences numerous physiological and pathological processes in the host. The present study aims to investigate whether the intestinal metabolite butyrate reduces sympathetic activation in rats with heart failure (HF) and the underlying mechanisms involved. Sprague-Dawley rats (220-250 g) are anaesthetized with isoflurane, and the left anterior descending artery is ligated to model HF. Then, the rats are treated with or without butyrate sodium (NaB, a donor of butyrate, 10 g/L in water) for 8 weeks. Blood pressure and renal sympathetic nerve activity (RSNA) are recorded to assess sympathetic outflow.
Cardiac function is improved (mean ejection fraction, 22.6%±4.8% vs 38.3%±5.3%), and sympathetic activation is decreased (RSNA, 36.3%±7.9% vs 23.9%±7.6%) in HF rats treated with NaB compared with untreated HF rats. The plasma and cerebrospinal fluid levels of norepinephrine are decreased in HF rats treated with NaB. The infusion of N-methyl-D-aspartic acid (NMDA) into the paraventricular nucleus (PVN) of the hypothalamus of HF model rats increases sympathetic nervous activity by upregulating the NMDA receptor. Microglia polarized to the M2 phenotype and inflammation are markedly attenuated in the PVN of HF model rats after NaB administration. In addition, HF model rats treated with NaB exhibit enhanced intestinal barrier function and increased levels of GPR109A, zona occludens-1, and occludin, but decreased levels of lipopolysaccharide-binding protein and zonulin.
In conclusion, butyrate attenuates sympathetic activation and improves cardiac function in rats with HF. The improvements in intestinal barrier function, reductions in microglia-mediated inflammation and decreases in NMDA receptor 1 expression in the PVN are all due to the protective effects of NaB.