Stilling Roman M, van de Wouw Marcel, Clarke Gerard, Stanton Catherine, Dinan Timothy G, Cryan John F
APC Microbiome Institute, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork Ireland.
APC Microbiome Institute, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork Ireland.
Neurochem Int. 2016 Oct;99:110-132. doi: 10.1016/j.neuint.2016.06.011. Epub 2016 Jun 23.
Several lines of evidence suggest that brain function and behaviour are influenced by microbial metabolites. Key products of the microbiota are short-chain fatty acids (SCFAs), including butyric acid. Butyrate is a functionally versatile molecule that is produced in the mammalian gut by fermentation of dietary fibre and is enriched in butter and other dairy products. Butyrate along with other fermentation-derived SCFAs (e.g. acetate, propionate) and the structurally related ketone bodies (e.g. acetoacetate and d-β-hydroxybutyrate) show promising effects in various diseases including obesity, diabetes, inflammatory (bowel) diseases, and colorectal cancer as well as neurological disorders. Indeed, it is clear that host energy metabolism and immune functions critically depend on butyrate as a potent regulator, highlighting butyrate as a key mediator of host-microbe crosstalk. In addition to specific receptors (GPR43/FFAR2; GPR41/FFAR3; GPR109a/HCAR2) and transporters (MCT1/SLC16A1; SMCT1/SLC5A8), its effects are mediated by utilisation as an energy source via the β-oxidation pathway and as an inhibitor of histone deacetylases (HDACs), promoting histone acetylation and stimulation of gene expression in host cells. The latter has also led to the use of butyrate as an experimental drug in models for neurological disorders ranging from depression to neurodegenerative diseases and cognitive impairment. Here we provide a critical review of the literature on butyrate and its effects on multiple aspects of host physiology with a focus on brain function and behaviour. We find fundamental differences in natural butyrate at physiological concentrations and its use as a neuropharmacological agent at rather high, supraphysiological doses in brain research. Finally, we hypothesise that butyrate and other volatile SCFAs produced by microbes may be involved in regulating the impact of the microbiome on behaviour including social communication.
多项证据表明，大脑功能和行为受微生物代谢产物的影响。微生物群的关键产物是短链脂肪酸（SCFA），包括丁酸。丁酸是一种功能多样的分子，由膳食纤维在哺乳动物肠道中发酵产生，在黄油和其他乳制品中含量丰富。丁酸与其他发酵衍生的短链脂肪酸（如乙酸、丙酸）以及结构相关的酮体（如乙酰乙酸和d-β-羟基丁酸）在包括肥胖症、糖尿病、炎症性（肠）疾病、结直肠癌以及神经疾病在内的各种疾病中显示出有前景的作用。事实上，很明显宿主能量代谢和免疫功能严重依赖丁酸作为一种强效调节剂，这突出了丁酸作为宿主-微生物相互作用的关键介质。除了特定的受体（GPR43/FFAR2；GPR41/FFAR3；GPR109a/HCAR2）和转运体（MCT1/SLC16A1；SMCT1/SLC5A8）外，其作用还通过β-氧化途径作为能量来源以及作为组蛋白脱乙酰酶（HDAC）的抑制剂来介导，促进组蛋白乙酰化并刺激宿主细胞中的基因表达。后者也导致丁酸在从抑郁症到神经退行性疾病和认知障碍等神经疾病模型中用作实验药物。在这里，我们对关于丁酸及其对宿主生理学多个方面影响的文献进行了批判性综述，重点关注大脑功能和行为。我们发现在生理浓度下的天然丁酸与其在大脑研究中以相当高的超生理剂量用作神经药理学药物之间存在根本差异。最后，我们假设微生物产生的丁酸和其他挥发性短链脂肪酸可能参与调节微生物群对包括社交交流在内的行为的影响。
