Reuter Melanie A, Moreno Rosalinda, Agabao-Tucker Madelynn E, Shishani Rahaf, Bustamante Jessica Miranda, Marfori Zara, Richieri Taylor, Valenzuela Anthony E, Taha Ameer Y, Lein Pamela J, Nandakumar Renu, Cummings Bethany P
Department of Surgery, Center for Alimentary and Metabolic Science, School of Medicine, University of California-Davis, Sacramento, California, USA.
Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
Compr Physiol. 2025 Aug;15(4):e70034. doi: 10.1002/cph4.70034.
Low but biologically relevant levels of bile acids are found in the brain and are altered in patients with Alzheimer's disease (AD). However, the regulation of brain bile acid levels and what drives brain bile acid dynamics are poorly understood. Bile acids are synthesized in the liver and further metabolized by bacteria in the gut. Therefore, bile acids are mediators of the liver-brain axis and the gut-brain axis. Additionally, whether the bile acid profile differs between brain regions and whether the brain region-specific bile acid profile is impacted by disease, such as AD, is unknown. Therefore, we tested the hypothesis that the brain bile acid profile is influenced by peripheral bile acid metabolism, differs between brain regions, and that these dynamics change in AD. To this end, we assessed the bile acid profile in the cortex and hippocampus of wild-type mice maintained on different diets. To test the effect of AD, we used the TgF344-AD rat model. We found that the brain bile acid profile in mice was mildly altered by diet and, in both mice and rats, differs substantially between brain regions. For example, cholic acid and taurocholic acid are enriched in the cortex relative to the hippocampus in both mice and rats. Further, using a rat model of AD, we found that brain region differences in bile acid profiles are attenuated in AD. Together, these data demonstrate that both peripheral and central regulatory mechanisms maintain bile acid homeostasis in specific brain regions and that these homeostatic mechanisms are disrupted in AD.
在大脑中发现了低水平但具有生物学相关性的胆汁酸，且阿尔茨海默病（AD）患者的胆汁酸水平会发生改变。然而，人们对大脑胆汁酸水平的调节以及驱动大脑胆汁酸动态变化的因素了解甚少。胆汁酸在肝脏中合成，并在肠道中由细菌进一步代谢。因此，胆汁酸是肝脑轴和肠脑轴的介质。此外，大脑不同区域之间的胆汁酸谱是否存在差异，以及特定脑区的胆汁酸谱是否会受到诸如AD等疾病的影响，目前尚不清楚。因此，我们检验了以下假设：大脑胆汁酸谱受外周胆汁酸代谢的影响，在不同脑区之间存在差异，且这些动态变化在AD中会发生改变。为此，我们评估了食用不同饮食的野生型小鼠皮质和海马中的胆汁酸谱。为了测试AD的影响，我们使用了TgF344-AD大鼠模型。我们发现，小鼠的大脑胆汁酸谱会因饮食而轻度改变，并且在小鼠和大鼠中，不同脑区之间的胆汁酸谱存在显著差异。例如，在小鼠和大鼠中，相对于海马，皮质中的胆酸和牛磺胆酸含量更高。此外，使用AD大鼠模型，我们发现AD中胆汁酸谱的脑区差异会减弱。总之，这些数据表明，外周和中枢调节机制共同维持特定脑区的胆汁酸稳态，且这些稳态机制在AD中会被破坏。
