Psychiatric Institute, University of Illinois Center on Depression and Resilience, and Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois.
Biol Psychiatry. 2023 Oct 15;94(8):609-618. doi: 10.1016/j.biopsych.2023.04.025. Epub 2023 May 6.
The gut microbiome regulates emotional behavior, stress responses, and inflammatory processes by communicating with the brain. How and which neurobiological mediators underlie this communication remain poorly understood. PPAR-α (peroxisome proliferator-activated receptor α), a transcription factor susceptible to epigenetic modifications, regulates pathophysiological functions, including metabolic syndrome, inflammation, and behavior. Mood disorders, inflammatory processes, and obesity are intertwined phenomena that are associated with low blood concentrations of the anti-inflammatory and "endogenous tranquilizer" neurosteroid allopregnanolone and poor PPAR-α function. Stress and consumption of obesogenic diets repress PPAR function in brain, enterocytes, lipocytes, and immune modulatory cells favoring inflammation, lipogenesis, and mood instability. Conversely, micronutrients and modulators of PPAR-α function improve microbiome composition, dampen systemic inflammation and lipogenesis, and improve anxiety and depression. In rodent stress models of anxiety and depression, PPAR activation normalizes both PPAR-α expression downregulation and decreased allopregnanolone content and ameliorates depressive-like behavior and fear responses. PPAR-α is known to regulate metabolic and inflammatory processes activated by short-chain fatty acids; endocannabinoids and congeners, such as N-palmitoylethanolamide, drugs that treat dyslipidemias; and micronutrients, including polyunsaturated fatty acids. Both PPAR-α and allopregnanolone are abundantly expressed in the colon, and they exert potent anti-inflammatory actions by blocking the toll-like receptor-4-nuclear factor-κB pathway in peripheral immune cells, neurons, and glia. The perspective that PPAR-α regulation in the colon by gut microbiota or metabolites influences central allopregnanolone content after trafficking to the brain, thereby serving as a mediator of gut-brain axis communications, is examined in this review.
肠道微生物组通过与大脑交流来调节情绪行为、应激反应和炎症过程。这种交流的机制和哪些神经生物学介质是基础，目前仍知之甚少。PPAR-α（过氧化物酶体增殖物激活受体-α）是一种易受表观遗传修饰影响的转录因子，它调节包括代谢综合征、炎症和行为在内的病理生理功能。心境障碍、炎症过程和肥胖是相互交织的现象，与抗炎和“内源性镇静剂”神经甾体 allo 孕烷醇酮的血液浓度降低以及 PPAR-α功能差有关。应激和食用致肥胖饮食会抑制大脑、肠上皮细胞、脂肪细胞和免疫调节细胞中的 PPAR 功能，有利于炎症、脂肪生成和情绪不稳定。相反，微量营养素和 PPAR-α 功能调节剂可以改善微生物组组成，抑制全身炎症和脂肪生成，并改善焦虑和抑郁。在焦虑和抑郁的啮齿动物应激模型中，PPAR 激活可使 PPAR-α 表达下调和 allo 孕烷醇酮含量降低恢复正常，并改善抑郁样行为和恐惧反应。已知 PPAR-α 可调节由短链脂肪酸、内源性大麻素和类似物（如 N-棕榈酰乙醇酰胺）、治疗血脂异常的药物以及包括多不饱和脂肪酸在内的微量营养素激活的代谢和炎症过程。PPAR-α 和 allo 孕烷醇酮在结肠中大量表达，通过阻断外周免疫细胞、神经元和神经胶质细胞中的 toll 样受体 4-核因子-κB 途径发挥强大的抗炎作用。本文综述了肠道微生物群或代谢物在结肠中对 PPAR-α 的调节是否会影响 allo 孕烷醇酮在大脑中的含量，进而作为肠道-大脑轴通讯的介质。
