The Role of Short-Chain Fatty Acid Sensing in Regulating Hepatic Glucose Production

糖尿病的患病率在美国继续有增无减，造成了严重的 社会和经济负担。目前的药物治疗只是适度的 有效地降低血糖，而代谢手术是有效的，但具有高度侵入性。 有趣的是，这两种治疗方案都改变了肠道微生物区系，即所有 驻留在胃肠道中的微生物，强调肠道微生物在 糖尿病的发展和改善。这个项目的长期目标是更好地 了解肠道微生物区系影响血糖动态平衡的机制。 益生菌代表了一种更有希望改变肠道的饮食策略 微生物区系组成和改善代谢失调。低聚果糖治疗 (OFS)，一种不可消化的纤维，降低血糖水平，改善葡萄糖耐量，以及 增加远端肠道中短链脂肪酸(SCFAs)的生成。因此，SCFA 治疗还会带来新陈代谢方面的好处，包括减轻体重和改善血糖 宽容。尽管如此，单链脂肪酸是如何改善血糖稳态的，以及这些 益生元的有益作用需要机制，目前尚不清楚。为 例如，小肠丙酸输注激活肠道-脑-肝轴以降低肝脏 葡萄糖的产生，但这一途径是否存在于结肠中，在那里大多数SCFA 都是生产出来的，是未知的。此外，单链脂肪酸可以进入门静脉并作用于肝脏， 但它们在肝脏葡萄糖调节中的作用尚不清楚。有趣的是，丁酸盐和丙酸酯 可以作为表观遗传调节器，抑制组蛋白脱乙酰酶(HDAC)，但目前尚不清楚 单链脂肪酸是否影响直接调节肝脏的下游转录因子 糖异生作用。这与我们的初步数据一起，导致了这样的假设：SCFA可以改善 直接和间接靶向肝糖生成(HGP)的糖耐量，两者 其通路负责调节OFS治疗的有益效果。通过 在糖耐量测试期间使用复杂的体内手术和病毒操作 胰腺钳，这一假设将在3个目标中得到验证：1)确定吸收前期的SCFA 激活结肠-脑-肝轴以降低HGP，2)检测门静脉SCFAs抑制HGP的能力 HDAC活性以降低HGP，以及3)确定肠-脑-肝轴信号或肝脏HDAC 抑制是益生元的糖调节益处的原因，因为增加了单链脂肪酸。 更好地理解益生元和单链脂肪酸是如何改善血糖稳态的 用于降低糖尿病期间慢性升高的HGP的靶向治疗。

The prevalence of diabetes continues to rise unabated in the United States, creating a grave social and economic burden. Current pharmacological treatments are only moderately effective at lowering glycemia, while metabolic surgery is effective, yet highly invasive. Interestingly, both therapeutic options alter the gut microbiota, the collection of all the microbes residing in the gastrointestinal tract, highlighting the role of gut microbes in the development and amelioration of diabetes. The long-term goal of this project is to better understand the mechanisms of the gut microbiota impacting glucose homeostasis. Prebiotics represent one of the more promising dietary strategies to alter the gut microbiota composition and improve metabolic dysregulation. Treatment with oligofructose (OFS), a non-digestible fiber, lowers blood glucose levels, improves glucose tolerance, and increases production of short-chain fatty acids (SCFAs) in the distal intestine. As such, SCFA treatment also results in metabolic benefits, including weight loss and improved glucose tolerance. Despite this, how SCFAs improves glucose homeostasis, and whether these mechanisms are required for the beneficial effects of prebiotics, remains unknown. For example, small intestinal propionate infusion activates a gut-brain-liver axis to lower hepatic glucose production, but whether this pathway exists in the colon, where the majority of SCFAs are produced, is unknown. Furthermore, SCFAs can enter the portal vein and act on the liver, but their role in hepatic glucose regulation is not clear. Interestingly, butyrate and propionate can act as epigenetic regulators, inhibiting histone deacetylases (HDACs), but it is unknown whether SCFAs affect downstream hepatic transcription factors that directly regulate hepatic gluconeogenesis. This, with our preliminary data, led to the hypothesis that SCFAs improve glucose tolerance by directly and indirectly targeting hepatic glucose production (HGP), both pathways of which are responsible for mediating the beneficial effects of OFS treatment. By utilizing sophisticated in-vivo surgical and viral manipulations during glucose tolerance tests or pancreatic clamps, this hypothesis will be tested in 3 aims: 1) determine if preabsorptive SCFAs activates a colonic-brain-liver axis to lower HGP, 2) examine the ability of portal SCFAs to inhibit HDAC activity to lower HGP, and 3) determine if gut-brain-liver axis signaling or hepatic HDAC inhibition are responsible for the glucoregulatory benefits of prebiotics due to increased SCFAs. A better understanding of how prebiotics and SCFAs improve glucose homeostasis could lead to targeted therapies that reduce chronically elevated HGP during diabetes.