Microbiota and Inflammation in Adiposity: The Ground Squirrel Model

在肥胖的发展过程中，改变饮食会导致肠道微生物区系的变化，包括减少 某些门的多样性和相对丰度的变化。这导致了促炎的肠道环境， 远处组织(如脂肪)的炎症、脂肪的堆积和最终的胰岛素抵抗(IR)。 目前的啮齿动物脂肪堆积模型集中在一个病因上，并使用近交系实验室菌株； 然而，将这些研究转化为人类医学是有限的，大概是因为a)人类是 与实验室啮齿动物相比，具有更多变化的微生物区系的异质远交种群，以及b) 肥胖和胰岛素抵抗的发生是饮食、代谢和遗传因素共同作用的结果。 冬眠的哺乳动物，如13线地松鼠(Ictidomys Tridecemlineatus)，自然会增加肥胖 每年在“冬眠前的育肥阶段”。我们之前已经证明，这种肥胖症增加 伴随着代谢组织的炎症。我们目前获奖的结果表明，盲肠微生物区系 从瘦松鼠身上移植或补充粘液阿克曼氏菌可减轻一些炎症 在育肥的地松鼠身上。肠道特异性抗炎药美沙拉秦治疗效果显著 抑制肠道和脂肪组织的炎症，增加卡路里摄入量，而不影响体重。 该提案中概述的实验采取了下一步，使用肠道微生物区系转移(GMT)来重申 通过使用GMT将表型转移到小鼠身上来研究微生物区系在地松鼠中的致胖作用。我们 然后将在小鼠和地面上测试益生素(以增加微生物区系多样性)和美沙拉秦治疗 评估同时操纵微生物区系和免疫系统是否可以抑制肥胖和 信息检索的发展。这项研究的假设是：1)肠道微生物群的变化和 松鼠从冬眠中苏醒后不久的免疫系统促进非冬眠动物的肥胖 冬眠者和2)通过含有益生素的饮食结合 美沙拉秦治疗可更有效地改善脂肪堆积、代谢性炎症和胰岛素抵抗 而不是任何一种单独的治疗。建议的实验方法使用育肥地松鼠的GMT。 以阐明松鼠微生物区系的肥胖特性。通过使用GMT的 冬眠后在不同地点采集的样本，特定目标1将确定地面 松鼠的微生物群从饮食中获得了最多的能量。在具体目标2中，我们将处理育肥场地 松鼠和杂交小鼠在GMT后用益生元、美沙拉秦或两者一起评估累积情况 促进微生物区系多样性和抑制炎症对肥胖的影响。我们的实验承诺 进一步阐明肠道微生物区系和免疫系统在脂肪堆积和 在冬眠和非冬眠物种中IR的发展，最终有助于我们的总体 了解脂肪堆积和胰岛素抵抗是如何诱发的。

During development of obesity, an altered diet leads to changes in the gut microbiota, including decreased diversity and shifts in relative abundance of certain phyla. This leads to a pro-inflammatory gut environment, inflammation in distant tissues (i.e., adipose), accumulation of fat and eventually insulin resistance (IR). Current rodent models of fat accumulation focus on one etiological cause and use in-bred laboratory strains; however, translation of these studies to human medicine has been limited, presumably because a) humans are a heterogeneous outbred population with a more variable microbiota than laboratory rodents, and b) the development of obesity and IR results from a combination of dietary, metabolic and genetic factors. Hibernating mammals like 13-lined ground squirrels (Ictidomys tridecemlineatus) naturally increase adiposity each year during a “pre-hibernation fattening phase”. We have previously shown that this increased adiposity is accompanied by inflammation of metabolic tissues. Results of our current award show that cecal microbiota transfer from lean squirrels or supplementation with Akkermansia muciniphila ameliorated some inflammation in fattening ground squirrels. Treatment with the gut-specific anti-inflammatory drug mesalazine significantly suppressed inflammation in gut and adipose tissues and increased caloric intake without affecting body mass. The experiments outlined in this proposal take the next step by using gut microbiota transfer (GMT) to reaffirm the obesogenic role of the microbiota in ground squirrels by using GMT to transfer the phenotype to mice. We will then test prebiotic (to increase microbiota diversity) and mesalazine treatments in mice and ground squirrels to assess whether manipulating the microbiota and immune system together can curb adiposity and the development of IR. The hypotheses for this investigation are that 1) changes in the gut microbiome and immune system of squirrels soon after emergence from hibernation encourage adiposity in non- hibernators and 2) boosting gut microbial diversity with a diet containing prebiotics in conjunction with mesalazine treatment will ameliorate fat accumulation, metabolic inflammation and IR more effectively than either treatment alone. The proposed experimental approach uses GMT from fattening ground squirrels into outbred mouse strains to elucidate the obesogenic properties of the squirrel microbiota. By using GMT of samples collected at different points post-hibernation, Specific Aim 1 will identify the point at which the ground squirrel’s microbiota harvest the most energy from the diet. In Specific Aim 2 we will treat fattening ground squirrels and outbred mice after GMT with prebiotics, mesalazine or both together to evaluate the cumulative effect of promoting microbiota diversity and curbing inflammation on adiposity. Our experiments promise to further clarify the role of the gut microbiota and immune system in the accumulation of fat and development of IR in hibernating and non-hibernating species, ultimately contributing to our overall knowledge of how fat accumulation and IR are induced.