Microbiota and Inflammation in Adiposity: The Ground Squirrel Model

在肥胖症的发展过程中，饮食的改变导致肠道微生物群的变化，包括减少 多样性和某些门相对丰度的变化。这导致了一个促炎的肠道环境， 远处组织中的炎症（即，脂肪）、脂肪积累和最终的胰岛素抵抗（IR）。 目前的啮齿动物脂肪蓄积模型集中在一个病因学原因和使用近交实验室菌株; 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 具有比实验室啮齿动物更易变的微生物群的异质远系繁殖群体，和B） 肥胖和IR的发展是由饮食、代谢和遗传因素的组合引起的。 冬眠的哺乳动物，如13-lined地松鼠（Ictidomys tridecemlineatus）， 在"冬眠前的增肥阶段"。我们以前已经证明，这增加了肥胖， 伴随着代谢组织的炎症。我们目前的研究结果表明，盲肠微生物群 从瘦松鼠转移或补充嗜粘蛋白阿克曼氏菌减轻了一些炎症 在养肥地松鼠方面。用肠道特异性抗炎药美沙拉秦治疗， 抑制肠道和脂肪组织的炎症，增加热量摄入，而不影响体重。 该提案中概述的实验通过使用肠道微生物群转移（GMT）来再次确认 通过使用GMT将表型转移到小鼠中，研究了地松鼠中微生物群的致肥胖作用。我们 然后将在小鼠和地面上测试益生元（以增加微生物群的多样性）和美沙拉秦治疗 松鼠，以评估是否操纵微生物群和免疫系统一起可以遏制肥胖， 这项研究的假设是：1）肠道微生物组的变化， 松鼠从冬眠中苏醒后不久免疫系统会促使非哺乳动物肥胖， 冬眠动物和2）用含有益生元的饮食结合 美沙拉秦治疗能更有效地改善脂肪堆积、代谢性炎症和IR 比单独使用任何一种疗法都要好拟议的实验方法使用GMT从育肥地松鼠 远系繁殖的小鼠品系，以阐明松鼠微生物群的致肥胖特性。通过使用GMT 在冬眠后的不同地点收集的样本，具体目标1将确定地面 松鼠的微生物群从食物中获得最多的能量。在具体目标2中，我们将处理肥田 GMT后，用益生元、5-氨基水杨酸或两者同时给药， 促进微生物群多样性和抑制炎症对肥胖的影响。我们的实验保证 进一步阐明肠道微生物群和免疫系统在脂肪积累中的作用， 在冬眠和非冬眠物种的IR的发展，最终有助于我们的整体 了解脂肪积聚和IR是如何诱导的。

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.