Doctoral Dissertation Research: Physiological tradeoffs arising from early-life disruption of the gut microbiome

博士论文研究：生命早期肠道微生物组破坏引起的生理权衡

• 批准号: 2142073
• 负责人: Rachel Carmody
• 金额: $ 3.38万
• 依托单位: Harvard University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2142073&HistoricalAwards=false
• 关键词: Doctoral; Dissertation; Research; Physiological; tradeoffs

The gut microbiome – the term used to refer to the collective community of microbes that live in the gastrointestinal tract – is a key player in the creation and use of energy for the host. Studies show that disrupting the course of development of the gut microbiome with antibiotics can increase body fat and the linked risk of obesity and disease later in life. These effects can differ between females and males. This doctoral dissertation research investigates how antibiotic use causes increased body fat, frames this effect in an evolutionary context, and examines why sex differences in this effect arise. Combining these areas of focus allows this investigation of cause-effect relationships important for understanding how factors experienced in early life impact health outcomes later in life, and in addition to the potential to inform public health research, the results speak to larger theoretical frameworks in biological anthropology. This research provides intensive training for a female graduate student and opportunities for undergraduate students, particularly members of groups currently underrepresented in STEM fields to gain robust research experience. Environmental adversity during early life can cue developmental changes in young animals that promote metabolic diseases in adults such as obesity. The gut microbiome plays critical roles in the regulation of host energy balance, with disruption of the gut microbiome through antibiotic use causing short-term weight and fat loss. Notably, despite short-term energy losses, exposure to antibiotics in early life has been linked to obesity and overweight in adulthood in humans, mice, livestock, and other animals. However, the physiological mechanisms underlying these long-term obesogenic effects remain unclear. The investigators hypothesize that gut microbiota depletion during the critical period of early life constrains energy budgets, necessitating energy allocation tradeoffs that persist in adulthood at the cost of fitness. To test this hypothesis, the investigators profile the gut microbiome and host energy allocation over the course of development in a conventional mouse model of early-life antibiotic treatment, followed by direct evaluation of immune and reproductive fitness in adulthood. The proposed study provides novel evidence linking disciplines concerned with the developmental origins of health and disease to those concerned with the gut microbiota and host-microbial interactions. The results of this research contribute to theoretical discussions regarding trade-offs following early life influence and illuminates the factors contributing to rising rates of metabolic diseases across the globe.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

肠道微生物群——这个术语用来指生活在胃肠道中的微生物集体——是宿主创造和利用能量的关键角色。研究表明，用抗生素扰乱肠道微生物群的发育过程会增加体脂，并增加晚年肥胖和疾病的相关风险。这些影响在女性和男性之间是不同的。这篇博士论文研究了抗生素的使用是如何导致体脂增加的，在进化的背景下构建了这种影响，并研究了为什么这种影响会出现性别差异。结合这些重点领域，可以对因果关系进行调查，这对于理解生命早期经历的因素如何影响生命后期的健康结果非常重要，除了有可能为公共卫生研究提供信息外，研究结果还说明了生物人类学中更大的理论框架。这项研究为女研究生提供了强化培训，为本科生提供了机会，特别是目前在STEM领域代表性不足的群体成员，以获得丰富的研究经验。幼年时期的环境逆境会引发幼龄动物的发育变化，从而导致成年动物患上代谢性疾病，如肥胖。肠道微生物群在调节宿主能量平衡中起着关键作用，使用抗生素破坏肠道微生物群会导致短期体重和脂肪减少。值得注意的是，尽管有短期的能量损失，但在生命早期接触抗生素与人类、小鼠、牲畜和其他动物成年后的肥胖和超重有关。然而，这些长期致肥效应的生理机制尚不清楚。研究人员假设，在生命早期的关键时期，肠道微生物群的消耗限制了能量预算，需要能量分配的权衡，这种权衡以健康为代价持续到成年。为了验证这一假设，研究人员在早期抗生素治疗的传统小鼠模型中描述了肠道微生物群和宿主能量分配，随后直接评估了成年期的免疫和生殖健康。这项拟议的研究提供了新的证据，将与健康和疾病的发育起源有关的学科与肠道微生物群和宿主-微生物相互作用有关的学科联系起来。这项研究的结果有助于关于早期生活影响后权衡的理论讨论，并阐明了导致全球代谢性疾病发病率上升的因素。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。