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.

肠道微生物组（该术语用于指居住在胃肠道中的微生物群落）是宿主产生和使用能量的关键角色。研究表明，破坏肠道微生物组的发育过程。抗生素会增加身体脂肪，并导致女性和男性在以后的生活中出现肥胖和疾病的相关风险。这篇博士论文研究调查了抗生素的使用如何导致身体脂肪增加，从进化的角度分析了这种影响，并探讨了原因。性别结合这些重点领域，可以对因果关系进行调查，这对于了解早年经历的因素如何影响晚年的健康结果非常重要，而且除了有可能为公共卫生研究提供信息外，结果也很重要。这项研究为女研究生提供了强化培训，并为本科生（特别是目前在 STEM 领域代表性不足的群体的成员）提供了获得丰富研究经验的机会。促进成人代谢疾病的动物肠道微生物群在调节宿主能量平衡中发挥着关键作用，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，尽管短期能量损失，但早期接触抗生素。生命与人类、小鼠、牲畜和其他动物成年后的肥胖和超重有关，然而，研究人员对生命早期关键时期的肠道微生物群耗竭的生理机制仍不清楚。约束能量为了验证这一假设，研究人员在早期抗生素治疗的传统小鼠模型的发育过程中分析了肠道微生物组和宿主的能量分配，然后进行了研究。这项研究提供了将关注健康和疾病的发育起源的学科与关注肠道微生物群和宿主微生物相互作用的学科联系起来的新证据。权衡该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。