Developmental and evolutionary trade-offs with early-life disruption of the gut microbiota

Abstract

Environmental adversity during early life can cue developmental changes in young animals that promote metabolic diseases, such as obesity, in adults. The gut microbiota plays critical roles in the regulation of host energy balance, can undergo lasting changes in response to transient environmental influences, and is subject to vertical transmission from mother to offspring, raising the possibility that environmental influences on the microbiota can initiate developmental tradeoffs and adult metabolic disease. Notably, disruption of the gut microbiome in early life via exposure to antibiotics has been linked to increased adiposity in humans, mice, and other animals, but the physiological mechanisms (proximate) and evolutionary adaptations (ultimate) underlying this effect remain unclear. In this dissertation, we use an intergenerational mouse model to evaluate the general hypothesis that microbiota disruption during the critical period of early life is a signal of environmental adversity or volatile energy availability, necessitating energy allocation tradeoffs that promote adiposity in adulthood at the cost of fitness. First, we introduce a framework to understand the energetic, developmental, and evolutionary mechanisms of obesity associated with early-life antibiotic exposure (ELA). Second, we show that early-life exposure to both therapeutic and non-therapeutic antimicrobial compounds, including common dietary preservatives, can alter gut microbial composition in vitro and in vivo, with differing consequences for host metabolism. Third, we establish that pulsed therapeutic and chronic subtherapeutic doses of antibiotics in early life have variable effects on host energy status in the short-term, but nevertheless act through similar physiological mechanisms to promote obesity in the long-term, primarily by inducing metabolic thrift in males. Females proved resistant to the development of metabolic thrift and subsequently showed no evidence of obesity in response to ELA treatment. Last, we evaluate the fitness trade-offs involved in ELA-induced obesity, demonstrating that the development of metabolic thrift in males as a response to ELA treatment helps them better buffer against periods of food limitation in adulthood, while the lack of such metabolic thrift in ELA-treated females impairs their ability to produce high-quality offspring and maintain body mass in an energy- limited environment. Altogether, this work synthesizes perspectives from microbiology, developmental biology, clinical medicine, and evolutionary theory to advance our understanding of the physiological underpinnings and health implications of early-life disruption of the gut microbiome.