THE GUT MICROBIOME REGULATES THERMOGENESIS AND CONTRIBUTES TO HIGH-ALTITUDE ADAPTATION IN DEER MICE (Peromyscus maniculatus)

Abstract

High-altitude environments present significant challenges for endothermic animals, as low temperatures increase the metabolic demands of body heat generation (thermogenesis) but reduced oxygen levels (hypoxia) constrain aerobic metabolism. High-altitude natives have adapted to overcome these challenges by enhancing thermogenic capacity in hypoxia. The gut microbiome is a potential key regulator of host thermogenesis, by producing metabolites that communicate with host thermogenic tissues and generating heat itself, but the role of the microbiome in high-altitude adaptation is largely unknown. To assess this role, deer mice (Peromyscus maniculatus) native to high and low altitudes were born and raised in lab conditions before acclimation to warm (25°C) normoxia or cold (5°C) hypoxia (12 kPa O2) for 6 weeks. A subset of mice were treated with broad-spectrum antibiotics to disrupt the microbiome. Among microbiome-intact mice, the high-altitude population had greater cold endurance and cold-induced rates of aerobic metabolism in hypoxia, as well as increased abundance of Clostridia taxa and microbially-derived metabolites in the caecum. Microbiome disruption significantly impaired cold endurance, but only in high-altitude mice, suggesting an increased influence of host-microbiome interactions on thermogenic performance. To assess whether population differences in the microbiome were dependent on the deer mouse host, cecum contents from high- and low-altitude populations were transferred to domestic germ-free mice. Among these recipient mice, microbiome source had no effect on thermogenic performance, suggesting that the deer mouse host is necessary for shaping the host-microbiome relationship. These findings suggest that evolved changes in host-microbe interactions contribute to high-altitude adaptation in deer mice.