Gut microbiota rearrangement induced by cold temperature is crucial for browning in murine white adipose tissue. This study provides evidence that DUSP6, a host factor, plays a critical role in regulating cold-induced gut microbiota rearrangement. When exposed to cold, the downregulation of intestinal DUSP6 increased the capacity of gut microbiota to produce ursodeoxycholic acid (UDCA). The DUSP6-UDCA axis is essential for driving Lachnospiraceae expansion in the cold microbiota. In mice experiencing cold-room temperature (CR) transitions, prolonged DUSP6 inhibition via the DUSP6 inhibitor (E/Z)-BCI maintained increased cecal UDCA levels and cold-like microbiota networks. By analyzing DUSP6-regulated microbiota dynamics in cold-exposed mice, we identified Marvinbryantia as a genus whose abundance increased in response to cold exposure. When inoculated with human-origin Marvinbryantia formatexigens, germ-free recipient mice exhibited significantly enhanced browning phenotypes in white adipose tissue. Moreover, M. formatexigens secreted the methylated amino acid Nε-methyl-L-lysine, an enriched cecal metabolite in Dusp6 knockout mice that reduces adiposity and ameliorates nonalcoholic steatohepatitis in mice. Our work revealed that host-microbiota coadaptation to cold environments is essential for regulating the browning-promoting gut microbiome.

低温诱导的肠道微生物群重排对于小鼠白色脂肪组织的褐变至关重要。这项研究提供了证据，证明宿主因子 DUSP6 在调节寒冷诱导的肠道微生物群重排中发挥着关键作用。当暴露于寒冷时，肠道 DUSP6 的下调增加了肠道微生物群产生熊去氧胆酸 (UDCA) 的能力。DUSP6-UDCA 轴对于驱动毛螺菌科在冷微生物群中的扩张至关重要。在经历冷室温度 (CR) 转变的小鼠中，通过 DUSP6 抑制剂 (E/Z)-BCI 延长 DUSP6 抑制可维持盲肠 UDCA 水平和冷样微生物群网络的增加。通过分析冷暴露小鼠中 DUSP6 调节的微生物群动态，我们发现Marvinbryantia是一个其丰度随着冷暴露而增加的属。当接种人源Marvinbryantia formatexigens时，无菌受体小鼠的白色脂肪组织表现出显着增强的褐变表型。此外，M. formatexigens分泌甲基化氨基酸 Nε-甲基-L-赖氨酸，这是Dusp6敲除小鼠中丰富的盲肠代谢物，可减少小鼠肥胖并改善非酒精性脂肪性肝炎。我们的工作表明，宿主微生物群对寒冷环境的共同适应对于调节促进褐变的肠道微生物组至关重要。