Intestinal dual-specificity phosphatase 6 regulates the cold-induced gut microbiota remodeling to promote white adipose browning

• Published in: NPJ biofilms and microbiomes Vol. 10; no. 1; p. 22
• Main Authors: Chen, Pei-Chen, Tsai, Tzu-Pei, Liao, Yi-Chu, Liao, Yu-Chieh, Cheng, Hung-Wei, Weng, Yi-Hsiu, Lin, Chiao-Mei, Kao, Cheng-Yuan, Tai, Chih-Cheng, Ruan, Jhen-Wei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.03.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/326/2565/2134; 631/326/2565/855; Adipose tissue; Amino acids; Animal models; Biomedical and Life Sciences; Body fat; Cecum; Coadaptation; Cold; Digestive system; Fatty liver; Gastrointestinal tract; Germfree; Intestinal microflora; Intestine; Life Sciences; Lysine; Medical Microbiology; Microbial Ecology; Microbial Genetics and Genomics; Microbiology; Microbiomes; Microbiota; Phenotypes; Ursodeoxycholic acid
• ISSN: 2055-5008; 2055-5008
• DOI: 10.1038/s41522-024-00495-8

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.