The role of the gut microbiome in the regulation of high‐altitude adaptation

Abstract Hypoxia and cold temperatures are major limiting factors for animals reared at high altitudes. Previous adaptation studies have primarily focused on genetic and genomic aspects, while the mechanisms by which the gut microbiome contributes to this adaptation are still not fully understood. We used ruminants as both naturally adapted (yaks) and non‐adapted (Holstein cows) models to investigate the role of gut microbiome in high‐altitude adaptation by applying multi‐omics approaches. First, 20 yaks and 20 Holstein cows that had been reared at approximately 4000 m altitude since birth were fed the same diet for 44 days prior to sampling to eliminate the short‐term effects of nutrition and altitude adaptation. The yak rumen microbiome showed significant enrichment in carbon metabolism, particularly central carbon metabolism pathways, such as glycolysis/gluconeogenesis, pyruvate metabolism, and the pentose phosphate pathway, whereas that of Holstein cows was enriched in starch, sucrose, pentose, and glucuronate interconversions. Compared with those of Holstein cows kept at high altitudes for their entire life, the yak rumen epithelial cells, as determined by single‐nucleus RNA sequencing, exhibited higher elevated scores for ketone body biosynthesis and fatty acid beta‐oxidation. Second, mixed rumen fluid was transplanted from 10 yaks to 10 Holstein cows. Holstein cows then showed better milk production performance. A progressive decline in carbon metabolism activity from 6 h to 7 and 28 days post‐transplantation was verified. In conclusion, the rumen microbiome and host epithelial function appear to support high‐altitude adaptation by improving the energy supply of the host.