The High‐Altitude Adaptation Characteristics of Microbiota‐Host Cross‐Talk in Yak Gastrointestinal Track

Abstract The yak, an ideal model for studying high‐altitude hypoxia adaptation, possesses unique gastrointestinal tract (GIT) adaptability. However, understanding of cellular‐level mechanisms underlying host‐metabolite‐microbe within GIT that are crucial for growth in extreme environments remains significantly limited. Therefore, this study constructs the first comprehensive multi‐tissue cellular atlas of the yak GIT, encompassing 54 distinct cell types. Cross‐species and cross‐tissue comparative analyses combined with large‐scale population genetic data identify HNF4A and SREBF2 as GIT‐specific transcription factors targeting the key gene MYO6 , revealing unique transcriptional patterns and the significant influence of epithelial cells on yak body weight in GIT. Alongside the characterization of microorganisms and metabolites along the GIT, the important microorganism Bacillus infection has cell‐type specificity, and affects the accumulation of key products such as Succinate and lactic acid through the interaction between different epithelial cell metabolic activities and microorganisms and the communication between different cell types (key receptors SLC27A5 , PPARA ), thereby affecting glycolysis and TCA cycle and other processes to strengthen the adaptability of yak GIT in extreme environments. This work provides novel insights into the unique gastrointestinal adaptations of yaks to extreme environments and holds significant implications for understanding precision breeding in yaks and mammal gastrointestinal responses to hypoxia.