2.2.4. Gut microbiota
The gut microbiota plays a central role in drug metabolism and personalized medicine, and high-altitude hypoxia damages the gut structure and mucosal barrier, altering the species and abundance of the gut microbiota (Zhang et al., 2018). Gut microbiota may regulate CYP expression (Toda et al., 2009; Togao et al., 2021; Selwyn et al., 2016). Our group performed a study on gut microbiota and CYP expression under high-altitude hypoxia and found that the decrease in protein and mRNA expression of CYP3A1 under high-altitude hypoxia was substantially correlated with changes in the structural composition and diversity of the gut microbiota, which was mainly attributed to the upregulation of CYP3A4 protein and mRNA expression mediated by the gut microbiota through the release of extracellular vesicles (Bai et al., 2022), and the study demonstrated the effects of high-altitude hypoxia on the gut microbiota as a potential mechanism for changes in CYP expression.
As research on CYPs has advanced, it has become evident that these mechanisms do not function autonomously. For example, the presence of nuclear receptors is affected by epigenetic modifications, inflammatory factors, and HIF, all of which are controlled by epigenetic modifications. miRNAs modulate the activity of epigenetic enzymes, as well as the expression of CYPs and nuclear receptors. Conversely, DNA methylation and histone modification influence miRNA expression. In summary, these mechanisms, in conjunction with hypoxia, create an intricate network of CYP gene regulation (Figure 1).