At high altitudes, the host microbiome undergoes significant changes due to reduced pressure and low oxygen levels. Both acute and chronic exposure to hypobaric hypoxia lead to alterations in the diversity, abundance, and composition of the gut and oral microbiota. These variations help the body to adapt to extreme environmental conditions, which pose serious health risks. The altered gut and oral microbiome can weaken the mucosal lining, leading to many gastrointestinal and oral problems and increased susceptibility to various symptoms and diseases. Results revealed that short-term exposure to high altitudes can harm the gut barrier, and prolonged exposure to low oxygen levels may further deteriorate the barrier by disrupting immune functions, mucous secretion and ultimately leading to dysbiosis. Preliminary studies have shown that hypobaric hypoxia may exacerbate intestinal damage by reducing blood flow to the intestine and increasing oxygen deficiency, thereby leading to additional stress on the body. In this chapter, we first summarize the R&D work done so far globally to demonstrate the effect of high altitude on gut and oral microbiota. Microbiome-targeted therapies are being investigated for their potential to modulate the microbiome and improve gut and oral health. As research continues to uncover the multifaceted relationships between the host and microbiome, we may see the emergence of therapeutic strategies to promote overall well-being and avert systemic diseases.