A healthy gut microbiome, particularly including probiotic microorganisms that metabolize complex carbohydrates and produce short-chain fatty acids (SCFAs), plays a critical role in maintaining intestinal homeostasis and is generally associated with improved health outcomes. Stressors, both physical and psychological, result in the release of stress-related neurochemicals to which gastrointestinal bacteria are particularly sensitive. This can lead to gastrointestinal distress and inflammation, and a dysbiotic gut microbiome can lead to anxiety and depression. During spaceflight, astronauts are exposed to numerous stressors such as microgravity, radiation, sleep disruption, and isolation, which can lead to challenges such as muscle wasting, immune dysfunction, and neuro-ocular syndrome. However, the impact of space conditions on the human microbiome is not well understood. Since the availability of samples from astronauts during spaceflight is limited, bed rest studies on Earth offer a great opportunity to study the simulated effects of spaceflight-induced changes in the human body in more detail and with a larger number of subjects. In particular, head-down tilt (HDT) bed rest studies provide valuable insights into the effects of microgravity on the human body. The DLR Institute of Aerospace Medicine has conducted several HDT studies, including "AGBRESA", "SANS-CM" and "SMC", to evaluate the influence of different countermeasures on physiological changes. Subjects underwent 30 to 60 days of HDT with countermeasures such as exercise and centrifugation. To assess microbiome changes, stool samples were collected from subjects in these bedrest studies at baseline, during HDT, and after recovery and analyzed using next-generation sequencing of the 16S rRNA gene. Results show high stability of gut microbial communities but interindividual variability in gut microbiome composition. Improving this understanding of the interactions between the gut microbiome and individual host responses to prolonged bed rest, might provide valuable insights to help mitigate the risks associated with long-duration space missions.