Longitudinal multi-omics analysis uncovers the altered landscape of gut microbiota and plasma metabolome in response to high altitude

Abstract Background Gut microbiota is significantly influenced by altitude. However, the dynamics of gut microbiota in relation to altitude remains undisclosed. Methods In this study, we investigated the microbiome profile of 610 healthy young men from three different places in China, grouped by altitude, duration of residence, and ethnicity. We conducted widely targeted metabolomic profiling and clinical testing to explore metabolic characteristics. Results Our findings revealed that as the Han individuals migrated from low altitude to high latitude, the gut microbiota gradually converged towards that of the Tibetan populations but reversed upon returning to lower altitude. Across different cohorts, we identified 51 species specifically enriched during acclimatization and 57 species enriched during deacclimatization to high altitude. Notably, Prevotella copri was found to be the most enriched taxon in both Tibetan and Han populations after ascending to high altitude. Furthermore, significant variations in host plasma metabolome and clinical indices at high altitude could be largely explained by changes in gut microbiota composition. Similar to Tibetans, 41 plasma metabolites, such as lactic acid, sphingosine-1-phosphate, taurine, and inositol, were significantly elevated in Han populations after ascending to high altitude. Germ-free animal experiments demonstrated that certain species, such as Escherichia coli and Klebsiella pneumoniae , which exhibited altitude-dependent variations in human populations, might play crucial roles in host purine metabolism. Conclusions This study provides insights into the dynamics of gut microbiota and host plasma metabolome with respect to altitude changes, indicating that their dynamics may have implications for host health at high altitude and contribute to host adaptation.