Moderate altitude exposure impacts extensive host-microbiota multi-kingdom connectivity with serum metabolome and fasting blood glucose

The contributions and interactions of multi-kingdom microbiota (i.e. bacteriome, mycobiome, archaeaome, and phageome) with serum metabolome and host phenome in healthy individuals under moderate altitude exposure remain unclear. We applied shotgun metagenomic sequencing in faeces and targeted metabolomics technology in serum to explore how the human gut multi-kingdom microorganisms influence the serum metabolome and phenome in healthy Chinese individuals following moderate altitude exposure. The results indicated that individuals with moderate altitude exposure exhibited more substantial alterations in gut bacteriome and phageome compared to those in mycobiome and archaeaome. Both intra-kingdom and inter-kingdom correlations at baseline were denser than those following moderate altitude exposure. Bacteriophages-host interactions analysis revealed symbiosis between bacteriophages and <i>Bacteroidetes</i>, <i>Proteobacteria</i>, and short-chain fatty acids (SCFAs) producers. Furthermore, bacteriophage <i>Shirahamavirus PTm1</i> (odds ratio (OR) = 3.82; 95% confidence interval (CI): 1.20-12.16), archaeon <i>Crenarchaeota</i> (OR = 3.70; 95% CI: 1.35-10.14) and bacterium <i>Bacteroidetes</i> (OR = 3.69; 95% CI: 1.34-10.15) showed a positive association with lowered fasting blood glucose (FBG) benefits, while bacteriophage <i>Candidatus Nitrosopelagicus brevis</i> (OR = 0.30; 95% CI: 0.10-0.89) and butyric acid (OR = 0.07; 95% CI: 0.01-0.37) exhibited a negative association with lowered FBG benefits. These findings suggest that targeting gut multi-kingdom microorganisms could serve as an alternative therapeutic approach to mitigate dysglycemia and its associated metabolic disorders.