Moderate altitude exposure impacts host fasting blood glucose and serum metabolome by regulation of the intestinal flora

Moderate altitude exposure has shown beneficial effects on diabetes incidence but the underlying mechanisms are not understood. Our study aimed to investigate how the human gut microbiome impacted the serum metabolome and associated with glucose homeostasis in healthy Chinese individuals upon moderate-altitude exposure. Faecal microbiome composition was assessed using shotgun metagenomic sequencing. Serum metabolome was acquired by untargeted metabolomics technology, and amino acids (AAs) and propionic acid in serum were quantified by targeted metabolomics technology. The results indicated that the moderate-altitude exposed individuals presented lowered fasting blood glucose (FBG) and propionic acid, increased circulating L-Glutamine but decreased L-Glutamate and L-Valine, which correlated with enriched Bacteroidetes and decreased Proteobacteria. Additionally, the silico causality associations among gut microbiota, serum metabolome and host FBG were analyzed by mediation analysis. It showed that increased Bacteroides ovatus (B. ovatus) and decreased Escherichia coli (E. coli) were identified as the main antagonistic species driving the association between L-Glutamate and FBG in silico causality. Furthermore, the high-fat diet (HFD) fed mice subjected to faecal microbiota transplantation (FMT) were applied to validate the cause-in-fact effects of gut microbiota on the beneficial glucose response. We found that microbiome in the moderate-altitude exposed donor could predict the extent of the FBG response in recipient mice, which showed lowered FBG, L-Glutamate and Firmicutes/Bacteroidetes ratio. Our findings suggest that moderate-altitude exposure targeting gut microbiota and circulating metabolome, may pave novel avenues to counter dysglycemia. [Display omitted] •The moderate-altitude exposed healthy individuals presented lowered fasting blood glucose.•The moderate-altitude exposed healthy individuals showed increased Bacteroides ovatus and decreased Escherichia coli in feces.•The moderate-altitude exposed healthy individuals displayed increased circulating L-Glutamine but decreased L-Glutamate, L-Valine, and propionic acid.•Bacteroides ovatus and Escherichia coli were the main antagonistic species driving the association between L-Glutamate and FBG in silico causality.•Faecal microbiota transplantation experiments in high-fat-diet fed mice validated the beneficial glucose response of moderate-altitude exposure in human.