Gut microbiota imbalance mediates intestinal barrier damage in high‐altitude exposed mice

The environmental conditions in high-altitude areas can induce gastrointestinal disorders and changes in gut microbiota. The gut microbiota is closely related to a variety of gastrointestinal diseases, although the underlying pathogenic mechanisms are not well-identified. The present study aimed to investigate the regulatory effect of high altitude on intestinal dysfunction via gut microbiota disturbance. Forty C57BL/6J mice were divided into four groups: one plain control group (CON) and three high-altitude exposure groups (HAE) (altitude: 4000 m a.s.l.; oxygen content: 12.7%; 1-, 2- and 4-week exposure). Another set of 40 mice was divided into two CON and two HAE subgroups. Antibiotic cocktails were administered to one CON and HAE groups and autoclaved water was administered to the second CON and HAE groups for 4 weeks, respectively. In the fecal microbiota transplantation experiment, there were four transplantation groups, which received, respectively: phosphate-buffered saline for 2 weeks, feces from CON for 2 weeks, feces from HAE-4W for 2 weeks, and HAE-4W for 4 weeks. Hematoxylin and eosin staining, periodic acid-Schiff staining, a terminal deoxynucleotidyl transferase dUTP nick end labeling assay and a quantitative reverse transcriptase-polymerase chain reaction were applied to detect changes in intestinal cellular structure, morphology, apoptosis and intestinal inflammatory response. Fecal microbiota was analyzed using 16S rDNA amplicon sequencing. A high-altitude environment changed the ecological balance of gut microbiota in mice and caused damage to the intestinal structure and mucosal barrier. Interestingly, similar damage, which was inhibited by antibiotic cocktails at high altitude, was observed in mice transplanted with fecal microbiota from HAE. A high-altitude environment contributes to dyshomeostasis of gut microbiota, thereby impairing the intestinal mucosal barrier, eventually inducing and exacerbating intestinal damage.