Meta-analysis identifying gut microbial biomarkers of Qinghai-Tibet Plateau populations and the functionality of microbiota-derived butyrate in high-altitude adaptation

ABSTRACT

The extreme environmental conditions of a plateau seriously threaten human health. The relationship between gut microbiota and human health at high altitudes has been extensively investigated. However, no universal gut microbiota biomarkers have been identified in the plateau population, limiting research into gut microbiota and high-altitude adaptation. 668 16s rRNA samples were analyzed using meta-analysis to reduce batch effects and uncover microbiota biomarkers in the plateau population. Furthermore, the robustness of these biomarkers was validated. Mendelian randomization (MR) results indicated that Tibetan gut microbiota may mediate a reduced erythropoietic response. Functional analysis and qPCR revealed that butyrate may be a functional metabolite in high-altitude adaptation. A high-altitude rat model showed that butyrate reduced intestinal damage caused by high altitudes. According to cell experiments, butyrate may downregulate hypoxia-inducible factor-1α (HIF-1α) expression and blunt cellular responses to hypoxic stress. Our research found universally applicable biomarkers and investigated their potential roles in promoting human health at high altitudes.

KEYWORDS:

• Qinghai-Tibet plateau
• gut microbiota biomarker
• butyrate
• high altitude adaptation
• HIF-1α

Acknowledgments

We would like to express our gratitude to Professor Yu Zhengquan from China Agricultural University for generously providing the NCM460 cell line. Our sincere appreciation goes to Associate Professor Cao Qinhong from China Agricultural University for granting us access to the experimental site for our cell research.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors contributions

Conceptualization: JS Yang

Methodology: JS Yang and HW Zhao

Sample collection: JS Yang, B Shi, Ci-ren Qu-zong, HW Zhao and YP Zhang

Investigation: HW Zhao, LJ Sun

Visualization: HW Zhao, LJ Sun

Supervision: JS Yang, JL Liu, Tsechoe Dorji, TY Wang and HL Yuan

Resources: JS Yang, JL Liu, Tsechoe Dorji, TY Wang and HL Yuan

Writing – original draft: HW Zhao

Writing – review & editing: HW Zhao and JS Yang

Availability of supporting data and code

The raw 16S rRNA gene sequencing data are available from the Sequence Read Archive (SRA) (https://www.ncbi.nlm.nih.gov/sra) 、European Nucleotide Archive (ENA) (https://www.ncbi.nlm.nih.gov/) and Genome Sequence Archive(GSA) (https://ngdc.cncb.ac.cn/gsa/), with project ID: PRJCA001483, PRJNA381333, PRJNA507100, PRJNA665364, PRJNA699380, PRJCA002832 and PRJNA57800. The remaining data are available within the Article, Supplementary Information. The codes and scripts are available at https://github.com/Yangjsh1999/plateau.

Ethical approval and consent to participate

Human feces samples collection were approved by Human Research Ethics Committee of China Agricultural University. All participants were informed and aware of the study. All animal experiments were conducted in accordance with the requirements of China Agricultural University Laboratory Animal Welfare and Animal Experiment Ethics Committee.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2350151

Additional information

Funding

This work was supported by the second Tibetan Plateau Scientific Expedition and Research Program (STEP) [No. 2019QZKK0608], the Open project of State Key Laboratory of Animal Biotech Breeding (Grant No. 2024SKLAB6-6) and 2115 Talent Development Program of China Agricultural University.