[en] Yaks (Bos grunniens), native to the Qinghai-Tibet Plateau, have evolved extraordinary physiological resilience to chronic hypoxia, cold, and nutritional scarcity. However, the integrated metabolic and microbial mechanisms underlying these adaptations remain poorly defined. Here, a comprehensive multi-omics analysis was performed on thirty grazing heifer yaks (2.5 years old) from three altitudes-3,600 m (low altitude [LA]), 4,000 m (middle altitude [MA]), and 4,500 m (high altitude [HA])-to investigate how altitude affects host physiology, metabolism, and gut microbial ecology. Increasing altitude significantly reduced serum total protein, globulin, blood urea nitrogen, and alkaline phosphatase, indicating suppressed anabolic metabolism and nitrogen-sparing strategies. Antioxidant capacity (total superoxide dismutase, total antioxidant capacity) and pro-inflammatory cytokines (interleukin-2 [IL-2], IL-6, tumor necrosis factor-α, interferon-γ) increased (P < 0.05), while glutathione peroxidase, IL-4, IL-10, growth hormone, insulin-like growth factor-1, and growth hormone-releasing hormone declined (P < 0.05), reflecting energy reallocation from growth toward antioxidation and immune maintenance under hypoxia. Plasma metabolomics revealed distinct altitude-dependent reprogramming, with enrichment of retinol metabolism at 4,000 m and α-linolenic acid metabolism, tricarboxylic acid (TCA) cycle, and branched-chain amino acid biosynthesis at 4,500 m. These pathways link lipid remodeling, oxidative balance, and oxygen utilization. The gut microbiota displayed altitude-specific shifts, characterized by enrichment of Christensenellaceae_R-7_group and Monoglobus and reduced UCG-005 and Rikenellaceae_RC9_gut_group, accompanied by lower fecal volatile fatty acids (P < 0.05). Correlation analyses confirmed tight associations between fermentative taxa and volatile fatty acids production. Collectively, our results establish a serum-metabolome-microbiota axis as a central mechanism supporting yak adaptation to high altitude.IMPORTANCEThis study demonstrates that the gut microbiota plays a crucial role in how yaks adapt to high-altitude hypoxia. Rising altitude not only alters the composition of gut microbes but also shifts their metabolic activity toward improving fermentation efficiency and antioxidant capacity. These microbial changes are closely linked with host metabolism, forming a coordinated serum-metabolome-microbiota network that helps maintain energy balance and immune stability when oxygen is limited. The enrichment of retinol and α-linolenic acid metabolism as altitude-responsive pathways further highlights the metabolic interplay between host and microbes in supporting physiological resilience. Overall, our findings show that microbial flexibility and metabolic cooperation are key factors enabling ruminants to survive in extreme environments, providing a scientific basis for microbiome-informed strategies to enhance yak health and productivity on the Qinghai-Tibet Plateau.
Disciplines :
Animal production & animal husbandry
Author, co-author :
Xie, Yining ✱; Université de Liège - ULiège > TERRA Research Centre ; Institute of Animal Husbandry and Veterinary Medicine, Xizang Academy of Agricultural and Animal Husbandry Sciences, Lhasa, China ; State Key Laboratory of Animal Nutrition and Feeding, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
Cidan, Yangji; Institute of Animal Husbandry and Veterinary Medicine, Xizang Academy of Agricultural and Animal Husbandry Sciences, Lhasa, China
Zhu, Yanbin ; Institute of Animal Husbandry and Veterinary Medicine, Xizang Academy of Agricultural and Animal Husbandry Sciences, Lhasa, China
Cisang, Zhuoma; Institute of Animal Husbandry and Veterinary Medicine, Xizang Academy of Agricultural and Animal Husbandry Sciences, Lhasa, China
Ciwang, Renzeng; Institute of Animal Husbandry and Veterinary Medicine, Xizang Academy of Agricultural and Animal Husbandry Sciences, Lhasa, China
Liu, Guifang; Institute of Animal Husbandry and Veterinary Medicine, Xizang Academy of Agricultural and Animal Husbandry Sciences, Lhasa, China
Wu, Dan; Institute of Animal Husbandry and Veterinary Medicine, Xizang Academy of Agricultural and Animal Husbandry Sciences, Lhasa, China
Cideng, Duoji; Nie Rong County Agriculture and Animal Husbandry Comprehensive Service Center, Nagqu City, China
Chilie, Jiacuo; Nie Rong County Agriculture and Animal Husbandry Comprehensive Service Center, Nagqu City, China
Kang, Jilam; Institute of Scientific and Technical Information of Xizang Autonomous Region, Lhasa, China
Basang, Wangdui; Institute of Animal Husbandry and Veterinary Medicine, Xizang Academy of Agricultural and Animal Husbandry Sciences, Lhasa, China
✱ These authors have contributed equally to this work.
Language :
English
Title :
Effect of altitudes on serum parameters, metabolome, and gut microbiota in yaks on the Qinghai-Tibet Plateau.
This research was funded by the National Key Research and Development Program of China (2022YFD1302101), the China Agriculture Research System Beef Cattle and Yak Industry Technology System (CARS-37), and the Regional Collaborative Innovation Program in Gesangtang, Linzhou County (QYXTZX-LS2020-01).
1. Ma J, Zhu Y, Wang Z, Yu X, Hu R, Wang X, Cao G, Zou H, Shah AM, Peng Q, Xue B, Wang L, Zhao S, Kong X. 2020. Comparing the bacterial community in the gastrointestinal tracts between growth-retarded and normal yaks on the qinghai-tibetan plateau. Front Microbiol 11:600516. https://doi.org/10.3389/fmicb.2020.600516
2. Ji Q-M, Xin J-W, Chai Z-X, Zhang C-F, Dawa Y, Luo S, Zhang Q, Pingcuo Z, Peng M-S, Zhu Y, Cao H-W, Wang H, Han J-L, Zhong J-C. 2021. A chromosome-scale reference genome and genome-wide genetic
4. Suo H, Zhao X, Qian Y, Sun P, Zhu K, Li J, Sun B. 2016. Lactobacillus fermentum Suo attenuates HCl/Ethanol Induced Gastric Injury in Mice through its antioxidant effects. Nutrients 8:155. https://doi.org/10.3390/nu8030155
5. Bai J, Li L, Li Y, Zhang L. 2022. Genetic and immune changes in Tibetan high-altitude populations contribute to biological adaptation to hypoxia. Environ Health Prev Med. https://doi.org/10.1265/ehpm.22000 40
6. Vargas A, Mkrtchyan K, Penuelas V, Pham K, Frost S, Moya EA, Yu JJ. 2024. Acute exposure to high-altitude results in changes to immune cell populations. Physiology (Bethesda) 39. https://doi.org/10.1152/physiol.2024.39.S1.2515
7. Pham K, Vargas A, Frost S, Shah S, Heinrich EC. 2024. Changes in immune cell populations during acclimatization to high altitude. Physiol Rep 12:e70024. https://doi.org/10.14814/phy2.70024
8. Mishra KP, Ganju L. 2010. Influence of high altitude exposure on the immune system: a review. Immunol Invest 39: 219–234. https://doi.org/10.3109/08820131003681144
9. Xie Y, Cidan Y, Cisang Z, Gusang D, Danzeng Q, Basang W, Zhu Y. 2025. Effects of warm-season feeding on yak growth, antioxidant capacity, immune function, and fecal microbiota. Microbiol Spectr 13:e01001–01025. https://doi.org/10.1128/spectrum.01001-25
10. Liu D, Chen D, Xiao J, Wang W, Zhang L-J, Peng H, Han C, Yao H. 2024. High-altitude-induced alterations in intestinal microbiota. Front Microbiol 15:1369627. https://doi.org/10.3389/fmicb.2024.1369627
11. Yu W, Yang J, Teng L-W, Zhao X-L, Zhu Z-Y, Cui S, Du W-G, Liu Z-S, Zeng ZG. 2025. Reciprocal translocation experiments reveal gut microbiome plasticity and host specificity in a Qinghai-Xizang Plateau lizard. Zool Res 46: 139–151. https://doi.org/10.24272/j.issn.2095-8137.2024.284
12. Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K. 2017. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res 45:D353–D361. https://doi.org/10.1093/nar/gkw1092
13. Ahmat M, Cheng J, Abbas Z, Cheng Q, Fan Z, Ahmad B, Hou M, Osman G, Guo H, Wang J, Zhang R. 2021 Effects of Bacillus amyloliquefaciens LFB112 on growth performance, carcass traits, immune, and serum biochemical response in broiler chickens. Antibiotics (Basel) 10:1427. htt ps://doi.org/10.3390/antibiotics10111427
14. Onyeneke E, Njoya H, Ebot M, Uchungo G, Eriyamremu G, Alumanah E. 2004. Liver function status in some nigerian children with protein energy malnutrition. Orient J Med 15. https://doi.org/10.4314/ojm.v15i1. 29048
15. Jain A, Jadhav AA, Varma M. 2013. Relation of oxidative stress, zinc and alkaline phosphatase in protein energy malnutrition. Arch Physiol Biochem 119: 15–21. https://doi.org/10.3109/13813455.2012.737809
16. Zhang X, Cao Z, Yang HC, Wang Y, Wang W, Li S. 2024. Effect of high altitude on serum biochemical parameters, immunoglobulins, and rumen metabolism of sanhe heifers. Fermentation 10:170. https://doi.org/10.3390/fermentation10030170
17. Gokulakrishnan M, Kumar R, Pillai BR, Nanda S, Bhuyan SK, Kumari R, Debbarma J, Ferosekhan S, Siddaiah GM, Sundaray JK. 2022. Dietary brewer’s spent yeast enhances growth, hematological parameters, and innate immune responses at reducing fishmeal concentration in the diet of climbing perch, Anabas testudineus fingerlings. Front Nutr 9:982572. h ttps://doi.org/10.3389/fnut.2022.982572
18. Storz JF. 2007. Hemoglobin function and physiological adaptation to hypoxia in high-altitude mammals. J Mammal. https://doi.org/10.1644/06mamms199r1.1
19. Hidalgo AJM, Rio-Moreno MD, Pérez-Gómez JM, Luque RM, Kineman RD. 2025. Update on regulation of GHRH and its actions on GH secretion in health and disease. Rev Endocr Metab Disord. https://doi.org/10.1007/s1 115402509943y
20. Bioletto F, Varaldo E, Gasco V, Maccario M, Arvat E, Ghigo E, Grottoli S. 2024. Central and peripheral regulation of the GH/IGF-1 axis: GHRH and beyond. Rev Endocr Metab Disord. https://doi.org/10.1007/s1115402409 9336
21. Huang M, Zhang X, Yan W, Liu J, Wang H. 2022. Metabolomics reveals potential plateau adaptability by regulating inflammatory response and oxidative stress-related metabolism and energy metabolism pathways in yak. J Anim Sci Technol 64: 97–109. https://doi.org/10.5187/jast.2021.e12 9
22. Zhang X, Huang S, Li S, Wang W. 2022. Effects of altitude on the digestion performance, serum antioxidative characteristics, rumen fermentation parameters, and rumen bacteria of sanhe heifers. Front Microbiol 13:875323. https://doi.org/10.3389/fmicb.2022.875323
23. Rytz CL, Pun M, Mawhinney JA, Mounsey CA, Mura M, Martin A, Pialoux V, Hartmann SE, Furian M, Rawling JM, Lopez I, Soza D, Moraga FA, Lichtblau M, Bader PR, Ulrich S, Bloch KE, Frise MC, Poulin MJ. 2022. Differential effects of high-altitude exposure on markers of oxidative stress, antioxidant capacity, and iron profiles. Am J Physiol Regul Integr Comp Physiol 323:R445–R456. https://doi.org/10.1152/ajpregu.00321.20 21
24. Hasnat MA, Cheang I, Dankers W, Lee JP, Truong LM, Pervin M, Jones SA, Morand EF, Ooi JD, Harris J. 2022. Investigating immunoregulatory effects of myeloid cell autophagy in acute and chronic inflammation. Immunol Cell Biol 100: 605–623. https://doi.org/10.1111/imcb.12562
25. Yin J, Lv J, Yang S, Wang Y, Huang Z, Wang X, Hou G, Zhou W, Liu Y, Wang W, et al. 2025. Multi-omics reveals immune response and metabolic profiles during high-altitude mountaineering. Edited by J Yin, J. Lv, S. Yang, Y. Wang, Z. Huang, X. Wang, G. Hou, W. Zhou, Y. Liu, W. Wang, X. Lin, Y. Huang, Y. Zheng, C. Wei, Y. Yuan, Y. Huang, C. Liu, H. Tao, H. Liu, R. Liu, and J. Wang. Cell Rep 44:115134. https://doi.org/10.1016/j.celrep.2024.115134
26. Aramwit P, Luplertlop N, Kanjanapruthipong T, Ampawong S. 2018. Effect of urea-extracted sericin on melanogenesis: potential applications in post-inflammatory hyperpigmentation. Biol Res 51:54. https://doi.org/10.1186/s4065901802045
27. Wang H, Li R, Rao Y, Liu S, Hu C, Zhang Y, Meng L, Wu Q, Ouyang Q, Liang H, Qin M. 2022. Enhancement of the bioavailability and anti-inflammatory activity of glycyrrhetinic acid via novel soluplus - a glycyrrhetinic acid solid dispersion. Pharmaceutics 14:1797. https://doi.org/10.3390/pharmaceutics14091797
28. Hartmann G, Tschöp M, Fischer R, Bidlingmaier C, Riepl R, Tschöp K, Hautmann H, Endres S, Toepfer M. 2000. High altitude increases circulating interleukin-6, interleukin-1 receptor antagonist and C-reactive protein. Cytokine 12: 246–252. https://doi.org/10.1006/cyto.1999.0533
29. Pham K, Parikh K, Heinrich EC. 2021. Hypoxia and inflammation: insights from high-altitude physiology. Front Physiol 12:676782. https://doi.org/10.3389/fphys.2021.676782
30. Cyr A, Kohut L, Chambers L, Stratimirovic S, Zuckerbraun B. 2021. Circulating metabolomic analysis following cecal ligation and puncture in young and aged mice reveals age-associated temporal shifts in nicotinamide and histidine/histamine metabolic pathways. Oxid Med Cell Longev 2021:5534241. https://doi.org/10.1155/2021/5534241
31. Wang Hai-meng, Wu C, Jiang Y, Wang W, Jin H. 2020. Retinol and vitamin A metabolites accumulate through RBP4 and STRA6 changes in a psoriasis murine model. Nutr Metab (Lond) 17:5. https://doi.org/10.1186/s12986-019-0423-y
32. Xu H, Ma Z, Lu J, Li Y, Li Q, Yin S, He H, Xiong Y, Xiong X, Li J, Lan D, Fu W. 2024. Integrative analysis of transcriptome and metabolome reveals the heterogeneity of ovarian follicles between high-altitude Yak (Bos grunniens) and Low-altitude cattle (Bos taurus). Livest Sci 289:105557. ht tps://doi.org/10.1016/j.livsci.2024.105557
33. Guo T, Wang X, Zhang Q, Jia Y, Liu H, Hu L, Zhao N, Xu S, Duan Y, Jia K. 2024. Transcriptomics and metabolomics insights into the seasonal dynamics of meat quality in yak on the Qinghai-Tibetan Plateau. BMC Genomics 25:1194. https://doi.org/10.1186/s12864024110935
34. Atallah R, Olschewski A, Heinemann A. 2022. Succinate at the crossroad of metabolism and angiogenesis: roles of SDH, HIF1α and SUCNR1. Biomedicines 10:3089. https://doi.org/10.3390/biomedicines10123089
35. Ma X, Duan C, Wang X, Tao Y, Yang L, Teng Y, Pan Y, Zhang M, Xu J, Sheng J, Wang X, Jin P. 2025. Human gut microbiota adaptation to high-altitude exposure: longitudinal analysis over acute and prolonged periods. Microbiol Spectr 13:e0291624. https://doi.org/10.1128/spectrum.02916-24
36. Sieme D, Griesinger C, Rezaei-Ghaleh N. 2022. Metal binding to sodium heparin monitored by quadrupolar NMR. Int J Mol Sci 23:13185. https://doi.org/10.3390/ijms232113185
37. Tanino Y, Wang X, Nikaido T, Misa K, Sato Y, Togawa R, Kawamata T, Kikuchi M, Frevert CW, Tanino M, Kojima T, Shibata Y. 2019. Syndecan-4 inhibits the development of pulmonary fibrosis by attenuating TGF-β signaling. Int J Mol Sci 20:4989. https://doi.org/10.3390/ijms20204989
38. Wang X, Zhang Z, Li B, Hao W, Yin W, Ai S, Han J, Wang R, Duan Z. 2022. Depicting fecal microbiota characteristic in yak, cattle, yak-cattle hybrid and tibetan sheep in different eco-regions of qinghai-tibetan plateau. Microbiol Spectr 10:e0002122. https://doi.org/10.1128/spectrum.00021-22
39. Li L, Li K, Bian Z, Chen Z, Li B, Cui K, Wang F. 2022. Association between body weight and distal gut microbes in Hainan black goats at weaning age. Front Microbiol 13:951473. https://doi.org/10.3389/fmicb.2022.951 473
40. Waters JL, Ley RE. 2019. The human gut bacteria Christensenellaceae are widespread, heritable, and associated with health. BMC Biol 17:83. https://doi.org/10.1186/s12915-019-0699-4
41. He S, Zhao S, Wang Z, Dai S, Mao H, Wu D. 2024. Impact of seasonal variation in pasture on rumen microbial community and volatile fatty acids in grazing yaks: insights from high-altitude environments. Microorganisms 12:1701. https://doi.org/10.3390/microorganisms12081 701
42. Shaopeng C, Changze C, Youpeng Q, Baohong M, Meixian Z, Chenyue J, Chune Z, Xiangyan W, Jiang H, Bingang S, Xueming M, Zhidong Z, Xiaolan Z. 2024. Studies on fatty acids and microbiota characterization of the gastrointestinal tract of Tianzhu white yaks. Front Microbiol 15:1508468. https://doi.org/10.3389/fmicb.2024.1508468
43. Wang X, Zhang Q, Guo T, Li S, Jia Y, Xu S. 2025. Multi-omics analysis reveals host-microbe interactions driving divergent energy allocation strategies in Tibetan sheep under cold-season feeding regimes. J Anim Sci Biotechnol 16:122. https://doi.org/10.1186/s40104-025-01259-w
44. Yang X, Fan X, Jiang H, Zhang Q, Zhang Q, Dang S, Long R, Huang X. 2022. Simulated seasonal diets alter yak rumen microbiota structure and metabolic function. Front Microbiol 13:1006285. https://doi.org/10.3389/fmicb.2022.1006285
45. Cui X, Wang Z, Guo P, Li F, Chang S, Yan T, Zheng H, Hou F. 2023. Shift of feeding strategies from grazing to different forage feeds reshapes the rumen microbiota to improve the ability of tibetan sheep (Ovis aries) to adapt to the cold season. Microbiol Spectr 11:e0281622. https://doi.org/10.1128/spectrum.02816-22
