Oral homeostasis imbalance under hypoxia

doi:10.7518/hxkq.2026.2025427

Abstract

Abstract:

Hypoxia disrupts oral homeostasis through multiple interconnected pathways, including interference with tooth germ development, impairment of salivary gland function and salivary buffering capacity, compromise of the oral mucosal barrier, imbalance in jawbone and alveolar bone remodeling, and alterations in the diversity and functionality of the oral microbiome. These disturbances collectively contribute to the onset and progression of oral diseases. Moreover, disruption of oral homeostasis may, in turn, affect systemic homeostasis, increasing the risk of disorders in other organ systems through mechanisms involving inflammatory mediator release and microbial translocation. Here, we systematically review the effects and underlying mechanisms of hypoxia exposure on oral homeostasis, and further explore the interconnections between hypoxia-induced oral dysregulation and systemic homeostatic imbalance. This review aims to provide a comprehensive understanding of the regulatory networks linking oral and systemic homeostasis under hypoxia, thereby offering potential insights for maintaining homeostatic balance.

Key words: hypoxia, oral homeostasis, salivary gland, oral mucosal barrier, jawbone, oral microbiome, systemic homeostasis

CLC Number:

Xu Yifan, Wang Songling, Zhou Jian. Oral homeostasis imbalance under hypoxia[J]. West China Journal of Stomatology, 2026, 44(2): 215-223.

Figures/Tables 1

References 48

[1]	Peng X, Cheng L, You Y, et al. Oral microbiota in human systematic diseases[J]. Int J Oral Sci, 2022, 14(1): 14.
[2]	Pignatelli P, Mrakic-Sposta S, Bondi D, et al. The effect of acute high-altitude exposure on oral pathogenic bac-teria and salivary oxi-inflammatory markers[J]. J Clin Med, 2024, 13(20): 6266.
[3]	Chalmers JC, Hernandez-Kapila YL. The role of the oral microbiome, host response, and periodontal disease treatment in Alzheimer’s disease: a primer[J]. Periodontol 2000, 2025. doi: 10.1111/prd.12631 .
[4]	Lu YM, Kobayashi Y, Niki Y, et al. Possible role of superoxide dismutase 3 in hypoxia-induced developmental defects in murine molars[J]. J Oral Biosci, 2025, 67(1): 100611.
[5]	Hutami IR, Arinawati DY, Rahadian A, et al. Roles of calcium in ameloblasts during tooth development: a scoping review[J]. J Taibah Univ Med Sci, 2025, 20(1): 25-39.
[6]	Tynior W, Hudy D, Gołąbek K, et al. Expression of AMELX, AMBN, ENAM, TUFT1, FAM83H and MMP-20 genes in buccal epithelial cells from patients with molar incisor hypomineralization (MIH)-a pilot study[J]. Int J Mol Sci, 2025, 26(2): 766.
[7]	Zhou B, Zhan HX, Tin L, et al. TUFT1 regulates metastasis of pancreatic cancer through HIF1-Snail pathway induced epithelial-mesenchymal transition[J]. Cancer Lett, 2016, 382(1): 11-20.
[8]	Almulhim B. Molar and incisor hypomineralization[J]. JNMA J Nepal Med Assoc, 2021, 59(235): 295-302.
[9]	Kaufman DS. HIF hits Wnt in the stem cell niche[J]. Nat Cell Biol, 2010, 12(10): 926-927.
[10]	Malekan M, Ebrahimzadeh MA, Sheida F. The role of hypoxia-inducible factor-1 alpha and its signaling in me-lanoma[J]. Biomed Pharmacother, 2021, 141: 111873.
[11]	Kumar N, Dhiman RK, Arora V, et al. Changes in salivary output after induction at high-altitude areas and its effects on dental caries among Indian army troops[J]. Med J Armed Forces India, 2019, 75(3): 288-292.
[12]	Trentini P, Ferrante M, Dolci M, et al. Enzymatic analysis of the gingival crevicular fluid in hypoxia of high altitude (Everest)[J]. Int J Immunopathol Pharmacol, 2007, 20(1 ): 1-4.
[13]	Scott J, Gradwell E. A quantitative study of the effects of chronic hypoxia on the histological structure of the rat major salivary glands[J]. Arch Oral Biol, 1989, 34(5): 315-319.
[14]	Tiollier E, Schmitt L, Burnat P, et al. Living high-trai-ning low altitude training: effects on mucosal immunity[J]. Eur J Appl Physiol, 2005, 94(3): 298-304.
[15]	Rasica L, Porcelli S, Limper U, et al. Beet on Alps: time-course changes of plasma nitrate and nitrite concentrations during acclimatization to high-altitude[J]. Nitric Oxide, 2021, 107: 66-72.
[16]	李冬梅, 王琳, 王志强, 等. 基于单中心就医人群分析甘肃地区口腔黏膜疾病流行情况[J]. 临床口腔医学杂志, 2021, 37(7): 403-406.
	Li DM, Wang L, Wang ZQ, et al. The prevalence of oral mucosal diseases in Gansu was analyzed based on single center population[J]. J Clin Stomatol, 2021, 37(7): 403-406.
[17]	Kim S, Park S, Moon EH, et al. Hypoxia disrupt tight junctions and promote metastasis of oral squamous cell carcinoma via loss of par3[J]. Cancer Cell Int, 2023, 23(1): 79.
[18]	Li J, Li WJ, Li LY, et al. Induction of peroxiredoxin 1 by hypoxia promotes cellular autophagy and cell proliferation in oral leukoplakia via HIF-1α/BNIP3 pathway[J]. J Mol Histol, 2024, 55(4): 403-413.
[19]	Zhu Y, Wan M, Fu Y, et al. Platelet methyltransferase-like protein 4-mediated mitochondrial DNA metabolic disorder exacerbates oral mucosal immunopathology in hypoxia[J]. Int J Oral Sci, 2025, 17(1): 49.
[20]	Terrizzi AR, Rugolo G, Bozzini C, et al. Mandibular biomechanical behavior of rats submitted to chronic intermittent or continuous hypoxia and periodontitis[J]. Sch-laf Atmung, 2021, 25(1): 519-527.
[21]	Lucateli RL, Silva PHF, Salvador SL, et al. Probiotics enhance alveolar bone microarchitecture, intestinal morphology and estradiol levels in osteoporotic animals[J]. J Periodontal Res, 2024, 59(4): 758-770.
[22]	李迎春, 肖剑锐. 高海拔低氧环境对种植体骨结合的影响[J]. 实用口腔医学杂志, 2012, 28(1): 10-13.
	Li YC, Xiao JR. The influence of high-altitude and hypoxia on implant osseointegration[J]. J Pract Stomatol, 2012, 28(1): 10-13.
[23]	郭婷婷, 刘怡, 周建. 生理性低氧及缺氧再复氧对小鼠骨髓间充质干细胞增殖及成骨分化的影响[J]. 北京口腔医学, 2023, 31(2): 82-87.
	Guo TT, Liu Y, Zhou J. Effects of physiological hypoxia and anoxia-reoxygenation on proliferation and osteoge-nic differentiation of mouse bone marrow mesenchymal stem cells[J]. Beijing J Stomatol, 2023, 31(2): 82-87.
[24]	罗婷, 祁琳, 李杰, 等. 氯化钴模拟低氧条件下红景天苷对小鼠成骨细胞的调节作用[J]. 医学信息, 2024, 37(9): 101-106.
	Luo T, Qi L, Li J, et al. Regulatory effect of salidroside on mouse osteoblasts under hypoxic conditions simula-ted by cobalt chloride[J]. Med Inform, 2024, 37(9): 101-106.
[25]	Zhu YF, Wan MC, Gao P, et al. Fibrocyte: a missing piece in the pathogenesis of fibrous epulis[J]. Oral Dis, 2024, 30(7): 4376-4389.
[26]	Li JX, Dang YM, Liu MC, et al. Fibroblasts in heteroto-pic ossification: mechanisms and therapeutic targets[J]. Int J Biol Sci, 2025, 21(2): 544-564.
[27]	Huang YF, Wang XY, Lin H. The hypoxic microenvironment: a driving force for heterotopic ossification progression[J]. Cell Commun Signal, 2020, 18(1): 20.
[28]	Usategui-Martín R, Rigual R, Ruiz-Mambrilla M, et al. Molecular mechanisms involved in hypoxia-induced alterations in bone remodeling[J]. Int J Mol Sci, 2022, 23(6): 3233.
[29]	熊雨婷, 潘已汇, 兰红, 等. 口腔微生物组的致病机制及影响因素研究进展[J]. 同济大学学报(医学版), 2025, 46(1): 125-131.
	Xiong YT, Pan YH, Lan H, et al. Research progress on the pathogenic mechanisms and influencing factors of the oral microbiome[J]. J Tongji Univ(Med Sci), 2025, 46(1): 125-131.
[30]	Kumari M, Bhushan B, Eslavath MR, et al. Impact of high altitude on composition and functional profiling of oral microbiome in Indian male population[J]. Sci Rep, 2023, 13(1): 4038.
[31]	Zhang QJ, Hutchison ER, Pan C, et al. Systems genetics uncovers associations among host amylase locus, gut microbiome, and metabolic traits in mice[J]. Microbiome, 2025, 13(1): 101.
[32]	Liu F, Liang T, Zhang ZY, et al. Effects of altitude on human oral microbes[J]. AMB Express, 2021, 11(1): 41.
[33]	Gupta R, Gupta N. Bacterial response to oxygen availa-bility[M]//Gupta R, Gupta N. Oxygen sensing and microbial response. Singapore: Springer Nature, 2021: 459-478.
[34]	Zhou Q, Chen YH, Liu GZ, et al. A preliminary study of the salivary microbiota of young male subjects before, during, and after acute high-altitude exposure[J]. PeerJ, 2023, 11: e15537.
[35]	Cai JZ, Liu J, Yan J, et al. Impact of Resolvin D1 on the inflammatory phenotype of periodontal ligament cell response to hypoxia[J]. J Periodontal Res, 2022, 57(5): 1034-1042.
[36]	Martín-Hernández D, Martínez M, Robledo-Montaña J, et al. Neuroinflammation related to the blood-brain bar-rier and sphingosine-1-phosphate in a pre-clinical model of periodontal diseases and depression in rats[J]. J Clin Periodontol, 2023, 50(5): 642-656.
[37]	Kong L, Li JJ, Gao L, et al. Periodontitis-induced neuroinflammation triggers IFITM3-Aβ axis to cause Alzhei-mer’s disease-like pathology and cognitive decline[J]. Alzheimers Res Ther, 2025, 17(1): 166.
[38]	Miao F, Lei YY, Guo YF, et al. Increased caveolin 1 by human antigen R exacerbates Porphyromonas gingivali-induced atherosclerosis by modulating oxidative stress and inflammatory responses[J]. Cytojournal, 2024, 21: 42.
[39]	Dai D, Cao GQ, Huang SY, et al. Porphyromonas gingivalis exacerbates experimental autoimmune encephalomyelitis by driving Th1 differentiation via ZAP70/NF-κB signaling[J]. Front Immunol, 2025, 16: 1549102.
[40]	Fu E, Huang KF, Chang HH, et al. Periodontitis increa-ses gingival, serum and hippocampus β-amyloid expressions but reduces neurovascular coupling in basilar artery of rats[J]. J Clin Periodontol, 2025, 52(5): 762-772.
[41]	Kunath BJ, De Rudder C, Laczny CC, et al. The oral-gut microbiome axis in health and disease[J]. Nat Rev Microbiol, 2024, 22(12): 791-805.
[42]	Wu HY, Wei ZL, Shi DY, et al. Simulated gastric acid promotes the horizontal transfer of multidrug resistan-ce genes across bacteria in the gastrointestinal tract at elevated pH levels[J]. Microbiol Spectr, 2023, 11(3): e0482022.
[43]	Zeise KD, Woods RJ, Huffnagle GB. Interplay between candida albicans and lactic acid bacteria in the gastrointestinal tract: impact on colonization resistance, micro-bial carriage, opportunistic infection, and host immunity[J]. Clin Microbiol Rev, 2021, 34(4): e0032320.
[44]	Sun JH, Wang XX, Xiao JH, et al. Autophagy mediates the impact of Porphyromonas gingivalis on short-chain fatty acids metabolism in periodontitis-induced gut dysbiosis[J]. Sci Rep, 2024, 14(1): 26291.
[45]	Qu R, Li M, Li P, et al. Mitigation of P. gingivalis-exa-cerbated intestinal inflammation by paeoniflorin through alteration of the gut microbiota[J]. Microbiol Spectr, 2025, 13(8): e0000224.
[46]	Xu YF, Sa YQ, Zhang CM, et al. A preventative role of nitrate for hypoxia-induced intestinal injury[J]. Free Ra-dic Biol Med, 2024, 213: 457-469.
[47]	Yamazaki K, Kato T, Tsuboi Y, et al. Oral pathobiont-induced changes in gut microbiota aggravate the pathology of nonalcoholic fatty liver disease in mice[J]. Front Immunol, 2021, 12: 766170.
[48]	de Lange IH, van Gorp C, Massy KRI, et al. Hypoxia-driven changes in a human intestinal organoid model and the protective effects of hydrolyzed whey[J]. Nu-trients, 2023, 15(2): 393.