# From mechanisms to therapeutics: molecular insights into gastrointestinal injury under high-altitude hypoxia

**Authors:** Yonglu Yu, Yan Zhang, Yunsheng Yang

PMC · DOI: 10.3389/fmicb.2026.1707886 · Frontiers in Microbiology · 2026-02-06

## TL;DR

This paper reviews how high-altitude hypoxia causes gut damage and explores natural treatments that may help prevent it.

## Contribution

The paper provides a comprehensive review of mechanisms and therapeutic strategies for high-altitude-induced gastrointestinal injury.

## Key findings

- High-altitude hypoxia causes oxidative stress and gut microbiota imbalance, leading to intestinal damage.
- Natural bioactive molecules and probiotics show protective effects against high-altitude-induced gut injury.
- The paper identifies potential therapeutic targets for managing high-altitude-related gastrointestinal disorders.

## Abstract

The extreme environmental conditions of a plateau have an important impact on the economic development of the area, including tourism and employment. High-altitude environments, characterized by hypoxia, low atmospheric pressure, and intense ultraviolet radiation, are recognized as key contributors to gastrointestinal injury. These environmental stresses promote oxidative stress, inflammatory responses, and gut microbiota dysbiosis, resulting in intestinal barrier disruption, increased permeability, and immune imbalance, which collectively predispose individuals to gastrointestinal disorders and multi-organ dysfunction. Accumulating evidence suggests that natural bioactive molecules, probiotics, and synbiotics exert protective effects against high-altitude-induced intestinal injury via diverse mechanisms. Accordingly, this review focuses on the key mechanisms of high-altitude hypoxia-induced intestinal injury and discusses the therapeutic potential of intestinal function-enhancing molecules. This work aims to offer a theoretical framework and identify potential intervention targets for the management of gastrointestinal disorders associated with high-altitude exposure.

## Full-text entities

- **Genes:** Tlr4 (toll-like receptor 4) [NCBI Gene 21898] {aka Lps, Ly87, Ran/M1, Rasl2-8}, GLP1R (glucagon like peptide 1 receptor) [NCBI Gene 2740] {aka GLP-1, GLP-1-R, GLP-1R}, Crp (C-reactive protein, pentraxin-related) [NCBI Gene 12944], IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, GCG (glucagon) [NCBI Gene 2641] {aka GLP-1, GLP1, GLP2, GRPP}, Cdh1 (cadherin 1) [NCBI Gene 12550] {aka ARC-1, E-cad, Ecad, L-CAM, UVO, Um}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, Nt5e (5' nucleotidase, ecto) [NCBI Gene 23959] {aka 2210401F01Rik, 5'-NT, CD73, NT, Nt5, eNT}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, TLR4 (toll like receptor 4) [NCBI Gene 7099] {aka ARMD10, CD284, TLR-4, TOLL}, Ocln (occludin) [NCBI Gene 18260] {aka Ocl}, Mapk8 (mitogen-activated protein kinase 8) [NCBI Gene 26419] {aka JNK, JNK1, Prkm8, SAPK1}, Cat (catalase) [NCBI Gene 12359] {aka 2210418N07, Cas-1, Cas1, Cs-1}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, Il1b (interleukin 1 beta) [NCBI Gene 16176] {aka IL-1beta, Il-1b}, MLN (motilin) [NCBI Gene 4295], CRP [NCBI Gene 20468888], Mylk3 (myosin light chain kinase 3) [NCBI Gene 213435] {aka D830007F02Rik, MLCK}, Myd88 (myeloid differentiation primary response gene 88) [NCBI Gene 17874], Pik3r1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 18708] {aka PI3K, p50alpha, p55alpha, p85alpha}, Tjp1 (tight junction protein 1) [NCBI Gene 21872] {aka ZO1}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, Lrp6 (low density lipoprotein receptor-related protein 6) [NCBI Gene 16974] {aka C030016K15Rik, Cd, Gw, ska26, ska<m26Jus>, skax26}, Atg9a (autophagy related 9A) [NCBI Gene 245860] {aka Apg9l1, Atg9, Atg9l1}, GAST (gastrin) [NCBI Gene 2520] {aka GAS}, Igha (immunoglobulin heavy constant alpha) [NCBI Gene 238447] {aka IgA, Igh-2}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, COX2 (cytochrome c oxidase subunit II) [NCBI Gene 17709], VIP (vasoactive intestinal peptide) [NCBI Gene 7432] {aka PHM27}, Pkm (pyruvate kinase, muscle) [NCBI Gene 18746] {aka Pk-2, Pk-3, Pk3, Pkm2}, Ifng (interferon gamma) [NCBI Gene 15978] {aka IFN-g, If2f, Ifg}, IL1RN (interleukin 1 receptor antagonist) [NCBI Gene 3557] {aka CRMO2, DIRA, ICIL-1RA, IL-1RN, IL-1ra, IL-1ra3}, Cdc42 (cell division cycle 42) [NCBI Gene 12540], Arnt (aryl hydrocarbon receptor nuclear translocator) [NCBI Gene 11863] {aka D3Ertd557e, Drnt, ESTM42, Hif1b, bHLHe2, mKIAA4051}, Cxcl12 (C-X-C motif chemokine ligand 12) [NCBI Gene 20315] {aka Pbsf, Scyb12, Sdf1, Tlsf, Tpar1}, Il10 (interleukin 10) [NCBI Gene 16153] {aka CSIF, If2a, Il-10}, Gck (glucokinase) [NCBI Gene 103988] {aka GLK, Gk, Gls006, HK4, HKIV, HXKP}, Nos2 (nitric oxide synthase 2, inducible) [NCBI Gene 18126] {aka MAC-NOS, NOS-II, Nos-2, Nos2a, i-NOS, iNOS}, Nlrp3 (NLR family, pyrin domain containing 3) [NCBI Gene 216799] {aka AGTAVPRL, AII/AVP, Cias1, FCAS, FCU, MWS}, MBTPS1 (membrane bound transcription factor peptidase, site 1) [NCBI Gene 8720] {aka CAOP, PCSK8, S1P, SEDKF, SKI-1}, Hif1a (hypoxia inducible factor 1, alpha subunit) [NCBI Gene 15251] {aka HIF-1-alpha, HIF1-alpha, HIF1alpha, MOP1, bHLHe78}, Pdc (phosducin) [NCBI Gene 20028] {aka Rpr-1, Rpr1}, Cldn1 (claudin 1) [NCBI Gene 12737], Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, Mpo (myeloperoxidase) [NCBI Gene 17523] {aka mKIAA4033}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, Ctnnb1 (catenin beta 1) [NCBI Gene 12387] {aka Bfc, Catnb, Mesc}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, CCL4 (C-C motif chemokine ligand 4) [NCBI Gene 6351] {aka ACT2, AT744.1, G-26, HC21, LAG-1, LAG1}, TAC1 (tachykinin precursor 1) [NCBI Gene 6863] {aka Hs.2563, NK2, NKNA, NPK, TAC2}, Cxcl15 (C-X-C motif chemokine ligand 15) [NCBI Gene 20309] {aka Il8, Scyb15, lungkine, weche}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}
- **Diseases:** AMS (MESH:D000532), Microbial dysbiosis (MESH:D064806), dyspnea (MESH:D004417), anorexia (MESH:D000855), edema (MESH:D004487), atrophy (MESH:D001284), GI injury (MESH:D014947), conditions (MESH:D020763), Digestive symptoms (MESH:D012817), Inflammatory (MESH:D007249), gastroenteritis (MESH:D005759), gut dysfunction (MESH:C535334), Neuroendocrine dysregulation (MESH:D018358), ischemia (MESH:D007511), metabolic dysregulation (MESH:D021081), metabolic and (MESH:D008659), Hypoxia (MESH:D000860), vomiting (MESH:D014839), HH (MESH:D006432), multi-organ dysfunction (MESH:D009102), nausea (MESH:D009325), gastric and intestinal mucosal injury (MESH:D013274), hypoxic (MESH:D002534), pulmonary and cerebral edema (MESH:D001929), diarrhea (MESH:D003967), gastrointestinal diseases (MESH:D005767), colitis (MESH:D003092), infections (MESH:D007239), dizziness (MESH:D004244), acidosis (MESH:D000138), weight loss (MESH:D015431), epithelial (MESH:D009375), endotoxemia (MESH:D019446), thrombosis (MESH:D013927), organomegaly (MESH:D016878), necrosis (MESH:D009336), intestinal damage (MESH:D007410), ileal injury (MESH:D007077), colonic (MESH:D003108), impaired cognitive and behavioral performance (MESH:D003072), tissue injury (MESH:D017695), mucosal damage (MESH:D052016), IBD (MESH:D015212), proinflammatory cytokines (MESH:D000080424), bacterial (MESH:D001424), dysfunction (MESH:D006331), loss of appetite (MESH:D001068)
- **Chemicals:** urate (MESH:D014527), Salidroside (MESH:C009172), vitamin E (MESH:D014810), STA (MESH:C005695), polysaccharides (MESH:D011134), alpha-lipoic acid (MESH:D008063), pectin (MESH:D010368), fructooligosaccharides (MESH:C116580), L-methionine (MESH:D008715), O2 (MESH:D010100), allopurinol (MESH:D000493), Nitrate (MESH:D009566), ascorbic acid (MESH:D001205), essential amino acids (MESH:D000601), DAO (MESH:C030358), RSV (MESH:D000077185), NO (MESH:D009569), nicotinamide (MESH:D009536), phospholipids (MESH:D010743), tyrosine (MESH:D014443), TXA2 (MESH:D013928), Paeoniflorin (MESH:C015423), Butyrate (MESH:D002087), LTs (MESH:D015289), catecholamine (MESH:D002395), niacin (MESH:D009525), thiol (MESH:D013438), phosphocreatine (MESH:D010725), creatine (MESH:D003401), selenium (MESH:D012643), carbohydrates (MESH:D002241), malondialdehyde (MESH:D008315), fatty acid (MESH:D005227), L-arginine (MESH:D001120), Curcumin (MESH:D003474), CTPE (-), 2-ketoglutaric acid (MESH:D007656), SCFA (MESH:D005232), Berberine (MESH:D001599), ROS (MESH:D017382), flavonoids (MESH:D005419), sodium butyrate (MESH:D020148), Glutamine (MESH:D005973), alpha-tocopherol (MESH:D024502), LPS (MESH:D008070), lipid (MESH:D008055)
- **Species:** Coprococcus (genus) [taxon 33042], Mus musculus (house mouse, species) [taxon 10090], Prevotella (genus) [taxon 838], Lacticaseibacillus rhamnosus GG (strain) [taxon 568703], Escherichia coli (E. coli, species) [taxon 562], Sus scrofa (pig, species) [taxon 9823], Allobaculum (genus) [taxon 174708], Bacteroides (genus) [taxon 816], Brassica rapa (field mustard, species) [taxon 3711], Lactococcus (lactic streptococci, genus) [taxon 1357], Staphylococcus (genus) [taxon 1279], Bifidobacterium (genus) [taxon 1678], Homo sapiens (human, species) [taxon 9606], Clostridium (genus) [taxon 1485], Corynebacterium (genus) [taxon 1716], Akkermansia muciniphila (species) [taxon 239935], Eggerthella (genus) [taxon 84111], Robinia pseudoacacia (black locust, species) [taxon 35938], Bacteroidia (class) [taxon 200643], Enterobacteriaceae (enterobacteria, family) [taxon 543], Bacillota (clostridial firmicutes, phylum) [taxon 1239], Rhodiola (genus) [taxon 202994]
- **Cell lines:** IEC-6 — Rattus norvegicus (Rat), Finite cell line (CVCL_0343), RAW264.7 — Mus musculus (Mouse), Mouse leukemia, Cancer cell line (CVCL_0493), T84 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0555), Caco-2 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0025)

## Full text

_Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12920582/full.md

## Figures

2 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12920582/full.md

## References

93 references — full list in the complete paper: https://tomesphere.com/paper/PMC12920582/full.md

---
Source: https://tomesphere.com/paper/PMC12920582