Investigate causal relationships between gut microbiome specificity and chronic respiratory diseases based on multi-omics approaches analysis_Chinese Journal of Evidence-Based Medicine

Authors：

CHEN Qi ^1,2 , WANG Bohan ¹ ,  XU Yanqiu ¹ , ZHANG Chaofeng ^1,2

1. Affiliated Jiangning Hospital of Chinese Medicine, China Pharmaceutical University (Nanjing Jiangning Hospital of Chinese Medicine), Nanjing 211198, P. R. China;
2. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, P. R. China;

Corresponding?author：

XU Yanqiu, Email: jnzyyxyq@126.com

Keywords：

Gut microbiome; Chronic respiratory diseases; Serum metabolites; Mendelian randomization; Cross-sectional observational analysis; Gut-lung axis

DOI：

10.7507/1672-2531.202510062

Video：

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Objective To explore causal relationships between the gut microbiome and chronic respiratory diseases (asthma and chronic obstructive pulmonary disease (COPD)) and to dissect the underlying biological mechanisms. Methods Cross-sectional observational study: using data from 3 662 participants in the U.S. National Health and Nutrition Examination Survey (NHANES 2007–2012), dietary information was collected as a proxy for gut-microbiome features and linked to lung-function parameters and respiratory symptoms. Two-sample Mendelian randomization (MR): leveraging summary statistics from the Dutch Microbiome Project and Canada serum-metabolite genome-wide association studies (GWAS), we tested the causal effects of 412 gut-microbiome traits (207 taxa and 205 functional pathways) on asthma, COPD, and lung-function indices (FEV₁, FVC, FEV₁/FVC). Mediation MR was further performed to quantify the mediating roles of 1 091 serum metabolites. Functional validation: single-nucleotide polymorphism (SNP)-based gene mapping was used to prioritize candidate genes, which were then interrogated in COPD and asthma transcriptomic datasets (GSE38974 and GSE69683). Results Observational findings: higher probiotic intake was associated with increased asthma risk (OR=1.76, 95%CI 1.01 to 3.05, P=0.036) but reduced emphysema risk (OR=6.144×10^?7, 95%CI 3.059×10^?7 to 6.144×10^?7, P<0.001). Dietary fiber intake correlated with lower cough prevalence (OR=0.97, 95%CI 0.96 to 0.99, P=0.006) and improved lung function. MR results: 23 microbial taxa and 21 metabolic pathways showed significant causal effects on asthma or COPD. For instance, adolescentis-group Bifidobacterium and Oxalobacter exacerbated asthma, whereas the phospholipid biosynthesis I pathway conferred protection. Lachnospiraceae bacterium 7_1_58FAA and Parasutterella excrementihominis increased COPD risk, while the reductive incomplete TCA cycle and aspartate pathway were protective. Among serum metabolites, 87 and 97 metabolites-including taurochenodeoxycholate-3-sulfate (protective against asthma) and sphingomyelin (protective against COPD)-significantly mediated the causal influences of the gut microbiome. Bioinformatic analyses: gut-microbiome-linked genes (e.g., FXYD1, SCN3B) were differentially expressed in COPD and asthma and were enriched in ion-channel transport, muscle contraction, and blood-circulation processes. Conclusion By integrating observational data, MR, and transcriptomics, this study provides the first multi-omics evidence that specific gut microbes and their metabolic pathways exert causal effects on asthma and COPD through serum metabolite mediation. These effects likely operate via modulation of ion homeostasis, muscle contraction, and blood circulation, offering novel avenues for early diagnosis and targeted intervention in chronic respiratory diseases.

Citation： CHEN Qi, WANG Bohan, XU Yanqiu, ZHANG Chaofeng. Investigate causal relationships between gut microbiome specificity and chronic respiratory diseases based on multi-omics approaches analysis. Chinese Journal of Evidence-Based Medicine, 2026, 26(4): 390-400. doi: 10.7507/1672-2531.202510062 Copy

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1. Viegi G, Maio S, Fasola S, et al. Global burden of chronic respiratory diseases. J Aerosol Med Pulm Drug Deliv, 2020, 33(4): 171-177.
2. To T, Stanojevic S, Moores G, et al. Correction to: global asthma prevalence in adults: findings from the cross-sectional world health survey. BMC Public Health, 2021, 21(1): 1809.
3. Al Meslamani AZ. Gut-lung axis and microbiome interplay in type 2 high asthma. Expert Rev Respir Med, 2025, 2025: 2581339.
4. Reibman J, Marmor M, Filner J, et al. Asthma is inversely associated with Helicobacter pylori status in an urban population. PLoS One, 2008, 3(12): e4060.
5. Chen Y, Blaser MJ. Helicobacter pylori colonization is inversely associated with childhood asthma. J Infect Dis, 2008, 198(4): 553-560.
6. Wang F, Liu J, Zhang Y, et al. Association of Helicobacter pylori infection with chronic obstructive pulmonary disease and chronic bronchitis: a meta-analysis of 16 studies. Infect Dis (Lond), 2015, 47(9): 597-603.
7. Kozakova H, Schwarzer M, Tuckova L, et al. Colonization of germ-free mice with a mixture of three lactobacillus strains enhances the integrity of gut mucosa and ameliorates allergic sensitization. Cell Mol Immunol, 2016, 13(2): 251-262.
8. Huang CF, Chie WC, Wang IJ. Efficacy of lactobacillus administration in school-age children with asthma: a randomized, placebo-controlled trial. Nutrients, 2018, 10(11): 1678.
9. Davies G, Jordan S, Brooks CJ, et al. Long term extension of a randomised controlled trial of probiotics using electronic health records. Sci Rep, 2018, 8(1): 7668.
10. Rose MA, Stieglitz F, K?ksal A, et al. Efficacy of probiotic Lactobacillus GG on allergic sensitization and asthma in infants at risk. Clin Exp Allergy, 2010, 40(9): 1398-1405.
11. Lin J, Zhang Y, He C, et al. Probiotics supplementation in children with asthma: a systematic review and meta-analysis. J Paediatr Child Health, 2018, 54(9): 953-961.
12. Shi J, Swanson SA, Diemer EW, et al. Mendelian randomization, lipids, and coronary artery disease: trade-offs between study designs and assumptions. Am J Epidemiol, 2025, 194(12): 3581-3589.
13. Zipf G, Chiappa M, Porter KS, et al. National health and nutrition examination survey: plan and operations, 1999-2010. Vital Health Stat 1, 2013, 56: 1-37.
14. Zmora N, Suez J, Elinav E. You are what you eat: diet, health and the gut microbiota. Nat Rev Gastroenterol Hepatol, 2019, 16(1): 35-56.
15. O'Connor LE, Gahche JJ, Herrick KA, et al. Nonfood prebiotic, probiotic, and synbiotic use has increased in US adults and children from 1999 to 2018. Gastroenterology, 2021, 161(2): 476-486.
16. Marco ML, Hutkins R, Hill C, et al. A classification system for defining and estimating dietary intake of live microbes in US adults and children. J Nutr, 2022, 152(7): 1729-1736.
17. O'Keefe SJ. Diet, microorganisms and their metabolites, and colon cancer. Nat Rev Gastroenterol Hepatol, 2016, 13(12): 691-706.
18. Cirillo DJ, Agrawal Y, Cassano PA. Lipids and pulmonary function in the third National Health and Nutrition Examination Survey. Am J Epidemiol, 2002, 155(9): 842-848.
19. Lopera-Maya EA, Kurilshikov A, van der Graaf A, et al. Effect of host genetics on the gut microbiome in 7, 738 participants of the Dutch Microbiome Project. Nat Genet, 2022, 54(2): 143-151.
20. Chen Y, Lu T, Pettersson-Kymmer U, et al. Genomic atlas of the plasma metabolome prioritizes metabolites implicated in human diseases. Nat Genet, 2023, 55(1): 44-53.
21. Gu Y, Jin Q, Hu J, et al. Causality of genetically determined metabolites and metabolic pathways on osteoarthritis: a two-sample Mendelian randomization study. J Transl Med, 2023, 21(1): 357.
22. Wang C, Zhu D, Zhang D, et al. Causal role of immune cells in schizophrenia: Mendelian randomization (MR) study. BMC Psychiatry, 2023, 23(1): 590.
23. Long Y, Tang L, Zhou Y, et al. Causal relationship between gut microbiota and cancers: a two-sample Mendelian randomisation study. BMC Med, 2023, 21(1): 66.
24. Sanderson E, Windmeijer F. A weak instrument [Formula: see text]-test in linear IV models with multiple endogenous variables. J Econom, 2016, 190(2): 212-221.
25. Sanderson E, Spiller W, Bowden J. Testing and correcting for weak and pleiotropic instruments in two-sample multivariable Mendelian randomization. Stat Med, 2021, 40(25): 5434-5452.
26. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
27. Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted Median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
28. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
29. Akay HK, Bahar Tokman H, Hatipoglu N, et al. The relationship between bifidobacteria and allergic asthma and/or allergic dermatitis: a prospective study of 0-3 years-old children in Turkey. Anaerobe, 2014, 28: 98-103.
30. Ouwehand AC, Isolauri E, He F, et al. Differences in Bifidobacterium flora composition in allergic and healthy infants. J Allergy Clin Immunol, 2001, 108(1): 144-145.
31. Waligora-Dupriet AJ, Campeotto F, Romero K, et al. Diversity of gut Bifidobacterium species is not altered between allergic and non-allergic French infants. Anaerobe, 2011, 17(3): 91-96.
32. Hoppe B, Pellikka PA, Dehmel B, et al. Effects of Oxalobacter formigenes in subjects with primary hyperoxaluria type 1 and end-stage renal disease: a phase II study. Nephrol Dial Transplant, 2021, 36(8): 1464-1473.
33. Fedoseev GB, Petrova MA, Sha?lieva LO, et al. Clinical characteristics and condition of the bronchial tree in patients with bronchial asthma and chronic obstructive pulmonary disease in combination with hyperoxaluria. Ter Arkh, 2007, 79(3): 37-41.
34. Mussabay K, Kozhakhmetov S, Dusmagambetov M, et al. Gut microbiome and cytokine profiles in post-COVID syndrome. Viruses, 2024, 16(5): 722.
35. Xu S, Karmacharya N, Woo J, et al. Starving a cell promotes airway smooth muscle relaxation: inhibition of glycolysis attenuates excitation-contraction coupling. Am J Respir Cell Mol Biol, 2023, 68(1): 39-48.
36. Flores-Díaz M, Alape-Girón A, Persson B, et al. Cellular UDP-glucose deficiency caused by a single point mutation in the UDP-glucose pyrophosphorylase gene. J Biol Chem, 1997, 272(38): 23784-23791.
37. Li Z, Tang Y, Wu Y, et al. Structural insights into the committed step of bacterial phospholipid biosynthesis. Nat Commun, 2017, 8(1): 1691.
38. Manni ML, Heinrich VA, Buchan GJ, et al. Nitroalkene fatty acids modulate bile acid metabolism and lung function in obese asthma. Sci Rep, 2021, 11(1): 17788.
39. Meeusen JW, Donato LJ, Bryant SC, et al. Plasma ceramides. Arterioscler Thromb Vasc Biol, 2018, 38(8): 1933-1939.
40. Xu W, Vebrosky EN, Armbrust KL. Potential toxic effects of 4-OH-chlorothalonil and photodegradation product on human skin health. J Hazard Mater, 2020, 394: 122575.
41. Sestini P, Pieroni MG, Refini RM, et al. Time-limited protective effect of inhaled frusemide against aspirin-induced bronchoconstriction in aspirin-sensitive asthmatics. Eur Respir J, 1994, 7(10): 1825-1829.
42. Li J, Li X, Liu X, et al. Untargeted metabolomic study of acute exacerbation of pediatric asthma via HPLC-Q-Orbitrap-MS. J Pharm Biomed Anal, 2022, 215: 114737.
43. Chen Q, Liu M, Lin Y, et al. Topography of respiratory tract and gut microbiota in mice with influenza A virus infection. Front Microbiol, 2023, 14: 1129690.
44. Gong GC, Song SR, Su J. Pulmonary fibrosis alters gut microbiota and associated metabolites in mice: an integrated 16S and metabolomics analysis. Life Sci, 2021, 264: 118616.
45. Budden KF, Shukla SD, Bowerman KL, et al. Faecal microbial transfer and complex carbohydrates mediate protection against COPD. Gut, 2024, 73(5): 751-769.
46. Anderson JR, Lam NB, Jackson JL, et al. Progressive sub-MIC exposure of klebsiella pneumoniae 43816 to cephalothin induces the evolution of beta-lactam resistance without acquisition of beta-lactamase genes. Antibiotics (Basel), 2023, 12(5): 887.
47. Zheng XL, Yang Y, Wang BJ, et al. Synchronous dynamic research on respiratory and intestinal microflora of chronic bronchitis rat model. Chin J Integr Med, 2017, 23(3): 196-200.
48. Ma C, Liao K, Wang J, et al. L-Arginine, as an essential amino acid, is a potential substitute for treating COPD via regulation of ROS/NLRP3/NF-κB signaling pathway. Cell Biosci, 2023, 13(1): 152.
49. Fan LC, McConn K, Plataki M, et al. Alveolar type II epithelial cell FASN maintains lipid homeostasis in experimental COPD. JCI Insight, 2023, 8(16): e163403.
50. Li X, Cheng J, Shen Y, et al. Metabolomic analysis of lung cancer patients with chronic obstructive pulmonary disease using gas chromatography-mass spectrometry. J Pharm Biomed Anal, 2020, 190: 113524.
51. Hasegawa K, Stewart CJ, Celedón JC, et al. Circulating 25-hydroxyvitamin D, nasopharyngeal airway metabolome, and bronchiolitis severity. Allergy, 2018, 73(5): 1135-1140.
52. Labarrere CA, Kassab GS. Glutathione: a Samsonian life-sustaining small molecule that protects against oxidative stress, ageing and damaging inflammation. Front Nutr, 2022, 9: 1007816.
53. Esteves P, Blanc L, Celle A, et al. Crucial role of fatty acid oxidation in asthmatic bronchial smooth muscle remodelling. Eur Respir J, 2021, 58(5): 2004252.
54. Makhija L, Krishnan V, Rehman R, et al. Chemical chaperones mitigate experimental asthma by attenuating endoplasmic reticulum stress. Am J Respir Cell Mol Biol, 2014, 50(5): 923-931.
55. Ghosh N, Choudhury P, Kaushik SR, et al. Metabolomic fingerprinting and systemic inflammatory profiling of asthma COPD overlap (ACO). Respir Res, 2020, 21(1): 126.
56. Zhao F, An R, Wang L, et al. Specific gut microbiome and serum metabolome changes in lung cancer patients. Front Cell Infect Microbiol, 2021, 11: 725284.
57. Seibert B, Cáceres CJ, Carnaccini S, et al. Pathobiology and dysbiosis of the respiratory and intestinal microbiota in 14 months old Golden Syrian hamsters infected with SARS-CoV-2. PLoS Pathog, 2022, 18(10): e1010734.
58. Lai HC, Lin TL, Chen TW, et al. Gut microbiota modulates COPD pathogenesis: role of anti-inflammatory Parabacteroides goldsteinii lipopolysaccharide. Gut, 2022, 71(2): 309-321.
59. Pamart G, Gosset P, Le Rouzic O, et al. Kynurenine pathway in respiratory diseases. Int J Tryptophan Res, 2024, 17: 11786469241232871.
60. Uhlig S, Gulbins E. Sphingolipids in the lungs. Am J Respir Crit Care Med, 2008, 178(11): 1100-1114.
61. Busch R, Qiu W, Lasky-Su J, et al. Differential DNA methylation marks and gene comethylation of COPD in African-Americans with COPD exacerbations. Respir Res, 2016, 17(1): 143.
62. Wujak ?A, Blume A, Balo?lu E, et al. FXYD1 negatively regulates Na(+)/K(+)-ATPase activity in lung alveolar epithelial cells. Respir Physiol Neurobiol, 2016, 220: 54-61.
63. Adachi K, Toyota M, Sasaki Y, et al. Identification of SCN3B as a novel p53-inducible proapoptotic gene. Oncogene, 2004, 23(47): 7791-7798.
64. Wang M, Guo X, Zhao H, et al. Adenosine A2B receptor activation stimulates alveolar fluid clearance through alveolar epithelial sodium channel via cAMP pathway in endotoxin-induced lung injury. Am J Physiol Lung Cell Mol Physiol, 2020, 318(4): L787-L800.
65. Dunham-Snary KJ, Wu D, Sykes EA, et al. Hypoxic pulmonary vasoconstriction: from molecular mechanisms to medicine. Chest, 2017, 151(1): 181-192.
66. Rodriguez-Roisin R. Acute severe asthma: pathophysiology and pathobiology of gas exchange abnormalities. Eur Respir J, 1997, 10(6): 1359-1371.
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Chinese Journal of Evidence-Based Medicine

Investigate causal relationships between gut microbiome specificity and chronic respiratory diseases based on multi-omics approaches analysis

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