COPD & the gut-lung axis
| Educator
12th Jul, 2022Quick read

COPD and gut-lung axis


Chronic obstructive pulmonary disease (COPD) refers to a group of lung conditions, primarily emphysema  and chronic bronchitis , which make breathing difficult. COPD is a multidimensional progressive inflammatory lung disease with pathological changes in the large and small airways (1,2). It is a lifelong condition involving irreversible lung damage, which is different from upper respiratory tract infections. It is characterised by increasing breathlessness, wheezing, chronic cough, and sputum production associated with irreversible, progressive inflammation and significant lung destruction with airflow limitation (3). A person with advanced COPD may be unable to perform daily tasks such as climbing stairs or cooking.

COPD is a common but poorly recognised disease, affecting over 400 million people worldwide (4). The exact pathogenesis of COPD remains largely unknown. Environmental risk factors such as cigarette smoking (including second-hand smoke exposure), bacterial or viral infection, and environmental pollution exposure can affect a range of potential lung function trajectories throughout life. Asthma symptoms may be part of COPD, and a history of asthma can increase the risk of developing the condition. Genetics may also play a role in developing COPD.

There is no cure for COPD, and early diagnosis and treatment from a multidisciplinary approach are critical for preventing or slowing progression and reducing mortality (5). Treatments include quitting smoking, oxygen therapy, medications that widen the airway, including nebulisers and inhalers and surgery.

Disturbance in gut microbiota impacts multiple distant organs, including the lung. The gut-lung axis  facilitates the passage of endotoxins, microbial metabolites, cytokines, and hormones into the bloodstream connecting the gut and lung, impacting immune response and homeostasis in the lungs and airway. In addition, changes in the intestinal microbiota can alter the composition of lung bacteria and vice versa (6,7,8,9). Therefore, the intestinal tract's bacteria can positively or negatively affect lung health.

Although primarily considered a respiratory disease, COPD commonly co-occurs with chronic gastrointestinal (GI) tract diseases (9,10,11). Growing evidence indicates that dysbiosis of the gut microbiota is considered an important component in COPD pathophysiology (12,13,14,15,16). COPD is usually associated with decreased GI microbial diversity and immune system disturbance, contributing to chronic inflammation (5). In addition, increased GI permeability has been observed in patients with severe acute exacerbations of COPD (17) and altered gut microbiota is associated with COPD disease progression (18).

Mechanisms by which the microbiome affects COPD development and vice-versa (Figure 1):

  • Regulation of the inflammatory environment.
  • DNA methylation is affected by metabolites produced by gut bacteria (19) and is associated with gene expression profiles in COPD lung tissue (20).
  • Histone modification - reduced histone enzymes in COPD may increase inflammation (21,22,23). The gut microbiome can modulate histone-producing enzyme activity by producing short-chain fatty acids (SCFAs) (24).
  • The gut microbiome regulates microRNAs  (miRNAs) (25), and miRNAs are capable of suppressing or preventing COPD development (26).


Figure 1 Gut-lung axis involvement in COPD. Adapted from (5) CC BY

  COPD and gut-lung axis Fig1


Several risk factors, including smoking, diet, antibiotics, steroid treatments, and fibre intake affect the gut-lung axis  in COPD.


Cigarette smoke exposure

Cigarette smoking is the most significant risk factor for COPD. Approximately 80% of COPD patients are past or current smokers (5). Tobacco smoke has a significant deleterious effect on lung tissue and the composition and relative abundance of the lung microbiome (27,28,29,30). Cigarette smoking has also been shown to reduce the diversity of the gut microbiome (5).

Dysbiosis in the gut can be modified through faecal transplantation in the cigarette-smoking-based model, indicating that gut microbiota may play a causal role in COPD pathogenesis (12).


Fibre, vitamin and folic acid intake

Individuals that consume less fibre, vitamins, and folic acid are prone to develop airflow limitations and COPD (31). The gut microbiome produces many metabolites, e.g. SCFAs, through fermentation of fibre. SCFAs are potent anti-inflammatory molecules. When absorbed into the systemic circulation, they can influence lung health. Dietary fibre leads to altered composition of gut and lung microbiota (32), and a lack of fermentable fibres can lead to malnourishment of the microbiota, resulting in gut dysbiosis and altered lung physiology (33,34).

Several studies indicate an inverse association between total and cereal dietary fibre intake and COPD incidence (35,36,37). In addition, preliminary evidence shows that dietary supplementation of probiotics Lactobacillus rhamnosus and Bifidobacterium breve prevents airway inflammation and lung damage in COPD mice (38).



While current management strategies prevent COPD exacerbation and relieve symptoms, new approaches are required to target the underlying disease process and reverse lung function deterioration. Gut dysbiosis in COPD may be a modifiable factor to be developed as a non-drug therapeutical strategy for preventing and managing the disease. Meanwhile, probiotic supplementation and faecal transplantation have also shown positive outcomes in experimental COPD models.

1Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004 Jun 24;350(26):2645–53.
2Holtzman MJ, Byers DE, Alexander-Brett J, Wang X. The role of airway epithelial cells and innate immune cells in chronic respiratory disease. Nat Rev Immunol. 2014 Oct;14(10):686–98.
3Raherison C, Girodet PO. Epidemiology of COPD. Eur Respir Rev. 2009 Dec;18(114):213–21.
4Agustí A, Vogelmeier C, Faner R. COPD 2020: changes and challenges. Am J Physiol Lung Cell Mol Physiol. 2020 Nov 1;319(5):L879–83.
5Qu L, Cheng Q, Wang Y, Mu H, Zhang Y. COPD and Gut-Lung Axis: How Microbiota and Host Inflammasome Influence COPD and Related Therapeutics. Front Microbiol. 2022;13:868086.
6Mateer SW, Maltby S, Marks E, Foster PS, Horvat JC, Hansbro PM, et al. Potential mechanisms regulating pulmonary pathology in inflammatory bowel disease. J Leukoc Biol. 2015 Nov;98(5):727–37.
7Budden KF, Gellatly SL, Wood DLA, Cooper MA, Morrison M, Hugenholtz P, et al. Emerging pathogenic links between microbiota and the gut-lung axis. Nat Rev Microbiol. 2017;15(1):55–63.
8Budden KF, Shukla SD, Rehman SF, Bowerman KL, Keely S, Hugenholtz P, et al. Functional effects of the microbiota in chronic respiratory disease. Lancet Respir Med. 2019 Oct;7(10):907–20.
9Raftery AL, Tsantikos E, Harris NL, Hibbs ML. Links Between Inflammatory Bowel Disease and Chronic Obstructive Pulmonary Disease. Front Immunol. 2020;11:2144.
10Rutten EPA, Lenaerts K, Buurman WA, Wouters EFM. Disturbed intestinal integrity in patients with COPD: effects of activities of daily living. Chest. 2014 Feb;145(2):245–52.
11Keely S, Talley NJ, Hansbro PM. Pulmonary-intestinal cross-talk in mucosal inflammatory disease. Mucosal Immunol. 2012 Jan;5(1):7–18.
12Lai HC, Lin TL, Chen TW, Kuo YL, Chang CJ, Wu TR, et al. Gut microbiota modulates COPD pathogenesis: role of anti-inflammatory Parabacteroides goldsteinii lipopolysaccharide. Gut. 2022 Feb;71(2):309–21.
13Chotirmall SH, Gellatly SL, Budden KF, Mac Aogain M, Shukla SD, Wood DLA, et al. Microbiomes in respiratory health and disease: An Asia-Pacific perspective. Respirology. 2017 Feb;22(2):240–50.
14Shukla SD, Budden KF, Neal R, Hansbro PM. Microbiome effects on immunity, health and disease in the lung. Clin Transl Immunology. 2017 Mar;6(3):e133.
15Chunxi L, Haiyue L, Yanxia L, Jianbing P, Jin S. The Gut Microbiota and Respiratory Diseases: New Evidence. J Immunol Res. 2020;2020:2340670.
16Bowerman KL, Rehman SF, Vaughan A, Lachner N, Budden KF, Kim RY, et al. Disease-associated gut microbiome and metabolome changes in patients with chronic obstructive pulmonary disease. Nat Commun. 2020 Nov 18;11(1):5886.
17Sprooten RTM, Lenaerts K, Braeken DCW, Grimbergen I, Rutten EP, Wouters EFM, et al. Increased Small Intestinal Permeability during Severe Acute Exacerbations of COPD. Respiration. 2018 May;95(5):334–42.
18Li N, Dai Z, Wang Z, Deng Z, Zhang J, Pu J, et al. Gut microbiota dysbiosis contributes to the development of chronic obstructive pulmonary disease. Respiratory research. 2021 Oct 25;22(1).
19Ansari I, Raddatz G, Gutekunst J, Ridnik M, Cohen D, Abu-Remaileh M, et al. The microbiota programs DNA methylation to control intestinal homeostasis and inflammation. Nat Microbiol. 2020 Apr;5(4):610–9.
20Lee MK, Hong Y, Kim SY, Kim WJ, London SJ. Epigenome-wide association study of chronic obstructive pulmonary disease and lung function in Koreans. Epigenomics. 2017 Jul;9(7):971–84.
21Barnes PJ. Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol. 2009;71:451–64.
22Rajendrasozhan S, Yang SR, Kinnula VL, Rahman I. SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008 Apr 15;177(8):861–70.
23Ito K, Ito M, Elliott WM, Cosio B, Caramori G, Kon OM, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med. 2005 May 12;352(19):1967–76.
24Yuille S, Reichardt N, Panda S, Dunbar H, Mulder IE. Human gut bacteria as potent class I histone deacetylase inhibitors in vitro through production of butyric acid and valeric acid. PLoS One. 2018;13(7):e0201073.
25Malmuthuge N, Guan LL. Noncoding RNAs: Regulatory Molecules of Host-Microbiome Crosstalk. Trends Microbiol. 2021 Aug;29(8):713–24.
26Zhang L, Valizadeh H, Alipourfard I, Bidares R, Aghebati-Maleki L, Ahmadi M. Epigenetic Modifications and Therapy in Chronic Obstructive Pulmonary Disease (COPD): An Update Review. COPD. 2020 Jun;17(3):333–42.
27Erb-Downward JR, Thompson DL, Han MK, Freeman CM, McCloskey L, Schmidt LA, et al. Analysis of the lung microbiome in the ‘healthy’ smoker and in COPD. PLoS One. 2011 Feb 22;6(2):e16384.
28Zhang R, Chen L, Cao L, Li KJ, Huang Y, Luan XQ, et al. Effects of smoking on the lower respiratory tract microbiome in mice. Respir Res. 2018 Dec 14;19(1):253.
29Bagaitkar J, Demuth DR, Scott DA. Tobacco use increases susceptibility to bacterial infection. Tob Induc Dis. 2008 Dec 18;4:12.
30Garmendia J, Morey P, Bengoechea JA. Impact of cigarette smoke exposure on host-bacterial pathogen interactions. Eur Respir J. 2012 Feb;39(2):467–77.
31Jung YJ, Lee SH, Chang JH, Lee HS, Kang EH, Lee SW. The Impact of Changes in the Intake of Fiber and Antioxidants on the Development of Chronic Obstructive Pulmonary Disease. Nutrients. 2021 Feb 10;13(2):580.
32Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom-Bru C, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med. 2014 Feb;20(2):159–66.
33Makki K, Deehan EC, Walter J, Bäckhed F. The Impact of Dietary Fiber on Gut Microbiota in Host Health and Disease. Cell Host Microbe. 2018 13;23(6):705–15.
34Vaughan A, Frazer ZA, Hansbro PM, Yang IA. COPD and the gut-lung axis: the therapeutic potential of fibre. J Thorac Dis. 2019 Oct;11(Suppl 17):S2173–80.
35Varraso R, Willett WC, Camargo CA. Prospective study of dietary fiber and risk of chronic obstructive pulmonary disease among US women and men. Am J Epidemiol. 2010 Apr 1;171(7):776–84.
36Kaluza J, Harris H, Wallin A, Linden A, Wolk A. Dietary Fiber Intake and Risk of Chronic Obstructive Pulmonary Disease: A Prospective Cohort Study of Men. Epidemiology. 2018 Mar;29(2):254–60.
37Szmidt MK, Kaluza J, Harris HR, Linden A, Wolk A. Long-term dietary fiber intake and risk of chronic obstructive pulmonary disease: a prospective cohort study of women. Eur J Nutr. 2020 Aug;59(5):1869–79.
38De Sá Fialho AKC, Miranda MTF, Carvalho JLC, Brito AA, Albertini R, Aimbire F. Role of probiotics Bifidobacterium breve and Lactobacillus rhamnosus on inflammation lung in an experimental model of chronic obstructive pulmonary disease. The FASEB Journal. 2019;33(S1):516.4-516.4.