The Bidirectional Gut-Lung Axis in Chronic Obstructive Pulmonary Disease

Abstract

Epidemiological studies indicate that chronic obstructive pulmonary disease (COPD) is associated with the incidence of changes in intestinal health. Cigarette smoking, as one of the major causes of COPD, can have an impact on the gastrointestinal system and promotes intestinal diseases. This points to the existence of gut-lung interactions, but an overview of the underlying mechanisms of the bidirectional connection between the lungs and the gut in COPD is lacking. The interaction between the lungs and the gut can occur through circulating inflammatory cells and mediators. Moreover, gut microbiota dysbiosis, observed in both COPD and intestinal disorders, can lead to a disturbed mucosal environment, including the intestinal barrier and immune system, and hence may negatively affect both the gut and the lungs. Furthermore, systemic hypoxia and oxidative stress that occur in COPD may also be involved in intestinal dysfunction and play a role in the gut-lung axis. In this review, we summarize data from clinical research, animal models, and in vitro studies that may explain the possible mechanisms of gut-lung interactions associated with COPD. Interesting observations on the possibility of promising future add-on therapies for intestinal dysfunction in patients with COPD are highlighted.

Keywords: gut–lung axis; hypoxia; lung diseases; microbiota; systemic inflammation.

Figure 1.

Background of chronic obstructive pulmonary disease (COPD) and the gut–lung axis in COPD. COPD, including emphysema and bronchitis, causes shortness of breath, coughing, and sputum production and is triggered mainly by cigarette smoking. COPD is associated with gastrointestinal symptoms. External (e.g., cigarette smoking) and internal (e.g., proinflammatory and oxidative stress mediators) danger signals can induce gastrointestinal dysfunction, including IBD, and other gastrointestinal diseases, such as colorectal cancer, gastesophageal reflux disease, periodontitis, and gallbladder disease. IBD = inflammatory bowel disease. Created with BioRender.com (39).

Figure 2.

Proposed connections between the gut and lungs in chronic obstructive pulmonary disease (COPD). COPD is characterized by immune cell infiltration, proinflammatory mediators in the lungs, impaired epithelial barrier function, oxidative stress, and hypoxia in the lungs. (1) Damaged and activated lung cells further stimulate the innate immune response through elevated proinflammatory mediators (e.g., TNF-α, IFN-γ, IL-6, IL-8, CRP, ROS) (2). Those proinflammatory mediators (and cigarette smoke particles) can migrate to the gastrointestinal tract, (partly) via the systemic circulation, exacerbating intestinal impairments, including increased inflammatory immune infiltration, epithelial barrier damage, oxidative stress, and hypoxia in the gastrointestinal tract. Moreover, (long-term) cigarette smoking and inflammatory immune cell infiltration in the gut can change the microbiota composition, leading to decreased abundance of health-promoting commensal bacteria (3). In addition, soluble cigarette smoke particles may directly affect the gastrointestinal tract by entering the bloodstream after inhalation, or these particles may reach the gastrointestinal tract due to mucociliary clearance in the airways or direct swallowing of cigarette smoke (4). Impaired gut function not only increases the production and entry of proinflammatory mediators into the systemic circulation but also attenuates nutrient absorption, antioxidant capacity, and protection from pathogens and other environmental stimuli, further exacerbating COPD. Dietary intervention, such as fibers, can manipulate the gut microbiota composition to promote host health, increasing the abundance of health-promoting commensal bacteria, decreasing the permeability of intestinal mucosa, and enhancing the bacterial synthesis of immune-modulating compounds (e.g., SCFAs). This may decrease proinflammatory mediators and alleviate the symptoms in the lung. CRP = C-reactive protein; GI = gastrointestinal; ROS = reactive oxygen species; SCFA = short-chain fatty acid; TNF-α = tumor necrosis factor α; VEGF = vascular endothelial growth factor. Created with BioRender.com (39).