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Lung-Gut Cross TalkLung-Gut Cross Talk: A Potential Mechanism for Intestinal Dysfunction in Patients With COPD FREE TO VIEW

Simon Keely, PhD; Philip M. Hansbro, PhD
Author and Funding Information

From the Viruses, Infection, Immunity, Vaccine and Asthma (VIVA) Program, Hunter Medical Research Institute (HMRI); and School of Biomedical Science and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia.

Correspondence to: Simon Keely, PhD, School of Biomedical Science and Pharmacy, University of Newcastle, Callaghan, 2308, NSW, Australia; e-mail: simon.keely@newcastle.edu.au


Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(2):199-200. doi:10.1378/chest.13-2077
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COPD describes a group of conditions that are characterized by loss of the functional capacity of the lungs, which is due to reduced and obstructed airflow.1 This disease exerts a large and increasing health burden worldwide and is often caused by exposure to tobacco smoking. Although primarily considered a respiratory disease, there is growing clinical interest in secondary organ manifestations of COPD, particularly in the GI tract. Indeed, GI disease is more prevalent in patients with COPD than in healthy populations.2 A population-based cohort study performed by Ekbom et al,3 showed a 2.72 times higher risk of Crohn’s disease (an inflammatory bowel disease) in COPD sufferers than that in healthy control subjects, greater than the risk reported for smoking alone. Specific intestinal complications include atrophic gastritis and nutritional absorption deficiency in the small intestine.4,5 Thus, there is a clear link between inflammatory diseases in the respiratory and intestinal systems. However, there have been surprisingly few research studies that have investigated the nature of the cross talk involved, and while several mechanisms have been proposed,6 to date there have been few studies that have aimed to elucidate these connections.

The study by Rutten et al7 in this issue (see page 245) provides evidence of intestinal compromise and, importantly, evidence of an associated mechanism for intestinal dysfunction in patients with COPD. They proposed that the increased metabolic demands that are associated with the physical activities of patients with COPD result in a reduction in intestinal perfusion causing ischemia in these tissues. The authors demonstrated increased intestinal permeability in patients with COPD at rest, compared with healthy individuals. However, physical exertion, represented by day-to-day activities, significantly increased the intestinal permeability of the small intestine in patients with COPD, which was assessed by measurement of the excretion of orally ingested sugar probes. This increased permeability was associated with acute enterocyte damage, which occurs rapidly during physical exertion and continues after the completion of activities. Importantly, there was no evidence of increased enterocyte damage in patients with COPD at rest, suggesting that the physical activity itself precipitates the epithelial damage. Of note, the authors demonstrated that performing the study exercise activities placed a higher metabolic demand on patients with COPD, and that metabolic load, measured as serum lactic acid, correlated with intestinal permeability in these patients. Thus, an intriguing hypothesis presents whereby patients with COPD, unable to cope with the metabolic demand of daily activities, are susceptible to intestinal ischemia and associated enterocyte damage.

This is surprising as, although chronic intestinal ischemia promotes intestinal permeability, there is a large body of evidence that suggests that the intestinal mucosa, in particular intestinal epithelial cells, have a number of adaptive pathways to augment acute ischemic damage,8 such as in the study by Rutten et al.7 Indeed, there have been numerous studies that have focused on manipulating these pathways.9 Whether the increased permeability observed overwhelms these protective pathways or whether the pathways are merely dysfunctional has yet to be determined.

Of interest in this study was the fact that a minority of the patients with COPD were current smokers. Some important demonstrations of the lung-gut axis have been the observation that active smoking exacerbates Crohn’s disease and that cigarette smoke itself is implicated in GI pathology.10 Cigarette smoke drives bronchitis in patients with COPD as the smoke exposure damages the airway epithelia and epithelial tight junctions,11 and we have hypothesized that this toxic effect may extend systemically to the intestinal epithelium.6 However, it is known that once initiated, the pathogenesis of COPD continues to progress and the patient’s condition continues to deteriorate even upon smoking cessation. Here, Rutten et al7 have demonstrated that epithelial damage may occur in patients with COPD, independently or as a sequelae of cigarette smoking. The suggestion that impaired lung capacity and increased metabolic demand promotes intestinal ischemia offers far-reaching implications across a number of extrapulmonary manifestations of COPD, and future insight may be gained from the investigation of animal models that recapitulate the hallmark features of COPD12 and inflammatory bowel disease.9 In particular, the functional implications of absorptive enterocyte loss in terms of nutrient absorption remain to be determined. Crucially, in the present study, the loss of intestinal integrity in patients with COPD under increased metabolic demand through daily activities may represent an initiating event in the development of GI pathologies that are associated with COPD.7 The mucosal epithelium forms a selective barrier, separating the interstitium and the underlying tissues from the milieu of antigenic material and pathogens in the mucosal lumen, while simultaneously absorbing critical nutrients.8 Thus, maintenance of epithelial barrier function is critical for preserving the healthy state in both the respiratory and GI mucosa.9 Consequently, ischemia-driven loss of barrier function may represent an underlying cause and chronic nature of many GI diseases in patients with COPD.

References

Roth M. Pathogenesis of COPD. Part III. Inflammation in COPD. Int J Tuberc Lung Dis. 2008;12(4):375-380. [PubMed]
 
Nielsen HM, Rodsgaard PA, Weinreich UM. Chronic obstructive pulmonary disease as comorbidity in patients admitted to a university hospital-a cross-sectional study [published online ahead of print August 1, 2013]. Clin Respir J. doi:10.1111/crj.12050.
 
Ekbom A, Brandt L, Granath F, Löfdahl CG, Egesten A. Increased risk of both ulcerative colitis and Crohn’s disease in a population suffering from COPD. Lung. 2008;186(3):167-172. [CrossRef] [PubMed]
 
Fedorova TA, Spirina Llu, Chernekhovskaia NE, et al. The stomach and duodenum condition in patients with chronic obstructive lung diseases [in Russian]. Klin Med (Mosk). 2003;81(10):31-33. [PubMed]
 
Beloborodova EI, Akimova LA, Asanova AV, et al. Trophologic insufficiency and absorptive function of small intestine in patients with chronic obstructive pulmonary disease [in Russian]. Klin Med (Mosk). 2009;87(3):59-63. [PubMed]
 
Keely S, Talley NJ, Hansbro PM. Pulmonary-intestinal cross-talk in mucosal inflammatory disease. Mucosal Immunol. 2012;5(1):7-18. [CrossRef] [PubMed]
 
Rutten EPA, Lenaerts K, Buurman WA, Wouters EFM. Disturbed intestinal integrity in patients with COPD: effects of activities of daily living. Chest. 2014;145(2):245-252.
 
Goggins BJ, Chaney C, Radford-Smith GL, Horvat JC, Keely S. Hypoxia and integrin-mediated epithelial restitution during mucosal inflammation. Front Immunol. 2013;4:272. [CrossRef] [PubMed]
 
Keely S, Campbell EL, Baird AW, et al. Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis [published online ahead of print May 22, 2013]. Mucosal Immunol. doi:10.1038/mi.2013.29.
 
Birrenbach T, Böcker U. Inflammatory bowel disease and smoking: a review of epidemiology, pathophysiology, and therapeutic implications. Inflamm Bowel Dis. 2004;10(6):848-859. [CrossRef] [PubMed]
 
Heijink IH, Brandenburg SM, Postma DS, van Oosterhout AJ. Cigarette smoke impairs airway epithelial barrier function and cell-cell contact recovery. Eur Respir J. 2012;39(2):419-428.
 
Beckett EL, Stevens RL, Jarnicki AG, et al. A new short-term mouse model of chronic obstructive pulmonary disease identifies a role for mast cell tryptase in pathogenesis. J Allergy Clin Immunol. 2013;131(3):752-762. [CrossRef] [PubMed]
 

Figures

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References

Roth M. Pathogenesis of COPD. Part III. Inflammation in COPD. Int J Tuberc Lung Dis. 2008;12(4):375-380. [PubMed]
 
Nielsen HM, Rodsgaard PA, Weinreich UM. Chronic obstructive pulmonary disease as comorbidity in patients admitted to a university hospital-a cross-sectional study [published online ahead of print August 1, 2013]. Clin Respir J. doi:10.1111/crj.12050.
 
Ekbom A, Brandt L, Granath F, Löfdahl CG, Egesten A. Increased risk of both ulcerative colitis and Crohn’s disease in a population suffering from COPD. Lung. 2008;186(3):167-172. [CrossRef] [PubMed]
 
Fedorova TA, Spirina Llu, Chernekhovskaia NE, et al. The stomach and duodenum condition in patients with chronic obstructive lung diseases [in Russian]. Klin Med (Mosk). 2003;81(10):31-33. [PubMed]
 
Beloborodova EI, Akimova LA, Asanova AV, et al. Trophologic insufficiency and absorptive function of small intestine in patients with chronic obstructive pulmonary disease [in Russian]. Klin Med (Mosk). 2009;87(3):59-63. [PubMed]
 
Keely S, Talley NJ, Hansbro PM. Pulmonary-intestinal cross-talk in mucosal inflammatory disease. Mucosal Immunol. 2012;5(1):7-18. [CrossRef] [PubMed]
 
Rutten EPA, Lenaerts K, Buurman WA, Wouters EFM. Disturbed intestinal integrity in patients with COPD: effects of activities of daily living. Chest. 2014;145(2):245-252.
 
Goggins BJ, Chaney C, Radford-Smith GL, Horvat JC, Keely S. Hypoxia and integrin-mediated epithelial restitution during mucosal inflammation. Front Immunol. 2013;4:272. [CrossRef] [PubMed]
 
Keely S, Campbell EL, Baird AW, et al. Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis [published online ahead of print May 22, 2013]. Mucosal Immunol. doi:10.1038/mi.2013.29.
 
Birrenbach T, Böcker U. Inflammatory bowel disease and smoking: a review of epidemiology, pathophysiology, and therapeutic implications. Inflamm Bowel Dis. 2004;10(6):848-859. [CrossRef] [PubMed]
 
Heijink IH, Brandenburg SM, Postma DS, van Oosterhout AJ. Cigarette smoke impairs airway epithelial barrier function and cell-cell contact recovery. Eur Respir J. 2012;39(2):419-428.
 
Beckett EL, Stevens RL, Jarnicki AG, et al. A new short-term mouse model of chronic obstructive pulmonary disease identifies a role for mast cell tryptase in pathogenesis. J Allergy Clin Immunol. 2013;131(3):752-762. [CrossRef] [PubMed]
 
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