Homeostasis and its disruption in the lung microbiome

Abstract

The disciplines of physiology and ecology are united by the shared centrality of the concept of homeostasis: the stability of a complex system via internal mechanisms of self-regulation, resilient to external perturbation. In the past decade, these fields of study have been bridged by the discovery of the lung microbiome. The respiratory tract, long considered sterile, is in fact a dynamic ecosystem of microbiota, intimately associated with the host inflammatory response, altered in disease states. If the microbiome is a "newly discovered organ," ecology is the language we use to explain how it establishes, maintains, and loses homeostasis. In this essay, we review recent insights into the feedback mechanisms by which the lung microbiome and the host response are regulated in health and dysregulated in acute and chronic lung disease. We propose three explanatory models supported by recent studies: the adapted island model of lung biogeography, nutritional homeostasis at the host-microbiome interface, and interkingdom signaling and the community stress response.

Keywords: 16S; culture-independent; ecology; equilibrium; homeostasis; lung; microbial ecology; physiology; pulmonary.

Fig. 1.

The adapted island model of lung biogeography. The community of the lung microbiome is determined by 3 ecological factors (A): immigration, elimination, and the effects of regional growth conditions on the reproduction rates of community members. In health, the community is primarily determined by the balance of immigration (from microaspiration) and elimination (via cough, mucociliary clearance, and immune defenses). The number of species present at a given site in the respiratory tract in health is a steady state of dynamic equilibrium, determined by the balance of immigration and elimination factors, influenced by anatomical, functional and clinical factors (B). In an experimental validation of this model (C), proximity to the source community of the upper respiratory tract was associated with increased microbial immigration and increased community richness. A adapted from Ref. . B adapted from Ref. with permission of John Wiley & Sons Ltd. C adapted from Ref. with permission of the American Thoracic Society. Lung drawing adapted from original by Patrick J. Lynch, medical illustrator, and C. Carl Jaffe, M.D., cardiologist, via Creative Commons Attribution 2.5 license 2006 (http://goo.gl/xuJRCO).

Fig. 2.

Nutritional homeostasis at the host-microbiome interface. In health, the lungs are a nutrient-poor environment for bacteria, as evidenced by the low protein content of bronchoalveolar lavage (BAL) fluid (A). This changes in acute respiratory distress syndrome (ARDS) and pneumonia, when protein-rich edema fills the alveolar space. B: in homeostasis, the growth of a single bacterial species is inhibited by 2 negative feedback loops: increased bacterial growth provokes increased local inflammation, which kills and clears bacteria, inhibiting further bacterial growth (arrow A); and as bacteria grow they consume their available nutrient supply, inhibiting subsequent growth (arrow E). But if the provoked inflammation results in enough endothelial and epithelial injury (arrow B) to result in leak of protein- and nutrient-rich fluid into the alveolar compartment (arrow C), the growth-limiting nutrient supply is restored (arrow D) and bacterial growth is promoted (arrow E). The specific composition of available nutrients influences the relative growth rates of community members, shaping community membership. A: figure generated with data from Ref. . B: adapted from Ref. .

Fig. 3.

Interkingdom signaling and the lung microbiome. Host-derived catecholamines, including norepinephrine (NE) and dopamine, promote the in vitro growth of Pseudomonas aeruginosa (A, adapted from Ref. with permission of the American College of Chest Physicians). Intra-alveolar catecholamine concentrations are strongly associated with collapse of the respiratory ecosystem around a single dominant pathogen (B, adapted from Ref. with permission of the American Thoracic Society). These observations suggest a positive feedback loop (C) that can propel the explosive disruption of homeostasis observed in respiratory infections with select bacteria. Similar bacterial growth promotion has been reported with other host inflammatory response molecules, including TNF-α, IL-1, IL-6, IL-8, and glucocorticoids (30, 31, 42, 43).