Page 1 of 8 © Annals of Esophagus. All rights reserved. Ann Esophagus 2021 | http://dx.doi.org/10.21037/aoe-2020-ebmg-04 The Human Microbiome Project represents a huge scientific effort to further the understanding of the microbiome and its importance for human life on earth. The initial phase of the project characterized microbial communities in healthy people, with different sites of the body studied (1). This therefore began an ambitious description and understanding of the microbial systems in the body and the role of a normal microbiome, associated with health. The nasal passages, oral cavity, skin, gastrointestinal (GI) Review Article A narrative review of the potential role of microaspiration and a dysregulated aerodigestive microbiome in lung disease Abdullah Althuwaybi 1 , Amal Alamer 1 , Melissa J. McDonnell 1,2 , Michelle Brennan 2 , Robert M. Rutherford 2 , Matthew Wilcox 3 ^, Peter Chater 3 ^, Jeffrey Pearson 3 , Chris Ward 1 ^ 1 Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; 2 Respiratory Medicine, Galway University Hospitals, Galway, Ireland; 3 Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK Contributions: (I) Conception and design: All Authors; (II) Administrative support: All Authors; (III) Provision of study materials or patients: All Authors; (IV) Collection and assembly of data: All Authors; (V) Data analysis and interpretation: All Authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Prof. Chris Ward. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. Email: Chris.ward@ncl.ac.uk. Abstract: When initiated the human microbiome project did not include the lungs and airways in its sampling sites, indicating an under appreciation of the role of the human lung microbiome in health and disease. This paradigm has recently changed through the use of culture independent methods to characterise the human lung microbiome. The original thinking, that the normal lung was essentially sterile, had previously been challenged by fndings of microaspiration in normal volunteers and in patients with decreased levels of consciousness. The sterile lung was also questioned by fndings of clinically occult infection markers in lung allograft recipients. What is arguably a “rediscovery” of the importance of the human lung microbiome may still underappreciate physiological and patho-physiological inter-relationships between organ systems, studied in separate research disciplines. In particular, microaspiration may be an important, direct mechanism through which the lung microbiome is modulated. As well as aspiration related to gastro-oesophageal refux and microaspiration the authors feel that the importance of dysphagia in chronic lung disease, will be increasingly recognised in frailty related microbiome exchange between the oropharynx into the lung. This review therefore discusses interconnections in the human microbiome, with a focus on the potential for aerodigestive pathophysiology and microaspiration. Potential connections with human lung disease are discussed and contextualised within a developing literature. This review therefore highlights much needed new targets for translational intervention in lung pathophysiology and underlies the importance of a mixed disciplinary team approach for the future. Keywords: Oesophagus; microaspiration; aerodigestive microbiome Received: 31 October 2020; Accepted: 12 January 2021. doi: 10.21037/aoe-2020-ebmg-04 View this article at: http://dx.doi.org/10.21037/aoe-2020-ebmg-04 ^ ORCID: Matthew Wilcox, 0000-0003-0150-0106; Peter Chater, 0000-0001-8679-0004; Chris Ward, 0000-0002-6954-9611.