Progression Of Respiratory Diseases Research Articles

Restoring the epigenetic landscape of lung microbiome: potential therapeutic approach for chronic respiratory diseases.

Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and bronchiectasis, present significant threats to global health. Recent studies have revealed the crucial role of the lung microbiome in the development of these diseases. Pathogens have evolved complex strategies to evade the immune response, with the manipulation of host cellular epigenetic mechanisms playing a pivotal role. There is existing evidence regarding the effects of Pseudomonas on epigenetic modifications and their association with pulmonary diseases. Therefore, this study aims to directly assess the connection between Pseudomonas abundance and chronic respiratory diseases. We hope that our findings will shed light on the molecular mechanisms behind lung pathogen infections. We analyzed data from 366 participants, including individuals with COPD, acute exacerbations of COPD (AECOPD), bronchiectasis, and healthy individuals. Previous studies have given limited attention to the impact of Pseudomonas on these groups and their comparison with healthy individuals. Two independent datasets from different ethnic backgrounds were used for external validation. Each dataset separately analyzed bacteria at the genus level. The study reveals that Pseudomonas, a bacterium, was consistently found in high concentrations in all chronic lung disease datasets but it was present in very low abundance in the healthy datasets. This suggests that Pseudomonas may influence cellular mechanisms through epigenetics, contributing to the development and progression of chronic respiratory diseases. This study emphasizes the importance of understanding the relationship between the lung microbiome, epigenetics, and the onset of chronic pulmonary disease. Enhanced recognition of molecular mechanisms and the impact of the microbiome on cellular functions, along with a better understanding of these concepts, can lead to improved diagnosis and treatment.

Investigating the Bidirectional Influence of Genetic Damage, Genetic Repair Mechanisms and Inflammation in Lung Injuries

The respiratory system is continually exposed to various harmful agents, which is why DNA repair is required. This comprises injury, inflammation, and other contents that are toxic and can cause damage to its genes. To eliminate the impact of DNA damage and restore cellular function, three pathways of repair are induced as follows: base excision repair, nucleotide excision repair (NER), and double-strand break pathway. However, such healing responses can be downregulated by long-term or severe injuries resulting in decreased recovery ability and predisposition to various diseases, such as lung cancer, chronic obstructive pulmonary disease (COPD), and fibrosis of the lungs. The generation of reactive oxygen species (ROS) during inflammation alters DNA and damages tissues. Despite this, inflammation will affect the initiation of tissue repair as well as DNA damage through the creation of ROS in this intricate process that occurs partly through innate immune responses and cytokine signaling. Cytotoxic processes hamper these fixing pathways of damaged genetic materials by inhibiting enzymes involved in DNA reparations and genes linked to repairs, thereby enhancing the risks of mutagenesis, carcinogenesis, and progressive diseases. Hence, the relationship between DNA repair and inflammatory reactions is crucial for lung health. It plays a major role in the pathophysiology of illnesses, such as cancer, COPD, fibrosis, and asthma. Inflammation and DNA damage are positively associated because they form a positive feedback loop that promotes disease and tissue pathology progression. DNA injury activates inflammation because immune cells are attracted to the site of injury, which in turn produces more oxidant molecules damaging the DNA. The evaluation of this relationship may help find approaches for reducing DNA damage, protecting genomic integrity, and preventing the progression of respiratory diseases.

Home-spirometry exacerbation profiles in children with cystic fibrosis.

Pulmonary exacerbations (PEx) are strong predictors of respiratory disease progression in children with cystic fibrosis (CwCF) and may be associated with persistent decreased lung function after acute management. Telemonitoring devices can be used for early detection and monitoring of PEx, but its utility is debated. Which symptoms and telemonitoring spirometry characterics are related to outcome dynamics following initial PEx management? This retrospective study included CwCF followed at Bordeaux University Hospital, France. All severe PEx episodes treated with intravenous (IV) antibiotics (ATB) between 1 January 2017 and 31 December 2021 in CwCF using home telemonitoring were analyzed. Symptoms and home spirometry data were collected 45 days before and up to 60 days after each IV ATB course. We defined three response profiles based on terciles of baseline forced expiratory volume in 1 s (FEV1 ) recovery. A total of 346 IV ATB courses for PEx were administered to 65 CwCF during the study period. The drop in FEV1 became significant 8 days before IV ATB initiation. Forty-one percent of IV ATB courses failed to restore baseline FEV1 . The magnitude of FEV1 drop and a greater delay in the initiation of treatment correlated with a low response level. On the 14th day of the IV treatment, a FEV1 recovery less than 94% of baseline was associated with a nonresponder profile. Home spirometry may facilitate the early recognition of PEx to implement earlier interventions. This study also provides an outcome lung function threshold which identifies low responders to IV ATB.

Microphysiological Models of Lung Epithelium-Alveolar Macrophage Co-Cultures to Study Chronic Lung Disease.

The interactions between immune cells and epithelial cells influence the progression of many respiratory diseases, such as chronic obstructive pulmonary disease (COPD). In vitro models allow for the examination of cells in controlled environments. However, these models lack the complex 3D architecture and vast multicellular interactions between the lung resident cells and infiltrating immune cells that can mediate cellular response to insults. In this study, three complementary microphysiological systems are presented to delineate the effects of cigarette smoke and respiratory disease on the lung epithelium. First, the Transwell system allows the co-culture of pulmonary immune and epithelial cells to evaluate cellular and monolayer phenotypic changes in response to cigarette smoke exposure. Next, the human and mouse precision-cut lung slices system provides a physiologically relevant model to study the effects of chronic insults like cigarette smoke with the dissection of specific interaction of immune cell subtypes within the structurally complex tissue environment. Finally, the lung-on-a-chip model provides an adaptable system for live imaging of polarized epithelial tissues that mimic the in vivo environment of the airways. Using a combination of these models, a complementary approach is provided to better address the intricate mechanisms of lung disease.

Effects of Hormone Replacement Therapy on Women's Lung Health and Disease.

This review provides an overview of menopausal hormone therapy and pulmonary disease risk, with a focus on the effect of hormone replacement therapy (HRT) on pulmonary function and its relation to lung diseases. This summary is based on authors' knowledge in the field of HRT and supplemented by a PubMed search using the terms "menopause hormone therapy," "asthma", "lung cancer", "chronic obstructive pulmonary disease", "lung function", and "pulmonary hypertension". Available evidence indicates that there is limited research on the role of sex hormones in the susceptibility, severity, and progression of chronic respiratory diseases. However, some studies suggest that the hormonal changes that occur during the menopausal transition may have an impact on pulmonary function and respiratory diseases. Women are in need of convenient access to a safe and effective modality for personalized HRT based on an artificial intelligence (AI)-driven platform that will enable them to receive personalized hormonal treatment through frequent, convenient, and accurate measurements of hormone levels in peripheral blood.

Downregulation of NOX4 improves airway remodeling and inflammation by the TGF-β1-Smad2/3 pathway in asthma.

Asthma is a respiratory inflammatory disease, and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is involved in the progression of respiratory diseases. However, the role of NOX4 in asthma remains unclear. In the present study, we aimed to explore the effects of NOX4 on airway remodeling and inflammation. NOX4 expression was measured using immunocytochemistry (IHC), western blot, and real-time PCR (qPCR). Lung tissues were stained using the H&E assay. ELISA was used to examine the levels of airway remodeling-related indicators, and qPCR was used to detect airway inflammatory factors. The results indicated that NOX4 is highly expressed in lung tissues, bronchoalveolar lavage fluid (BALF), and serum of OVA-treated mice. Inhibition of NOX4 alleviated OVA-induced airway remodeling and inflammation. Similarly, TGF-β1 was also upregulated in BALF and serum OVA-induced mice. Inhibition of TGF-β1 signaling also improved airway remodeling and inflammation induced by OVA. Moreover, the downregulation of NOX4 inactivated the TGF-β1-Smad2/3 pathway, and TGF-β1 decreased Smad2/3 expression. Moreover, inhibition of the TGF-β1 was enhanced, while TGF-β1 reversed the effects on airway remodeling and inflammation induced by NOX4 inhibition. Taken together, the downregulation of NOX4 improves airway remodeling and inflammation via inactivation of the TGF-β1-Smad2/3 pathway in asthma mice, suggesting that NOX4 may be a therapeutic target for asthma.

Risk factors for severity in seasonal respiratory viral infections and how they guide management in hematopoietic cell transplant recipients.

Seasonal respiratory virus infections (RVIs) often progress to severe diseases in hematopoietic cell transplant (HCT) recipients. This review summarizes the current evidence on risk factors for the severity of RVIs in this high-risk population and provides clinical management. The likelihood of the respiratory viral disease progression depends on the immune status of the host and the type of virus. Conventional host factors, such as the immunodeficiency scoring index and the severe immunodeficiency criteria, have been utilized to estimate the risk of progression to severe disease, including mortality. Recent reports have suggested nonconventional risk factors, such as hyperglycemia, hypoalbuminemia, prior use of antibiotics with broad anaerobic activity, posttransplant cyclophosphamide, and pulmonary impairment after RVIs. Identifying novel and modifiable risk factors is important with the advances of novel therapeutic and preventive interventions for RVIs. Validation of recently identified risk factors for severe RVIs in HCT recipients is required. The development of innovative interventions along with appropriate risk stratification is critical to improve outcomes in this vulnerable population.

Periodontopathogens Porphyromonas gingivalis and Fusobacterium nucleatum and Their Roles in the Progression of Respiratory Diseases.

The intricate interplay between oral microbiota and the human host extends beyond the confines of the oral cavity, profoundly impacting the general health status. Both periodontal diseases and respiratory diseases show high prevalence worldwide and have a marked influence on the quality of life for the patients. Accumulating studies are establishing a compelling association between periodontal diseases and respiratory diseases. Here, in this review, we specifically focus on the key periodontal pathogenic bacteria Porphyromonas gingivalis and Fusobacterium nucleatum and dissect their roles in the onset and course of respiratory diseases, mainly pneumonia, chronic obstructive pulmonary disease, lung cancer, and asthma. The mechanistic underpinnings and molecular processes on how P. gingivalis and F. nucleatum contribute to the progression of related respiratory diseases are further summarized and analyzed, including: induction of mucus hypersecretion and chronic airway inflammation; cytotoxic effects to disrupt the morphology and function of respiratory epithelial cells; synergistic pathogenic effects with respiratory pathogens like Streptococcus pneumoniae and Pseudomonas aeruginosa. By delving into the complex relationship to periodontal diseases and periodontopathogens, this review helps unearth novel insights into the etiopathogenesis of respiratory diseases and inspires the development of potential therapeutic avenues and preventive strategies.

Resveratrol mitigates miR-212-3p mediated progression of diesel exhaust-induced pulmonary fibrosis by regulating SIRT1/FoxO3

BackgroundDiesel exhaust (DE) exposure contributes to the progression of chronic respiratory diseases and is associated with dysregulation of microRNA expression. The present study aims to investigate the involvement of miRNAs and target genes in DE-induced lung fibrosis. MethodsC57BL/6 mice were divided into three groups. Group 1 mice were exposed to filtered air (Control). Group 2 mice were exposed to DE for 30 min per day, 5 days per week, for 8 weeks (DE). Group 3 mice received DE exposure along with resveratrol on alternate days for the last 2 weeks (DE + RES). Mice were sacrificed to isolate RNA from lung tissue for miRNA microarray profiling. Bronchoalveolar lavage fluid and lung tissues were collected for cell count and biochemical analysis. ResultsDE exposure resulted in differential expression of 28 miRNAs with fold change >2 (p < 0.05). The upregulated miR-212-3p was selected for further analysis. Consensus analysis revealed enrichment of SIRT1 in the FoxO pathway, along with a co-annotation of reduced body weight (p < 0.05). A549 cells transfected with a miR-212-3p inhibitor showed a dose-dependent increase in SIRT1 expression, indicating SIRT1 as a direct target. Treatment with resveratrol restored SIRT1 and miR-212-3p expression and led to a reduction in inflammatory cytokines (p < 0.05). The modulation of SIRT1 correlated negatively with macrophage infiltration, confirming its role in regulating cellular infiltration and lung inflammation. Fibronectin, alpha-SMA, and collagen levels were significantly decreased in DE + RES compared to DE group suggesting modulation of cellular functions and resolution of lung fibrosis. Furthermore, a significant decrease in FoxO3a and TGF-β gene expressions was observed upon resveratrol administration thereby downregulating pro-fibrotic pathway. ConclusionsThe present study demonstrates resveratrol treatment stabilizes SIRT1 gene expression by attenuating miR-212-3p in DE-exposed mice, leading to downregulation of TGF-β and FoxO3a expressions. The study highlights the therapeutic role of resveratrol in the treatment of DE-induced pulmonary fibrosis.

The Effectiveness of Supplementation with Key Vitamins, Minerals, Antioxidants and Specific Nutritional Supplements in COPD-A Review.

Currently, an increasing amount of evidence supports the notion that vitamins C, D and E, carotenoids, and omega-3 fatty acids may protect against the progression of chronic respiratory diseases. Although chronic obstructive pulmonary disease (COPD) primarily affects the lung, it is often accompanied by extrapulmonary manifestations such as weight loss and malnutrition, skeletal muscle dysfunction, and an excess of harmful oxidants, which can lead to a decline in quality of life and possible death. Recently, the role of various vitamins, minerals, and antioxidants in mitigating the effects of environmental pollution and smoking has received significant attention. Therefore, this review evaluates the most relevant and up-to-date evidence on this topic. We conducted a literature review between 15 May 2018 and 15 May 2023, using the electronic database PubMed. Our search keywords included COPD, chronic obstructive pulmonary disease, FEV1, supplementation: vitamin A, vitamin D, vitamin E, vitamin C, vitamin B, omega-3, minerals, antioxidants, specific nutrient supplementations, clinical trials, and randomized controlled trials (RCTs). We focused on studies that measured the serum levels of vitamins, as these are a more objective measure than patient self-reports. Our findings suggest that the role of appropriate dietary supplements needs to be reconsidered for individuals who are predisposed to or at risk of these conditions.

Macrophage-derived exosomal TNF-α promotes pulmonary surfactant protein expression in PM2.5-induced acute lung injury

Short-term high-concentration exposure to airborne fine particulate matter (PM2.5) is strongly associated with the risk of acute lung injury (ALI). It has been recently reported that exosomes (Exos) involve in the progression of respiratory diseases. However, the molecular mechanisms by which exosome-mediated intercellular signaling exacerbate PM2.5-induced ALI remains largely unaddressed. In the present study, we firstly investigated the effect of macrophage-derived exosomal tumor necrosis factor α (TNF-α) on pulmonary surfactant proteins (SPs) expression in epithelial MLE-12 cells after PM2.5 exposure. The higher levels of exosomes in the bronchoalveolar lavage fluid (BALF) of PM2.5-induced ALI mice were found. BALF-exosomes significantly up-regulated SPs expression in MLE-12 cells. Moreover, we found that remarkably high expression of TNF-α in exosomes secreted by PM2.5-treated RAW264.7 cells. Exosomal TNF-α promoted thyroid transcription factor-1 (TTF-1) activation and SPs expression in MLE-12 cells. Furthermore, intratracheal instillation of macrophage-derived TNF-α-containing exosomes increased epithelial cell SPs expression in the lungs of mice. Taken together, these results suggest that macrophages-secreted exosomal TNF-α can trigger epithelial cell SPs expression, which provides new insight and potential target in the mechanism of epithelial cell dysfunction in PM2.5-induced ALI.

The associations between gut microbiota and chronic respiratory diseases: a Mendelian randomization study.

Growing evidence indicates that variations in the composition of the gut microbiota are linked to the onset and progression of chronic respiratory diseases (CRDs), albeit the causal relationship between the two remains unclear. We conducted a comprehensive two-sample Mendelian randomization (MR) analysis to investigate the relationship between gut microbiota and five main CRDs, including chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), sarcoidosis, and pneumoconiosis. For MR analysis, the inverse variance weighted (IVW) method was utilized as the primary method. The MR-Egger, weighted median, and MR-PRESSO statistical methods were used as a supplement. To detect heterogeneity and pleiotropy, the Cochrane and Rucker Q test, MR-Egger intercept test, and MR-PRESSO global test were then implemented. The leave-one-out strategy was also applied to assess the consistency of the MR results. Based on substantial genetic data obtained from genome-wide association studies (GWAS) comprising 3,504,473 European participants, our study offers evidence that several gut microbial taxa, including 14 probable microbial taxa (specifically, 5, 3, 2, 3 and 1 for COPD, asthma, IPF, sarcoidosis, and pneumoconiosis, respectively) and 33 possible microbial taxa (specifically, 6, 7, 8, 7 and 5 for COPD, asthma, IPF, sarcoidosis, and pneumoconiosis, respectively) play significant roles in the formation of CRDs. This work implies causal relationships between the gut microbiota and CRDs, thereby shedding new light on the gut microbiota-mediated prevention of CRDs.

P203 Volatile organic compounds in adults with cystic fibrosis by real-time proton-transfer reaction mass spectrometry

To study of exhaled volatile organic compounds (eVOCs) as diagnostic markers, assessment of the progression of respiratory diseases is becoming more widespread. Due to its noninvasive character, detection of eVOCs with a using real-time proton mass spectrometry of exhaled air (PTR-MS) in patients with cystic fibrosis (CF) seems to be particularly attractive.

A One Health review of aerodigestive disease in dogs

This review article seeks to define and describe aerodigestive disease in dogs, and review current and emerging methods of diagnostic evaluation.Aspiration of gastric contents into the respiratory tract is associated with the development and progression of numerous respiratory diseases in humans. In veterinary medicine the term "aspiration" is considered synonymous with "aspiration pneumonia" which, while frequently encountered, does not accurately reflect the breadth of aspiration associated respiratory syndromes (AARS). In the clinical veterinary literature, the effect of alimentary dysfunction on respiratory disease and vice versa (aerodigestive disease) is rarely investigated despite evidence in the human literature, animal models, and some studies and case reports linking alimentary and respiratory disease in small animals. Current methods of investigating aerodigestive diseases in veterinary patients are limitedbyinadeqatesensitivityorspecificity, potential for bias, cost, and availability. This necessitates investigations into advanced diagnostics to identify potentially underrecognized animals with AARS. Additionally, similarities in anatomy, physiology, and several disorders between dogs and humans, make experimental and naturally occurring canine modelsofAARS integral to translational research. Thus, evaluating dogs with aerodigestive disease might represent an area of substantial clinical relevance in human as well as veterinary medicine.

Additive value of lung ultrasound to clinical parameters for prognosticating COVID-19.

The inclusion of LUS with simple, point-of-care clinical parameters have potential to improve COVID-19 prognostication above that from standard clinical care delivery. https://bit.ly/3InePYK.

Interactions between extracellular vesicles and microbiome in human diseases: New therapeutic opportunities.

In recent decades, accumulating research on the interactions between microbiome homeostasis and host health has broadened new frontiers in delineating the molecular mechanisms of disease pathogenesis and developing novel therapeutic strategies. By transporting proteins, nucleic acids, lipids, and metabolites in their versatile bioactive molecules, extracellular vesicles (EVs), natural bioactive cell-secreted nanoparticles, may be key mediators of microbiota-host communications. In addition to their positive and negative roles in diverse physiological and pathological processes, there is considerable evidence to implicate EVs secreted by bacteria (bacterial EVs [BEVs]) in the onset and progression of various diseases, including gastrointestinal, respiratory, dermatological, neurological, and musculoskeletal diseases, as well as in cancer. Moreover, an increasing number of studies have explored BEV-based platforms to design novel biomedical diagnostic and therapeutic strategies. Hence, in this review, we highlight the recent advances in BEV biogenesis, composition, biofunctions, and their potential involvement in disease pathologies. Furthermore, we introduce the current and emerging clinical applications of BEVs in diagnostic analytics, vaccine design, and novel therapeutic development.

The association between respiratory diseases and periodontitis: A systematic review and meta-analysis.

To evaluate (1) whether periodontitis has an influence on the prevalence/incidence of respiratory diseases (chronic obstructive pulmonary disease [COPD], asthma, community-acquired pneumonia [CAP], obstructive sleep apnoea [OSA] and COVID-19), and (2) what is the impact of periodontal therapy on the onset or progression of respiratory diseases. An electronic search was performed on Pubmed, Cochrane Library and Scopus databases up to October 2021, to identify studies answering the PECOS and PICOS questions. Seventy-five articles were selected. Meta-analyses identified statistically significant associations of periodontitis with COPD (nstudies = 12, odds ratio [OR]=1.28, 95% confidence interval [CI] [1.16; 1.42], p< .001), and OSA (ns = 6, OR=1.65, 95% CI [1.21; 2.25], p= .001), but not for asthma (ns = 9, OR=1.53, 95% CI [0.82; 2.86], p= .181). For acute conditions, two studies were found for CAP, while for COVID-19, significant associations were found for the need of assisted ventilation (ns = 2, OR=6.24, 95% CI [2.78; 13.99], p< .001) and COVID-related mortality (ns = 3, OR=2.26, 95% CI [1.36, 3.77], p= .002). Only four intervention studies were found, showing positive effects of periodontal treatment on COPD, asthma and CAP. A positive association between periodontitis and COPD, OSA and COVID-19 complications has been found, while there is a lack of intervention studies.

Diffuse lung involvement in rheumatoid arthritis: a respiratory physician's perspective.

The lungs are one of the most common extra-articular organs involved in rheumatoid arthritis (RA), which is reported to occur in up to 60% to 80% of RA patients. Respiratory complications are the second leading cause of death due to RA. Although there is a wide spectrum of RA-associated respiratory diseases, interstitial lung disease is the most common manifestation and it impacts the prognosis of RA. There has been progress in understanding the management and progression of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and RA-associated respiratory diseases recently, for example, opportunistic pulmonary infectious diseases and toxicity from RA therapies. From a chest physicians' perspective, we will update the diagnosis and treatment of RA-associated ILD, methotrexate-associated lung disease, and the complication of Pneumocystis jiroveci pneumonia in RA in this review.

Non-Coding RNAs in Pulmonary Diseases: Comparison of Different Airway-Derived Biosamples.

Due to their structural conservation and functional role in critical signalling pathways, non-coding RNA (ncRNA) is a promising biomarker and modulator of pathological conditions. Most research has focussed on the role of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). These molecules have been investigated both in a cellular and an extracellular context. Sources of ncRNAs may include organ-specific body fluids. Therefore, studies on ncRNAs in respiratory diseases include those on sputum, bronchoalveolar lavage fluid (BALF) and exhaled breath condensate (EBC). It is worth identifying the limitations of these biosamples in terms of ncRNA abundance, processing and diagnostic potential. This review describes the progress in the literature on the role of ncRNAs in the pathogenesis and progression of severe respiratory diseases, including cystic fibrosis, asthma and interstitial lung disease. We showed that there is a deficit of information on lncRNAs and circRNAs in selected diseases, despite attempts to functionally bind them to miRNAs. miRNAs remain the most well-studied, but only a few investigations have been conducted on the least invasive biosample material, i.e., EBC. To summarise the studies conducted to date, we also performed a preliminary in silico analysis of the reported miRNAs, demonstrating the complexity of their role and interactions in selected respiratory diseases.

Research status and prospects of indoor airborne microbiome based on respiratory health effects

<p indent="0mm">Indoor environment is an important repository of microbiome. Environmental microbiome can influence immune protection through changing the commensal flora of the respiratory tract. The interaction between environment airborne microbiome and human microbiome contributes to human microbial diversity, provides immunomodulatory effects, and thus reduces the risk of respiratory diseases. Lack of immune modulation acquired through microbial exposure may lead to risk of chronic respiratory diseases. Clinical parameters, such as susceptibility, progression, and severity of respiratory disease, are associated with microbial changes. Chronic obstructive pulmonary disease, cystic fibrosis, asthma, and lung cancers are associated with airway microbial dysbiosis. The changes of microbiome during the disease period are mainly characterized by a decrease in overall bacterial diversity, a decrease in the number of commensal bacteria, and an increase in the number of potential pathogenic bacteria. Based on the perception that pathogenic or conditional pathogenic microbiome is responsible for the infection and transmission of respiratory and non-respiratory diseases, public health policies have long favored keeping indoors at lower concentrations of microbiome or even absolutely sterile. However, in the past decade, an in-depth understanding of the microbiology of the environment and human health has shifted researchers’ view of indoor microbiome from a purely pathogenic and infectious negative role to a potentially protective, preventive positive role. Facing with the dual health effects of indoor airborne microbiome, the ideal control strategy should be to increase the microbial diversity and the proportion of beneficial microbiome, while reducing the concentration of pathogenic microbiome for regions, seasons, and sensitive populations. However, there is still no paradigm shift in built environment microbiology due to technical bottlenecks that prevent researchers from establishing a causal relationship between indoor microbiome and health effects. Currently, the types and properties of indoor airborne microbiome are yet to be fully screened and understood. The characteristics of indoor microbiome when they exert health effects are yet to quantify, including microbial metabolization and reproduction in the respiratory tract, corresponding protective effects, and dose-response effects and individual variation in health effects. The answer to the question “What is a healthy indoor air microbial environment”, that is, the characterization of indoor airborne microbiome based on respiratory health effects, is hindered by respiratory microbial sampling, in-depth analysis of microbial data, and the accuracy of <italic>in vitro</italic> experiments. Subsequent research needs to focus on the development of the following techniques: Microbial sampling tools with low invasiveness, high efficiency and low cost; statistical tools with complex source identification, interference factor quantification and causal relationship judgment functions; and experimental tools capable of simulating real, complex respiratory environments and revealing molecular mechanisms of action <italic>in vivo</italic>. “What is a healthy indoor air microbial environment” will gradually become clear as these questions are resolved. A clear and quantitative mechanism will serve as a scientific basis to guide the improvement of indoor microbial control standards and the rational use of practical interventions.