Genetic Insights into the Gut-Lung Axis: Mendelian Randomization Analysis on Gut Microbiota, Lung Function, and COPD.

Background: Chronic obstructive pulmonary disease (COPD) is a respiratory disorder with a complex etiology involving genetic and environmental factors. The dysbiosis of gut microbiota has been implicated in COPD. Mendelian Randomization (MR) provides a tool to investigate causal links using genetic variants as instrumental variables. This study aims to employ MR analysis to explore the causal relationship between gut microbiota, lung function, and COPD. Methods: We utilized genome-wide association study (GWAS) data from MiBioGen, UK Biobank and FinnGen, which were related to gut microbial taxa, lung function parameters including forced vital capacity in one second (FEV1), forced vital capacity (FVC), and percentage of predicted FEV1 (FEV1%pred), as well as GWAS data for COPD. MR analysis was conducted to assess the causal effects of gut microbiota on lung function and the risk of COPD. Sensitivity analysis was utilized to examine the stability of the causal relationships. Multiple testing and reverse analysis were employed to evaluate the robustness of these relationships. Results: Using the IVW method, 64 causal correlations were identified. Through conducting sensitivity analysis, multiple testing, and reverse analysis, we identified 14 robust and stable causal relationships. The bacterial taxa that showed a positive association with lung function included Desulfovibrionaceae, Erysipelotrichales, Desulfovibrionales, Clostridiales, Clostridia, Deltaproteobacteria and Erysipelotrichia, while Selenomonadales and Negativicutes showed a negative association with lung function. The abundance of Holdemanella were positively correlated with the risk of COPD, while FamilyXIII exhibited a negative correlation with the risk of COPD. Conclusion: Several microbial taxa were discovered to have a positive causal correlation with lung function, offering potential insights into the development of probiotics. The presence of microbial taxa negatively correlated with lung function and positively correlated with COPD emphasized the potential impact of gut microbiota dysbiosis on respiratory health.

ROS induced the Rab26 promoter hypermethylation to promote cigarette smoking-induced airway epithelial inflammation of COPD through activation of MAPK signaling.

Cigarette smoking (CS) exposure-induced airway inflammatory responses drive the occurrence and development of emphysema and chronic obstructive pulmonary disease (COPD). However, its precise mechanisms have not been fully elucidated. In this study, we explore the role of Rab26 in CS exposure modulating the inflammatory response of airway epithelium and the novel mechanism of CS exposure regulation Rab26. These data showed that CS exposure and H2O2 (a type of ROS) suppressed the expression of Rab26 and increased the expression of DNMT3b in vivo and in vitro. GEO data analysis found the level of Rab26 was decreased in the lung tissue of COPD patients. CSE-induced ROS promoted DNA methylation of the Rab26 promoter and inhibited its promoter activity by elevating the DNMT3b level. Antioxidants N-Acetyl-l-cysteine (NAC), 5-Aza-2'-deoxycytidine (5-AZA) (DNA methylation inhibitor) and DNMT3B siRNA alleviated CSE's inhibitory effect on Rab26 expression in vitro. Importantly, NAC alleviated the improved expression of Rab26 and reduced DNMT3B expression, in the airway of smoking exposure as well as attenuated the inflammatory response in vivo. Overexpression of Rab26 attenuated CSE-induced production of inflammatory mediators through part inactivation of p38 and JNK MAPK. On the contrary, silencing Rab26 enhanced p38 and JNK activation and aggravated inflammatory response. These findings suggest that ROS-mediated Rab26 promoter hypermethylation is a critical step in cigarette smoking-induced airway epithelial inflammatory response. Restoring Rab26 in the airway epithelium might be a potential strategy for treating airway inflammation and COPD.

Prevention of exacerbation in patients with moderate-to-very severe COPD with the intent to modulate respiratory microbiome: a pilot prospective, multi-center, randomized controlled trial.

Introduction: Considering the role of bacteria in the onset of acute exacerbation of COPD (AECOPD), we hypothesized that the use of influenza-Streptococcus pneumoniae vaccination, oral probiotics or inhaled amikacin could prevent AECOPD. Methods: In this pilot prospective, muti-central, randomized trial, moderate-to-very severe COPD subjects with a history of moderate-to-severe exacerbations in the previous year were enrolled and assigned in a ratio of 1:1:1:1 into 4 groups. All participants were managed based on the conventional treatment recommended by GOLD 2019 report for 3 months, with three groups receiving additional treatment of inhaled amikacin (0.4 g twice daily, 5-7 days monthly for 3 months), oral probiotic Lactobacillus rhamnosus GG (1 tablet daily for 3 months), or influenza-S. pneumoniae vaccination. The primary endpoint was time to the next onset of moderate-to-severe AECOPD from enrollment. Secondary endpoints included CAT score, mMRC score, adverse events, and survival in 12 months. Results: Among all 112 analyzed subjects (101 males, 96 smokers or ex-smokers, mean ± SD age 67.19 ± 7.39 years, FEV1 41.06 ± 16.09% predicted), those who were given dual vaccination (239.7 vs. 198.2 days, p = 0.044, 95%CI [0.85, 82.13]) and oral probiotics (248.8 vs. 198.2 days, p = 0.017, 95%CI [7.49, 93.59]) had significantly delayed onset of next moderate-to-severe AECOPD than those received conventional treatment only. For subjects with high symptom burden, the exacerbations were significantly delayed in inhaled amikacin group as compared to the conventional treatment group (237.3 vs. 179.1 days, p = 0.009, 95%CI [12.40,104.04]). The three interventions seemed to be safe and well tolerated for patient with stable COPD. Conclusion: The influenza-S. pneumoniae vaccine and long-term oral probiotic LGG can significantly delay the next moderate-to-severe AECOPD. Periodically amikacin inhalation seems to work in symptomatic patients. The findings in the current study warrants validation in future studies with microbiome investigation.Clinical trial registration:https://clinicaltrials.gov/, identifier NCT03449459.

Optimizing inhalation therapy in the aspect of peak inhalation flow rate in patients with chronic obstructive pulmonary disease or asthma.

BACKGROUND: Pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs) are commonly used drug-delivering devices for patients with chronic airway diseases. Appropriate peak inhalation flow rate (PIFR) and inhaler technique is essential for effective therapy. We aimed at optimizing inhalation therapy through the analysis of PIFRs in patients with chronic obstructive pulmonary disease (COPD) or asthma as well as the effect of technique training using In-Check DIAL® to help patients to achieve their optimal inspiratory flow rates. METHODS: The study continuously enrolled patients who were diagnosed as COPD or asthma from respiratory clinics. PIFRs were described and analyzed between the newly-diagnosed and follow-up patients, and the stable and acute exacerbation patients, respectively. Every participant was trained inhaler technique using In-Check DIAL®. PIFRs before and after training was compared by self-control analysis. RESULTS: Among a total of 209 patients, the average age was 56.9 years. For DPIs users, 10.8% patients had a PIFR < 30 L/min and 44.1% patients had a PIFR ≥ 60 L/min before technique training. After technique training, scarcely patient (1.5%) had a PIFR < 30 L/min, and 60.5% patients had a PIFR ≥ 60 L/min. The patient's average PIFR increased by 5.6L/min after training. The increase in PIFR before and after training was significant (p < 0.001) for most patients, but no significant variation was found in patients with acute exacerbation (p = 0.822). CONCLUSIONS: A considerable number of patients with COPD or asthma were not able to achieve the minimum or optimal PIFR for DPIs. Inhaler training can increase patients' PIFRs and improve their ability to use DPIs. Trail registration The study has registered in chictr.org.cn (ChiCTR1900024707) and been approved by the Ethics Committee of Zhongshan Hospital of Fudan University (B2019-142).

Predictors of acute cardiovascular events following acute exacerbation period for patients with COPD: a nested case-control study.

BACKGROUND: It has been noted that there is an increase in the incidence of acute cardiovascular events (CVEs) in patients with chronic obstructive pulmonary disease (COPD) during an acute exacerbation (AE), thereby causing increased inpatient mortality. Thus, we have tried to identify predictors of acute CVEs in patients with AECOPD via a nested case-control study. METHODS: A total of 496 cases hospitalized for AECOPD were included in this study, and followed-up for up to 6 months after discharge. Acute CVEs in the AE period were defined as a new or worsening acute coronary syndrome (ACS), arrhythmia, or left ventricular disfunction (LVD). Predictors of CVEs were selected from several variables, including baseline characteristics and treatments in the stable period as well as symptoms, laboratory tests, complications and treatments in the AE period. RESULTS: Thirty cases (6.05%) had acute CVEs, namely 2 had ACS, 13 had LVD and 19 experienced some form of arrhythmia. Four deaths were observed in the CVE group, with significantly increased death risk compared with the non-CVE group (P = 0.001, OR = 5.81). Moreover, patients who had CVEs were more prone to have re-exacerbation within 3 months. Multivariate analysis showed that previous LVD history (P = 0.004, OR = 5.06), 20% increase in heart rate (HR) (P = 0.003, OR = 10.19), electrolyte disturbance (P = 0.01, OR = 4.24) and diuretics (P = 0.002, OR = 6.37) were independent predictors of CVEs. In addition, usage of theophylline, fluoroquinolone and inhaled beta agonists in the AE period were not statistically associated with acute CVEs. CONCLUSIONS: Our preliminary study indicates that patients hospitalized for AECOPD with previous LVD history or increased HR need close observation and diuretics should be cautiously used with regular electrolyte monitoring. These findings need to be confirmed in a large cohort.

Prevention of Acute Exacerbation in Subjects with Moderate-to-very Severe COPD by Modulating Lower Respiratory Microbiome: Protocol of a Prospective, Multicenter, Randomized Controlled Trial.

Background: COPD is a global respiratory disease that has produced a worldwide health care burden. Acute exacerbation of COPD (AECOPD) is the leading cause of death in patients with COPD and accounts for the majority of expenditure of COPD management. The colonization of potential pathogenic bacteria in the lower respiratory tract is an important cause of the acute exacerbation especially in patients with moderate and severe COPD. Some clinical studies have shown the potential of oral probiotics, aerosol-inhaled amikacin and combined vaccination to prevent AECOPD. Methods and Analysis: We hypothesize that patients with stable COPD will benefit from aerosol-inhaled amikacin, oral probiotics or combined vaccination in terms of preventing acute exacerbation of COPD, slowing the progression of the disease and improving their quality of life. The trial aimsto investigate the efficacy and safety of the above interventions to decolonize bacteria in the lower respiratory tract and prevent acute exacerbation of COPD. In the study, 144 patients with stable phase of moderate-to-very severe COPD will be recruited and randomized into aerosol-inhaled amikacin group, oral probiotics group, combined vaccination group and the control group at a 1:1:1:1 ratio. The primary outcome is time to the first COPD exacerbation. Other endpoints include colonization of potential pathogenic bacteria in induced sputum, microbiome in induced sputum, pulmonary function and symptoms of patients, inflammation level and adverse events, serious adverse events, and death.

Mediated Drug Release from Nanovehicles by Black Phosphorus Quantum Dots for Efficient Therapy of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is an intractable disease involving a sticky mucus layer and nanoagents with mucus-penetrating capability offer a new way to deliver drugs. However, drug release from nanovehicles requires optimization to enhance the therapeutic effects of COPD therapy. Herein, black phosphorus quantum dots (BPQDs) are combined with PEGylated chitosan nanospheres containing the antibiotic amikacin (termed PEG@CS/BPQDs-AM NPs). As a drug-delivery system, the hydrophilicity of PEG and positive charge of CS facilitate the penetration of nanovehicles through the mucus layer. The nanovehicles then adhere to the mucous membrane. Furthermore, the BPQDs degrade rapidly into nontoxic PO43- and acidic H+ , thereby promoting the dissociation of PEGylated CS nanospheres, accelerating the release of AM, decreasing the vitality of biofilms for ease of eradication. Our results reveal that drug delivery mediated by BPQDs is a feasible and desirable strategy for precision medicine and promising for the clinical therapy of COPD.