Causal associations between gut microbiota, metabolites and asthma: a two-sample Mendelian randomization study.

BACKGROUND: While several traditional observational studies have suggested associations between gut microbiota and asthma, these studies are limited by factors such as participant selection bias, confounders, and reverse causality. Therefore, the causal relationship between gut microbiota and asthma remains uncertain. METHODS: We performed two-sample bi-directional Mendelian randomization (MR) analysis to investigate the potential causal relationships between gut microbiota and asthma as well as its phenotypes. We also conducted MR analysis to evaluate the causal effect of gut metabolites on asthma. Genetic variants for gut microbiota were obtained from the MiBioGen consortium, GWAS summary statistics for metabolites from the TwinsUK study and KORA study, and GWAS summary statistics for asthma from the FinnGen consortium. The causal associations between gut microbiota, gut metabolites and asthma were examined using inverse variance weighted, maximum likelihood, MR-Egger, weighted median, and weighted model and further validated by MR-Egger intercept test, Cochran's Q test, and "leave-one-out" sensitivity analysis. RESULTS: We identified nine gut microbes whose genetically predicted relative abundance causally impacted asthma risk. After FDR correction, significant causal relationships were observed for two of these microbes, namely the class Bacilli (OR = 0.84, 95%CI = 0.76-0.94, p = 1.98 × 10-3) and the order Lactobacillales (OR = 0.83, 95%CI = 0.74-0.94, p = 1.92 × 10-3). Additionally, in a reverse MR analysis, we observed a causal effect of genetically predicted asthma risk on the abundance of nine gut microbes, but these associations were no longer significant after FDR correction. No significant causal effect of gut metabolites was found on asthma. CONCLUSIONS: Our study provides insights into the development mechanism of microbiota-mediated asthma, as well as into the prevention and treatment of asthma through targeting specific gut microbiota.

Association between n-3 PUFA and lung function: results from the NHANES 2007-2012 and Mendelian randomisation study.

This study aimed to investigate the association between n-3 PUFA and lung function. First, a cross-sectional study was conducted based on the National Health and Nutrition Examination Survey (NHANES) 2007-2012 data. n-3 PUFA intake was obtained from 24-h dietary recalls. A multivariable linear regression model was used to assess the observational associations of n-3 PUFA intake with lung function. Subsequently, a two-sample Mendelian randomisation (MR) was performed to estimate the potential causal effect of n-3 PUFA on lung function. Genetic instrumental variables were extracted from published genome-wide association studies. Summary statistics about n-3 PUFA was from UK Biobank. Inverse variance weighted was the primary analysis approach. The observational study did not demonstrate a significant association between n-3 PUFA intake and most lung function measures; however, a notable exception was observed with significant findings in the highest quartile for forced vital capacity (FVC) and % predicted FVC. The MR results also showed no causal effect of circulating n-3 PUFA concentration on lung function (forced expiratory volume in one second (FEV1), ß = 0·01301, se = 0·01932, P = 0·5006; FVC, ß = -0·001894, se = 0·01704, P = 0·9115; FEV1:FVC, ß = 0·03118, se = 0·01743, P = 0·07359). These findings indicate the need for further investigation into the impact of higher n-3 PUFA consumption on lung health.

Omega-3 polyunsaturated fatty acids ameliorate PM2.5 exposure induced lung injury in mice through remodeling the gut microbiota and modulating the lung metabolism.

Short-term or long-term exposure to fine particulate matter (PM2.5) is related to increased incidences of respiratory diseases. This study aimed to investigate the influences of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) supplementation on oxidative stress, inflammation, lung metabolic profile, and gut microbiota in PM2.5-induced lung injury mice. Mice were divided into four groups (n = 15, per group): two unsupplemented groups, control group and PM2.5 group, and two supplemented groups with ω-3 PUFAs, ω-3 PUFAs group, and ω-3 PUFAs + PM2.5 group. Mice in the supplemented groups were placed on an ω-3 PUFAs-enriched diet (ω-3 PUFAs, 21 g/kg). During the 5th to 6th week of dietary supplementation, mice were exposed to PM2.5 by intra-tracheal instillation. ω-3 PUFAs ameliorate lung histopathological injury, reduce inflammatory responses and oxidative stress, affect lung metabolite profile, and modulate gut microbiota in PM2.5-induced lung injury mice. Thus, supplementary ω-3 PUFAs showed effectiveness in attenuation of PM2.5-induced lung injury, indicating that the interventions exhibited preventive and therapeutic potential.

Human host status inference from temporal microbiome changes via recurrent neural networks.

With the rapid increase in sequencing data, human host status inference (e.g. healthy or sick) from microbiome data has become an important issue. Existing studies are mostly based on single-point microbiome composition, while it is rare that the host status is predicted from longitudinal microbiome data. However, single-point-based methods cannot capture the dynamic patterns between the temporal changes and host status. Therefore, it remains challenging to build good predictive models as well as scaling to different microbiome contexts. On the other hand, existing methods are mainly targeted for disease prediction and seldom investigate other host statuses. To fill the gap, we propose a comprehensive deep learning-based framework that utilizes longitudinal microbiome data as input to infer the human host status. Specifically, the framework is composed of specific data preparation strategies and a recurrent neural network tailored for longitudinal microbiome data. In experiments, we evaluated the proposed method on both semi-synthetic and real datasets based on different sequencing technologies and metagenomic contexts. The results indicate that our method achieves robust performance compared to other baseline and state-of-the-art classifiers and provides a significant reduction in prediction time.

PM2.5 exposure perturbs lung microbiome and its metabolic profile in mice.

Fine particulate matter (PM2.5) have become a major public health concern because of their adverse effects on health. Lungs are considered the primary organ affected by PM2.5. In order to understand the mechanism underlying PM2.5-induced lung injury, 16S rRNA gene sequencing, and liquid chromatography-mass spectrometry (LC-MS) metabolomics analysis were conducted to investigate the impact of PM2.5 exposure on lung microbiome and its metabolic profile. Mice were exposed to PM2.5 through intratracheal instillation and a lung injury model was established. 16S rRNA gene sequencing indicated that PM2.5 exposure significantly altered the richness, evenness, and composition of the lung microbiome. Metabolomics profiling showed that the levels of lung metabolites were perturbed after PM2.5 exposure. The altered metabolites mainly belonged to metabolic pathways, such as the citrate cycle, glyoxylate and dicarboxylate metabolism, pyruvate metabolism, purine and pyrimidine metabolism, and valine, leucine, and isoleucine metabolism. The altered lung microbiota showed significant correlations with lung metabolites. The levels of fumaric acid negatively correlated with the relative abundance of Ruminococcaceae, Enterobacteriaceae, and Pseudomonadaceae. These results revealed that PM2.5 exposure not only significantly altered the lung microbiome composition but also perturbed a number of metabolites involved in diverse metabolic pathways. This study improves our understanding of the mechanism of lung injury after PM2.5 exposure.

Fibroblast growth factor 10 alleviates particulate matter-induced lung injury by inhibiting the HMGB1-TLR4 pathway.

Exposure to particulate matter (PM) is associated with increased incidence of respiratory diseases. The present study aimed to investigate the roles of fibroblast growth factor 10 (FGF10) in PM-induced lung injury. Mice were intratracheally instilled with FGF10 or phosphate-buffered saline at one hour before instillation of PM for two consecutive days. In addition, the anti-inflammatory impact of FGF10 in vitro and its effect on the high-mobility group box 1 (HMGB1)-toll-like receptor 4 (TLR4) pathway was investigated. It was found that PM exposure is associated with increased inflammatory cell infiltration into the lung and increased vascular protein leakage, while FGF10 pretreatment attenuated both of these effects. FGF10 also decreased the PM-induced expression of interleukin (IL)-6, IL-8, tumor necrosis factor-α and HMGB1 in murine bronchoalveolar lavage fluid and in the supernatants of human bronchial epithelial cells exposed to PM. FGF10 exerted anti-inflammatory and cytoprotective effects by inhibiting the HMGB1-TLR4 pathway. These results indicate that FGF10 may have therapeutic values for PM-induced lung injury.

Evidence for the critical role of the PI3K signaling pathway in particulate matter-induced dysregulation of the inflammatory mediators COX-2/PGE2 and the associated epithelial barrier protein Filaggrin in the bronchial epithelium.

Particulate matter (PM) is an environmental pollutant closely associated with human airway inflammation. However, the molecular mechanisms of PM-related airway inflammation remains to be fully elucidated. It is known that COX-2/PGE2 play key roles in the pathogenesis of airway inflammation. Filaggrin is a transmembrane protein contributing to tight junction barrier function. As such, Filaggrin prevents leakage of transported solutes and is therefore necessary for the maintenance of epithelial integrity. The objective of the present study was to investigate the regulatory mechanisms of COX-2/PGE2 and Filaggrin upon PM exposure both in vivo and in vitro. C57BL/6 mice received intratracheal instillation of PM for two consecutive days. In parallel, human bronchial epithelial cells (HBECs) were exposed to PM for 24 h. PM exposure resulted in airway inflammation together with upregulation of COX-2/PGE2 and downregulation of Filaggrin in mouse lungs. Corresponding dysregulation of COX-2/PGE2 and Filaggrin was also observed in HBECs subjected to PM. PM exposure led to the phosphorylation of ERK, JNK, and PI3K signaling pathways in a time-dependent manner, while blockade of PI3K with the specific molecular inhibitor LY294002 partially reversed the dysregulation of COX-2/PGE2 and Filaggrin. Moreover, pretreatment of HBECs with NS398, a specific molecular inhibitor of COX-2, and AH6809, a downstream PGE2 receptor inhibitor, reversed the downregulation of Filaggrin upon PM exposure. Taken together, these data demonstrated that the PI3K signaling pathway upregulated COX-2 as well as PGE2 and acted as a pivotal mediator in the downregulation of Filaggrin.

Fibroblast growth factor 10 protects against particulate matter-induced airway inflammatory response through regulating inflammatory signaling and apoptosis.

Chronic respiratory disorders are some of the most frequent and severe chronic diseases in China. Epidemiological research has shown that particulate matter (PM) is a risk factor and is closely correlated to the progression of numerous respiratory diseases. Fibroblast growth factor 10 (FGF10) is a mesenchymal-epithelial signaling messenger essential for the development and environmental stability of several tissues. Nevertheless, its role in PM-induced airway inflammation remains unclear. The present study aimed to explore the mechanisms underlying the FGF10-related slowing of lung injury and inflammation in vivo and in vitro, as well as the therapeutic potential of these phenomena. Mice were intraperitoneally injected with a vehicle (PBS) or FGF10 (0.5 mg/kg) at one hour before intratracheal treatment with vehicle (PBS) or PM (4 mg/kg) for two consecutive days. Human airway epithelial BEAS-2B cells were exposed to a vehicle (PBS) or FGF10 (10 ng/ml) in vitro at one hour prior to incubation with a vehicle or PM (200 ug/ml) for 24 hours. Then, the impact on inflammatory molecules was investigated. In vivo, it was found that FGF10 diminished the inflammatory cell aggregation and reduced the apoptosis. Interestingly, in the PM group, the level of FGF10 increased in the bronchoalveolar lavage fluid (BALF). However, the pre-treatment with FGF10 markedly impaired the PM-induced increase in IL-6, IL-8, TNF-α and PGE2 levels in BALF and the cell supernatant. In conclusion, the present findings indicate that FGF10 attenuates PM-induced airway inflammation by inhibiting apoptosis and inflammation. This may be exploited for the prevention and management of PM-induced airway inflammation.