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Review

Air-Pollution-Mediated Microbial Dysbiosis in Health and Disease: Lung–Gut Axis and Beyond

by
Md Habibul Hasan Mazumder
1,2,3 and
Salik Hussain
1,2,4,*
1
Department of Physiology, Pharmacology & Toxicology, School of Medicine, West Virginia University, Morgantown, WV 26506, USA
2
Center for Inhalation Toxicology (iTOX), School of Medicine, West Virginia University, Morgantown, WV 26506, USA
3
Department of Pharmaceutical and Pharmacological Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26506, USA
4
Department of Microbiology, School of Medicine, West Virginia University, Morgantown, WV 26506, USA
*
Author to whom correspondence should be addressed.
J. Xenobiot. 2024, 14(4), 1595-1612; https://doi.org/10.3390/jox14040086
Submission received: 13 August 2024 / Revised: 14 October 2024 / Accepted: 16 October 2024 / Published: 21 October 2024
(This article belongs to the Topic Disease Risks and Toxic Pathway from Environmental Chemical Exposure)
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Abstract

:
Growing evidence suggests physiological and pathological functions of lung and gut microbiomes in various pathologies. Epidemiological and experimental data associate air pollution exposure with host microbial dysbiosis in the lungs and gut. Air pollution through increased reactive oxygen species generation, the disruption of epithelial barrier integrity, and systemic inflammation modulates microbial imbalance. Microbiome balance is crucial in regulating inflammation and metabolic pathways to maintain health. Microbiome dysbiosis is proposed as a potential mechanism for the air-pollution-induced modulation of pulmonary and systemic disorders. Microbiome-based therapeutic approaches are increasingly gaining attention and could have added value in promoting lung health. This review summarizes and discusses air-pollution-mediated microbiome alterations in the lungs and gut in humans and mice and elaborates on their role in health and disease. We discuss and summarize the current literature, highlight important mechanisms that lead to microbial dysbiosis, and elaborate on pathways that potentially link lung and lung microbiomes in the context of environmental exposures. Finally, we discuss the lung–liver–gut axis and its potential pathophysiological implications in air-pollution-mediated pathologies through microbial dysbiosis.

Graphical Abstract

1. Introduction

According to the World Health Organization, approximately 99% of the world’s population breathes unhealthy levels of air pollutants [1]. The air-pollution-related diseases cause 7.2 million premature deaths worldwide, making air pollution a major environmental health risk [2,3]. Poor air quality is associated with idiopathic pulmonary fibrosis [4], hypersensitivity pneumonitis [5], and chronic obstructive pulmonary disease [6]. Moreover, epidemiological evidence also suggests an association between chronic gastrointestinal diseases, such as gastrointestinal cancer [7] and inflammatory bowel disease [8] and air pollution. Moreover, it has been associated with impaired respiratory function, lung development, and inflammation [9,10,11].
Air pollution is a mixture of substances, including particulate matter (PM) and gases [12]. PM is a heterogeneous mixture of metals, ions, organic matter, polycyclic aromatic hydrocarbons, sulfates, and nitrates [13]. Meanwhile, carbon dioxide, carbon monoxide, sulfur dioxide, and ozone are the most common gases in air pollution [14]. Air pollutants are mostly generated from atmospheric oxidation reactions [15], the combustion of fossil fuels [16], industrial emissions [17], and agricultural emissions [18]. Epidemiological studies demonstrate a correlation between air pollution exposure and mortality, morbidity, and a decrease in life expectancy in human cohorts [19,20,21]. Several studies demonstrate the deleterious effects of air pollution on host immunity and microbiome [13,22,23,24,25].
Microbiota specifies the microbial community comprising bacteria, fungi, archaea, and viruses associated with the host, and the total genome of this community is known as the microbiome [26,27]. The microbiome has a crucial role in regulating inflammation and metabolic pathways, thus maintaining health. The community profiles and the composition of the microbiome differ between individuals and are influenced by environmental and host-associated factors (lifestyle, food, habitat, etc.). A delicate balance between host and microbial populations is crucial. This balance plays a vital role in the development and functioning of the immune response, growth, digestion, and neural development [28]. A shift in the balance of the microbial communities makes the host prone to pathogenic invasion and, thus, disease. Microbial dysbiosis refers to an alteration in microbial composition from optimal in a specific niche [29,30]. The composition and function of the microbiome varies based on location and disease status. The lung, which was previously thought of as a sterile organ, has a unique microbial signature compared to the gut [31]. In the lungs, microbiota regulates defense against pathogenic infiltration [32]. In the gut, microbiota helps to maintain gut immunity, motility, and intestinal barrier permeability [33,34], whereas, in the liver, microbes regulate metabolism to reduce enterotoxicity [35,36]. Several studies found that respiratory and GI tract microbiomes communicate and influence each other [37,38]. Thus, it is important to understand the communication between the lungs and the gut to alleviate pollution-mediated negative health impacts in these organs. Moreover, manipulating the microbiome to support healthy microbial composition and intestinal health could have added value in promoting lung health. Balance in microbiomes and different factors influencing microbiome dysbiosis and vice versa is presented in Figure 1.
The human microbiome comprises nearly 100 trillion microbes that are mostly bacteria and to a lesser extent protozoa, archaea, fungi, and viruses [39]. The composition of the microbiome differs depending on the site and age. Corynebacteria, Streptococcus, Prevotella, Haemophilus, Rothia, and Fusobacterium are the prominent microbiome in the oral cavity and oropharynx [40,41]. The respiratory tract microbiome is mostly comprised of Prevotella, Neisseria, Haemophilus, Fusobacterium, and Streptococcus [42], whereas the gut microbiome contains Actinobacteria, Fusobacteria, Proteobacteria, Firmicutes, and Bacteroidetes [43]. A list of bacterial communities based on the body site is presented in Table 1.

2. Respiratory Microbiome

The Human Microbiome Project (HMP) was started in 2007 to study the diversity, function and categories of the human microbiome [44]. Yet, upon HMP initiation, lungs were not sampled believing that healthy lungs are sterile. Metagenomics and 16 s ribosomal RNA sequencing by next-generation sequencing (NGS) led to the frequent detection of bacterial communities in lungs [45].
The respiratory tract microbiome varies with anatomy and physiology. The oral cavity contains Prevotella, Streptococcus, Veillonella, Fusobacterium, Corynebacteria, Haemophilus, and Neisseria [46]. The upper respiratory tract contains Staphylococcus, Propionibacterium, Prevotella, Leptotrichis, Dolosigranulum, Veillonella, Rothia, Corynebacterium, Moraxella, Streptococcus, and Haemophilus [47,48]. The resident upper airway microbiome is the main source of the lower airway microbiota. It has been proposed that bacteria may reach LRT through oropharyngeal secretion, micro-aspiration, or direct inhalation [49]. LRT mostly harbors Streptococcus, Veillonella, Prevotella, Acidobacteria, and Actinobacteria [40,50].

2.1. Characteristics of the Respiratory Microbiome

The microbial composition of the lungs is heterogeneous and changes in response to physiological conditions. The crosstalk between microbial immigration, elimination, and relative production determines the load of microbiome in the lungs [51,52]. In the lungs, the prominent phyla are Firmicutes, Proteobacteria, Bacteroidetes, and Actinobacteria. The most common genera are Veillonella, Fusobacterium, Prevotella, Streptococcus, Porphyromonas, and Neisseria [53]. The microbiome composition is significantly changed by the host’s disease status. Table 2 presents a summary of microbiota in different disease states.

2.2. Air Pollution and Respiratory Microbiome

Air pollution can have a direct (through the physical interaction of pollutants and microbes) and/or indirect impact (through the induction of inflammation and oxidant stress) on the respiratory microbiome [63]. Research findings for both human and animal models are summarized in Table 3 and Table 4. The analysis of saliva and sputum samples demonstrated higher alpha diversity indices in highly polluted areas [64]. Throat swab samples from 114 individuals demonstrated a positive correlation between polluted air and the relative abundance of Actinobacteria and Proteobacteria [65]. Another study demonstrated that the abundance of Streptococcus and Neisseria significantly increased in air-pollution-exposed subjects [66]. Indoor/household air pollution reduced alpha diversity and Betaproteobacteria abundance and increased Fusobacteria in the sputum microbiome [67]. Controlled ozone exposure in young adults reduced alpha diversity and the abundance of Actinobacteria and Firmicutes, whereas it increased Moraxellaceae and Pseudomonadaceae [68]. This demonstrates a complex relationship between pollution and microbial changes in the host. An increased level of PM correlates with the increased relative abundance of Staphylococcus, Hemophilus, Streptococcus, and Moraxella [69]. Additionally, greater bacterial load is associated with impaired respiratory function and with increases in Streptococcus, Prevotella, Neisseria, and Fusobacterium [70]. In another study, PM2.5 and PM10 exposure in healthy subjects was inversely correlated with Shannon, Chao1, and PD_Whole_Tree alpha diversity indices and reduced the abundance of Actinobacteria and Proteobacteria [71]. In lung cancer patients, a low alpha diversity correlated with low PM10, while Legionella and Thermus abundance had a positive association with PM10 exposure [72]. Moreover, increased bacterial abundance was found in the saliva samples of asthmatic children. Additionally, a significant negative association between microbial indices (species richness and observed species) and short-term PM2.5 or ozone exposure in asthmatic children was reported [73]. These studies demonstrated that alteration in the microbial composition depends on several factors such as host site, the type of exposure, the route of exposure, etc.
Several animal models were also investigated in addition to human studies to evaluate the effect of air pollution on the respiratory microbiome. A reduced Shannon, Fisher, and observed ASV index, a higher abundance of Firmicutes, and reduced Bacteroidetes and Fusobacteria were observed in the bronchoalveolar lavage from PM2.5 exposed Balb/c male mice [76]. Ambient PM2.5 exposure resulted in a decreased Lachnospiraceae and Psuedomonadaceae in the lungs of nuclear factor E2-related factor 2 knock-out (Nrf-2 KO) mice [77]. A similar study on traffic-generated emissions also found an increase in Proteobacteria in the lung homogenates and a decrease in the alpha diversity index [78,79].
In contrast, PM2.5 exposure in mice increased alpha diversity, Bacteroidetes, and Cyanobacteria abundance. In addition, alterations in serum and BALF cytokine levels (IL-17, IL-6, IL-1b, and TNF-alpha) were also reported [77]. Similarly, an increase in bacterial relative abundance, Chao1, observed species index, and Proteobacteria abundance have also been reported in rat lungs [80]. Daniel et al. reported an increase in Proteobacteria and a reduction in Firmicutes and Bacteroidetes in a model of DEP combined with diet manipulation [78]. Collectively, these studies indicated a unique and bi-directional relationship between air pollution exposure and lung microbiome change.
Table 4. Animal studies performed on air pollution and microbial respiratory dysbiosis.
Table 4. Animal studies performed on air pollution and microbial respiratory dysbiosis.
Study PopulationExposureSample TypeResults Summary
BALB/c mice, male [76]PM2.5Bronchoalveolar lavageShannon ↓, observed ASV ↓, Fisher ↓,
weighted UniFrac (+)
C57BL/6 mice, male [77]PM2.5Lung tissueShannon ↓, Simpson ↓
C57BL/6N mice, male [81]PM2.5Bronchoalveolar lavage(+) Serum and BALF: IL-1B, IL-6, IL-17, TNF-a,
Simpson ↑, Shannon ↑, ACE ↑, Chao1 ↑,
metabolic pathway alteration (+)
C57BL/6 mice, male [82]Carbon black, ozone, CB + O3Lung tissueNeutrophils ↑, eosinophils ↑,
Shannon ↓, total bacterial load ↓
Fischer 344 rat, male [83]TRAPLung tissueLung function ↓: PEF, FVC, FEV
Sprague Dawley rats, male [80]Biomass fuel, motor vehicle exhaustBronchoalveolar lavageBALF macrophage ↑, IgA ↑, IgG ↓,
Out ↑, Chao1 ↑, PD whole tree ↑, observed species ↑
C57BL/6 mice, male [78]Diesel exhaust particleBronchoalveolar lavage↑ BALF: IgA, IgG; ↑ lung: TNF-a, IL-10
↑ increase in index, ↓ decrease in index, (+) positive correlation to exposure.
From all of the studies, we can conclude that microbial alterations in response to different air pollutants are inconsistent, although Staphylococcus, Hemophilus, Streptococcus, Neisseria, Moraxella, and Pseudomonas are commonly altered. Changes in the microbiome depend upon several factors, including but not limited to pollutant characteristics, the route of exposure, host body site, and exposure time. Nevertheless, research on the impacts of air pollution on airway microbiome and disease progression requires more focus.

3. Gut Microbiome

The microbiome in the gut is associated with energy metabolism, nutrition, physiology, gut barrier integrity, immune function, etc. [84]. In the human GI tract, Bacteroidetes and Firmicutes are the most prominent, though more than 50 phyla have been identified [85]. Due to physiological and structural dissimilarities, different parts of the gut harbor diverse bacterial populations, e.g., Bacteroides, Streptococcus, Enterococcus, Bifidobacterium, Lactobacillus, Clostridium, and Ruminococcus are mostly found in feces, whereas only Lactobacillus, Clostridium, and Enterococcus are detected in the gut microbiome [86].

Air Pollution and Gut Microbiome

The evaluation of the causal effect of air pollution (PM2.5, PM10, and NO2) indicated a significant correlation between particulate matter exposure and different diseases such as hypertension, obesity, and type 2 diabetes [23,87,88,89]. Gaseous or solid polycyclic aromatic hydrocarbon (PAH) exposure in 3 to 5-year-old children resulted in a positive correlation with a relative abundance of Bacteroidetes, Actinobacteria and Proteobacteria [90]. In another study, an increase in Firmicutes and Bacteroides was reported [91]. PM1 and PM2.5 exposure reduced the alpha diversity profile and showed a negative correlation with Firmicutes, Proteobacteria, and Verrucomicrobia abundance [88]. Another study on PM2.5 and PM10 showed no significant change in alpha diversity, although an increased abundance of Bifidobacteriaceae, Porphyromonadaceae, Rikenellaceae, and Streptococcaceae was observed [92]. Traffic-related air pollution (TRAP) reduced Bacteroidaceae and increased Coriobacteriaceae and was found to be correlated directly with the abundance of Actinobacteria and, inversely, with an abundance of Proteobacteria [93]. These studies showed that although the respiratory tract is the primary organ for pollution-mediated microbiome alteration, distal organs such as the gut can also be significantly impacted [83]. Human studies on the effects of air pollution on the gastrointestinal microbiome are presented in Table 5.
Studies in rodents reported that air pollution exposure, through inhalation or ingestion, can alter gut microbiota (Table 6). PM2.5 has been found to alter gut microbial diversity and induce an increased abundance in Escherichia, Parabacteroides, Oscillibacter, and Akkermansia [95]. Exposure to PM2.5 increased alpha diversity and beta diversity and is associated with an increased abundance of Bacteroidetes and a reduced abundance of Firmicutes [96]. Similarly, an increased abundance of Firmicutes and reduced Bacteroidetes, Cyanobacteria, and Proteobacteria was observed in Sprague Dawley rats exposed to PM2.5 [97]. This study also reported increased PM2.5 levels positively correlated with alpha and beta diversity alterations. A similar response was reported in Balb/c mice when exposed to PM2.5, although a decrease in the number of OTUs was observed [98]. In contrast, diesel exhaust particle (DEP) exposure in an apolipoprotein E knockout mice model resulted in a reduced Shannon and Simpson diversity index and increased the abundance of Roseburia, Helicobacter, and Rikenellaceae RC9 [99]. In another study, DEP exposure increased the abundance of Firmicutes and reduced Proteobacteria and Actinobacteria [79]. Similar to DEP exposure, exposure to concentrated ambient fine particulate matter (CAP) correlated with reduced alpha diversity, reduced Clostridium, Papillibacter, and Turibacter, and increased glucose intolerance and insulin resistance [100]. Distinct from particle exposure, gaseous exposure (nitric oxide) increased the abundance of Sphingomonas, Actinomarina, and Bradyrhizobium and decreased the abundance of Rothia, Turibacter, and Corynebacterium [101].
Taken collectively, all of these studies demonstrated an association between air pollution and gut microbiota; however, results vary greatly due to the varied composition of air pollutants, exposure route and duration, and the site of sample collection.

4. Potential Mechanism of Air-Pollution-Induced Respiratory Microbiome Dysbiosis

4.1. Alteration in Airway Physiological Environment

Exposure to air pollution alters the physiological environment of the airways, which is accompanied by an increase in oxidative stress and local inflammation accompanied by pH changes and local oxygenation [107,108]. Metabolites produced by microbes activate the NF-kB pathway through pattern recognition receptors to release pro-inflammatory cytokines. On the other hand, alveolar macrophages and T cells induce immune response by preventing bacterial overgrowth. Air pollution is reported to alter these interactions, thus leading to adverse effects on immune regulation [57,108]. Studies have also found that air pollution alters lactic acid, fumaric acid, and D-glyceric acid in the lungs, which are negatively correlated with the relative abundance of Enterobacteriaceae, Ruminococcaceae, and Pseudomonadacea [68,81].

4.2. Oxidative Stress

Oxidative stress responses can induce inflammation, cell death, and the generation of reactive oxygen species (ROS) and alter antimicrobial response [109]. PM contains organic and inorganic ROS-inducing components that can cause oxidative stress, leading to the destruction of epithelial and endothelial cells in the lungs and gut [110,111]. Free radicals generated by the RNS and ROS induce oxidation and damage in DNA strands and modify DNA repair proteins. Moreover, ROS also activate NFkB, which promotes epithelial–mesenchymal transition [112,113]. Cytokines (IL-33, IL-25, TSLP, and GM-CSF) produced by epithelial cells promote type 2 immune response by activating Th2 cells, macrophages, basophils, and eosinophils. Induced inflammatory response and increased ROS levels function in the disruption of cell–cell junctions, leading to the increased permeability of the epithelial barrier [114,115].

4.3. Disrupted Barrier Integrity

Epithelial barrier damage is one of the most common effects of air pollution. Airway epithelium acts as a physical and biological barrier between the outside environment and the intracellular compartment. It helps to maintain immune homeostasis and normal physiological functioning [116]. Epithelial barriers comprise three components: adherence junction, tight junction, and desmosomes. Pollutants disrupt barrier integrity by increasing inflammatory mediators and ROS, the dysregulation of transcription, and the expression of tight junctional markers like E-cadherin [117,118]. Studies have reported that PM can cause the degradation of junctional proteins via ROS production and impair lung function, facilitating bacterial invasion and dissemination in the blood [119]. Organic pollutants like PAH and inorganic materials (metals) in PM2.5 exposure have also been linked to inducing epithelial lesions by cytochrome p450 activation, the confluence of inflammatory cells, increased intestinal permeability, altered mucin production and secretion, and the decreased expression of the tight junctional protein, claudin-1, and desmosome [118,120,121]. Moreover, they also activated pathways (EGFR and ERK signaling), further destabilizing barrier integrity by disrupting tight junctions and adherence junctions. Pollutants also induced the release of amphiregulin and high-mobility group box 1 (HMGB1), which further promoted the breakdown of the barrier [122,123]. Therefore, the disruption of epithelial barrier integrity can result in altered immune homeostasis and induce inflammatory response, ROS production, microbial toxin, and LPS release in blood, thus leading to the initiation and aggravation of disease severity.

4.4. Disrupted Lipid Homeostasis and Systemic Inflammation

Lipids play an important role in regulating the inflammatory process through pro and anti-inflammatory lipid mediators. Alterations in lipid mediators have been linked to exacerbating systemic inflammation [124]. Zhivaki et al. [125] reported that air pollution is associated with elevated levels of blood lipid biomarkers, which potentially activate innate immune cells to initiate systemic pro-inflammatory response. The inflammatory response can also be induced by air pollution by facilitating the entry of pathogens into the systemic circulation. Such induction leads to the production and systemic release of inflammatory cytokines (TNF-alpha, IL-1b, and IL-6) [126]. This cumulatively contributes to the aggravated loss of barrier function, thus inducing systemic inflammation in distant organs [127].
In sum, the mechanisms that disrupt the microbiome in the lungs (and in the gut) are centered around central processes of redox imbalance and inflammation. These processes create changes in airway physiology and homeostasis, leading to an altered microenvironment in the lung airways and parenchyma that facilitate a disease phenotype. In the case of the gut, the central process seems to be altered intestinal barrier integrity, which facilitates the systemic manifestations of microbial dysbiosis.

5. Lung–Gut–Liver Axis

The lung–gut–liver axis pertains to the sequence of events in the lungs, gastrointestinal tract, and liver in conjunction with their role in the immune system, microbial regulation, and metabolic reaction [38,128]. The impacts of air pollutants on the microbiome can be direct or indirect. Air pollutants reach the gut mainly through ingestion to modify the microbiome [96,129]. Some active processes that follow the pulmonary deposition of air pollutants, such as an inflammatory response, redox imbalance, alteration in the airway microenvironment, disruption in air–blood barrier integrity, and changes in pulmonary lipid homeostasis can impact microbiome composition locally in the lungs and systemically. As such, the production of microbiota-derived signaling molecules (LPS, short-chain fatty acids—SCFAs) is altered in response to air pollution exposure, which disturbs immune response. Studies have found that Bacteroides spp. produced LPS-activated immune responses and were associated with autoimmune disease progression [130]. In addition, altered circulatory levels of microbiota-derived compounds can lead to systemic inflammation and distal organ dysfunction [131]. In the healthy state, SCFAs and microbe-associated molecular patterns (MAMPs) derived from gut microbiota maintain immune homeostasis by generating anti-inflammatory mediators, regulatory T cells, and IgA [132,133]. SCFAs and Toll-like receptors (TLR) together support the generation of tight junction proteins, which are important to maintain barrier integrity [134]. Moreover, G-protein coupled receptors (GPCRs) recognize SCFAs in the lungs, leading to anti-inflammatory effects and the regulation of epithelial cellular integrity in the lungs [37]. G proteins mediate their effects through the activation of mitogen-activated protein kinase (MAPK), phosphoinositide 3 kinase (PI3K), and mTOR [135]. Another mechanism of SCFA’s modulation of immune response is through the inhibition of histone deacetylase (HDAC). Moreover, SCFAs enter cells via passive diffusion or absorption and exert a suppressive effect through SLC5A8 (high-affinity Na+-coupled monocarboxylate transporter) or low-affinity H+ couple carrier SLC16A1 [87,136]. Air-pollution-induced alterations in microbial composition, SCFAs, MAMP levels, and ROS production induce pro-inflammatory response, disrupt lipid homeostasis, and destroy epithelial integrity, leading to barrier function loss (Figure 2) [37,129]. Bacteroides fragilis-derived polysaccharide A induces IL-10 production by T cells and protects chemically induced intestinal inflammatory response [137]. Moreover, some bacteria produce cell membrane components (e.g., sphingolipids) that decrease the number of natural killer T cells, which have been correlated with the development of colitis [138].
The gut microbiota depletion induced a significant increase in inflammatory response in the lung and a 30% increase in mortality in a pneumonia mouse model [139]. The gut microbiome increases lung inflammatory cell infiltration against bacterial challenge and induces neutrophil accumulation through TLR4 [140]. The depletion of the gut microbiome was found to reduce TGF-b and granulomas in the lung, indicating gut–lung communication and the role of microbial dysbiosis in disease pathology. This study also indicated gut alpha and beta diversity shifted due to carbon nanotube exposure in the lungs, showing a bidirectional relation [106]. Studies have also found a link between changes in gut and lung microbiome and liver metabolism alteration. This bidirectional communication integrates dietary, genetic, and environmental signals [141]. The dysregulation of gut microbiota can cause hepatic inflammation [142]. In the case of chronic liver disease and hepatic fibrosis, gut dysbiosis leads to reduced hepatic anti-inflammatory mechanism by increased TLR4 activation through the TGF-beta signaling pathway [143,144]. Bile acids derived from the liver function as a metabolic health gatekeeper can also regulate the composition and community profiling of the gut microbiome [145]. Similarly, the liver–lung axis is also reported to have a significant correlation [146,147,148]. All of these suggest that the lung, gut, and liver orchestrate a microbiome-mediated production of secondary substances to regulate immune-modulatory functions [128]. An overview of this pathway is presented in Figure 3.

6. Microbiome as a Therapeutic Approach and Target

The alteration of the microbiome is a powerful and innovative tool that can improve healthcare efficiency. Complementary biotic approaches (probiotics, prebiotics, and synbiotics) and fecal microbiota transplantation have been proposed to manipulate the microbiome [149]. Studies have shown that microbe-based therapies can alleviate the pathophysiological effects of allergic airway disease, ulcerative colitis, insulin resistance, type 2 diabetes, etc. [150,151]. Although promising results are observed in microbiome-based therapeutic approaches, there are several facets to altering bacterial community. These can be broadly combined into three categories: (1) the selection of the microbiome, (2) the analysis of the microbiota to harbor in a specific niche, and (3) balance between residing and newly introduced microbiomes [152]. First, the microbiome of healthy individuals serves as a prototype for selecting an ideal microbiome though age, sex, and epigenetic background have a strong role to play. Secondly, the recent advancement in sequencing and metabolomics helps to identify shifts in microbiome clustering patterns among healthy and diseased individuals [153]. Microbiome composition varies significantly based on the anatomical location; thus, the molecular and metabolic analysis of region-specific microbiome is important. Finally, the modified microbial community interacts with residing microbes and competes to adapt to the host environment. Thus, multi-omics comparisons are required to analyze hundreds of potential community interactions.

7. Conclusions and Future Perspectives

The influence of the microbiome on the host depends not only on the health status of the host but also on the microbiome function and composition, metabolites released by microbes, and local and systemic innate and adaptive immune responses of the host. The impact of air pollution exposure varies depending on pollutant composition, the origin of pollutants, exposure route, and host health status. Compelling evidence demonstrates a correlation between microbiome alterations and impaired lung function, lung development, immune modulation, and barrier function, especially in different diseases. While the literature points towards a strong association between microbial dysbiosis and air pollution exposure, further research should focus on whether dysbiosis is a cause of exposure-induced pathology or its consequence. An interesting unanswered question is whether environmental exposures have a unique dysbiosis signature or whether different pollutant exposures can be grouped based on their dysbiosis signature to streamline intervention approaches. Although this review describes potential interactions between the lung and gut microbiome, further research is warranted to elaborate mechanistic pathways. Overall, looking at the current reported literature, we identify that while this is an expanding field of research that has yielded very valuable insights into different physiological and pathological processes, studies reporting on microbiomes are not following a consensus approach for performing and reporting experimental findings. Several shortcomings that need to be addressed in future studies concerning microbiome and air pollution include the use of relevant models for exposure (e.g., realistic inhalation exposure), the use of environmental samples (e.g., PM2.5 collected from the air), the complete identification/reporting of not just bacterial but also viral and fungal microbiomes, reporting species level changes, and the need to go beyond the association of different exposures and changes in microbiome to causality relationships. In addition, clinical trials evaluating microbiome homeostasis and SCFA-mediated regulation can be of future importance. Finally, another critical need is to establish cellular mechanisms and processes that are directly vs. indirectly impacted by the microbiome. These studies are essential to establish the contributing role of the microbiome in the pathophysiology of different diseases and will enable the development of potential therapeutic strategies.

Author Contributions

M.H.H.M.: conceptualization, data collection, summarizing, and writing—original draft. S.H.: conceptualization, visualization, writing—original draft, reviewing, and editing, and funding acquisition. All authors have read and agreed to the published version of the manuscript.

Funding

This study was funded and supported by the National Institute of Health/NIEHS and funded by grants R01ES031253 (SH) and R01ES03125304S1 (SH).

Data Availability Statement

No new data was created, and data sharing does not apply to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

AJ—Adherent junction, ARDS—Acute respiratory distress syndrome, ASV—Amplicon sequence variants, ARI—Acuter respiratory infection, BALF—Bronchoalveolar lavage fluid, CAP—Concentrated ambient particulate matter, CCK—Cholecystokinin, CF—Cystic fibrosis, CFTR—Cystic fibrosis transmembrane conductance regulator, COVID—Corona virus disease, COPD—Chronic obstructive pulmonary disease, DC—Dendritic cells, DEP—Diesel exhaust particle, FEV—Forced expiratory volume, FMT—Fecal microbiota transplantation, FOS—Fructo oligosaccharide, FVC—Forced vital capacity, GI—Gastrointestinal tract, GLP—Glucagon like peptide, GOS—Galacto oligosaccharide, GPCR—G-protein coupled receptor, HMP—Human microbiome project, IBD—Inflammatory bowel disease, IBS—Irritable bowel syndrome, IL—Interleukin, IPF—Idiopathic pulmonary fibrosis, LPS—Lipopolysaccharide, LRT—Lower respiratory tract, MAMP—Microbe associated molecular pattern, MCT1—Monocarboxylate transporter1, NGS—Next generation sequencing, PAH—Polycyclic aromatic hydrocarbon, PM—Particulate matter, ppb—parts per billion, ROS—Reactive oxygen species, SCFA—Short chain fatty acid, SMCT1—Sodium coupled monocarboxylate transporter-1, TJ—Tight junction, TLR—Toll like receptor, TRAP—traffic-related air pollution, UC—Ulcerative colitis, URT—Upper respiratory tract, WHO—World Health Organization.

References

  1. Kelly, F.J.; Fussell, J.C. Air Pollution and Public Health: Emerging Hazards and Improved Understanding of Risk. Environ. Geochem. Health 2015, 37, 631–649. [Google Scholar] [CrossRef] [PubMed]
  2. Anderson, H.R. Air Pollution and Mortality: A History. Atmos. Environ. 2009, 43, 142–152. [Google Scholar] [CrossRef]
  3. Harrison, R.M. Airborne Particulate Matter. Philos. Trans. R. Soc. A 2020, 378, 20190319. [Google Scholar] [CrossRef] [PubMed]
  4. Liang, L.; Cai, Y.; Lyu, B.; Zhang, D.; Chu, S.; Jing, H.; Rahimi, K.; Tong, Z. Air Pollution and Hospitalization of Patients with Idiopathic Pulmonary Fibrosis in Beijing: A Time-Series Study. Respir. Res. 2022, 23, 81. [Google Scholar] [CrossRef] [PubMed]
  5. Holgate, S.T.; Devlin, R.B.; Wilson, S.J.; Frew, A.J. Health Effects of Acute Exposure to Air Pollution. Part II: Healthy Subjects Exposed to Concentrated Ambient Particles. Res. Rep. Health Eff. Inst. 2003, 112, 31–50; discussion 51–67. [Google Scholar]
  6. Garshick, E. Effects of Short- and Long-Term Exposures to Ambient Air Pollution on COPD. Eur. Respir. J. 2014, 44, 558–561. [Google Scholar] [CrossRef]
  7. Chen, J.; Dan, L.; Sun, Y.; Yuan, S.; Liu, W.; Chen, X.; Jiang, F.; Fu, T.; Zhang, H.; Deng, M.; et al. Ambient Air Pollution and Risk of Enterotomy, Gastrointestinal Cancer, and All-Cause Mortality among 4,708 Individuals with Inflammatory Bowel Disease: A Prospective Cohort Study. Environ. Health Perspect. 2023, 131, 77010. [Google Scholar] [CrossRef]
  8. Raftery, A.L.; Tsantikos, E.; Harris, N.L.; Hibbs, M.L. Links between Inflammatory Bowel Disease and Chronic Obstructive Pulmonary Disease. Front. Immunol. 2020, 11, 2144. [Google Scholar] [CrossRef]
  9. Korten, I.; Ramsey, K.; Latzin, P. Air Pollution during Pregnancy and Lung Development in the Child. Paediatr. Respir. Rev. 2017, 21, 38–46. [Google Scholar] [CrossRef]
  10. Veras, M.M.; de Oliveira Alves, N.; Fajersztajn, L.; Saldiva, P. Before the First Breath: Prenatal Exposures to Air Pollution and Lung Development. Cell Tissue Res. 2017, 367, 445–455. [Google Scholar] [CrossRef]
  11. Zielinska, M.A.; Hamulka, J. Protective Effect of Breastfeeding on the Adverse Health Effects Induced by Air Pollution: Current Evidence and Possible Mechanisms. Int. J. Environ. Res. Public Health 2019, 16, 4181. [Google Scholar] [CrossRef] [PubMed]
  12. Brunekreef, B.; Holgate, S.T. Air Pollution and Health. Lancet 2002, 360, 1233–1242. [Google Scholar] [CrossRef] [PubMed]
  13. Brook, R.D.; Rajagopalan, S. Particulate Matter, Air Pollution, and Blood Pressure. J. Am. Soc. Hypertens. 2009, 3, 332–350. [Google Scholar] [CrossRef] [PubMed]
  14. Kampa, M.; Castanas, E. Human Health Effects of Air Pollution. Environ. Pollut. 2008, 151, 362–367. [Google Scholar] [CrossRef]
  15. Lodovici, M.; Bigagli, E. Oxidative Stress and Air Pollution Exposure. J. Toxicol. 2011, 2011, 487074. [Google Scholar] [CrossRef]
  16. Perera, F.P. Multiple Threats to Child Health from Fossil Fuel Combustion: Impacts of Air Pollution and Climate Change. Environ. Health Perspect. 2017, 125, 141–148. [Google Scholar] [CrossRef]
  17. Sofia, D.; Gioiella, F.; Lotrecchiano, N.; Giuliano, A. Mitigation Strategies for Reducing Air Pollution. Environ. Sci. Pollut. Res. 2020, 27, 19226–19235. [Google Scholar] [CrossRef]
  18. Giannadaki, D.; Giannakis, E.; Pozzer, A.; Lelieveld, J. Estimating Health and Economic Benefits of Reductions in Air Pollution from Agriculture. Sci. Total Environ. 2018, 622, 1304–1316. [Google Scholar] [CrossRef]
  19. Anenberg, S.C.; West, J.J.; Fiore, A.M.; Jaffe, D.A.; Prather, M.J.; Bergmann, D.; Cuvelier, K.; Dentener, F.J.; Duncan, B.N.; Gauss, M. Intercontinental Impacts of Ozone Pollution on Human Mortality; ACS Publications: Washington, DC, USA, 2009; ISBN 0013-936X. [Google Scholar]
  20. Pope, C.A., III; Coleman, N.; Pond, Z.A.; Burnett, R.T. Fine Particulate Air Pollution and Human Mortality: 25+ Years of Cohort Studies. Environ. Res. 2020, 183, 108924. [Google Scholar] [CrossRef]
  21. Samek, L. Overall Human Mortality and Morbidity Due to Exposure to Air Pollution. Int. J. Occup. Med. Environ. Health 2016, 29, 417. [Google Scholar] [CrossRef]
  22. Liu, C.-X.; Liu, Y.-B.; Peng, Y.; Peng, J.; Ma, Q.-L. Causal Effect of Air Pollution on the Risk of Cardiovascular and Metabolic Diseases and Potential Mediation by Gut Microbiota. Sci. Total Environ. 2024, 912, 169418. [Google Scholar] [CrossRef] [PubMed]
  23. Zhao, L.; Fang, J.; Tang, S.; Deng, F.; Liu, X.; Shen, Y.; Liu, Y.; Kong, F.; Du, Y.; Cui, L.; et al. PM2.5 and Serum Metabolome and Insulin Resistance, Potential Mediation by the Gut Microbiome: A Population-Based Panel Study of Older Adults in China. Environ. Health Perspect. 2022, 130, 27007. [Google Scholar] [CrossRef] [PubMed]
  24. Carré, J.; Gatimel, N.; Moreau, J.; Parinaud, J.; Léandri, R. Does Air Pollution Play a Role in Infertility?: A Systematic Review. Environ. Health 2017, 16, 82. [Google Scholar] [CrossRef] [PubMed]
  25. Huang, J.; Deng, F.; Wu, S.; Lu, H.; Hao, Y.; Guo, X. The Impacts of Short-Term Exposure to Noise and Traffic-Related Air Pollution on Heart Rate Variability in Young Healthy Adults. J. Expo. Sci. Environ. Epidemiol. 2013, 23, 559–564. [Google Scholar] [CrossRef] [PubMed]
  26. Cho, I.; Blaser, M.J. The Human Microbiome: At the Interface of Health and Disease. Nat. Rev. Genet. 2012, 13, 260–270. [Google Scholar] [CrossRef]
  27. Ursell, L.K.; Metcalf, J.L.; Parfrey, L.W.; Knight, R. Defining the Human Microbiome. Nutr. Rev. 2012, 70, S38–S44. [Google Scholar] [CrossRef]
  28. Pflughoeft, K.J.; Versalovic, J. Human Microbiome in Health and Disease. Annu. Rev. Pathol. Mech. Dis. 2012, 7, 99–122. [Google Scholar] [CrossRef]
  29. Hooks, K.B.; O’Malley, M.A. Dysbiosis and Its Discontents. MBio 2017, 8, e01492-17. [Google Scholar] [CrossRef]
  30. Levy, M.; Kolodziejczyk, A.A.; Thaiss, C.A.; Elinav, E. Dysbiosis and the Immune System. Nat. Rev. Immunol. 2017, 17, 219–232. [Google Scholar] [CrossRef]
  31. Whiteside, S.A.; McGinniss, J.E.; Collman, R.G. The Lung Microbiome: Progress and Promise. J. Clin. Investig. 2021, 131, e150473. [Google Scholar] [CrossRef]
  32. Ichinohe, T.; Pang, I.K.; Kumamoto, Y.; Peaper, D.R.; Ho, J.H.; Murray, T.S.; Iwasaki, A. Microbiota Regulates Immune Defense against Respiratory Tract Influenza A Virus Infection. Proc. Natl. Acad. Sci. USA 2011, 108, 5354–5359. [Google Scholar] [CrossRef] [PubMed]
  33. Tanes, C.; Bittinger, K.; Gao, Y.; Friedman, E.S.; Nessel, L.; Paladhi, U.R.; Chau, L.; Panfen, E.; Fischbach, M.A.; Braun, J.; et al. Role of Dietary Fiber in the Recovery of the Human Gut Microbiome and Its Metabolome. Cell Host Microbe 2021, 29, 394–407.e5. [Google Scholar] [CrossRef] [PubMed]
  34. Wang, X.; Liu, H.; Li, Y.; Huang, S.; Zhang, L.; Cao, C.; Baker, P.N.; Tong, C.; Zheng, P.; Qi, H. Altered Gut Bacterial and Metabolic Signatures and Their Interaction in Gestational Diabetes Mellitus. Gut Microbes 2020, 12, 1840765. [Google Scholar] [CrossRef] [PubMed]
  35. Pirola, C.J.; Salatino, A.; Quintanilla, M.F.; Castaño, G.O.; Garaycoechea, M.; Sookoian, S. The Influence of Host Genetics on Liver Microbiome Composition in Patients with NAFLD. eBioMedicine 2022, 76, 103858. [Google Scholar] [CrossRef] [PubMed]
  36. Le, H.H.; Lee, M.-T.; Besler, K.R.; Johnson, E.L. Host Hepatic Metabolism Is Modulated by Gut Microbiota-Derived Sphingolipids. Cell Host Microbe 2022, 30, 798–808.e7. [Google Scholar] [CrossRef] [PubMed]
  37. Dang, A.T.; Marsland, B.J. Microbes, Metabolites, and the Gut–Lung Axis. Mucosal Immunol. 2019, 12, 843–850. [Google Scholar] [CrossRef]
  38. Enaud, R.; Prevel, R.; Ciarlo, E.; Beaufils, F.; Wieërs, G.; Guery, B.; Delhaes, L. The Gut-Lung Axis in Health and Respiratory Diseases: A Place for Inter-Organ and Inter-Kingdom Crosstalks. Front. Cell. Infect. Microbiol. 2020, 10, 9. [Google Scholar] [CrossRef]
  39. Peterson, J.; Garges, S.; Giovanni, M.; McInnes, P.; Wang, L.; Schloss, J.A.; Bonazzi, V.; McEwen, J.E.; Wetterstrand, K.A.; Deal, C. The NIH Human Microbiome Project. Genome Res. 2009, 19, 2317–2323. [Google Scholar]
  40. Dickson, R.P.; Erb-Downward, J.R.; Freeman, C.M.; McCloskey, L.; Falkowski, N.R.; Huffnagle, G.B.; Curtis, J.L. Bacterial Topography of the Healthy Human Lower Respiratory Tract. MBio 2017, 8, e02287-16. [Google Scholar] [CrossRef]
  41. Yadav, B.; Bhattacharya, S.S.; Rosen, L.; Nagpal, R.; Yadav, H.; Yadav, J.S. Oro-Respiratory Dysbiosis and Its Modulatory Effect on Lung Mucosal Toxicity during Exposure or Co-Exposure to Carbon Nanotubes and Cigarette Smoke. Nanomaterials 2024, 14, 314. [Google Scholar] [CrossRef]
  42. Mathieu, E.; Escribano-Vazquez, U.; Descamps, D.; Cherbuy, C.; Langella, P.; Riffault, S.; Remot, A.; Thomas, M. Paradigms of Lung Microbiota Functions in Health and Disease, Particularly, in Asthma. Front. Physiol. 2018, 9, 1168. [Google Scholar] [CrossRef] [PubMed]
  43. Rinninella, E.; Raoul, P.; Cintoni, M.; Franceschi, F.; Miggiano, G.A.D.; Gasbarrini, A.; Mele, M.C. What is the Healthy Gut Microbiota Composition? A Changing Ecosystem across Age, Environment, Diet, and Diseases. Microorganisms 2019, 7, 14. [Google Scholar] [CrossRef] [PubMed]
  44. Turnbaugh, P.J.; Ley, R.E.; Hamady, M.; Fraser-Liggett, C.M.; Knight, R.; Gordon, J.I. The Human Microbiome Project. Nature 2007, 449, 804–810. [Google Scholar] [CrossRef] [PubMed]
  45. Deurenberg, R.H.; Bathoorn, E.; Chlebowicz, M.A.; Couto, N.; Ferdous, M.; García-Cobos, S.; Kooistra-Smid, A.M.; Raangs, E.C.; Rosema, S.; Veloo, A.C. Application of next Generation Sequencing in Clinical Microbiology and Infection Prevention. J. Biotechnol. 2017, 243, 16–24. [Google Scholar] [CrossRef] [PubMed]
  46. Dewhirst, F.E.; Chen, T.; Izard, J.; Paster, B.J.; Tanner, A.C.; Yu, W.-H.; Lakshmanan, A.; Wade, W.G. The Human Oral Microbiome. J. Bacteriol. 2010, 192, 5002–5017. [Google Scholar] [CrossRef]
  47. Wos-Oxley, M.L.; Chaves-Moreno, D.; Jáuregui, R.; Oxley, A.P.; Kaspar, U.; Plumeier, I.; Kahl, S.; Rudack, C.; Becker, K.; Pieper, D.H. Exploring the Bacterial Assemblages along the Human Nasal Passage. Environ. Microbiol. 2016, 18, 2259–2271. [Google Scholar] [CrossRef]
  48. Zhou, Y.; Mihindukulasuriya, K.A.; Gao, H.; La Rosa, P.S.; Wylie, K.M.; Martin, J.C.; Kota, K.; Shannon, W.D.; Mitreva, M.; Sodergren, E. Exploration of Bacterial Community Classes in Major Human Habitats. Genome Biol. 2014, 15, R66. [Google Scholar] [CrossRef]
  49. Segal, L.N.; Clemente, J.C.; Tsay, J.-C.J.; Koralov, S.B.; Keller, B.C.; Wu, B.G.; Li, Y.; Shen, N.; Ghedin, E.; Morris, A. Enrichment of the Lung Microbiome with Oral Taxa Is Associated with Lung Inflammation of a Th17 Phenotype. Nat. Microbiol. 2016, 1, 16031. [Google Scholar] [CrossRef]
  50. Dickson, R.P.; Erb-Downward, J.R.; Freeman, C.M.; McCloskey, L.; Beck, J.M.; Huffnagle, G.B.; Curtis, J.L. Spatial Variation in the Healthy Human Lung Microbiome and the Adapted Island Model of Lung Biogeography. Ann. Am. Thorac. Soc. 2015, 12, 821–830. [Google Scholar] [CrossRef]
  51. Dickson, R.P.; Martinez, F.J.; Huffnagle, G.B. The Role of the Microbiome in Exacerbations of Chronic Lung Diseases. Lancet 2014, 384, 691–702. [Google Scholar] [CrossRef]
  52. Marsland, B.J.; Yadava, K.; Nicod, L.P. The Airway Microbiome and Disease. Chest 2013, 144, 632–637. [Google Scholar] [CrossRef] [PubMed]
  53. Wypych, T.P.; Wickramasinghe, L.C.; Marsland, B.J. The Influence of the Microbiome on Respiratory Health. Nat. Immunol. 2019, 20, 1279–1290. [Google Scholar] [CrossRef] [PubMed]
  54. Hufnagl, K.; Pali-Schöll, I.; Roth-Walter, F.; Jensen-Jarolim, E. Dysbiosis of the Gut and Lung Microbiome Has a Role in Asthma. In Proceedings of the Seminars in Immunopathology; Springer: Berlin/Heidelberg, Germany, 2020; Volume 42, pp. 75–93. [Google Scholar]
  55. Erb-Downward, J.R.; Thompson, D.L.; Han, M.K.; Freeman, C.M.; McCloskey, L.; Schmidt, L.A.; Young, V.B.; Toews, G.B.; Curtis, J.L.; Sundaram, B. Analysis of the Lung Microbiome in the “Healthy” Smoker and in COPD. PLoS ONE 2011, 6, e16384. [Google Scholar] [CrossRef]
  56. Sze, M.A.; Dimitriu, P.A.; Suzuki, M.; McDonough, J.E.; Campbell, J.D.; Brothers, J.F.; Erb-Downward, J.R.; Huffnagle, G.B.; Hayashi, S.; Elliott, W.M. Host Response to the Lung Microbiome in Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 2015, 192, 438–445. [Google Scholar] [CrossRef] [PubMed]
  57. Mao, Q.; Jiang, F.; Yin, R.; Wang, J.; Xia, W.; Dong, G.; Ma, W.; Yang, Y.; Xu, L.; Hu, J. Interplay between the Lung Microbiome and Lung Cancer. Cancer Lett. 2018, 415, 40–48. [Google Scholar] [CrossRef]
  58. Yan, X.; Yang, M.; Liu, J.; Gao, R.; Hu, J.; Li, J.; Zhang, L.; Shi, Y.; Guo, H.; Cheng, J. Discovery and Validation of Potential Bacterial Biomarkers for Lung Cancer. Am. J. Cancer Res. 2015, 5, 3111. [Google Scholar]
  59. Caverly, L.J.; Zhao, J.; LiPuma, J.J. Cystic fibrosis lung microbiome: Opportunities to Reconsider Management of Airway Infection. Pediatr. Pulmonol. 2015, 50, S31–S38. [Google Scholar] [CrossRef]
  60. Tunney, M.M.; Field, T.R.; Moriarty, T.F.; Patrick, S.; Doering, G.; Muhlebach, M.S.; Wolfgang, M.C.; Boucher, R.; Gilpin, D.F.; McDowell, A. Detection of Anaerobic Bacteria in High Numbers in Sputum from Patients with Cystic Fibrosis. Am. J. Respir. Crit. Care Med. 2008, 177, 995–1001. [Google Scholar] [CrossRef]
  61. Molyneaux, P.L.; Cox, M.J.; Wells, A.U.; Kim, H.C.; Ji, W.; Cookson, W.O.; Moffatt, M.F.; Kim, D.S.; Maher, T.M. Changes in the Respiratory Microbiome during Acute Exacerbations of Idiopathic Pulmonary Fibrosis. Respir. Res. 2017, 18, 29. [Google Scholar] [CrossRef]
  62. Wang, J.; Lesko, M.; Badri, M.H.; Kapoor, B.C.; Wu, B.G.; Li, Y.; Smaldone, G.C.; Bonneau, R.; Kurtz, Z.D.; Condos, R. Lung Microbiome and Host Immune Tone in Subjects with Idiopathic Pulmonary Fibrosis Treated with Inhaled Interferon-γ. ERJ Open Res. 2017, 3, 8. [Google Scholar] [CrossRef]
  63. Klimkaite, L.; Liveikis, T.; Kaspute, G.; Armalyte, J.; Aldonyte, R. Air Pollution-Associated Shifts in the Human Airway Microbiome and Exposure-Associated Molecular Events. Future Microbiol. 2023, 18, 607–623. [Google Scholar] [CrossRef] [PubMed]
  64. Niemeier-Walsh, C.; Ryan, P.H.; Meller, J.; Ollberding, N.J.; Adhikari, A.; Reponen, T. Exposure to Traffic-Related Air Pollution and Bacterial Diversity in the Lower Respiratory Tract of Children. PLoS ONE 2021, 16, e0244341. [Google Scholar] [CrossRef] [PubMed]
  65. Li, X.; Sun, Y.; An, Y.; Wang, R.; Lin, H.; Liu, M.; Li, S.; Ma, M.; Xiao, C. Air Pollution during the Winter Period and Respiratory Tract Microbial Imbalance in a Healthy Young Population in Northeastern China. Environ. Pollut. 2019, 246, 972–979. [Google Scholar] [CrossRef] [PubMed]
  66. Rylance, J.; Kankwatira, A.; Nelson, D.E.; Toh, E.; Day, R.B.; Lin, H.; Gao, X.; Dong, Q.; Sodergren, E.; Weinstock, G.M. Household Air Pollution and the Lung Microbiome of Healthy Adults in Malawi: A Cross-Sectional Study. BMC Microbiol. 2016, 16, 182. [Google Scholar] [CrossRef] [PubMed]
  67. Hosgood, H.D., III; Mongodin, E.F.; Wan, Y.; Hua, X.; Rothman, N.; Hu, W.; Vermeulen, R.; Seow, W.J.; Rohan, T.; Xu, J. The Respiratory Tract Microbiome and Its Relationship to Lung Cancer and Environmental Exposures Found in Rural China. Environ. Mol. Mutagen. 2019, 60, 617–623. [Google Scholar] [CrossRef]
  68. Niu, Y.; Chen, R.; Wang, C.; Wang, W.; Jiang, J.; Wu, W.; Cai, J.; Zhao, Z.; Xu, X.; Kan, H. Ozone Exposure Leads to Changes in Airway Permeability, Microbiota and Metabolome: A randomised, double-blind, crossover trial. Eur. Respir. J. 2020, 56, 2000165. [Google Scholar] [CrossRef]
  69. Qin, T.; Zhang, F.; Zhou, H.; Ren, H.; Du, Y.; Liang, S.; Wang, F.; Cheng, L.; Xie, X.; Jin, A. High-level PM2. 5/PM10 Exposure is Associated with Alterations in the Human Pharyngeal Microbiota Composition. Front. Microbiol. 2019, 10, 54. [Google Scholar] [CrossRef]
  70. Wang, L.; Cheng, H.; Wang, D.; Zhao, B.; Zhang, J.; Cheng, L.; Yao, P.; Di Narzo, A.; Shen, Y.; Yu, J. Airway Microbiome is Associated with Respiratory Functions and Responses to Ambient Particulate Matter Exposure. Ecotoxicol. Environ. Saf. 2019, 167, 269–277. [Google Scholar] [CrossRef]
  71. Mariani, J.; Favero, C.; Spinazzè, A.; Cavallo, D.M.; Carugno, M.; Motta, V.; Bonzini, M.; Cattaneo, A.; Pesatori, A.C.; Bollati, V. Short-Term Particulate Matter Exposure Influences Nasal Microbiota in a Population of Healthy Subjects. Environ. Res. 2018, 162, 119–126. [Google Scholar] [CrossRef]
  72. Yu, G.; Gail, M.H.; Consonni, D.; Carugno, M.; Humphrys, M.; Pesatori, A.C.; Caporaso, N.E.; Goedert, J.J.; Ravel, J.; Landi, M.T. Characterizing Human Lung Tissue Microbiota and Its Relationship to Epidemiological and Clinical Features. Genome Biol. 2016, 17, 163. [Google Scholar] [CrossRef]
  73. Residential Greenness and Air Pollution’s Association with Nasal Microbiota among Asthmatic Children—ScienceDirect. Available online: https://www.sciencedirect.com/science/article/pii/S0013935122024227 (accessed on 3 July 2024).
  74. Association of Short-Term PM2.5 Exposure with Airway Innate Immune Response, Microbiota and Metabolism Alterations in Human Airways—ScienceDirect. Available online: https://www.sciencedirect.com/science/article/pii/S0269749124001490 (accessed on 3 July 2024).
  75. Enrichment of Human Nasopharyngeal Bacteriome with Bacteria from Dust after Short-Term Exposure to Indoor Environment: A Pilot Study|BMC Microbiology. Available online: https://link.springer.com/article/10.1186/s12866-023-02951-5 (accessed on 3 July 2024).
  76. Chen, Y.-W.; Li, S.-W.; Lin, C.-D.; Huang, M.-Z.; Lin, H.-J.; Chin, C.-Y.; Lai, Y.-R.; Chiu, C.-H.; Yang, C.-Y.; Lai, C.-H. Fine Particulate Matter Exposure Alters Pulmonary Microbiota Composition and Aggravates Pneumococcus-Induced Lung Pathogenesis. Front. Cell Dev. Biol. 2020, 8, 570484. [Google Scholar] [CrossRef] [PubMed]
  77. The Effect of Real-Ambient PM2.5 Exposure on the Lung and Gut Microbiomes and the Regulation of Nrf2—ScienceDirect. Available online: https://www.sciencedirect.com/science/article/pii/S0147651323002063 (accessed on 3 July 2024).
  78. Daniel, S.; Phillippi, D.; Schneider, L.J.; Nguyen, K.N.; Mirpuri, J.; Lund, A.K. Exposure to Diesel Exhaust Particles Results in Altered Lung Microbial Profiles, Associated with Increased Reactive Oxygen Species/Reactive Nitrogen Species and Inflammation, in C57Bl/6 Wildtype Mice on A High-Fat Diet. Part. Fibre Toxicol. 2021, 18, 3. [Google Scholar] [CrossRef] [PubMed]
  79. Phillippi, D.T.; Daniel, S.; Pusadkar, V.; Youngblood, V.L.; Nguyen, K.N.; Azad, R.K.; McFarlin, B.K.; Lund, A.K. Inhaled Diesel Exhaust Particles Result in Microbiome-Related Systemic Inflammation and Altered Cardiovascular Disease Biomarkers in C57Bl/6 Male Mice. Part. Fibre Toxicol. 2022, 19, 10. [Google Scholar] [CrossRef] [PubMed]
  80. Li, N.; He, F.; Liao, B.; Zhou, Y.; Li, B.; Ran, P. Exposure to Ambient Particulate Matter alters the Microbial Composition and Induces Immune Changes in Rat Lung. Respir. Res. 2017, 18, 143. [Google Scholar] [CrossRef]
  81. Li, J.; Hu, Y.; Liu, L.; Wang, Q.; Zeng, J.; Chen, C. PM2. 5 Exposure Perturbs Lung Microbiome and Its Metabolic Profile in Mice. Sci. Total Environ. 2020, 721, 137432. [Google Scholar] [CrossRef]
  82. Mazumder, M.H.H.; Gandhi, J.; Majumder, N.; Wang, L.; Cumming, R.I.; Stradtman, S.; Velayutham, M.; Hathaway, Q.A.; Shannahan, J.; Hu, G. Lung-Gut Axis of Microbiome Alterations Following Co-Exposure to Ultrafine Carbon Black and Ozone. Part. Fibre Toxicol. 2023, 20, 15. [Google Scholar] [CrossRef]
  83. Laiman, V.; Lo, Y.-C.; Chen, H.-C.; Yuan, T.-H.; Hsiao, T.-C.; Chen, J.-K.; Chang, C.-W.; Lin, T.-C.; Li, S.-J.; Chen, Y.-Y.; et al. Effects of Antibiotics and Metals on Lung and Intestinal Microbiome Dysbiosis after Sub-Chronic Lower-Level Exposure of Air Pollution in Ageing Rats. Ecotoxicol. Environ. Saf. 2022, 246, 114164. [Google Scholar] [CrossRef]
  84. Harris, M.A.; Reddy, C.A.; Carter, G.R. Anaerobic Bacteria from the Large Intestine of Mice. Appl. Environ. Microbiol. 1976, 31, 907–912. [Google Scholar] [CrossRef]
  85. Schloss, P.D.; Handelsman, J. Status of the Microbial Census. Microbiol. Mol. Biol. Rev. 2004, 68, 686–691. [Google Scholar] [CrossRef]
  86. Swidsinski, A.; Loening-Baucke, V.; Lochs, H.; Hale, L.P. Spatial Organization of Bacterial Flora in Normal and Inflamed Intestine: A Fluorescence in Situ Hybridization Study in Mice. World J. Gastroenterol. WJG 2005, 11, 1131. [Google Scholar] [CrossRef]
  87. Bartolomaeus, H.; Balogh, A.; Yakoub, M.; Homann, S.; Markó, L.; Höges, S.; Tsvetkov, D.; Krannich, A.; Wundersitz, S.; Avery, E.G. Short-Chain Fatty Acid Propionate Protects from Hypertensive Cardiovascular Damage. Circulation 2019, 139, 1407–1421. [Google Scholar] [CrossRef] [PubMed]
  88. Liu, T.; Chen, X.; Xu, Y.; Wu, W.; Tang, W.; Chen, Z.; Ji, G.; Peng, J.; Jiang, Q.; Xiao, J. Gut Microbiota Partially Mediates the Effects of Fine Particulate Matter on Type 2 Diabetes: Evidence from a Population-Based Epidemiological Study. Environ. Int. 2019, 130, 104882. [Google Scholar] [CrossRef] [PubMed]
  89. Van Pee, T.; Nawrot, T.S.; van Leeuwen, R.; Hogervorst, J. Ambient Particulate Air Pollution and the Intestinal Microbiome; a Systematic Review of Epidemiological, in Vivo and, in Vitro Studies. Sci. Total Environ. 2023, 878, 162769. [Google Scholar] [CrossRef] [PubMed]
  90. Roslund, M.I.; Rantala, S.; Oikarinen, S.; Puhakka, R.; Hui, N.; Parajuli, A.; Laitinen, O.H.; Hyöty, H.; Rantalainen, A.-L.; Sinkkonen, A. Endocrine Disruption and Commensal Bacteria Alteration Associated with Gaseous and Soil PAH Contamination among Daycare Children. Environ. Int. 2019, 130, 104894. [Google Scholar] [CrossRef] [PubMed]
  91. Fouladi, F.; Bailey, M.J.; Patterson, W.B.; Sioda, M.; Blakley, I.C.; Fodor, A.A.; Jones, R.B.; Chen, Z.; Kim, J.S.; Lurmann, F. Air Pollution Exposure Is Associated with the Gut Microbiome as Revealed by Shotgun Metagenomic Sequencing. Environ. Int. 2020, 138, 105604. [Google Scholar] [CrossRef]
  92. Zheng, P.; Zhang, B.; Zhang, K.; Lv, X.; Wang, Q.; Bai, X. The Impact of Air Pollution on Intestinal Microbiome of Asthmatic Children: A Panel Study. BioMed Res. Int. 2020, 2020, 5753427. [Google Scholar] [CrossRef]
  93. Alderete, T.L.; Jones, R.B.; Chen, Z.; Kim, J.S.; Habre, R.; Lurmann, F.; Gilliland, F.D.; Goran, M.I. Exposure to Traffic-Related Air Pollution and the Composition of the Gut Microbiota in Overweight and Obese Adolescents. Environ. Res. 2018, 161, 472–478. [Google Scholar] [CrossRef]
  94. Association of Long-Term Exposure to Ambient PM2.5 and Its Constituents with Gut Microbiota: Evidence from a China Cohort—ScienceDirect. Available online: https://www.sciencedirect.com/science/article/pii/S0048969723021964 (accessed on 3 July 2024).
  95. Liu, Y.; Wang, T.; Si, B.; Du, H.; Liu, Y.; Waqas, A.; Huang, S.; Zhao, G.; Chen, S.; Xu, A. Intratracheally Instillated Diesel PM2. 5 Significantly Altered the Structure and Composition of Indigenous Murine Gut Microbiota. Ecotoxicol. Environ. Saf. 2021, 210, 111903. [Google Scholar] [CrossRef]
  96. Mutlu, E.A.; Comba, I.Y.; Cho, T.; Engen, P.A.; Yazıcı, C.; Soberanes, S.; Hamanaka, R.B.; Niğdelioğlu, R.; Meliton, A.Y.; Ghio, A.J. Inhalational Exposure to Particulate Matter Air Pollution Alters the Composition of the Gut Microbiome. Environ. Pollut. 2018, 240, 817–830. [Google Scholar] [CrossRef]
  97. Dong, X.; Yao, S.; Deng, L.; Li, H.; Zhang, F.; Xu, J.; Li, Z.; Zhang, L.; Jiang, J.; Wu, W. Alterations in the Gut Microbiota and Its Metabolic Profile of PM2. 5 Exposure-Induced Thyroid Dysfunction Rats. Sci. Total Environ. 2022, 838, 156402. [Google Scholar] [CrossRef]
  98. Dai, S.; Wang, Z.; Yang, Y.; Du, P.; Li, X. PM2. 5 Induced Weight Loss of Mice through Altering the Intestinal Microenvironment: Mucus Barrier, Gut Microbiota, and Metabolic Profiling. J. Hazard. Mater. 2022, 431, 128653. [Google Scholar] [CrossRef] [PubMed]
  99. van den Brule, S.; Rappe, M.; Ambroise, J.; Bouzin, C.; Dessy, C.; Paquot, A.; Muccioli, G.G.; Lison, D. Diesel Exhaust Particles Alter the Profile and Function of the Gut Microbiota upon Subchronic Oral Administration in Mice. Part. Fibre Toxicol. 2021, 18, 7. [Google Scholar] [CrossRef] [PubMed]
  100. Wang, W.; Zhou, J.; Chen, M.; Huang, X.; Xie, X.; Li, W.; Cao, Q.; Kan, H.; Xu, Y.; Ying, Z. Exposure to Concentrated Ambient PM2. 5 alters the Composition of Gut Microbiota in a Murine Model. Part. Fibre Toxicol. 2018, 15, 17. [Google Scholar] [CrossRef] [PubMed]
  101. Li, S.; Ma, Y.; Ye, S.; Guo, R.; Su, Y.; Du, Q.; Yin, S.; Xiao, F. Ambient NO2 Exposure Induced Cardiotoxicity Associated with Gut Microbiome Dysregulation and Glycerophospholipid Metabolism Disruption. Ecotoxicol. Environ. Saf. 2022, 238, 113583. [Google Scholar] [CrossRef] [PubMed]
  102. Subchronic Inhalation Exposure to Ultrafine Particulate Matter Alters the Intestinal Microbiome in Various Mouse Models—ScienceDirect. Available online: https://www.sciencedirect.com/science/article/pii/S0013935124001464 (accessed on 3 July 2024).
  103. Li, R.; Yang, J.; Saffari, A.; Jacobs, J.; Baek, K.I.; Hough, G.; Larauche, M.H.; Ma, J.; Jen, N.; Moussaoui, N. Ambient Ultrafine Particle Ingestion Alters Gut Microbiota in Association with Increased Atherogenic Lipid Metabolites. Sci. Rep. 2017, 7, 42906. [Google Scholar] [CrossRef] [PubMed]
  104. Fujimura, K.E.; Demoor, T.; Rauch, M.; Faruqi, A.A.; Jang, S.; Johnson, C.C.; Boushey, H.A.; Zoratti, E.; Ownby, D.; Lukacs, N.W. House Dust Exposure Mediates Gut Microbiome Lactobacillus Enrichment and Airway Immune Defense against Allergens and Virus Infection. Proc. Natl. Acad. Sci. 2014, 111, 805–810. [Google Scholar] [CrossRef]
  105. Lo Sasso, G.; Phillips, B.W.; Sewer, A.; Battey, J.N.; Kondylis, A.; Talikka, M.; Titz, B.; Guedj, E.; Peric, D.; Bornand, D. The Reduction of DSS-Induced Colitis Severity in Mice Exposed to Cigarette Smoke Is Linked to Immune Modulation and Microbial Shifts. Sci. Rep. 2020, 10, 3829. [Google Scholar] [CrossRef]
  106. Bhattacharya, S.S.; Yadav, B.; Rosen, L.; Nagpal, R.; Yadav, H.; Yadav, J.S. Crosstalk between Gut Microbiota and Lung Inflammation in Murine Toxicity Models of Respiratory Exposure or Co-Exposure to Carbon Nanotube Particles and Cigarette Smoke Extract. Toxicol. Appl. Pharmacol. 2022, 447, 116066. [Google Scholar] [CrossRef]
  107. Ghio, A.J.; Carraway, M.S.; Madden, M.C. Composition of Air Pollution Particles and Oxidative Stress in Cells, Tissues, and Living Systems. J. Toxicol. Environ. Health Part B 2012, 15, 1–21. [Google Scholar] [CrossRef]
  108. Glencross, D.A.; Ho, T.-R.; Camina, N.; Hawrylowicz, C.M.; Pfeffer, P.E. Air Pollution and Its Effects on the Immune System. Free Radic. Biol. Med. 2020, 151, 56–68. [Google Scholar] [CrossRef]
  109. Rao, X.; Zhong, J.; Brook, R.D.; Rajagopalan, S. Effect of Particulate Matter Air Pollution on Cardiovascular Oxidative Stress Pathways. Antioxid. Redox Signal. 2018, 28, 797–818. [Google Scholar] [CrossRef] [PubMed]
  110. Fang, T.; Lakey, P.S.; Weber, R.J.; Shiraiwa, M. Oxidative Potential of Particulate Matter and Generation of Reactive Oxygen Species in Epithelial Lining Fluid. Environ. Sci. Technol. 2019, 53, 12784–12792. [Google Scholar] [CrossRef] [PubMed]
  111. Leni, Z.; Künzi, L.; Geiser, M. Air Pollution Causing Oxidative Stress. Curr. Opin. Toxicol. 2020, 20, 1–8. [Google Scholar] [CrossRef]
  112. Shishodia, S.; Potdar, P.; Gairola, C.G.; Aggarwal, B.B. Curcumin (Diferuloylmethane) down-Regulates Cigarette Smoke-Induced NF-kappaB Activation through Inhibition of IkappaBalpha Kinase in Human Lung Epithelial Cells: Correlation with Suppression of COX-2, MMP-9 and Cyclin D1. Carcinogenesis 2003, 24, 1269–1279. [Google Scholar] [CrossRef] [PubMed]
  113. Milara, J.; Peiró, T.; Serrano, A.; Cortijo, J. Epithelial to Mesenchymal Transition Is Increased in Patients with COPD and Induced by Cigarette Smoke. Thorax 2013, 68, 410–420. [Google Scholar] [CrossRef]
  114. Caraballo, J.C.; Yshii, C.; Westphal, W.; Moninger, T.; Comellas, A.P. Ambient Particulate Matter Affects Occludin Distribution and Increases Alveolar Transepithelial Electrical Conductance. Respirology 2011, 16, 340–349. [Google Scholar] [CrossRef]
  115. Kish, L.; Hotte, N.; Kaplan, G.G.; Vincent, R.; Tso, R.; Gänzle, M.; Rioux, K.P.; Thiesen, A.; Barkema, H.W.; Wine, E. Environmental Particulate Matter Induces Murine Intestinal Inflammatory Responses and Alters the Gut Microbiome. PLoS ONE 2013, 8, e62220. [Google Scholar] [CrossRef]
  116. Invernizzi, R.; Lloyd, C.M.; Molyneaux, P.L. Respiratory Microbiome and Epithelial Interactions Shape Immunity in the Lungs. Immunology 2020, 160, 171–182. [Google Scholar] [CrossRef]
  117. Wang, T.; Wang, L.; Moreno-Vinasco, L.; Lang, G.D.; Siegler, J.H.; Mathew, B.; Usatyuk, P.V.; Samet, J.M.; Geyh, A.S.; Breysse, P.N. Particulate Matter Air Pollution Disrupts Endothelial Cell Barrier via Calpain-Mediated Tight Junction Protein Degradation. Part. Fibre Toxicol. 2012, 9, 35. [Google Scholar] [CrossRef]
  118. Woodby, B.; Schiavone, M.L.; Pambianchi, E.; Mastaloudis, A.N.; Hester, S.; M. Wood, S.; Pecorelli, A.; Valacchi, G. Particulate Matter Decreases Intestinal Barrier-Associated Proteins Levels in 3D Human Intestinal Model. Int. J. Environ. Res. Public Health 2020, 17, 3234. [Google Scholar] [CrossRef]
  119. Liu, J.; Chen, X.; Dou, M.; He, H.; Ju, M.; Ji, S.; Zhou, J.; Chen, C.; Zhang, D.; Miao, C. Particulate Matter Disrupts Airway Epithelial Barrier via Oxidative Stress to Promote Pseudomonas Aeruginosa Infection. J. Thorac. Dis. 2019, 11, 2617. [Google Scholar] [CrossRef] [PubMed]
  120. Li, X.; Cui, J.; Yang, H.; Sun, H.; Lu, R.; Gao, N.; Meng, Q.; Wu, S.; Wu, J.; Aschner, M. Colonic Injuries Induced by Inhalational Exposure to Particulate-Matter Air Pollution. Adv. Sci. 2019, 6, 1900180. [Google Scholar] [CrossRef] [PubMed]
  121. Okuda, K.; Chen, G.; Subramani, D.B.; Wolf, M.; Gilmore, R.C.; Kato, T.; Radicioni, G.; Kesimer, M.; Chua, M.; Dang, H. Localization of Secretory Mucins MUC5AC and MUC5B in Normal/Healthy Human Airways. Am. J. Respir. Crit. Care Med. 2019, 199, 715–727. [Google Scholar] [CrossRef] [PubMed]
  122. Min, H.J.; Kim, J.-H.; Yoo, J.E.; Oh, J.-H.; Kim, K.S.; Yoon, J.-H.; Kim, C.-H. ROS-Dependent HMGB1 Secretion Upregulates IL-8 in upper Airway Epithelial Cells under Hypoxic Condition. Mucosal Immunol. 2017, 10, 685–694. [Google Scholar] [CrossRef] [PubMed]
  123. Aghapour, M.; Raee, P.; Moghaddam, S.J.; Hiemstra, P.S.; Heijink, I.H. Airway Epithelial Barrier Dysfunction in Chronic Obstructive Pulmonary Disease: Role of Cigarette Smoke Exposure. Am. J. Respir. Cell Mol. Biol. 2018, 58, 157–169. [Google Scholar] [CrossRef]
  124. Wang, T.; Han, Y.; Li, H.; Wang, Y.; Xue, T.; Chen, X.; Chen, W.; Fan, Y.; Qiu, X.; Gong, J. Changes in Bioactive Lipid Mediators in Response to Short-Term Exposure to Ambient Air Particulate Matter: A Targeted Lipidomic Analysis of Oxylipin Signaling Pathways. Environ. Int. 2021, 147, 106314. [Google Scholar] [CrossRef]
  125. Zhivaki, D.; Kagan, J.C. Innate Immune Detection of Lipid Oxidation as a Threat Assessment Strategy. Nat. Rev. Immunol. 2022, 22, 322–330. [Google Scholar] [CrossRef]
  126. Jin, Y.; Lu, L.; Tu, W.; Luo, T.; Fu, Z. Impacts of Polystyrene Microplastic on the Gut Barrier, Microbiota and Metabolism of Mice. Sci. Total Environ. 2019, 649, 308–317. [Google Scholar] [CrossRef]
  127. Calderón-Garcidueñas, L.; Franco-Lira, M.; Torres-Jardón, R.; Henriquez-Roldán, C.; Barragán-Mejía, G.; Valencia-Salazar, G.; Gonzaléz-Maciel, A.; Reynoso-Robles, R.; Villarreal-Calderón, R.; Reed, W. Pediatric Respiratory and Systemic Effects of Chronic Air Pollution Exposure: Nose, Lung, Heart, and Brain Pathology. Toxicol. Pathol. 2007, 35, 154–162. [Google Scholar] [CrossRef]
  128. Young, R.P.; Hopkins, R.J.; Marsland, B. The Gut–Liver–Lung Axis. Modulation of the Innate Immune Response and Its Possible Role in Chronic Obstructive Pulmonary Disease. Am. J. Respir. Cell Mol. Biol. 2016, 54, 161–169. [Google Scholar] [CrossRef]
  129. Salim, S.Y.; Kaplan, G.G.; Madsen, K.L. Air Pollution Effects on the Gut Microbiota: A Link between Exposure and Inflammatory Disease. Gut Microbes 2014, 5, 215–219. [Google Scholar] [CrossRef] [PubMed]
  130. Vatanen, T.; Kostic, A.D.; d’Hennezel, E.; Siljander, H.; Franzosa, E.A.; Yassour, M.; Kolde, R.; Vlamakis, H.; Arthur, T.D.; Hämäläinen, A.-M.; et al. Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans. Cell 2016, 165, 842–853. [Google Scholar] [CrossRef] [PubMed]
  131. Budden, K.F.; Gellatly, S.L.; Wood, D.L.; Cooper, M.A.; Morrison, M.; Hugenholtz, P.; Hansbro, P.M. Emerging Pathogenic Links between Microbiota and the Gut–Lung Axis. Nat. Rev. Microbiol. 2017, 15, 55–63. [Google Scholar] [CrossRef] [PubMed]
  132. Kaur, H.; Ali, S.A. Probiotics and gut microbiota: Mechanistic Insights into Gut Immune Homeostasis through TLR Pathway Regulation. Food Funct. 2022, 13, 7423–7447. [Google Scholar] [CrossRef]
  133. Kelly, C.J.; Zheng, L.; Campbell, E.L.; Saeedi, B.; Scholz, C.C.; Bayless, A.J.; Wilson, K.E.; Glover, L.E.; Kominsky, D.J.; Magnuson, A. Crosstalk between Microbiota-Derived Short-Chain Fatty Acids and Intestinal Epithelial HIF Augments Tissue Barrier Function. Cell Host Microbe 2015, 17, 662–671. [Google Scholar] [CrossRef]
  134. Semin, I.; Ninnemann, J.; Bondareva, M.; Gimaev, I.; Kruglov, A.A. Interplay between Microbiota, Toll-like Receptors and Cytokines for the Maintenance of Epithelial Barrier Integrity. Front. Med. 2021, 8, 644333. [Google Scholar] [CrossRef]
  135. Thorburn, A.N.; Macia, L.; Mackay, C.R. Diet, Metabolites, and “Western-Lifestyle” Inflammatory Diseases. Immunity 2014, 40, 833–842. [Google Scholar] [CrossRef]
  136. Sivaprakasam, S.; Bhutia, Y.D.; Yang, S.; Ganapathy, V. Short-Chain Fatty Acid Transporters: Role in Colonic Homeostasis. Compr. Physiol. 2017, 8, 299–314. [Google Scholar] [CrossRef]
  137. Mazmanian, S.K.; Round, J.L.; Kasper, D.L. A Microbial Symbiosis Factor Prevents Intestinal Inflammatory Disease. Nature 2008, 453, 620–625. [Google Scholar] [CrossRef]
  138. Sharon, G.; Garg, N.; Debelius, J.; Knight, R.; Dorrestein, P.C.; Mazmanian, S.K. Specialized Metabolites from the Microbiome in Health and Disease. Cell Metab. 2014, 20, 719–730. [Google Scholar] [CrossRef]
  139. Chen, L.-W.; Chen, P.-H.; Hsu, C.-M. Commensal Microflora Contribute to Host Defense against Escherichia Coli Pneumonia through Toll-like Receptors. Shock 2011, 36, 67–75. [Google Scholar] [CrossRef] [PubMed]
  140. Tsay, T.-B.; Yang, M.-C.; Chen, P.-H.; Hsu, C.-M.; Chen, L.-W. Gut Flora Enhance Bacterial Clearance in Lung through Toll-like Receptors 4. J. Biomed. Sci. 2011, 18, 68. [Google Scholar] [CrossRef] [PubMed]
  141. Mohammed, A.N.; Yadav, J.S. Lung and Gut Microbiota Interactions with Air Pollution and Aging in Human Chronic Diseases. In Gut Microbiota in Aging and Chronic Diseases; Marotta, F., Ed.; Healthy Ageing and Longevity; Springer International Publishing: Cham, Switzerland, 2023; Volume 17, pp. 215–236. ISBN 978-3-031-14022-8. [Google Scholar]
  142. Tripathi, A.; Debelius, J.; Brenner, D.A.; Karin, M.; Loomba, R.; Schnabl, B.; Knight, R. The Gut–Liver Axis and the Intersection with the Microbiome. Nat. Rev. Gastroenterol. Hepatol. 2018, 15, 397–411. [Google Scholar] [CrossRef] [PubMed]
  143. Chen, J.; Hall, S.; Vitetta, L. Altered Gut Microbial Metabolites Could Mediate the Effects of Risk Factors in COVID-19. Rev. Med. Virol. 2021, 31, 1–13. [Google Scholar] [CrossRef] [PubMed]
  144. Seki, E.; De Minicis, S.; Osterreicher, C.H.; Kluwe, J.; Osawa, Y.; Brenner, D.A.; Schwabe, R.F. TLR4 Enhances TGF-Beta Signaling and Hepatic Fibrosis. Nat. Med. 2007, 13, 1324–1332. [Google Scholar] [CrossRef]
  145. Tilg, H.; Adolph, T.E.; Trauner, M. Gut-Liver Axis: Pathophysiological Concepts and Clinical Implications. Cell Metab. 2022, 34, 1700–1718. [Google Scholar] [CrossRef]
  146. Anand, S.; Mande, S.S. Host-Microbiome Interactions: Gut-Liver Axis and Its Connection with Other Organs. NPJ Biofilms Microbiomes 2022, 8, 89. [Google Scholar] [CrossRef]
  147. Hilliard, K.L.; Allen, E.; Traber, K.E.; Yamamoto, K.; Stauffer, N.M.; Wasserman, G.A.; Jones, M.R.; Mizgerd, J.P.; Quinton, L.J. The Lung-Liver Axis: A Requirement for Maximal Innate Immunity and Hepatoprotection during Pneumonia. Am. J. Respir. Cell Mol. Biol. 2015, 53, 378–390. [Google Scholar] [CrossRef]
  148. Herrero, R.; Sánchez, G.; Asensio, I.; López, E.; Ferruelo, A.; Vaquero, J.; Moreno, L.; de Lorenzo, A.; Bañares, R.; Lorente, J.A. Liver-Lung Interactions in Acute Respiratory Distress Syndrome. Intensive Care Med. Exp. 2020, 8, 48. [Google Scholar] [CrossRef]
  149. Petschow, B.; Doré, J.; Hibberd, P.; Dinan, T.; Reid, G.; Blaser, M.; Cani, P.D.; Degnan, F.H.; Foster, J.; Gibson, G. Probiotics, Prebiotics, and the Host Microbiome: The Science of Translation. Ann. N. Y. Acad. Sci. 2013, 1306, 1–17. [Google Scholar] [CrossRef]
  150. Chen, W.-X.; Ren, L.-H.; Shi, R.-H. Enteric Microbiota Leads to New Therapeutic Strategies for Ulcerative Colitis. World J. Gastroenterol. WJG 2014, 20, 15657. [Google Scholar] [CrossRef] [PubMed]
  151. Udayappan, S.D.; Hartstra, A.V.; Dallinga-Thie, G.M.; Nieuwdorp, M. Intestinal Microbiota and Faecal Transplantation as Treatment Modality for Insulin Resistance and Type 2 Diabetes Mellitus. Clin. Exp. Immunol. 2014, 177, 24–29. [Google Scholar] [CrossRef] [PubMed]
  152. Dietert, R.R.; Dietert, J.M. The Microbiome and Sustainable Healthcare. Healthcare 2015, 3, 100–129. [Google Scholar] [CrossRef] [PubMed]
  153. Petersen, C.; Round, J.L. Defining Dysbiosis and Its Influence on Host Immunity and Disease. Cell. Microbiol. 2014, 16, 1024–1033. [Google Scholar] [CrossRef]
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Figure 1. Environmental factors and host–microbiome interactions determine the fate of microbiome shift. While an increase in healthy microbiome composition suppresses pathogen invasion, dysbiosis leads to immune infiltration and disruption of tissue barrier integrity. An increase in Ruminococcus, Bifidobacterium, and Lactobacillus can lead to an increase in SCFA production and reduce pathogen colonization, whereas alteration in the balance of Streptococcus, Staphylococcus, and Clostridium impacts disease severity. Environmental factors such as air pollution, diet, and exposure to antibiotics modulate this balance and alter the cellular responses such as barrier integrity, increased neutrophilic infiltration, and increased ROS production.
Figure 1. Environmental factors and host–microbiome interactions determine the fate of microbiome shift. While an increase in healthy microbiome composition suppresses pathogen invasion, dysbiosis leads to immune infiltration and disruption of tissue barrier integrity. An increase in Ruminococcus, Bifidobacterium, and Lactobacillus can lead to an increase in SCFA production and reduce pathogen colonization, whereas alteration in the balance of Streptococcus, Staphylococcus, and Clostridium impacts disease severity. Environmental factors such as air pollution, diet, and exposure to antibiotics modulate this balance and alter the cellular responses such as barrier integrity, increased neutrophilic infiltration, and increased ROS production.
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Figure 2. Mechanism of air-pollution-mediated microbial alteration and inflammation. In the healthy state, short-chain fatty acids maintain immune homeostasis by inducing the production of anti-inflammatory mediators and balance between immune cells. In the case of air pollution, excessive production of ROS disrupts epithelial barriers, production of pro-inflammatory mediators (IL-17), and subsequent production of IgA and IgG, and increased NF-kB activity leads to a significant shift in innate and adaptive immunity. Gut-derived altered secondary metabolite production (CCK, GLP, and PYY) and SCFA imbalance reduce barrier integrity and increase Treg and DC infiltration. Acetate, propionate, and butyrate, through binding to lung receptors, modulate lung microbiome changes. Moreover, reduced expression of MCT1 and SMCT1 (transmembrane proteins) leads to decreased diffusion, thus increasing the accumulation of inflammatory mediators.
Figure 2. Mechanism of air-pollution-mediated microbial alteration and inflammation. In the healthy state, short-chain fatty acids maintain immune homeostasis by inducing the production of anti-inflammatory mediators and balance between immune cells. In the case of air pollution, excessive production of ROS disrupts epithelial barriers, production of pro-inflammatory mediators (IL-17), and subsequent production of IgA and IgG, and increased NF-kB activity leads to a significant shift in innate and adaptive immunity. Gut-derived altered secondary metabolite production (CCK, GLP, and PYY) and SCFA imbalance reduce barrier integrity and increase Treg and DC infiltration. Acetate, propionate, and butyrate, through binding to lung receptors, modulate lung microbiome changes. Moreover, reduced expression of MCT1 and SMCT1 (transmembrane proteins) leads to decreased diffusion, thus increasing the accumulation of inflammatory mediators.
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Figure 3. Gut–liver–lung’s axis regulation alteration by the microbiome. Factors such as diet, pollution, and antibiotics alter the gut microbiome, which produces SCFAs and other secondary metabolites. These metabolites travel through the portal vein and induce activation of macrophages and neutrophils. Induced cytokines, immune regulators, and secondary metabolites through systemic circulation regulate ROS generation, CRP production, and epithelial damage in the lungs. These also led to alterations in the diversity and richness of the lung microbiome. Microbiome change in the respiratory tract caused by air pollution also modulates the alteration of microbial balance in the gut through the lung–gut–liver axis.
Figure 3. Gut–liver–lung’s axis regulation alteration by the microbiome. Factors such as diet, pollution, and antibiotics alter the gut microbiome, which produces SCFAs and other secondary metabolites. These metabolites travel through the portal vein and induce activation of macrophages and neutrophils. Induced cytokines, immune regulators, and secondary metabolites through systemic circulation regulate ROS generation, CRP production, and epithelial damage in the lungs. These also led to alterations in the diversity and richness of the lung microbiome. Microbiome change in the respiratory tract caused by air pollution also modulates the alteration of microbial balance in the gut through the lung–gut–liver axis.
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Table 1. Dominant bacterial community profiles in various body sites (arranged in descending order).
Table 1. Dominant bacterial community profiles in various body sites (arranged in descending order).
Body SiteDominant Bacterial Communities
SkinCorynebacteria, Propionibacteria, Staphylococcus, Streptococcus, Moraxella, Dolosigranulum
Oral cavityPrevotella, Veillonella, Streptococcus, Corynebacteria, Neisseria, Haemophilus, Fusobacterium, Rothia
LungPrevotella, Streptococcus, Haemophilus, Fusobacterium, Actinobacteria
GutFirmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria
Urogenital tractPrevotella, Gardnerella, Atopobium, Lactobacillus, Escherichia, Enterococcus, Shigella, Streptococcus, Citrobacter
Table 2. Lung microbiota differs among healthy individuals and respiratory disease patients.
Table 2. Lung microbiota differs among healthy individuals and respiratory disease patients.
ConditionTaxa (Major Genera)
Healthy [53]Veillonella, Fusobacterium, Prevotella, Streptococcus, Porphyromonas, Neisseria
Asthma [54]Haemophilus, Streptococcus, Prevotella, Klebsiella, Moraxella
COPD [55,56]Moraxella, Streptococcus, Haemophilus, Streptococcus, Pseudomonas
Lung cancer [57,58]Streptococcus, Abiotrophia, Granulicatella, Veilonella, Staphylococcus, Haemophilus
Cystic fibrosis [59,60]Streptococcus, Prevotella, Veillonella, Gemella, Neissera, Rothia, Actynomyces, Haemophilus
Idiopathic pulmonary fibrosis [61,62]Hemophilus, Neisseria, Streptococcus, Staphylococcus, Veillonella
Table 3. Human studies performed on microbial dysbiosis and air pollution.
Table 3. Human studies performed on microbial dysbiosis and air pollution.
Study PopulationExposureSample TypeResults Summary
Healthy and COPD Volunteers [70]PM2.5Sputum sampleHigher FEV1/FVC ratio to bacterial load (+),
OTU (+)
Farmer’s Market Vendors [69]PM2.5−200 ug/m3, PM10−300 ug/m3Pharyngeal swabsChao1 ↑, ACE ↑,
correlation with microbiome: smog (+), gender (+), smoking (+), mask (−)
Healthy Volunteers [71]PM2.5, PM10Nasal swabShannon (−), Chao1 (−), PD whole tree (−)
Asthmatic Children [73]PM2.5 or ozoneBroncho alveolar lavageSpecies richness (−), observed species (−)
Young Adults [74]PM2.5SputumCytokine ↑: IL4, IL6, IL17, TNF−a, IFN−g
Healthy Volunteers [65]PM2.5, PM10, NOThroat swab Lung function ↓
Lung Cancer Patients [72]PM10Lung tissuesPD whole tree (+)
Children [64]Traffic-related air pollutionSaliva and sputumShannon ↑, observed ASV ↑, phylogenetic diversity ↑
Healthy and Lung Cancer Females [67]Household air pollutionSputumAlpha diversity (−), observed species (−), unweighted UniFrac (+)
Healthy Subjects [66]Household air pollutionBroncho alveolar lavageNo alpha, beta diversity change
Adults [75]Indoor dustNasopharyngeal swabsASV, Shannon
Healthy Young Adults [68]O3−200 ppb; 2 hNasal secretionSerum CC16 ↑, FEV1 ↓, FVC ↓, glucose ↑, lactic acid ↑, D−glyceric acid
ACE ↓, Simpson ↓, Shannon ↓, weighted UniFrac (#)
↑ increase in index, ↓ decrease in index, # distinct difference present, (+) positive correlation to exposure, (−) negative correlation to exposure.
Table 5. Human studies performed on air pollution and GI tract microbiome alterations.
Table 5. Human studies performed on air pollution and GI tract microbiome alterations.
Study PopulationExposureSample TypeResults Summary
Children between ages 3 and 5 [90]Air PAH levelSoil, stool, skinPPAR (+), adipocytokine signaling pathway (+)
Young adults [88]PM2.5, PM1Stool Type 2 diabetes (+), Shannon (−), Chao1 (−), PD whole tree (−)
Adults [94]PM2.5Stool Shannon ↓
Children [92]PM10, PM2.5, smogGutNo Shannon and Chao1 index difference
No weighted and unweighted UniFrac change
Adults [93]Traffic-related air pollution, nitrogen oxidesGutImpaired glucose homeostasis
Young adults [91]Air pollutionGutShannon ↑
↑ increase in index, ↓ decrease in index, (+) positive correlation to exposure, (−) negative correlation to exposure.
Table 6. Studies performed on air pollution and microbiome alteration in animals.
Table 6. Studies performed on air pollution and microbiome alteration in animals.
Study PopulationExposureSample TypeResults Summary
C57BL/6J mice, male [96]PM2.5Gut and gut content↑ Feces: observed OUT, Chao1, PD whole tree,
unweighted UniFrac (+), Bray–Curtis similarity (+)
BALB/c mice, male [98]PM2.5GutIL-6 ↑, IL-8 ↑, TNF-a ↑,
OTU ↓, Chao1 ↑, Shannon↑
C57BL/6 mice, male [82]CB, O3 and CB + O3Fecal contentTotal bacterial load ↑,
SCFA: acetate ↑, propionate ↑
Sprague Dawley rats, male [97]PM2.5StoolShannon ↑, Chao1 ↑, Simpson ↓, ACE ↑,
weighted UniFrac (+)
C57BL/6 mice, male [102]Ultra-fine particlesFecal contentASV ↑, Shannon ↑
Ldr KO mice [103]Ultra-fine particlesGut contentChao1 ↓, Faith PD ↓, Shannon ↓,
unweighted UniFrac (+), weighted UniFrac (+),
↑plasma: TNF-a, MCP-1, LPC18:1
C57BL/6J mice, male [100]Concentrated ambient particleFecesGlucose intolerance (+), insulin resistance (+),
ACE ↓, Chao1 ↓
C57BL/6 mice, female [99]Diesel exhaust particleGut contentShannon ↓, Simpson ↓,
weighted UniFrac (+)
Cecal SCFA ↓, triglycerides ↓
C57BL/6 mice, male [79]Diesel exhaust particleGut contentChao1 ↓, ACE ↓,
plasma LPS ↑, IL-13 ↑, G-CSF ↑, MIP-2 ↑, TNF-a ↑
C57BL/6J mice, male [95]Diesel exhaust particleFecesOUT ↓, Chao1 ↓, Shannon ↓, Goods coverage ↑,
unweighted UniFrac (+)
BABL/c mice, female [104]House dustGut contentFast UniFrac (+),
↓ lung: IL-13, IL-4
C57BL/6 mice, male [105]Cigarette smokeGut contentShannon ↓,
Muc5b ↑, Muc4 ↓
C57BL/6 mice [106]Carbon nanotube + cigarette smokeFecesShannon ↑, Chao1 ↑, total protein content ↑, CXCL1 ↑, TGF-beta ↑
Sprague Dawley rats, male [101]Ambient NO2Gut PD whole tree ↑, unweighted UniFrac (+),
cardiac mfn2 ↓, HSP70↓
↑ increase in index, ↓ decrease in index, (+) positive correlation to exposure.
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Mazumder, M.H.H.; Hussain, S. Air-Pollution-Mediated Microbial Dysbiosis in Health and Disease: Lung–Gut Axis and Beyond. J. Xenobiot. 2024, 14, 1595-1612. https://doi.org/10.3390/jox14040086

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Mazumder MHH, Hussain S. Air-Pollution-Mediated Microbial Dysbiosis in Health and Disease: Lung–Gut Axis and Beyond. Journal of Xenobiotics. 2024; 14(4):1595-1612. https://doi.org/10.3390/jox14040086

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Mazumder, Md Habibul Hasan, and Salik Hussain. 2024. "Air-Pollution-Mediated Microbial Dysbiosis in Health and Disease: Lung–Gut Axis and Beyond" Journal of Xenobiotics 14, no. 4: 1595-1612. https://doi.org/10.3390/jox14040086

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