Intestinal barrier damage is associated with fine particulate matter (PM2.5)-induced pathological aortic injury in mice

Xiangyong Hu; Ming Lei; Liping Du; Hongju Xiang; Jiaxin Hu; Jiaqi Yu; Zhixiong Liao; Yuyu Li

doi:10.1371/journal.pone.0345110

Abstract

Chronic exposure to air pollution is associated with an increased cardiovascular disease (CVD) risk, and inflammation induced by fine particulate matter (PM_2.5) exposure is a key driver in CVD development. However, the mechanism by which PM_2.5 causes cardiacovescular damage remains unclear. Here, Balb/c mice were intratracheally instilled with PM_2.5 suspension at doses of 2.0 mg/kg or 4.0 mg/kg body weight for 7 consecutive days to establish an aortic injury model. Pathological changes were assessed by hematoxylin and eosin (H&E), elastic Van Gieson, and Masson’s trichrome staining. Potential pathways were identified through GeneCards database analysis, R language, and Metascape pathway enrichment analysis. Immune cell profiles in the blood were analyzed by flow cytometry, and serum inflammatory cytokines were measured by enzyme-linked immunosorbent assay. Confocal microscopy was used to evaluate inflammatory cell infiltration in the aorta. Intestinal barrier integrity was assessed by transmission electron microscopy; H&E, and immunofluorescence staining; and western blotting. We found that high-dose PM_2.5 exposure led to inflammatory cell infiltration, disorganization of elastic fiber layers, and aortic tissue fibrosis. Pathway enrichment analyses indicated the involvement of pathways related to the regulation of inflammatory responses and responses to bacterial molecules. Increased inflammatory cells and pro-inflammatory cytokines were detected in the blood, accompanied by an increase in circulating lipopolysaccharide. PM_2.5 exposure disrupted the intestinal mucosal barrier, leading to reduced claudin-1 and occludin (tight junction protein) expression, which exacerbated systemic inflammation and induced aortic injury. In conclusion, PM_2.5 exposure caused pathological aortic damage and exacerbated systemic inflammation, potentially mediated by compromised intestinal barrier integrity.

Citation: Hu X, Lei M, Du L, Xiang H, Hu J, Yu J, et al. (2026) Intestinal barrier damage is associated with fine particulate matter (PM_2.5)-induced pathological aortic injury in mice. PLoS One 21(3): e0345110. https://doi.org/10.1371/journal.pone.0345110

Editor: Jordan Robin Yaron, Arizona State University, UNITED STATES OF AMERICA

Received: May 28, 2025; Accepted: March 2, 2026; Published: March 20, 2026

Copyright: © 2026 Hu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting information files.

Funding: This study was supported by the Zhangjiajie City Science and Technology Innovation Project (202448). And, the funders participated in the study design, data collection and analysis, decision to publish, and preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

In recent years, air pollution, particularly fine particulate matter with an aerodynamic diameter of ≤ 0.5 μm (PM_2.5), has become a major environmental factor threatening human health [1,2]. PM_2.5 carries a wide range of toxic substances, can remain suspended in the air for extended periods, and easily penetrates the alveolar walls, subsequently entering the circulatory system [3,4]. Epidemiological studies have demonstrated a strong association between PM_2.5 exposure and the occurrence and progression of cardiovascular disease (CVD) [5,6]. Moreover, animal experiments have confirmed that short-term exposure to environmental PM_2.5 can exacerbate cardiac injury [7]. According to the World Health Organization, approximately 17.3 million people die annually from CVD, accounting for 30% of deaths globally [8–10]. However, the precise mechanism underlying PM_2.5-induced cardiovascular damage remains unclear.

Inflammation is a crucial defense mechanism that occurs in response to cellular damage [11–14]. Evidence suggests that inflammation induced by PM_2.5 exposure is a key driver in the development and progression of CVD [7]. In recent years, the intestinal barrier and its associated microbiota have garnered significant research attention, with numerous studies showing that intestinal barrier disruption can lead to both acute and chronic inflammatory responses [15–17]. Damage to the intestinal barrier allows gut-derived contents, such as lipopolysaccharides (LPS) and bacterial ribosomal DNA, to enter the bloodstream. This exacerbates systemic inflammation by promoting the expression of pro-inflammatory factors and leading to the recruitment of inflammatory cells [18]. Emerging evidence supports the concept of a specific “gut-aorta axis,” where gut-derived mediators directly influence aortic health [19]. Studies show that microbiota-derived metabolites, such as trimethylamine N-oxide (TMAO), are elevated in patients with aortic pathologies like dissection and aneurysm and can promote disease progression in models [20,21]. Conversely, beneficial metabolites like short-chain fatty acids (SCFAs) from fiber fermentation can attenuate vascular inflammation and atherosclerosis [22]. A pivotal link in this axis is the intestinal barrier; its compromise permits translocation of bacterial products, such as LPS into systemic circulation, fueling a pro-inflammatory state that targets the vasculature. Therefore, the intestinal barrier serves as a critical interface, and its dysfunction may be a key mechanism translating systemic insults, such as PM_2.5 exposure, into aortic inflammation and injury.

However, it remains unclear whether PM_2.5-induced aortic injury is associated with intestinal barrier dysfunction. To investigate this potential link via the gut-aorta axis, we established a mouse model of repeated PM_2.5 exposure. As outlined in Fig 1, we hypothesize that inhaled PM_2.5 not only acts directly on the vasculature but also impairs the intestinal barrier integrity. This breach permits the translocation of microbial products LPS into the circulation, thereby amplifying systemic inflammation which subsequently targets and injures the aortic tissue. Our study specifically investigates this cascade by assessing PM_2.5-induced aortic damage concurrent with markers of intestinal permeability, systemic inflammation, and gut-derived endotoxemia.

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Fig 1. Schematic diagram showing the role of the gut–aorta axis in PM_2.5 injury.

SMC, smooth muscle cell. LPS, Lipopolysaccharides. PM_2.5, Particulate matter 2.5.

https://doi.org/10.1371/journal.pone.0345110.g001

In this study, we established a PM_2.5-induced mouse model of aortic injury and investigated the potential role of intestinal barrier dysfunction in the response to PM_2.5 (Fig 1). This research aims to elucidate the mechanisms linking PM_2.5 exposure, intestinal barrier damage, and aortic pathology.

Materials and methods

Animals

Thirty BALB/c mice (specific pathogen-free grade, 6–8 weeks old, female sex) were purchased from Beijing Vital River Laboratory Animal Technology Co. Ltd. The mice were housed in plastic cages with ad libitum access to food and water at the Enshi Central Hospital Animal Experimental Center (temperature 22°C ± 2°C, light cycle from 8 AM to 8 PM). All experimental procedures were approved by the Institutional Ethics Committee of the Central Hospital of Enshi Tujia and Miao Autonomous Prefecture and were conducted in strict accordance with the Guidelines for Animal Experiments.

Preparation of PM_2.5 samples

PM_2.5 samples were collected and prepared as described previously [23]. Briefly, PM_2.5 was collected on quartz microfiber filters with a high-flow sampler, and the filters were then sliced into small fragments, immersed in ultrapure water, and subjected to ultrasonic treatment for 1 hour. The suspension was filtered through gauze and freeze-dried for 48 hours using a vacuum freeze dryer to obtain PM_2.5 powder. The PM_2.5 powder was aliquoted and stored at −80°C.

PM_2.5 exposure

Twenty mice (n = 10 per group) were lightly anesthetized using isoflurane and subjected to intratracheal injection. On the basis of previous studies, the PM_2.5 doses used in this study were 2.0 mg/kg and 4.0 mg/kg body weight. Each mouse received daily PM_2.5 treatment (2.0 mg/kg or 4.0 mg/kg body weight) or saline for 7 consecutive days. Twenty-four hours after the last PM_2.5 dose, the mice were euthanized under 3% sodium pentobarbital anesthesia.

Aortic tissue pathology

After the aortic tissues had been excised, they were fixed in 4% paraformaldehyde (EE0001; Sparkjade Biotechnology, Shandong, China) for 48 hours, before being dehydrated in sucrose solutions of varying concentrations and embedded in OCT compound (Order Number 4583; SAKURA Tissue-Tek® O.C.T. Compound). Serial transverse sections were cut at a thickness of 5 μm for subsequent staining procedures.

Hematoxylin and eosin (H&E) staining

Aortic tissue sections were stained following standard H&E protocols. Briefly, sections were incubated with Mayer’s hematoxylin (Sparkjade) for 5 minutes, rinsed in distilled water, differentiated in Bluing Reagent, and counterstained with eosin Y solution for 2–3 minutes. Following dehydration through a graded ethanol series and clearing, slides were mounted with a synthetic resin. For quantitative analysis, whole slide images were acquired and analyzed using ImageJ software (NIH). The area of inflammatory cell infiltration was quantified by applying a color threshold to identify nuclei-dense regions, and the result was expressed as a percentage of the total aortic cross-sectional area.

Elastica Van Gieson (EVG) staining

EVG staining was performed according to the manufacturer’s instructions (Sigma-Aldrich). Sections were immersed in working Elastic Stain Solution for 15 minutes, rinsed, differentiated in a differentiating solution, and treated with sodium thiosulfate. Counterstaining was carried out with Van Gieson’s solution for 2–5 minutes, followed by dehydration and mounting. The integrity of elastic fibers was assessed quantitatively. Elastin breakage and disorganization were evaluated and scored by two independent pathologists who were blinded to the experimental groups.

Masson’s Trichrome staining

Staining was conducted using a standard Masson’s Trichrome kit (G1340; Solarbio Life Sciences, Beijing, China) to distinguish collagen (blue) from muscle fibers (red). The procedure involved sequential staining in Weigert’s iron hematoxylin, Biebrich scarlet-acid fuchsin, and aniline blue solutions, with differentiation in phosphomolybdic/phosphotungstic acid, as per the manufacturer’s protocol. To quantify fibrosis, stained sections were analyzed using ImageJ software. The fibrotic area (stained blue) was isolated via color deconvolution and thresholding, and collagen deposition was expressed as the percentage of the blue-positive area relative to the total tissue area.

Immunofluorescence staining

Fixed aortic sections were permeabilized with 0.3% Triton X-100 (Sigma-Aldrich) and blocked with 5% bovine serum albumin (BSA) for 1 hour at room temperature. Sections were then incubated overnight at 4°C with primary antibodies: rabbit anti-CD68 (1:200) and rat anti-Ly6G (1:200). After washing with PBS, sections were incubated with Alexa Fluor 488-conjugated goat anti-rabbit and Alexa Fluor 555-conjugated goat anti-rat secondary antibodies (1:500, Thermo Fisher) for 1–2 hours at room temperature in the dark. Nuclei were counterstained with DAPI (ZLI-9557; ZSGB-Bio, Beijing, China) for 5 minutes before mounting. Images were captured using a confocal laser scanning microscope (Olympus FluoView 3000). For quantitative analysis, the mean fluorescence intensity of CD68 and Ly6G signals was measured within defined regions of interest (ROIs) encompassing the aortic media and adventitia using ImageJ software. Background fluorescence from control areas was subtracted to obtain the final intensity values.

Bioinformatics analysis

According to our previously studies [24,25], Gene-related data were downloaded from the GeneCards database (https://www.genecards.org/). Venn diagrams were created using the Hiplot website (https://hiplot.com.cn/). Pathway enrichment analyses were performed using R language and the Metascape online tool (https://metascape.org/).

Flow cytometry

Flow cytometry analysis and gating strategy according to previous study [26]. Briefly, whole blood was collected from the mice with ethylenediaminetetraacetic acid anticoagulant. A 100 μL blood sample was treated with red blood cell lysis buffer (555899; BD Biosciences, San Jose, CA) and incubated at room temperature for 10 minutes. After washing with PBS, the samples were centrifuged to remove the supernatant. Fluorescently labeled monoclonal antibodies were added to the samples and incubated in the dark at 4°C for 1 hour. The samples were then washed with PBS. Sample analysis was performed using LSRFortessa (BD Biosciences, San Jose, CA), and FlowJo software (Ashland, OR) was used for flow cytometry data analysis.

Transmission electron microscopy (TEM)

Colonic tissues from the mice were cut into 3 mm³ blocks, fixed in electron microscopy fixative (P1126; Solarbio Life Sciences, Beijing, China) for 4 hours, and washed three times with PBS. The samples were then dehydrated in acetone. The samples were immersed in a 1:1 and 2:1 mixture of epoxy resin and acetone at room temperature for 2–4 hours, followed by overnight immersion in pure resin. The samples were transferred to embedding molds and filled with pure resin for embedding. Ultra-thin sections (50–90 nm) were obtained using an ultramicrotome. The sections were placed on copper or nickel grids and stained with 2% uranyl acetate for 15–30 minutes, followed by lead citrate staining for 5–15 minutes. The stained samples were observed and imaged by TEM.

Western blotting

Total protein was extracted from intestinal tissues and lysed in RIPA buffer supplemented with protease inhibitor (1861278; Thermo Fisher Scientific, USA) and protein phosphatase inhibitor (A32957; Thermo Fisher Scientific, USA) using a bead ruptor (OMNI Bead Ruptor 24; Omni Inc, USA). The homogenate was centrifuged at 12,000 × g for 15 minutes at 4°C. The supernatant protein concentration was determined using a bicinchoninic acid (BCA) protein assay kit (23227; Pierce, Thermo Scientific, USA). Equal amounts of protein (20−30 μg) were denatured, separated by 10% SDS-PAGE, and transferred to PVDF membranes (Millipore, Billerica, MA, #IPVH00010). Membranes were blocked with 5% BSA in TBST and incubated overnight at 4°C with primary antibodies against occludin (1:1000), claudin-1 (1:1000), and α-Tubulin (1:5000). After incubation with HRP-conjugated secondary antibodies (1:10000) at 37°C for 1 hour, protein bands were visualized using an enhanced chemiluminescence (ECL) detection system and imaged with an Amersham Imager 600. For quantification, band optical density was measured using the densitometry function in ImageJ software. The density of each target band (occludin, claudin-1) was normalized to that of the α-Tubulin loading control from the same lane to calculate the relative expression level.

Enzyme-linked immunosorbent assays

Cytokine concentration was measured by enzyme-linked immunosorbent assays (ELISA). TNF-α, IL-1β, IL-6 and CCL2 levels were detected using kits purchased from Fankew (Shanghai Kexing Trading Co., Ltd), and according to the manufacturer’s instructions.

Data analysis

GraphPad Prism 8.0 software (GraphPad Software, Inc., La Jolla, California, US) was used for graphing. The data are presented as the mean ± standard deviation. For pairwise comparisons, an unpaired Student’s t-test was utilized. For comparisons involving three groups with normally distributed data, a one-way analysis of variance (ANOVA) was conducted, followed by Tukey’s multiple comparison test. For non-normally distributed data, the Kruskal-Wallis test was used, with Dunn’s post-hoc tests for multiple comparisons. Statistical significance was determined using the following thresholds: *p < 0.05, **p < 0.01, and ***p < 0.001.

Results

Inflammation and fibrosis in the aortic tissues of mice after PM_2.5 exposure

To investigate the damage to aortic tissues caused by PM_2.5 exposure, we constructed an aortic injury model using low-dose and high-dose PM_2.5 exposure. H&E staining revealed significant inflammatory infiltration in the low-dose PM_2.5 exposure group, and this inflammation was markedly aggravated in the high-dose PM_2.5 exposure group (Fig 2A). Further analysis by EVG staining showed noticeable disruption of the elastic fiber layers in the aortae from the high-dose exposure group (Fig 2B). Masson’s trichrome staining suggested that PM_2.5 exposure aggravated collagen deposition in the vasculature (Fig 2C). Furthermore, immunofluorescence staining revealed significant recruitment of CD68-positive macrophages in the aortic tissue from the high-dose PM_2.5 group, while changes in LY6G-positive neutrophils were not as pronounced (Fig 2D). Overall, PM_2.5 exposure led to inflammatory infiltration and vascular damage in the aorta, with the severity of damage increasing in response to higher PM_2.5 concentrations.

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Fig 2. PM_2.5 exposure induces dose-dependent aortic injury characterized by inflammatory infiltration and structural disruption. A. Representative images of HE staining and the percentage of inflammatory cell infiltration in the aorta of mice treated with saline, low-dose PM_2.5 (2 mg/kg), or high-dose PM_2.5 (4 mg/kg) (n = 6).

Arrows indicate areas of inflammatory cell infiltration. Scale bars represent 200 μm and 50 μm. B. Representative images of aorta sections stained with EVG and Elastin break grades were analyzed (n = 6). Arrows indicate sites of elastic fiber layer disruption. Scale bars represent 200 μm and 50 μm. C. Representative images of aorta sections stained with Masson and the collagen expression level was analyzed (n = 6). Arrows indicate areas of collagen deposition. Scale bars represent 200 μm and 50 μm. D. Representative images and analysis of aorta sections labeled with antibodies against Ly6G (green) and CD68 (red), with nuclei stained using DAPI (blue) (n = 6). Scale bars represent 50 μm. Quantification graphs on the left and right represent the statistical results for Ly6G and CD68, respectively. *p < 0.05, **p < 0.01, and ***p < 0.001, data are presented as the mean ± SD, one-way ANOVA, Tukey’s multiple comparison test.

https://doi.org/10.1371/journal.pone.0345110.g002

The potential mechanism underpinning PM_2.5-induced aortic injury and inflammation

To explore the potential mechanisms underlying PM_2.5-induced aortic injury and inflammation, we used the GeneCards database (https://www.genecards.org/). Overall, 202 genes related to PM_2.5 exposure, 4,115 genes related to aortic endothelial cells, 6,533 genes related to aortic vascular smooth muscle cells, and 11,108 genes associated with aortic inflammation were extracted. These datasets were imported into the Hiplot platform (https://hiplot.com.cn/home/index.html). By analyzing the data, we identified 139 common genes, which were presented in a Venn diagram to show gene overlap (Fig 3A).

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Fig 3. Bioinformatic analysis identifies potential mechanisms and key pathways in PM2.5-induced aortic injury and inflammation. A. Venn diagrams of PM_2.5, aortic vascular smooth muscle, aortic endothelium, inflammation of the aorta, related genes from Genecards.

B. GO pathway enrichment analysis of the shared genes across different groups was performed using Metascape. C. KEGG pathway enrichment analysis of the common gene by R. Pathways are ordered by -log₁₀(p-value) from highest to lowest. D-F. GO pathway enrichment analysis by R (Cellular Component, Biological Process, Molecular Function). For panels D, E, and F, terms are ordered by p-value in ascending order from top to bottom.

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We also performed pathway enrichment analysis on these 139 common genes using various enrichment methods. Firstly, we used metascape (https://metascape.org/), confirming that the enriched pathways were primarily related to regulation of the inflammatory response, the response to molecules of bacterial origin, and the inflammatory response. Additionally, through protein–protein interaction analysis, several potential core molecules were identified (Fig 3B). Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated pathways such as regulation of inflammatory response, positive regulation of cytokine production, and response to molecules of bacterial origin (Fig 3C).

Further validation of Gene Ontology (GO) enrichment analysis using R software revealed that the Cellular Component (CC) category pointed to the RISC complex, RNAi effector complex, and vesicle lumen (Fig 3D). The Biological Process (BP) pathways were primarily involved in the regulation of inflammatory response and response to molecules of bacterial origin (Fig 3E). The Molecular Function (MF) category suggested pathways related to cytokine activity, mRNA base-pairing translational repressor activity, and translational repressor activity (Fig 3F). Overall, by using public datasets, we identified the genes associated with PM_2.5-induced aortic injury and inflammation, and the pathway enrichment analyses consistently identified regulation of the inflammatory response and the response to molecules of bacterial origin as key potential pathways involved in this process.

Inflammation was increased in the blood of PM_2.5-exposed mice

To investigate the cause of inflammatory infiltration in the aortic tissue, we assessed the inflammatory response by testing whole blood samples from the mice in each group (Fig 4A). We measured the concentrations of pro-inflammatory factors, including tumor necrosis factor-α, interleukin-1β, interleukin-6, and CCL2, in the serum. The results indicated that with the increase in PM_2.5 concentration, these pro-inflammatory cytokines and chemokines were significantly elevated (Fig 4B).

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Fig 4. PM_2.5 exposure elevates circulating inflammatory cytokines and immune cells in mice. A. Schematic of the experimental design in this study.

B. ELISA assessment of inflammatory cytokines TNF-α, IL-1β, IL-6, and CCL2 in murine serum across various groups (n = 6). C. Gating strategy for identification of monocytes and neutrophils in mouse blood. LY6C^high monocytes were identified as CD45⁺CD115⁺GR1⁺ and LY6C^low monocytes were identified as CD45⁺CD115⁺GR1^-, neutrophils were identified as CD45⁺CD115^-GR1⁺ . D. Representative flow cytometry analysis of circulating blood neutrophils, LY6C^high and LY6C^low monocytes in saline-, PM_2.5 lo- and PM_2.5 high-treated mice. E. Flow cytometry data were analyzed as depicted (n = 6). *p < 0.05, **p < 0.01, and ***p < 0.001, data are presented as the mean ± SD, one-way ANOVA, Tukey’s multiple comparison test.

https://doi.org/10.1371/journal.pone.0345110.g004

For the flow cytometry gating strategy, we first marked live and dead cells; labeled inflammatory cells with CD45; and used GR1⁺CD115⁻ to label neutrophils, GR1⁺CD115⁺ to label Ly6C^high monocytes, and GR1⁺CD115⁻ to mark Ly6C^low monocytes (Fig 4C). The flow cytometry results showed that PM_2.5 exposure significantly increased the number of CD45⁺ cells, neutrophils, and Ly6C^high monocytes. All of these cell types significantly increased with the increase in PM_2.5 concentration (Fig 4D-E). Interestingly, the number of Ly6C^low monocytes also increased. This could be related to the overall increase in monocytes or to collagen deposition in the aorta. Overall, PM_2.5 exposure increased both inflammatory cells and inflammatory factors in the blood of mice.

The compromised intestinal barrier in PM_2.5-exposed mice

Lipopolysaccharide (LPS) is known to induce a severe inflammatory response. We observed a significant increase in LPS in the serum of PM_2.5-exposed mice (Fig 5A). Coinciding with this, quantification of bacterial 16S rDNA in the blood confirmed an increased bacterial load in these mice (S1 Fig). On the basis of the results of the bioinformatics analysis, we hypothesized that PM_2.5 exposure may have led to intestinal barrier dysfunction, allowing lipopolysaccharide to pass through the compromised intestinal barrier and enter the circulation, thereby inducing the recruitment of inflammatory cells and the release of pro-inflammatory cytokines.

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Fig 5. PM_2.5 exposure compromises the intestinal barrier and increases circulating lipopolysaccharide. A. ELISA analysis of LPS in murine serum at the endpoint (n = 6).

B and C. Gross morphology of the gastrointestinal tract from saline-, low dose of PM_2.5 – and high dose of PM_2.5 – treated mice (n = 6). D. Representative TEM image of sections from the intestinal epithelium of different groups. E. Representative HE images of intestine of saline-, low dose of PM_2.5 – and high dose of PM_2.5 – treated mice. F. Intestinal injury evaluation through HE staining of the intestine, presented as Chiu scores (n = 6). G and H. Protein expression levels of occludin and claudin 1 (n = 3). I. Representative immunofluorescence images of occludin and claudin 1 in the intestine of Saline-, low dose of PM_2.5 – and high dose of PM_2.5 – treated mice. Scale bar = 50 μm. J. Quantification of fluorescence intensity in (I) (n = 6). *p < 0.05, **p < 0.01, and ***p < 0.001, data are presented as the mean ± SD, one-way ANOVA, Tukey’s multiple comparison test.

https://doi.org/10.1371/journal.pone.0345110.g005

Upon measuring the colon in mice from the low-dose and high-dose exposure groups, we found that the colon was significantly shortened in PM_2.5-exposed mice (Fig 5B-C). TEM revealed that PM_2.5 exposure caused damage to the intestinal microvilli structure (Fig 5D). Pathological staining further showed that PM_2.5 exposure aggravated damage to the jejunum and colon (Fig 5E-F). Additionally, western blotting analysis confirmed the decrease in occludin and claudin-1 protein expression in the colon tissue of PM_2.5-exposed mice (Fig 5G-H). These findings were corroborated by immunofluorescence staining, which revealed significant reductions in these tight junction proteins (Fig 5I-J).

Discussion

Air pollution has become a significant public health issue in both developing and developed countries, and epidemiological studies have demonstrated that PM_2.5 is involved in the development of CVD. Previous research has also reported that PM_2.5 suspensions contain high concentrations of heavy metals, such as aluminum, chromium, nickel, and selenium, as well as organic compounds, such as phenanthrene, benzo(a)pyrene, and benzo(b)fluoranthene. These components can be inhaled with PM_2.5 particles, penetrating the pulmonary vascular walls and entering the bloodstream, posing a threat to the body. Increasing evidence suggests that gut microbiota dysbiosis and intestinal barrier dysfunction are major contributors to the systemic inflammatory response and organ damage, and that PM_2.5 exposure can affect target organs by altering the composition of the gut microbiota and associated metabolites [27,28].

Recently, animal studies have shown that PM_2.5 can reach the brain via the gut–brain axis, causing adverse effects on the central nervous system [29]. Clinical sample-based research has also indicated that PM_2.5 exposure can influence the hypothalamic–pituitary–adrenal axis through the gastrointestinal microbiome (gut–brain axis mechanism), thereby increasing the risk of neurological disease and CVD [30]. Investigating the link between PM_2.5 and the gut microbiome within the gut–vascular axis provides evidence of the potential mechanisms underlying PM_2.5-induced dysfunction in the nervous and cardiovascular systems.

The PM_2.5 doses used in this study (2.0 and 4.0 mg/kg via intratracheal instillation) were selected based on established experimental models for investigating particulate matter toxicity [23]. While this acute exposure model does not directly equate to a specific ambient concentration in humans, it serves to elucidate dose-dependent pathological mechanisms under controlled conditions. Similar doses have been employed in other respiratory toxicity studies to effectively model PM_2.5-induced injury, such as lung damage and systemic inflammation [6,31]. These studies, alongside our findings, support the utility of such models in uncovering the fundamental pathways by which PM_2.5 exposure contributes to tissue damage and inflammation, thereby providing mechanistic insights relevant to understanding its broader health risks.

While the bioinformatics analysis provided a crucial directional clue by highlighting pathways like “response to bacterial molecules,” leading to our focus on the gut-aorta axis, the specific list of 139 common genes identified warrants further investigation. Due to the scope and resource constraints of the present study, we prioritized the experimental validation of the overarching hypothesis of intestinal barrier compromise. The functional roles and interactions of these individual candidate genes in mediating PM_2.5-induced vascular injury represent an important direction for future research.

Although extensive research has been conducted, the specific mechanism by which PM_2.5 induces intestinal barrier dysfunction and subsequently exacerbates CVD remains incompletely understood. In this study, severe pathological changes were observed in the aortic tissues of PM_2.5-exposed mice. A large number of inflammatory cells were observed in the aortic tissues of the PM_2.5-exposed mice, and similar PM_2.5-induced pathological changes in cardiac tissues have also been reported in recent studies [32]. Moreover, compared with the control group, the elastic fiber plate in the aortic tissues of PM_2.5-exposed mice showed significant disruption, a phenomenon that has also been corroborated by previous research [33]. Additionally, the infiltration of CD68-labeled macrophages significantly increased in the aortic tissues, while the infiltration of LY6G-labeled neutrophils was not as pronounced.

We used public data from GeneCards and conducted pathway enrichment analysis using various methods, which consistently identified the potential involvement of certain pathways, including Regulation of the inflammatory response and Response to molecules of bacterial origin. We validated these pathways, and flow cytometry revealed that the blood of PM_2.5-exposed mice exhibited a significant increase in CD45⁺ inflammatory cells, GR1⁺CD115⁻ neutrophils, and GR1⁺CD115⁺ Ly6C^high monocytes. Interestingly, we also observed an increase in the number of GR1⁻CD115⁺ Ly6C^low monocytes, which could be linked to the overall increase in monocyte number, and is possibly associated with collagen deposition in the aorta. The elevated concentrations of pro-inflammatory cytokines in the blood further support our findings. Importantly, we discovered that lipopolysaccharide was elevated in the blood of PM_2.5-exposed mice. In the absence of infection, lipopolysaccharide typically indicates a gut-origin source, which aligns with the results of the pathway enrichment analysis. In addition, we also comprehensively assessed both the macro- and microscopic structure and function of the gut. As expected, we found that PM_2.5 exposure damaged the intestinal structure and reduced the expression of the tight junction proteins occludin and claudin-1, thereby compromising the integrity of the intestinal barrier. Thus, we suggest that PM_2.5 exposure leads to intestinal barrier damage, allowing lipopolysaccharide from the gut to enter the bloodstream, which accelerates the recruitment of inflammatory cells and the release of pro-inflammatory factors, ultimately contributing to inflammatory infiltration in the aorta and aortic damage.

Another consideration is the experimental model used. In this study, PM_2.5 was administered via intratracheal instillation, a method commonly employed to ensure precise dosing and delivery to the lower respiratory tract. However, this approach bypasses the natural defense mechanisms of the upper airways and delivers PM_2.5 as a bolus, which may not fully replicate the kinetics and distribution of chronic, low-dose ambient inhalation exposure in humans. Consequently, the injury observed here might represent a more acute and pronounced response. Future studies utilizing controlled inhalation exposure systems would be valuable to further validate these findings under conditions that more closely mimic real-world environmental exposure.

However, it should be noted that this study exclusively used female mice. Given the well-documented sex-specific differences in immune responses, hormonal profiles, and cardiovascular pathophysiology, the generalizability of our findings may be limited. Future studies incorporating both male and female subjects are warranted to determine whether the observed gut-aorta axis mechanism in PM_2.5-induced aortic injury is sex-dependent.

In summary, our study demonstrates that PM_2.5 induces pathological damage in aortic tissues of mice. Public database analysis and experimental validation indicate that the underlying mechanisms involve pathways related to the regulation of inflammatory response and response to molecules of bacterial origin. We provide evidence that PM_2.5 exposure accelerates the systemic inflammatory response by inducing intestinal barrier disruption, which contributes to inflammatory cell infiltration and injury in aortic tissues.

Supporting information

S1 Fig. Quantification of blood bacterial load per millilitre based on 16S rDNA content after 7 days of PM_2.5 exposure (n = 6).

https://doi.org/10.1371/journal.pone.0345110.s001

(TIFF)

S1 Table. Antibodies for immunofluorescence and flow cytometry.

https://doi.org/10.1371/journal.pone.0345110.s002

(XLSX)

S1 File. Raw image.

https://doi.org/10.1371/journal.pone.0345110.s003

(PDF)

Acknowledgments

The authors are grateful to PhD Weiyao Chen (Sun Yat-sen University) for scientific advices.

All experiments followed The Animal Research: Reporting of in vivo Experiments [ARRIVE] guidelines.

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30. Li T, Fang J, Tang S, Du H, Zhao L, Wang Y, et al. PM2.5 exposure associated with microbiota gut-brain axis: Multi-omics mechanistic implications from the BAPE study. Innovation (Camb). 2022;3(2):100213. pmid:35243467
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Figures

Abstract

Introduction

Materials and methods

Animals

Preparation of PM2.5 samples

PM2.5 exposure

Aortic tissue pathology

Hematoxylin and eosin (H&E) staining

Elastica Van Gieson (EVG) staining

Masson’s Trichrome staining

Immunofluorescence staining

Bioinformatics analysis

Flow cytometry

Transmission electron microscopy (TEM)

Western blotting

Enzyme-linked immunosorbent assays

Data analysis

Results

Inflammation and fibrosis in the aortic tissues of mice after PM2.5 exposure

The potential mechanism underpinning PM2.5-induced aortic injury and inflammation

Inflammation was increased in the blood of PM2.5-exposed mice

The compromised intestinal barrier in PM2.5-exposed mice

Discussion

Supporting information

S1 Fig. Quantification of blood bacterial load per millilitre based on 16S rDNA content after 7 days of PM2.5 exposure (n = 6).

S1 Table. Antibodies for immunofluorescence and flow cytometry.

S1 File. Raw image.

Acknowledgments

References

Preparation of PM_2.5 samples

PM_2.5 exposure

Inflammation and fibrosis in the aortic tissues of mice after PM_2.5 exposure

The potential mechanism underpinning PM_2.5-induced aortic injury and inflammation

Inflammation was increased in the blood of PM_2.5-exposed mice

The compromised intestinal barrier in PM_2.5-exposed mice

S1 Fig. Quantification of blood bacterial load per millilitre based on 16S rDNA content after 7 days of PM_2.5 exposure (n = 6).