PM_2.5 refers to airborne particles with an aerodynamic diameter ≤ 2.5 μm, characterized by a large surface area and strong adsorptive capacity for toxic substances such as heavy metals and polycyclic aromatic hydrocarbons. After inhalation, these particles penetrate deep into the alveoli and may translocate via the bloodstream or lymphatic system to distal organs, including the gut, where they significantly alter the microbial ecosystem (Zareba et al., 2024; Dong et al., 2022). Epidemiological and experimental evidence consistently supports a dose- and time-dependent relationship between PM_2.5 exposure and gut microbial alterations.

In population studies, residents chronically exposed to high PM_2.5 levels, particularly those living near heavy traffic or industrial areas, show a marked reduction in α-diversity, indicating lower microbial richness and evenness (Li et al., 2023; Shao et al., 2024). Prenatal exposure has also been implicated in adverse pregnancy outcomes; for example, a large cohort study involving 168,852 mothers revealed that maternal PM_2.5 exposure during gestation was significantly associated with an increased risk of preterm birth (Shi et al., 2024). Animal studies further confirm these findings. Mice exposed chronically to concentrated particulate matter (CPM; 70.9 ± 26.8 μg/m3) exhibited disruption of the intestinal barrier and altered microbiota composition, potentially mediated through activation of the TLR2/5–MyD88–NLRP3 signaling axis (Ran et al., 2024). Another experiment exposing mice to 198.5 μg/m3 PM_2.5 resulted in transient weight loss followed by compensatory gain, accompanied by marked alterations in intestinal microenvironment and metabolic signaling pathways (Dai et al., 2022).

Mechanistic insights have been provided by Shao et al. (2024) using a Versatile Aerosol Concentration Enrichment System (VACES) to expose male C57BL/6J mice to concentrated ambient PM_2.5 (CAP) or filtered air (FA). Through antibiotic-induced microbiota depletion and fecal microbiota transplantation (FMT), the study demonstrated that PM_2.5-induced glucose metabolic disorders were mediated by gut microbiota imbalance. Further analysis identified changes in short-chain fatty acids (SCFAs), particularly acetate, as a key metabolic link, and acetate supplementation effectively ameliorated the metabolic abnormalities (Shao et al., 2024). Together, these findings suggest that the gut microbiota plays a critical mediating role in PM_2.5-related metabolic dysfunction.

Ozone (O₃), a triatomic oxygen molecule with strong oxidative capacity, exists in both the stratosphere (as the protective “ozone layer”) and the troposphere, where it acts as a major pollutant (Chen et al., 2020). Ground-level ozone has become one of the most serious environmental issues in China and other rapidly developing regions (Feng et al., 2015). Its impact on the gut microbiota is primarily mediated through oxidative stress and systemic inflammation. For example, Ramot et al. (2015) exposed healthy and cardiovascular disease–prone rats to various concentrations of ozone for 4 h and observed species-specific differences in pulmonary and renal inflammation. Although no direct gut injury was reported, systemic inflammatory responses were evident, suggesting a potential link to gut microbial alterations through immune–oxidative pathways (Ramot et al., 2015).

Nitrogen oxides (NO_x), including nitric oxide (NO) and nitrogen dioxide (NO₂), are another class of traffic-related air pollutants with emerging relevance to gut microbiota disturbances (Leclerc et al., 2021; Sayegh et al., 2016). Epidemiological data show that exposure to traffic-related air pollution (TRAP) correlates with both gut microbiome composition and fasting blood glucose levels. Specifically, TRAP exposure is associated with a decrease in Bacteroidaceae abundance (r = −0.48, p = 0.001) and an increase in Ruminococcaceae (r = 0.48, p < 0.001). Furthermore, Bacteroidaceae abundance negatively correlates with fasting glucose (r = −0.34, p = 0.04), while Ruminococcaceae shows a positive correlation (r = 0.41, p < 0.01). Path analysis revealed that changes in these two microbial taxa explained approximately 24%−29% of the association between TRAP exposure and elevated fasting glucose levels (Alderete et al., 2018). These findings indicate that air pollution may influence host glucose metabolism via microbiota-mediated pathways.

Arsenic exists in both inorganic (As³⁺, As⁵⁺) and organic forms (e.g., monomethyl and dimethyl arsenic), with inorganic arsenic being considerably more toxic (Ganie et al., 2024). Drinking water is the major exposure route for humans, particularly in endemic regions such as Bangladesh and parts of western China, where arsenic concentrations in groundwater often exceed 10 μg/L (Sadee et al., 2025). Epidemiological studies have shown that high arsenic exposure correlates with distinct alterations in gut microbial composition. For example, children from arsenic-contaminated areas exhibited higher abundances of Proteobacteria and enrichment of 332 SEED functional genes related to virulence and antibiotic resistance. Moreover, Escherichia coli strains isolated from these children carried unique arsenic resistance operons with increased gene expression levels (Dong et al., 2017).

Animal experiments further confirmed the impact of arsenic on the gut microbiota. In a long-term study, C57BL/6 mice exposed to 0, 5, or 10 ppm sodium arsenite (NaAsO₂) via drinking water for 6 months developed significant liver injury and microbial dysbiosis (Li H. et al., 2024). Using 16S rRNA gene sequencing, Lu et al. (2014) demonstrated that 4 weeks of exposure to 10 ppm inorganic arsenic profoundly altered the gut microbial community structure in C57BL/6 mice.

Metabolomic profiling further revealed that arsenic exposure caused widespread disturbances in metabolites across multiple biological matrices (blood, liver, feces), many of which were products of microbial metabolism, indicating a close link between microbial dysfunction and systemic metabolic imbalance (Lu et al., 2014).

Cadmium and lead are among the most prevalent environmental heavy metals and share similar mechanisms of gut toxicity. Both induce oxidative stress, promote the selection of resistant bacterial strains, and disrupt microbial homeostasis (Liu et al., 2023).

Cadmium contamination primarily occurs through dietary intake, especially from rice cultivated in polluted soils (Wang et al., 2019). In a study by Wang H. et al. (2025), mice exposed to 3 mg/L cadmium in drinking water for 9 weeks exhibited cognitive impairment secondary to gut dysbiosis. The exposure disrupted the intestinal barrier, altered inflammatory cytokines, affected hippocampal gene expression, and modified gut-derived neuroactive metabolites, providing evidence that cadmium neurotoxicity is mediated through the gut–brain axis, with the microbiota serving as a key target for prevention and intervention (Wang H. et al., 2025). Similarly, studies on the freshwater snail Cipangopaludina chinensis revealed that cadmium exposure inhibited respiratory metabolism and immune responses, induced oxidative stress, and upregulated genes related to energy metabolism, suggesting an adaptive response to chronic cadmium stress (Wu et al., 2023).

Lead exposure, comparable in pathway to cadmium, occurs mainly through contaminated food and water (Kim et al., 2014). A population study involving 696 participants demonstrated that urinary lead concentration was positively associated with both α-diversity and β-diversity shifts in the gut microbiota. Specifically, higher urinary lead levels correlated with increased abundance of Proteobacteria and Burkholderiales, indicating that lead exposure may promote the proliferation of opportunistic taxa capable of heavy-metal tolerance (Eggers et al., 2019).

Mercury can be converted in the environment into methylmercury (MeHg), a highly toxic and bioaccumulative compound that enters the human body primarily through consumption of fish, particularly large predatory species (Wang et al., 2020a; Nielsen et al., 2018). Experimental data from multiple fish species suggest that dietary MeHg exposure rarely causes acute lethality, but it significantly affects growth, reproduction, and behavior at concentrations above 0.2–0.5 μg/g wet weight (Depew et al., 2012). Field observations confirm that even low MeHg levels may disrupt population stability in wild fish, though relevant ecological studies remain limited. In humans and mammals, both inorganic divalent mercury (Hg²⁺) and MeHg induce neurotoxicity and immunotoxicity, mainly through gastrointestinal exposure. However, the direct effects on intestinal epithelium and microbiota have been less studied. Using the Caco-2 intestinal epithelial cell model, researchers demonstrated that exposure to 0.5–1 mg/L of Hg²⁺ or MeHg (comparable to concentrations found in contaminated food) disrupted redox homeostasis, increased cellular permeability, and damaged tight junction integrity (Vázquez et al., 2014). These findings suggest that mercury exposure compromises intestinal barrier function, providing an entry point for systemic toxicity.

Beyond compositional changes, gut microbiota play an active role in the biotransformation of heavy metals through enzymatic and redox-mediated processes. For instance, specific microbial taxa can methylate or demethylate mercury and arsenic, thereby altering their chemical speciation, toxicity, and bioavailability. Sulfate-reducing bacteria have been shown to convert inorganic mercury into methylmercury, a neurotoxic form with enhanced absorption potential (Tepper et al., 2025). Conversely, demethylation or sequestration pathways may mitigate toxicity. Additionally, microbial redox transformation of metals such as chromium (Cr) and selenium (Se) can alter their valence state and associated risks (Raab, 2003). These transformations are mediated by microbial genes encoding metal reductases, oxidases, and transporters, which may be enriched in the gut microbiome under chronic exposure scenarios. Thus, microbial biotransformation serves as a double-edged sword—modulating, amplifying, or detoxifying metal species within the gut ecosystem.

PCBs and TCDD are classic ligands of the aryl hydrocarbon receptor (AhR), a transcription factor that regulates xenobiotic metabolism and immune responses. Activation of AhR by these pollutants can alter both host and microbial gene expression, leading to dysbiosis and impaired intestinal function. PCBs, a class of chlorinated aromatic compounds, remain widespread in the environment despite decades of regulation (Kimbrough, 1995). Experimental studies have shown that maternal exposure to PCB-126 significantly reduces microbial richness and diversity in adult offspring, alters specific bacterial taxa, and potentially increases susceptibility to chronic diseases later in life—effects that appear independent of diet or physical activity (Agarwal et al., 2023). Mechanistically, PCB-induced AhR activation enhances the expression of proinflammatory cytokines such as IL-6 and TNF-α, creating a chronic inflammatory microenvironment that suppresses the growth of beneficial, inflammation-sensitive bacteria (Lee et al., 2015).

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), one of the most toxic dioxin congeners, exerts similar effects through sustained AhR activation (Garattini, 1982). In mice, TCDD exposure has been shown to alter bile acid metabolism and induce non-alcoholic fatty liver disease (NAFLD), accompanied by increases in secondary bile acids and specific bacterial taxa such as Lactobacillus. Metagenomic analysis further revealed changes in genes associated with bile acid synthesis, suggesting a gut–liver axis–mediated mechanism (Fling and Zacharewski, 2021). In another study, Li J. et al. (2022) investigated maternal and lactational TCDD exposure in mice and found that high-dose exposure led to both maternal and offspring dysbiosis, disrupted tryptophan metabolism, and increased abundance of pathogenic bacteria. Interestingly, low-dose exposure had partial protective effects, reducing pathogenic taxa in offspring, indicating dose-dependent and transgenerational impacts of TCDD on gut microbial ecology (Li J. et al., 2022).

Dichlorodiphenyltrichloroethane (DDT), a well-known organochlorine pesticide, has been banned in most countries but remains persistent in the environment due to its high stability (Sudharshan et al., 2012). PBDEs, commonly used as flame retardants in plastics, textiles, and electronics, are another group of widespread POPs with structural and toxicological similarity to PCBs (Jiang et al., 2024). Both can alter gut microbial communities, though their specific effects differ depending on exposure conditions (Figure 4).

A study examining perinatal PBDE-47 exposure found that it disrupted gut microbiota development, growth, and metabolism in offspring. However, maternal supplementation with Lactobacillus reuteri during pregnancy and lactation mitigated these effects in a sex-dependent manner, restoring microbial diversity and improving body weight and neurobehavioral performance in offspring (Denys et al., 2025). Similarly, Tian et al. (2014) explored short-term PBDE-47 exposure in the marine sponge Cymaeformis and observed a time- and dose-dependent shift in the bacterial community from autotrophic to heterotrophic dominance, with loss of sulfur-oxidizing symbionts and enrichment of heterotrophic bacteria harboring specific metabolic genes. These results indicate that PBDEs exert selective pressure on microbial populations, reshaping both composition and functional potential.

Microplastics (MPs, 1 μm to 5 mm) and nanoplastics (NPs, <1 μm) are small plastic fragments produced through environmental degradation or industrial processes. They are widespread in aquatic, terrestrial, and atmospheric systems (Thompson et al., 2004). The impacts of these particles on gut microbiota involve three interrelated mechanisms: physical stress, chemical toxicity, and carrier (vector) effects (Qiao et al., 2021; Hsu et al., 2025). The magnitude of toxicity depends on particle size, surface chemistry, and polymer type.

Antibiotic resistance genes (ARGs) are mobile genetic elements that confer antibiotic resistance to microorganisms and are now recognized as a novel class of environmental contaminants (Zhao Y. et al., 2025). ARGs are abundant in soil, water, and animal waste, and can enter the human gut through consumption of contaminated food (e.g., vegetables, meat) or drinking water (Tan et al., 2023). Once inside the gut, ARGs can be horizontally transferred into commensal or pathogenic bacteria via horizontal gene transfer (HGT) mechanisms, leading to an expanded intestinal “resistome” and heightened risk of antibiotic-resistant infections (Haug et al., 2011).

Current studies focus on the efficiency of ARG transfer and its influence on gut microbiota composition (Casals-Pascual et al., 2018). HGT in the gut microbiome commonly occurs via transduction and conjugation, which facilitate gene exchange between symbiotic and opportunistic bacteria. Novel bioinformatic tools have enabled the identification of specific ARG–host associations and quantification of HGT frequency within microbial communities, offering new insights for developing targeted interventions to limit resistance gene propagation (McInnes et al., 2020).

Animal experiments further confirm the ecological risks of dietary ARG exposure. Using high-throughput quantitative PCR and 16S rRNA sequencing, researchers compared mice fed organically and conventionally grown lettuce and wheat for 8 weeks. In the organic group, the abundance and diversity of ARGs (e.g., tetracycline and multidrug resistance genes), mobile genetic elements (MGEs), and potential antibiotic-resistant bacteria (ARBs) increased significantly over time, whereas no such trend was observed in the conventional group. Additionally, MGEs such as IS613 were shown to modulate ARG profiles, while resistant pathogens including Bacteroides and Streptococcus became more enriched (Zhuang et al., 2024). This suggests that organic produce may serve as an unrecognized vector for ARG dissemination in the gut microbiota, underscoring the need for comprehensive risk assessment. The proliferation of resistant bacteria increases the likelihood of clinical treatment failure, forming a vicious cycle: from environmental ARGs to intestinal resistant bacteria to therapeutic resistance, which poses a major challenge to public health management (Yuan et al., 2024).

Pharmaceuticals and personal care products (PPCPs), encompassing antibiotics, analgesics, antidepressants, hormones, antiseptics, UV filters, and cosmetic ingredients, are an increasingly prominent class of environmental pollutants. They enter the environment primarily through wastewater discharge and agricultural runoff and are often resistant to complete degradation in conventional treatment systems (Jiang et al., 2023). As such, PPCPs represent a chronic, low-dose exposure risk to both aquatic organisms and humans.

Mounting evidence suggests that PPCPs can disrupt gut microbiota composition, diversity, and function, even at environmentally relevant concentrations. For instance, triclosan, a widely used antimicrobial found in soaps and toothpaste, has been shown to reduce the relative abundance of butyrate-producing Lachnospiraceae and Ruminococcaceae while increasing pro-inflammatory taxa such as Proteobacteria (Sinicropi et al., 2022). In mice, chronic triclosan exposure altered microbial metabolic pathways, leading to impaired epithelial barrier function and exacerbated colitis (Lian et al., 2025).

Non-antibiotic PPCPs such as carbamazepine (an antiepileptic) and fluoxetine (an antidepressant) have been shown to modulate microbial gene expression related to neurotransmitter metabolism and stress responses. In zebrafish models, fluoxetine exposure led to increased abundance of Actinobacteria and shifts in amino acid biosynthesis pathways, potentially linking microbiota changes to neurobehavioral phenotypes (Pinto et al., 2024). Moreover, metagenomic and metabolomic profiling of human populations exposed to multiple PPCPs (including NSAIDs and UV filters) revealed altered bile acid metabolism and reduced short-chain fatty acid (SCFA) levels, with implications for systemic inflammation and metabolic syndrome (Cheng et al., 2025).

Despite these advances, knowledge gaps remain regarding long-term consequences, mixture effects, and inter-individual variability in microbiota responses. Notably, most functional studies to date are limited to in vivo rodent models or aquatic species, with fewer high-resolution, longitudinal studies in human cohorts (Jiang et al., 2023). Future research should prioritize integrating multi-omics approaches, such as metagenomics, metabolomics, and transcriptomics with environmental exposure assessment to unravel the causal pathways linking PPCPs to host-microbiota dysregulation.

Taken together, these findings underscore the complex and dynamic nature of pollutant-induced gut microbiota disturbances. While short-term exposures often lead to reversible or transient microbial changes, longer-term exposures, particularly in animal models, have been shown to induce persistent shifts in microbiota composition and function. However, in humans, evidence for the persistence of such changes remains scarce, and further longitudinal and interventional studies are warranted to better elucidate the temporal stability of pollutant-driven dysbiosis.

Exposure to pollutants such as PM_2.5, BPA, and heavy metals (Cd, Pb) markedly alters microbial community composition, reducing the abundance of beneficial SCFA-producing genera (Faecalibacterium, Roseburia, Akkermansia) while expanding opportunistic taxa such as Desulfovibrio and Enterobacteriaceae (Wu et al., 2022; Klemenak et al., 2015; Moreira de Gouveia et al., 2024). These compositional changes result in lower levels of butyrate and propionate, key metabolites that regulate intestinal epithelial energy supply and systemic glucose homeostasis through the GPR41/43–AMPK axis (Zhang et al., 2022). Butyrate depletion weakens epithelial integrity, promotes low-grade endotoxemia, and triggers chronic inflammation—recognized hallmarks of metabolic disease progression.

Environmental toxicants interfere with microbial metabolism in multiple ways: (1) disruption of bile acid metabolism: pollutants alter bacterial bile salt hydrolase (BSH) activity, affecting the ratio of primary to secondary bile acids and impairing signaling through farnesoid X receptor (FXR) and TGR5, both critical for lipid and glucose regulation (Liu et al., 2025); (2) induction of endotoxemia and insulin resistance: increased intestinal permeability following pollutant exposure allows translocation of LPS into circulation, activating TLR4–NF-κB signaling in adipose and hepatic tissues. This inflammatory activation reduces insulin receptor sensitivity and accelerates metabolic syndrome (Kim et al., 2012); and (3) oxidative and mitochondrial stress: heavy metals and POPs impair mitochondrial β-oxidation and ATP production, thereby altering energy metabolism and promoting lipid accumulation (Zhan et al., 2022).

Accumulating evidence suggests that pollutant-induced dysbiosis may reprogram host metabolic responses over the long term, a phenomenon often referred to as microbiota-mediated metabolic memory. Current support for this concept is derived largely from animal models and mechanistic studies, with limited direct evidence in humans. For example, perinatal exposure to bisphenol A (BPA) or polybrominated diphenyl ethers (PBDEs) has been shown in rodent models to alter early-life microbial colonization and to associate with epigenetic modifications of lipid metabolism–related genes, including PPARγ and SREBP-1c, thereby predisposing offspring to obesity and glucose intolerance (López-Moreno et al., 2025). Similarly, chronic PM_2.5 exposure in experimental systems shifts the intestinal microbiome toward a pro-obesogenic profile, characterized by elevated branched-chain amino acids (BCAAs) and reduced short-chain fatty acids (SCFAs), which correlates with aggravated insulin resistance (Salehi et al., 2010).

Collectively, these findings support the hypothesis that the gut microbiota can function as a metabolic and epigenetic interface translating environmental exposures into altered disease susceptibility. Mechanistically, environmental pollutants disrupt microbial communities and key metabolic circuits by reducing SCFA synthesis, altering bile acid transformation, and increasing lipopolysaccharide (LPS) translocation. These microbial perturbations may impair FXR/TGR5 and GPR41/43 signaling, thereby promoting insulin resistance, lipid accumulation, and chronic low-grade inflammation, ultimately contributing to metabolic disorders such as obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD; Figure 9).

However, it is important to note that although pathways such as SCFA–GPR41/43 and AhR–IL-22 signaling have been repeatedly implicated in pollutant-associated metabolic dysregulation, the majority of mechanistic evidence originates from animal or in vitro studies. For instance, reduced butyrate levels are consistently associated with impaired barrier function and insulin resistance, yet direct causal relationships in human populations remain limited (Perl et al., 2025). Likewise, the immunometabolic roles of microbial tryptophan-derived AhR ligands are well established in murine models, but their contribution to long-term metabolic programming in humans has not been definitively demonstrated (Duan et al., 2025). In addition, substantial inter-individual variability including genetic background, dietary patterns, and baseline microbiota composition may modulate these pathways and influence susceptibility in complex and context-dependent manners (Chen L. et al., 2022). Therefore, while microbiota-mediated metabolic memory represents a compelling conceptual framework, further longitudinal human studies integrating multi-omics profiling are required to establish causality, define dose–response relationships, and determine the persistence of microbiota-driven metabolic alterations following pollutant exposure.

Pollutant exposure profoundly alters microbial composition and metabolite signaling. Loss of Lactobacillus, Bifidobacterium, and Akkermansia muciniphila—key taxa involved in immunomodulation—reduces the production of short-chain fatty acids (SCFAs) and indole derivatives, both known to promote regulatory T cell (Treg) differentiation and IL-10 secretion (Pingitore et al., 2019). This metabolic deprivation weakens mucosal immune tolerance and skews immune balance toward proinflammatory Th1/Th17 responses.

In parallel, pollutants such as bisphenol A (BPA), cadmium, and PAHs activate pattern recognition receptors (PRRs), such as TLR on intestinal epithelial and immune cells, stimulating NF-κB and MAPK pathways. The resulting cytokine surge (IL-6, TNF-α, IL-1β) promotes local inflammation, recruits neutrophils and macrophages, and compromises barrier function (Song et al., 2025; Xi et al., 2019). Persistent activation of NLRP3 inflammasome further amplifies this inflammatory cascade, leading to chronic tissue injury (Figure 10; Paik et al., 2025).

Environmental pollutants alter gut microbial composition, decreasing SCFA and indole metabolite levels that normally sustain Treg/IL-10 anti-inflammatory signaling. Concurrently, pollutant-activated TLR4/NF-κB and NLRP3 pathways elevate proinflammatory cytokines (IL-6, TNF-α, IL-17), disrupt the Th17/Treg balance, and impair epithelial integrity. These synergistic effects promote chronic intestinal inflammation and heighten systemic immune reactivity, predisposing to immune-mediated diseases.

A hallmark of pollutant-induced immune dysfunction is the disruption of the Th17/Treg balance. BPA and dioxins enhance Th17 differentiation via STAT3 and RORγt activation while suppressing Foxp3⁺ Treg expansion, promoting sustained inflammation (Grover et al., 2021). Meanwhile, dysbiosis-driven depletion of tryptophan-derived AhR ligands (e.g., indole-3-aldehyde, FICZ) impairs IL-22 production, compromising epithelial defense and mucosal repair (Bahman et al., 2024). These findings underscore AhR's dual role as both a pollutant sensor and an immunoregulatory gatekeeper.

Chronic pollutant exposure results in translocation of microbial products such as lipopolysaccharides (LPS) and peptidoglycans into circulation, eliciting systemic immune activation. Epidemiological studies associate prolonged exposure to PM_2.5, heavy metals, and microplastics with increased incidence of inflammatory bowel disease (IBD), asthma, rheumatoid arthritis, and multiple sclerosis (Li F. R. et al., 2022; Liu et al., 2022; Sharif and Amital, 2014). Mechanistically, dysbiosis-induced cytokine overflow and ROS generation contribute to the systemic spread of inflammation through the gut–liver and gut–brain axes, forming a molecular bridge between environmental exposure and autoimmune pathogenesis.

Pollutant-induced gut dysbiosis reduces the abundance of beneficial taxa such as Lactobacillus and Bifidobacterium, which are essential for producing neuroactive metabolites including SCFAs and tryptophan derivatives (Kelly et al., 2017). Importantly, these bacteria also synthesize γ-aminobutyric acid (GABA) and serotonin precursors: for example, Lactobacillus rhamnosus and Bifidobacterium dentium produce GABA via glutamate decarboxylation, while Enterococcus and Streptococcus species contribute to 5-hydroxytryptophan (5-HTP) production from tryptophan (Kelly et al., 2017). SCFAs, particularly butyrate and propionate, modulate microglial maturation and anti-inflammatory function via GPR41/43–HDAC inhibition pathways. Their depletion leads to exaggerated microglial activation, elevated proinflammatory cytokines (IL-6, IL-1β, TNF-α), and impaired synaptic plasticity (Figure 11; Sun et al., 2025).

Pollutants such as PM_2.5, BPA, and heavy metals enhance intestinal permeability (“leaky gut”), facilitating systemic translocation of LPS and other microbial products that trigger neuroinflammation through TLR4–NF-κB signaling in brain-resident microglia (Sangkham et al., 2024; Bolan et al., 2021). This neuroimmune activation is accompanied by oxidative stress and mitochondrial dysfunction, key contributors to neuronal injury and cognitive decline.

Tryptophan metabolism is a key microbial–neuronal interface. Dysbiosis reduces conversion of tryptophan to indole-3-aldehyde and indole-3-propionic acid, weakening AhR–IL-22–mediated neuroprotection, while diverting tryptophan toward the kynurenine pathway, which generates neurotoxic metabolites such as quinolinic acid (Hou et al., 2023). Furthermore, gut bacteria such as Escherichia coli, Clostridium sporogenes, and Bacteroides fragilis play central roles in regulating host serotonin levels by modulating peripheral tryptophan metabolism. Dysbiosis-associated reductions in these taxa may impair 5-HT availability, contributing to emotional and behavioral disturbances including anxiety and depression (Zundel et al., 2022). These effects are further amplified by compromised vagal signaling and disrupted hypothalamic–pituitary–adrenal (HPA) axis feedback.

Both animal and epidemiological studies demonstrate pollutant-related neurological consequences mediated by gut dysbiosis: (1) chronic exposure to diesel exhaust particles alters microbial diversity, enhances microglial activation, and induces memory impairment and depressive-like behaviors in mice (Phillippi et al., 2022); (2) BPA and phthalates interfere with microbiota-driven serotonin metabolism, correlating with increased risk of autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) in children (Martínez-Ibarra et al., 2021); and (3) lead and cadmium exposure disrupt gut–brain communication by damaging enteric neurons and modifying microbial neurochemical signaling, contributing to cognitive and motor deficits (Porru et al., 2024).

Environmental pollutants such as PAHs, PCBs, and heavy metals (As, Cd) undergo microbial transformation in the gut, producing reactive intermediates that damage host DNA (Shimada and Fujii-Kuriyama, 2004; Rezazadegan et al., 2025). Dysbiotic microbiota exhibit increased nitroreductase, β-glucuronidase, and azoreductase activities, generating nitroso compounds and aromatic amines, both established mutagens in colorectal carcinogenesis (Boddu et al., 2021). Concurrently, disruption of bile acid metabolism elevates secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid (LCA), which induce oxidative stress, activate NF-κB and STAT3, and promote cell proliferation and DNA damage (Figure 12; Shi et al., 2023).

Pollutant-induced dysbiosis perpetuates low-grade inflammation and oxidative stress, two hallmarks of cancer initiation (Rio et al., 2024). Persistent activation of immune pathways (e.g., TLR4/NF-κB, NLRP3 inflammasome) increases IL-6 and TNF-α, stimulating epithelial proliferation and angiogenesis. Meanwhile, ROS generated by both pollutants and inflammatory cells cause DNA strand breaks, lipid peroxidation, and the formation of mutagenic adducts such as 8-hydroxy2′-deoxyguanosine (8-OHdG; Yu et al., 2024). These genotoxic events accumulate over time, facilitating oncogenic mutations and chromosomal instability.

Beyond direct mutagenesis, environmental pollutants induce epigenetic alterations mediated by microbiota-derived metabolites. Aberrant DNA methylation of tumor suppressor genes (p53, APC) and histone acetylation imbalance have been observed following exposure to Cd or PCBs, correlating with shifts in microbial SCFA production (Geissler et al., 2024). Moreover, dysregulated tryptophan–AhR signaling alters intestinal stem cell proliferation, linking microbial metabolism to tumor promotion (Zhu and Van den Eynde, 2024). These findings suggest that the gut microbiota not only mediates pollutant metabolism but also reprograms host gene expression, contributing to long-term cancer susceptibility.

Probiotics such as Lactobacillus plantarum, L. rhamnosus, and Bifidobacterium longum have demonstrated efficacy in mitigating cadmium, BPA, and PM_2.5 toxicity by restoring microbial balance, enhancing intestinal barrier integrity, and reducing oxidative stress. When combined with prebiotics such as inulin or galacto-oligosaccharides, these synbiotic formulations further improve colonization stability and functional resilience. Future research should emphasize strain-specific functions, such as pollutant-binding capacity, SCFA synthesis, or ROS scavenging activity.

Dietary modulation profoundly influences the microbiome's response to pollutants. Diets rich in fermentable fibers, polyphenols, and omega-3 fatty acids promote beneficial microbial taxa and anti-inflammatory metabolites. For example, resveratrol and curcumin attenuate PCB-induced oxidative injury by activating the Nrf2–Keap1 pathway, while green tea catechins counteract heavy metal toxicity through chelation and microbial detoxification. Designing nutritional countermeasures that harness microbiota-derived metabolites (e.g., butyrate, indole derivatives) may provide sustainable protection against pollutant exposure.

Emerging studies suggest that fecal microbiota transplantation (FMT) can reverse pollutant-induced metabolic and inflammatory disorders by re-establishing microbial homeostasis. Moreover, next-generation probiotics (NGPs) including A. muciniphila, Faecalibacterium prausnitzii, and engineered Lactobacillus strains offer targeted modulation of intestinal redox and immune environments. Integrating FMT and NGPs with precision diagnostics (e.g., microbiome signatures predictive of exposure response) could enable personalized microbiome therapies.

From a broader perspective, microbiome research should inform environmental risk assessment and policy. Incorporating microbial endpoints (e.g., microbiota diversity, SCFA levels, functional resilience) into pollutant toxicity evaluation may provide more sensitive biomarkers for ecological and human health monitoring. Policies that integrate pollutant reduction, microbiota-friendly agriculture, and sustainable food systems will be crucial to maintaining microbial and planetary health.