The Plasticene Paradigm: Microplastics, Gut Dysbiosis, and Food Allergy — A Critical Commentary

Abstract

Background

The increasing prevalence of food allergy (FA) in industrialized regions cannot be fully explained by traditional hygiene and biodiversity frameworks, suggesting the involvement of new environmental triggers. Microplastics (MPs), which are dietary contaminants now consistently found in human biological samples, have been proposed as a potential threat to gut-immune balance. However, direct evidence for this link in humans is still lacking.

Main Body

This commentary critically examines and advances the “Plasticene Paradigm”, which hypothesizes that dietary MP exposure disrupts the beneficial relationship between the host and its microbiota, thereby promoting the development of FA through microbiota-dependent mechanisms. The central mechanism proposed involves MP-induced dysbiosis, characterized by a reduction in short-chain fatty acid (SCFA) -producing bacteria. This reduction subsequently impairs the differentiation of regulatory T cells (Tregs), disrupts the balance between Th2 and Treg cells, and compromises the integrity of the intestinal barrier. While studies involving fecal microbiota transplantation in animal models offer causal evidence under experimental conditions, this evidence primarily comes from studies using supraphysiological doses of pristine polymers (mg/kg/day range). These doses exceed mass-based estimates of human daily intake (μg/kg/day range) by several orders of magnitude, although direct quantitative comparison is complicated by the use of heterogeneous exposure metrics (mass-based vs particle-count-based) across different estimation approaches. This significant difference in dosage fundamentally limits the applicability of these findings to human exposure levels found in the environment. We identify four obstacles to translating these findings: dose relevance, exposure complexity, challenges in model extrapolation, and analytical constraints. These barriers currently prevent drawing definitive conclusions about human risk.

Conclusion

The current evidence, which is predominantly preclinical, is constrained by issues of dose relevance, exposure complexity, and gaps in model extrapolation, with human data largely showing only associations. We propose a three-pronged research agenda: (I) establishing prospective birth cohorts with specific biomonitoring for polymers; (II) conducting mechanistic studies using environmentally relevant MP mixtures in FA models; and (III) developing microbiome-targeted interventions as needed. This framework aims to transform the Plasticene Paradigm from a hypothesis-driven mechanistic narrative into one supported by a stronger evidence base. This evidence may ultimately inform public health policy, food safety regulations, and precise prevention strategies for FA in an era of widespread plastic contamination.

Graphical Abstract

Introduction

The global incidence of food allergy (FA) has significantly increased in industrialized nations, a trend that established frameworks like the hygiene and biodiversity hypotheses only partially explain.^1–5 This suggests that new environmental exposures contribute to this rise. We propose examining this epidemiological puzzle through the lens of the “Plasticene”, an era defined by pervasive plastic pollution.⁶ Within this context, microplastics (MPs) are contaminants found in human blood, placenta, stool, and gallstones,^7–10 although direct epidemiological evidence linking MP exposure to FA remains scarce. The documented presence of MPs within the human body coincides with a critical developmental period during which the gut microbiota educates the mucosal immune system and establishes long-term susceptibility to allergies.^11–13 This continuous interaction between host and microbes now occurs in the presence of immunologically foreign MPs, raising a crucial question: could MP exposure disrupt this host-microbe communication, thereby contributing to the growing burden of FA? It is important to note that real-world MP exposure involves complex mixtures of polymers, varying sizes, shapes, additives, and adsorbed co-contaminants.^14,15 This heterogeneity complicates hazard identification and distinguishes environmental exposure from the simplified experimental paradigms discussed below.

To address this critical knowledge gap, we propose and rigorously evaluate the “Plasticene Paradigm” as a novel conceptual framework. While existing frameworks have primarily emphasized microbial deprivation or barrier dysfunction as drivers of allergic disease, the Plasticene Paradigm specifically focuses on the active immunotoxic potential of MPs as a direct disruptor of host-microbiota symbiosis. This hypothesis is grounded in the unique physicochemical properties of MPs—including their environmental persistence, bioavailability, and potential for bioaccumulation^16,17—which may systematically undermine oral tolerance. The proposed core pathway involves MP-induced gut dysbiosis, notably depleting SCFA-producing bacteria, compromising intestinal barrier integrity, and consequently skewing mucosal immune responses toward a pro-allergic Th2 phenotype.

Despite this mechanistically plausible narrative, translating it into actionable human health evidence remains challenging due to persistent conceptual and methodological barriers. The nascent and heterogeneous methodologies in MP research complicate the translation of experimental findings to human risk. Key challenges include the use of supra-physiological exposure doses in preclinical models, the oversimplification of MP exposure by relying on pristine polymers instead of complex environmental mixtures, fundamental limitations in human biomonitoring, and the complex confounding posed by the broader exposome.^16,18,19 MP exposure rarely occurs in isolation; diet, antibiotic use, urbanization, and other lifestyle factors also shape the gut microbiota and influence FA risk.^15,20 Disentangling the specific contribution of MPs from these interrelated exposures represents a major epidemiological challenge, creating a substantial translational gap.

This article proposes and critically evaluates the “Plasticene Paradigm” as an integrative framework linking dietary MP exposure to FA via gut–immune–microbiota crosstalk. This article has three main aims: first, to articulate the paradigm; second, to evaluate evidence across in vitro, animal, and human studies, focusing on the SCFA–Treg/Th2 axis; and third, to propose a translational research agenda that bridges mechanistic plausibility with human health risk assessment.

Methodological Considerations

This article is a Critical Commentary as defined by the journal’s article types—it presents a narrative synthesis and critical appraisal of the evidence linking dietary microplastic exposure to food allergy pathogenesis. It is not a formal systematic review or meta-analysis, and therefore does not include quantitative synthesis, formal risk-of-bias assessment using standardized tools (eg, GRADE, SYRCLE’s RoB), or prospective registry (eg, PROSPERO). Nevertheless, to ensure transparency in our evidence grading and study selection for Table 1 and Table 2, we report our literature identification process below. Nevertheless, given that the manuscript grades evidence and refers to a structured selection of key studies, we report our literature identification process to ensure transparency.

Table 1.

Critical Appraisal of Key Preclinical Evidence Supporting the Microplastic–Gut Microbiota–Food Allergy Axis

Pathway/Mechanism Investigated	Key Study Models & Polymers Tested	Exposure Dose/Concentration (vs Human Estimates)	Major Findings Associated with FA Pathogenesis	Evidence Strength & Key Translational Considerations
Core Immunotoxic Axis: Dysbiosis, SCFA Deficiency, Barrier Breakdown, Th2 Skewing	OVA-sensitized mice; PS, PVC MPs17,18	eg, 100 mg/kg/day (Mice) vs ~0.1–10 μg/kg/day (Human est.)20	Induced dysbiosis (↓Lactobacillus, ↓Bifidobacterium), reduced fecal SCFAs, decreased TJ protein expression, increased gut permeability, elevated serum OVA-specific IgE and Th2 cytokines.	Strength: Coherent, reproducible, causally supported by FMT in high-dose preclinical models. Consideration: Efficacy at human-relevant doses unknown; generalizability from pristine PS/PVC limited.
Direct Innate Immune Activation	In vitro DC/macrophage cultures; PVC-induced colitis model22,23	In vitro: µg/mL–mg/mL range; In vivo: high-dose gavage	PS/PVC MPs activated NLRP3 inflammasome in macrophages, aggravated colitis via IL-1β. Demonstrated adjuvant potential.	Strength: Mechanistically plausible for inflammation in non-FA models. Consideration: FA-relevance not tested; polymer-dependent effects; role in sensitization vs general inflammation unclear.
“Trojan Horse” and Co-pollutant Synergy	Zebrafish & rodent co-exposure studies; PS with Cd, antibiotics24,25	Varies; often high doses of both MPs and co-pollutants	Combined exposure caused substantially greater gut damage, oxidative stress, and dysbiosis than either pollutant alone.	Strength: Clear evidence of synergistic toxicity for hazard identification. Consideration: Risk assessment complicated by infinite mixture combinations; lacks an FA-specific endpoint.
Tryptophan Metabolism & AhR Signaling	Rodent study (general toxicity); PS MPs26	High-dose exposure (eg, mg/kg range)	PS MP exposure correlated with reduced colonic levels of AhR ligands (indole derivatives).	Strength: Speculative — extrapolated from non-FA models Consideration: Purely associative; necessitates further causal validation in FA models; no FA-specific endpoint assessed.
Bile Acid Signaling Disruption	MP-exposed mice (general toxicity)27,28	High-dose exposure	Altered hepatic and fecal bile acid profiles reported.	Strength: Speculative — extrapolated from non-FA models Consideration: Observations from non-FA models; mechanistic connection to FA entirely speculative; no FA-specific endpoint assessed.
Epigenetic Reprogramming	Review-based hypothesis29	N/A (Theoretical)	Proposed based on developmental origins of allergy and analogies from other pollutants. No FA-specific endpoint assessed.	Strength: Speculative — extrapolated from non-FA models Consideration: No direct evidence for MP-induced epigenetic changes in FA contexts; no FA-specific endpoint assessed

Notes: Symbol notation: ↓ indicates a decrease or reduction in the indicated parameter. Evidence grading and translation: “Strong (preclinical, high-dose)” denotes consistent causal evidence from FA-relevant animal models, but exclusively under supraphysiological exposure doses (mg/kg/day) that exceed mass-based estimates of human daily intake (μg/kg/day) by several orders of magnitude—a broad approximation given the heterogeneity of human exposure metrics. “Moderate” reflects supportive evidence with limitations; “Preliminary” represents limited or indirect evidence; “Speculative/Hypothetical” denotes mechanistically plausible pathways extrapolated from non-FA toxicity models or lacking any direct experimental validation in FA-relevant systems.

Abbreviations: AhR, aryl hydrocarbon receptor; FA, food allergy; FMT, fecal microbiota transplantation; MPs, microplastics; PS, polystyrene; PVC, polyvinyl chloride; SCFA, short-chain fatty acid; Th2, T helper type 2; TJ, tight junction; Treg, regulatory T cell.

Table 2.

Evidence Hierarchy and Analysis of the Translational Gap for the Microplastic–Food Allergy Axis

Evidence Tier	Primary Role & Value	Representative Findings & Exposure Context	Critical Limitations Contributing to the Translational Gap	Implications for Human Risk Assessment
In Vitro Models	Hazard identification; mechanistic plausibility	Barrier disruption (↓TEER, ↓TJ proteins) at µg/mL–mg/mL doses;16,45 reduced SCFA production in gut simulators;54 DC activation by pristine PS/PVC46	Dose-relevance gap; physiological oversimplification; exposure simplification	Low predictive value for integrated low-dose human outcomes; essential for understanding initiating events
Animal Models	Establishing causality; pathway validation	High-dose PS/PVC induces dysbiosis, barrier loss, Th2 skew, exacerbates FA;17–19 FMT transfers FA susceptibility18,32	Dose-relevance gap; model extrapolation gap; exposure complexity gap	Provides causally confirmed mechanistic roadmap under high-dose conditions, but cannot directly quantify human risk due to dose disparities and interspecies differences; critical for prioritizing hypotheses
Human Studies	Proof of internal exposure; hypothesis generation	Qualitative MP detection in stool linked to microbial shifts and elevated Th2 markers;38 exposure ubiquitous but poorly quantified	Analytical gap; causality gap; exposome confounding gap	Currently insufficient for causal inference or dose–response modeling; highlights urgent need for advanced biomonitoring and longitudinal designs

Note: Symbol notation: ↓ indicates a decrease or reduction in the indicated parameter. Table 2 presents a conceptual evidence hierarchy based on study design and translational relevance; it does not represent a subset of the 48 included studies but rather a framework for interpreting the evidence tiers.

A targeted literature search was conducted in PubMed/MEDLINE, Web of Science, and Scopus for publications published between January 1, 2014 and August 31, 2025. The final search was performed on August 15, 2025. The start date of 2014 was chosen to capture research published after the first major reports of microplastic detection in human biological samples—specifically, the detection of microplastics in human stool Schwabl etal, 2019, ref9 and the initial systematic assessments of dietary microplastic intake Cox etal, 2019, ref,²¹ both of which catalyzed research into human health implications. No language restrictions were applied, though non-English articles were included only if English-language abstracts were available and the full text could be adequately assessed.

The search employed combinations of the following terms: “microplastics”, “nanoplastics”, “gut microbiota”, “intestinal microbiome”, “dysbiosis”, “intestinal barrier”, “tight junction”, “immune regulation”, “T helper 2”, “regulatory T cell”, “short-chain fatty acid”, “butyrate”, and “food allergy”. Boolean operators (AND/OR) were used to combine terms. The complete search strategy for PubMed is provided in Supplementary File S1.

Eligibility criteria were defined prior to the search. Studies were eligible if they: (i) were original research articles (in vitro, animal, or human); (ii) examined the effects of microplastics (any polymer, size, or shape) on gut microbiota, intestinal barrier, immune regulation, or food allergy outcomes; and (iii) appeared in peer-reviewed journals. Exclusion criteria were: (i) conference abstracts, editorials, letters, and opinion pieces without original data; (ii) studies focused exclusively on nanoplastics (<100 nm) without parallel microplastic assessment, due to their distinct toxicokinetic properties; (iii) studies of additives or adsorbed co-pollutants without concurrent microplastic exposure; and (iv) studies not reporting original experimental or observational data.

Titles and abstracts of all retrieved records were screened independently by two authors (L.S. and P.W.) using Rayyan systematic review software. Discrepancies were resolved through discussion or by consultation with a third author (C.H). Full texts of potentially eligible studies were then assessed against the inclusion criteria. The selection process, including the number of records identified, screened, excluded, and ultimately included at each stage, is documented in the PRISMA-style flow diagram (Supplementary Figure S1). From this pool, the studies featured in Table 1 were selected as representative examples for each mechanistic pathway, prioritising those with the strongest evidence (eg, causal FMT data), clear dose–response reporting, and relevance to FA-specific endpoints. The full set of 48 studies, with individual evidence grades, is available in Supplementary Table S1. Reference lists of included articles and pertinent reviews were manually screened to identify additional relevant studies not captured by the database searches. The Supplementary Material accompanying this article comprises: Supplementary Table S1 (summary of key preclinical studies), Supplementary Table S2 (glossary of terms and abbreviations), Supplementary File S1 (complete database search strategies), Supplementary Figure S1 (PRISMA-style flow diagram), and Supplementary Note 1 (methodological considerations for microplastic detection in human biospecimens).

This methodological approach ensured systematic identification of the evidence base while acknowledging the commentary’s narrative and hypothesis-generating purpose, rather than aiming for exhaustive systematic review coverage. First, the dose-relevance dilemma arises from the substantial disparity between experimental exposures, often in the mg/kg/day range in animal studies,^17,19 and estimated human daily intake. Mass-based dietary surveys estimate human exposure at approximately 0.1 to 10 μg/kg/day.²¹ In contrast, probabilistic lifetime exposure models, which rely on different assumptions regarding particle size distribution and ingestion rates, estimate intake at 553–883 particles/day (equivalent to 184–583 ng/day, assuming spherical particles of standard density).³⁰ Considerable uncertainty exists across all estimation approaches.¹⁰ Crucially, these estimates are derived from disparate methodological frameworks (mass-based vs particle-count-based) and assume different particle sizes, shapes, and polymer densities, which precludes a direct arithmetic comparison. Nonetheless, irrespective of the estimation model applied, the consensus indicates that animal experimental doses exceed real-world human intake by several orders of magnitude. This gap raises fundamental questions about whether mechanisms observed at supraphysiological doses operate linearly or exhibit thresholds at environmentally relevant levels.^10,31 The “several orders of magnitude” disparity cited throughout this article represents a qualitative consensus across heterogeneous estimation approaches, rather than a numerically precise calculation derived from a single unified methodology.

Second, the extrapolation of findings is complicated by inherent model limitations. In vitro systems, while crucial for understanding mechanisms, inherently lack the dynamic interplay between the epithelium, microbiota, and immune cells.³² Animal models, despite offering causal evidence through fecal microbiota transplantation (FMT),^18,33 are subject to interspecies differences in gut physiology and immune development.³⁴ Moreover, while FMT studies demonstrate that a microbiota perturbed by MP is sufficient to confer FA susceptibility in mice, the compositional and functional distinctions between murine and human gut microbiota restrict the direct applicability of these causal findings to human populations. Third, the complexity of exposure is often oversimplified. Most studies utilize pristine polystyrene spheres, which inadequately represent real-world exposures involving mixtures of polymers (PE, PVC, PET), varying sizes, shapes, and weathered surfaces that carry adsorbed co-pollutants—a phenomenon often referred to as the “Trojan horse” effect.^17,24,35

Fourth, current analytical limitations in human biomonitoring hinder polymer-specific quantification, and studies often relying on qualitative methods prone to misclassification.^36,37 Finally, exposome confounding is a pervasive issue, as MP exposure is intricately linked to dietary patterns (eg, consumption of ultra-processed foods), socioeconomic factors, and lifestyle determinants, all of which are also associated with FA risk.^20,38 These five interconnected challenges—dose relevance, model extrapolation, exposure complexity, analytical constraints, and exposome confounding—constitute the analytical lens through which we evaluate the mechanistic evidence in Mechanistic Pathways. Critically, these barriers are mutually reinforcing: the dose-relevance dilemma compounds difficulties in model extrapolation, while exposure complexity magnifies analytical limitations and confounder adjustment challenges. This interdependence underscores the need for an integrated translational framework that bridges preclinical findings and real-world human risk assessment.

A final methodological consideration warrants acknowledgment: although we employed a systematic search strategy and transparent eligibility criteria to identify the core evidence base, this article remains a narrative commentary rather than a formal systematic review or meta-analysis. As such, we did not perform formal risk-of-bias assessment, quantitative synthesis, or registration in a prospective review registry (eg, PROSPERO). The evidence grading presented in Table 1 and Table 2 reflects the authors’ expert judgment based on study design, dose relevance, and experimental context, rather than a standardized tool such as GRADE or SYRCLE’s Risk of Bias. Readers should interpret the evidence hierarchy accordingly. Furthermore, the dose comparisons presented throughout this article should be interpreted with the understanding that human exposure estimates derive from heterogeneous methodologies (mass-based surveys, particle-count models, and extrapolations from environmental concentrations), each with distinct assumptions and limitations. The numerical ranges provided are approximations intended to illustrate the magnitude of the translational gap, not precise quantitative thresholds.

Mechanistic Pathways

Core Pathway: Dysbiosis–SCFA–Treg/Th2 Axis

The central mechanistic framework proposing a link between dietary MP exposure and FA pathogenesis involves a tripartite disturbance: MP-induced gut dysbiosis, subsequent depletion of short-chain fatty acids (SCFAs), and a resulting disruption of intestinal immune homeostasis. This core pathway, visually represented in the Graphical Abstract, synthesizes evidence from numerous preclinical models and has received causal support through fecal microbiota transplantation (FMT) studies in animal models.

Intestinal Barrier Compromise

The intestinal epithelial barrier, maintained by tight junction (TJ) complexes including occludin and ZO-1, acts as the primary defense against the influx of luminal antigens.¹⁶ Preclinical studies indicate that MP exposure, particularly to polystyrene (PS) and PVC, can downregulate the expression of tight junction proteins and thereby increase gut permeability. For example, oral administration of PVC MPs at 100 mg/kg/day for five weeks in mice significantly reduced occludin and ZO-1 levels in the colon¹⁷ (animal evidence, high-dose). However, it is important to note that not all studies have consistently observed these barrier effects. Variability in experimental conditions, including MP polymer type, particle size, dose, and animal strain, has led to heterogeneous outcomes.^24,39 These inconsistencies underscore the need for standardized experimental protocols to facilitate meaningful comparisons across studies. Nevertheless, this specific finding must be interpreted with extreme caution: the experimental dose (100 mg/kg/day) exceeds the mass-based estimates of human daily intake (0.1–10 μg/kg/day)²¹ by approximately four to six orders of magnitude, depending on the specific value used within that range. However, given the heterogeneity of human exposure metrics (mass vs particle count) and the lack of harmonised reference materials, this numerical range should be interpreted as a broad approximation rather than a precise quantitative threshold. Whether similar effects occur at environmentally relevant concentrations remains unknown, and linearity in the dose–response relationship cannot be assumed.

The mechanistic link between compromised intestinal barrier function and FA pathogenesis has been explored through investigations into MP-induced alterations of the gut microbiota in preclinical models. For instance, in OVA-sensitized BALB/c mice, oral exposure to PS MPs (50 mg/kg/day for 6 weeks) significantly depleted SCFA-producing bacteria, specifically Lactobacillus reuteri and Bifidobacterium. This depletion coincided with decreased fecal butyrate levels and diminished colonic ZO-1 expression, a key tight junction protein.¹⁸ Similar shifts in the microbiota, characterized by a reduction in Lactobacillus and Bifidobacterium species, have been observed following PVC MP exposure in C57BL/6 mice.¹⁷ The resulting deficit in butyrate, which serves as a primary energy source for colonocytes and an HDAC inhibitor, is hypothesized to impair epithelial cell metabolism and compromise tight junction (TJ) stability.^40,41 This weakened barrier likely facilitates the paracellular translocation of dietary allergens, thereby initiating the sensitization phase of FA.^17,18

SCFA Depletion and Immune Dysregulation

Beyond their role in epithelial bioenergetics, SCFAs are potent immunomodulators, acting through well-defined molecular mechanisms. Butyrate and propionate, for example, promote the differentiation and functional activity of regulatory T (Treg) cells, which are crucial for maintaining peripheral immune tolerance. They achieve this primarily by inhibiting histone deacetylase (HDAC) activity, which epigenetically modifies gene expression programs to favor Treg lineage commitment.^40,42 The reduction in SCFA-producing bacteria observed after MP exposure has been linked to impaired immune regulation, including alterations in Treg cell populations, as documented in models of MP-induced dysbiosis.^41,42

SCFAs also exert immunomodulatory effects by signaling through G-protein-coupled receptors, such as GPR43 (FFAR2), found on dendritic cells (DCs). This signaling pathway activates intracellular cascades that promote a tolerogenic DC phenotype, characterized by reduced production of pro-inflammatory cytokines and an enhanced capacity to induce Treg differentiation.⁴³ A loss of these crucial SCFA-mediated signals, combined with broader dysbiosis, may push DCs toward a pro-inflammatory state. This state is marked by the secretion of cytokines like IL-6 and IL-23, which drive the polarization of naïve T cells toward a Th2 phenotype.^43,44 Indeed, several studies have shown that MP-exposed murine models exhibit elevated levels of Th2 cytokines (IL-4, IL-13), reduced Treg proportions, and subsequent B cell class-switching to produce allergen-specific IgE.^17,18

The SCFA–Treg axis, a fundamental pathway in the immunomodulatory effects of dietary fiber, thus emerges as a key target of MP-induced dysbiosis. This observation raises the intriguing possibility that dietary interventions, such as fiber supplementation, could mitigate MP-associated immune dysregulation by restoring SCFA production. The observed depletion of SCFA-producing taxa like Bifidobacterium and Lactobacillus following MP exposure^17,19 suggests that prebiotic strategies, specifically designed to stimulate these beneficial bacteria, could offer a practical approach to counteracting MP-induced dysbiosis. Conversely, some studies have reported no significant changes in overall microbial diversity or specific bacterial taxa after MP exposure.^24,45 These divergent findings suggest that microbiome responses might be polymer-specific, dose-dependent, or influenced by the host’s baseline microbial composition, highlighting the current lack of a universal MP-associated dysbiotic signature. Critical reviews have emphasized the potential of prebiotic interventions in modulating allergic outcomes, particularly when administered during crucial developmental windows.⁴⁶ Furthermore, emerging evidence indicates that specific dietary fibers may directly influence the fate of MPs in the gut by promoting their aggregation and subsequent fecal excretion,⁴⁷ adding another dimension to the complex interplay between diet, MPs, the microbiota, and the immune system.

Causal Evidence from Fecal Microbiota Transplantation Studies

The most compelling evidence for a microbiota-driven pathway under experimental conditions comes from fecal microbiota transplantation (FMT) experiments. In these protocols, donor mice are typically exposed to MPs (eg, polystyrene or polyvinyl chloride) at 100 mg/kg/day for 5–6 weeks. Following this exposure, their cecal or fecal microbiota is transplanted into naive recipient mice. The recipients are then sensitized with ovalbumin (OVA) to assess their susceptibility to food allergy (FA).^18,33 These studies consistently show that microbiota from MP-exposed donors transfer increased FA susceptibility to naive recipients, even without subsequent MP exposure, thereby isolating the microbiota as a key mediator. Furthermore, 16S rRNA sequencing confirms that the gut microbiota composition of recipient mice closely mirrors that of their respective donors.³³ While these FMT studies provide causal evidence within the specific experimental conditions tested in a preclinical framework, it is important to note that these conditions involve supraphysiological exposure doses. As detailed in Methodological Considerations, this causal evidence is inherently limited by the dose-relevance gap: it demonstrates that MP-perturbed microbiota can confer FA susceptibility at experimental doses, but it does not establish that this mechanism operates at environmentally relevant human exposure levels. Therefore, the translational significance of these FMT findings depends on whether analogous microbiota alterations occur at real-world MP exposures.

Mechanistic Hypotheses Extrapolated from Non-FA Models

Beyond the well-characterized SCFA-Treg/Th2 axis, recent studies suggest that MPs may disrupt immune homeostasis through other, largely exploratory pathways. It is crucial to distinguish these non-canonical mechanisms—illustrated by the dashed and dotted arrows in Figure 1, as they lack direct validation in FA-specific models—from the core dysbiosis-SCFA-Treg cascade. The latter, backed by strong causal FMT evidence, is depicted by solid arrows in the schematic. These proposed pathways not only expand the theoretical framework of the Plasticene Paradigm but also pinpoint crucial directions for future mechanistic research.

Figure 1.

The conceptual framework of non-canonical mechanisms and evidence hierarchy in the microplastic-food allergy axis. This schematic illustrates hypothesized immunotoxic pathways that extend beyond the core SCFA-Treg-Th2 axis. To clearly distinguish the strength of supporting evidence, we employ a three-tiered coding system: (i) solid arrows indicate pathways validated in food allergy (FA)-relevant models with causal evidence (eg, via fecal microbiota transplantation [FMT]); (ii) dashed arrows denote pathways demonstrated in non-FA general toxicity models (eg, colitis, hepatotoxicity), whose relevance to allergic sensitization remains unconfirmed; and (iii) dotted arrows demonstrate purely speculative or associative mechanisms lacking direct experimental validation. In the central pathway, the green downward arrow (↓) indicates the suppression/depletion of regulatory T cells (Tregs), while the purple upward arrow (↑) denotes the polarization/increase of Th2 cells, leading to allergic sensitization.

Note: This figure was generated with the assistance of ChatCNS Extend (https://www.chatcns.com/extend) and has been reviewed and validated by the authors for scientific accuracy.

Abbreviations: AhR, aryl hydrocarbon receptor; DC, dendritic cell; FA, food allergy; FMT, fecal microbiota transplantation; MP, microplastic; SCFA, short-chain fatty acid; Th2, T helper type 2 cell; TLR4, Toll-like receptor 4; Treg, regulatory T cell; NLRP3, NOD-like receptor family pyrin domain containing 3.

The pathways discussed in this section stem from studies in general toxicity models (eg, colitis, hepatotoxicity, and general inflammation) and have not yet been investigated in FA-relevant systems. These pathways are presented not as established components of the Plasticene Paradigm, but rather as hypothesis-generating observations that could guide future research. Readers should be cautious about inferring mechanistic involvement in FA pathogenesis solely from these data. Their inclusion highlights crucial areas for future investigation, rather than asserting their role in FA pathogenesis.

Direct Innate Immune Activation

Source evidence: This section draws from in vitro dendritic cell/macrophage cultures and a PVC-induced colitis model (in vitro and animal evidence, non-FA model).^22,23 Certain MP polymers may function as direct innate immune adjuvants. In vitro evidence suggests that MPs can activate pattern recognition receptors, specifically TLR4 and NLRP3, on dendritic cells and macrophages, leading to the production of pro-inflammatory cytokines.^22,23 For instance, PVC MP fragments from environmental sources exacerbated colon inflammation in mice, suggesting a possible role for inflammasome activation via IL-1β.²³ While this mechanism illustrates direct immunostimulation, its specific contribution to initiating allergic sensitization versus promoting general inflammation needs validation in FA-relevant models. The adjuvant potential appears to be polymer-dependent, and whether this pathway contributes to Th2 skewing in FA pathogenesis is currently speculative and untested in FA models. Source evidence: The following observations derive from in vitro dendritic cell/macrophage cultures and a PVC‑induced colitis model^22,23—neither of which assessed FA‑relevant endpoints such as allergen‑specific IgE, Th2 cytokine profiles, or oral tolerance breakdown.

“Trojan Horse” Effect and Co-Pollutant Synergy

Source evidence: This section derives from zebrafish and rodent co-exposure studies^24,25 (animal evidence, non-FA model, FA endpoints not assessed). Due to their high surface area and hydrophobicity, environmental MPs can adsorb and concentrate various co-pollutants, including heavy metals, antibiotics, and persistent organic pollutants.^25,35,48 Upon ingestion, these adsorbed pollutants may desorb, leading to localized high-concentration exposures. Studies investigating combined exposure to MPs and contaminants, such as cadmium or antibiotics, show exacerbated gut damage and dysbiosis compared to exposure to either pollutant alone,^35,49 indicating potential synergistic toxicity. This “Trojan horse” effect introduces significant complexity to exposure assessment, making it difficult to attribute biological effects solely to the plastic polymer itself. However, the implications for FA pathogenesis remain speculative and require direct investigation in allergy models that incorporate environmentally relevant MP mixtures. Source evidence: The synergistic toxicity described above has been demonstrated in zebrafish and rodent co‑exposure studies^35,49 that did not evaluate FA‑related outcomes.

Tryptophan Metabolism and Aryl Hydrocarbon Receptor (AhR) Signaling

The microbial metabolism of dietary tryptophan produces immunoregulatory metabolites, including indole derivatives such as indole-3-aldehyde and indole-3-propionic acid, which act as ligands for the aryl hydrocarbon receptor (AhR).^26,27 Activation of AhR by these microbiota-derived ligands is crucial for maintaining intestinal immune homeostasis by promoting IL-22 production and supporting epithelial barrier function.²⁷ It is therefore hypothesized that MP-induced dysbiosis could disrupt this metabolic pathway—potentially through the depletion of tryptophan-metabolizing bacteria or altered enzymatic activity—thereby reducing AhR ligand production and compromising AhR-mediated immune regulation.²⁸ This proposed mechanism is a molecular hypothesis requiring direct experimental validation in FA-relevant models, as current supportive evidence is limited to associative observations from general toxicity studies, as reviewed in.²⁸ Source evidence: The associative observations linking MP exposure to reduced AhR ligand levels derive from a general toxicity study in rodents²⁶ that was not designed to assess allergic sensitization or FA endpoints.

Bile Acid Signaling and the Gut–Liver Axis

Alterations in host bile acid metabolism and associated signaling pathways represent a plausible yet speculative immunomodulatory axis. Studies using general toxicity models have reported changes in bile acid profiles following MP exposure.^29,50 These changes could potentially affect signaling through nuclear receptors such as FXR and TGR5, leading to downstream consequences for mucosal immunity. However, these observations come from research not designed to address FA, and any mechanistic link between MP-altered bile acid signaling and FA pathogenesis remains entirely hypothetical. Direct experimental validation in FA-relevant models is necessary before this pathway can be integrated into the Plasticene Paradigm. Source evidence: Alterations in bile acid profiles following MP exposure have been reported in general toxicity models^29,50 that did not examine FA‑relevant immunological outcomes.

Epigenetic Reprogramming

Early-life MP exposure presents a theoretically plausible mechanism for inducing persistent epigenetic changes, potentially imprinting lasting pro-allergic phenotypes through developmental programming.⁵¹ This hypothesis draws on established concepts from the developmental origins of health and disease (DOHaD) framework and analogies with other environmental exposures. Nevertheless, direct evidence connecting MP exposure to epigenetic alterations in immune-related genes within FA contexts is currently lacking. Investigations into DNA methylation patterns, histone modifications, and chromatin accessibility in immune cells following early-life MP exposure represent a critical frontier for future research. Source evidence: The epigenetic reprogramming hypothesis is theoretical, drawing on established DOHaD concepts and analogies with other pollutants;⁵¹ no direct evidence links MP exposure to epigenetic changes in FA contexts. Crucially, this mechanism has been demonstrated exclusively in general inflammatory models; its relevance to allergic sensitization—specifically to Th2 skewing in FA—remains entirely untested and speculative.

Critical Synthesis

Synthesizing the available evidence against the methodological framework established in Methodological Considerations reveals a tiered mechanistic landscape, which is concisely summarized in Table 1, with detailed experimental parameters for each key study provided in Supplementary Table S1 to support evidence transparency and reproducibility. The sequence of events involving gut dysbiosis, decreased SCFA production, intestinal barrier dysfunction, and Th2-polarized immunity constitutes the most consistently observed and replicated pathway in preclinical research. Causal support for this cascade is notably strengthened by FMT studies,^18,33 which demonstrate that an MP-perturbed microbiota is sufficient to confer FA susceptibility. However, the strength of evidence for this axis is inherently tempered by the dose-relevance dilemma (Section 2.1), as it is predominantly observed under high-dose conditions. Furthermore, reliance on pristine PS or PVC particles^17,18 introduces an exposure complexity gap (Section 2.3), limiting generalizability to real-world mixtures.

A critical caveat must be acknowledged: the core pathway evidence summarized above derives almost exclusively from studies using pristine, monodisperse polystyrene or polyvinyl chloride particles.^17,18 This experimental paradigm, however, fails to capture the physicochemical complexity of environmentally weathered MPs. Environmentally weathered MPs carry adsorbed co-pollutants, exhibit heterogeneous sizes and shapes, and possess surface chemistries that may profoundly alter their biological interactions.^25,35,48 The “Trojan horse” effect, where MPs serve as vectors for concentrated co-pollutants, represents a major unknown that could either attenuate or exacerbate the effects observed with pristine particles. Consequently, while the core pathway is mechanistically coherent and causally validated under controlled conditions, it cannot be assumed to operate identically with environmentally relevant MP mixtures. This limitation does not invalidate the paradigm but rather highlights that the current evidence establishes biological plausibility, not environmental risk. Given these constraints, the mechanistic evidence summarized above should be interpreted as hypothesis-generating rather than as definitive proof of causality in humans. While the core pathway demonstrates biological plausibility under controlled laboratory conditions, its relevance to environmentally relevant human exposure has yet to be determined.

A critical distinction must be drawn between the core pathway—supported by direct experimental evidence in FA‑relevant models, albeit under supraphysiological conditions—and the non‑canonical pathways discussed in Mechanistic Hypotheses Extrapolated from Non-FA Models, which derive exclusively from general toxicity studies. The latter are included not as established components of the Plasticene Paradigm, but as hypothesis‑generating observations intended to identify research gaps. Readers are cautioned against inferring mechanistic involvement in FA pathogenesis from these data alone. Direct experimental validation in FA‑specific models is an absolute prerequisite before any of these pathways can be incorporated into the paradigm as mechanistic components. It is also important to note studies that report minimal or negligible effects of MPs on the gut microbiota⁴⁵ or limited toxicity under specific exposure conditions.³⁹ These negative or inconclusive findings, though often underrepresented in the literature due to publication bias, are crucial for a balanced evaluation of the field. The diverse nature of study designs, characterized by variations in MP characteristics, exposure protocols, and outcome measures, complicates comparisons across studies. This heterogeneity highlights that while the current evidence is mechanistically coherent, it remains incomplete.

In summary, the MP–gut microbiota–FA axis is primarily supported by a core pathway involving dysbiosis, reduced SCFAs, compromised barrier integrity, and a Th2-skewed immune response. This pathway has received consistent experimental validation in preclinical models, particularly through FMT studies. In contrast, emerging non-canonical pathways remain speculative, largely derived from non-FA models. Their inclusion in this discussion aims to highlight research gaps and stimulate hypothesis-driven investigations, not to imply their established mechanistic role in FA. Direct experimental validation in FA-relevant models is an absolute prerequisite before these pathways can be integrated into the Plasticene Paradigm as confirmed mechanistic components. A pervasive uncertainty across all proposed mechanisms is the modulatory influence of the food matrix (Section 2.3). The nearly universal use of pristine or simplified MPs in preclinical studies^47,52 means that the potential for dietary components—such as lipids, fibers, and proteins—to fundamentally alter MP bioavailability, interactions, and biological impact remains largely unexplored. This knowledge gap represents one of the most critical frontiers for developing a physiologically relevant understanding of MP-associated FA risk.

Before the proposed mechanisms can be considered definitively established, the field requires greater emphasis on dose-response studies, exposure conditions that reflect environmental realities, and independent replication of key findings.

Discussion

Translational Gaps and Challenges

The preceding synthesis of mechanistic evidence (Mechanistic Pathways) provides a coherent framework linking dietary MP exposure to FA pathogenesis through microbiota-dependent mechanisms, although the causal evidence predominantly stems from preclinical models. However, translating this preclinical narrative into actionable insights for human health necessitates confronting a substantial, multidimensional translational gap. Drawing upon the methodological framework established in Methodological Considerations, we identify four interconnected gaps that currently impede definitive human risk assessment. These four gaps—causality, quantification, complexity, and analytical—are elaborated upon below.

The Causality Gap represents the most fundamental barrier. While fecal microbiota transplantation (FMT) studies in murine models offer compelling evidence that an MP-perturbed microbiota is sufficient to confer susceptibility to FA,^18,33 human evidence remains largely correlative and cross-sectional.³⁸ The temporal relationship between MP exposure and FA development—which is essential for causal inference—has not been established in any human study. Existing human investigations are predominantly cross-sectional,^38,45 making it impossible to determine whether MP exposure precedes disease onset or if observed associations reflect reverse causation or confounding. Furthermore, these studies have relied on qualitative or semi-quantitative MP detection methods,³⁷ which limits their ability to establish clear dose-response relationships. Residual confounding from socioeconomic status, dietary patterns, and other lifestyle factors²⁰ further complicates interpretation, as MP exposure is intricately linked to these variables. Therefore, prospective birth cohorts with repeated exposure assessments and longitudinal follow-up are urgently needed to determine whether MP exposure precedes and predicts FA onset, and whether the gut microbiota mediates this relationship.²⁰

The Quantification Gap highlights a significant discrepancy in dosage between preclinical models and actual human exposure to MPs. Mechanistic effects observed in animal studies typically involve MP doses ranging from 0.1–100 mg/kg/day,^17,19 which are orders of magnitude higher than estimated human daily intake. Human intake estimates vary widely depending on the methodology used: mass-based dietary surveys estimate approximately 0.1–10 μg/kg/day,²¹ while probabilistic lifetime exposure models, which rely on particle-count data and assumed size distributions, estimate 553–883 particles/day (equivalent to 184–583 ng/day under standard density assumptions),³⁰ with substantial uncertainty across both approaches.¹⁰ It is important to emphasise that these human intake estimates are not directly interchangeable with the mass-based animal dosing (mg/kg/day) due to diverging assumptions regarding particle size distribution, density, shape, and analytical detection limits. Nonetheless, irrespective of the specific estimation method, all models consistently place human exposure several orders of magnitude—interpreted as a broad approximation given the methodological heterogeneity—below the doses used in preclinical challenge studies. This disparity raises critical questions about the linearity of dose–response relationships and the existence of effect thresholds. It remains unclear whether the mechanisms identified under high-dose conditions are relevant at environmentally pertinent exposure levels. Addressing this requires integrating advanced biomonitoring with experimental toxicology. This dose difference is not a minor detail but a fundamental limitation that challenges the translational validity of the entire preclinical evidence base. Without established evidence of dose–response linearity or effect thresholds—neither of which has been confirmed, and given the approximate nature of the dose comparison across heterogeneous metrics—the proposed biological pathway merely demonstrates plausibility under artificial conditions, rather than validating an environmental risk mechanism.

The Complexity Gap stems from the inherent oversimplification within current experimental paradigms. Most preclinical studies utilize pristine, monodisperse polystyrene or polyvinyl chloride particles.^17,24 These particles poorly represent real-world MP mixtures, which are characterized by diverse polymers (PE, PET, PP), varying sizes, irregular shapes, weathered surfaces, and adsorbed co-pollutants, creating a “Trojan horse” effect.^25,35,48,49 The contribution of this complexity to FA pathogenesis remains largely unexplored, underscoring the urgent need for studies employing environmentally sourced MP mixtures.

The Analytical Gap originates from methodological constraints in human biomonitoring. Current detection methods, often relying on visual identification or qualitative spectroscopy, lack the necessary sensitivity, polymer specificity, and quantification capabilities for robust dose–response assessments^36,37,53 (see Supplementary Note 1 for a detailed technical overview). Without reliable metrics for internal exposure, epidemiological studies cannot progress beyond hypothesis generation to quantitative risk characterization. A foundational priority is the development and standardization of sensitive, polymer-specific analytical techniques, such as pyrolysis-gas chromatography-mass spectrometry (Py-GC/MS) mentioned in Supplementary Note 1, across relevant biological matrices (stool, blood, placenta).^54,55 While the current evidence base has benefited significantly from active research groups, particularly in China,^{17,18,24,42,56} Europe,^7,8,23,53 and North America,^21,30,40 the field remains fragmented. There is limited cross-laboratory standardization and replication. Strengthening the evidence base and facilitating more robust conclusions will require broader international collaboration and coordinated efforts to harmonize experimental protocols, including MP characterization, exposure conditions, and outcome measures.

These four gaps, summarized in Table 2 and conceptualized in Figure 2, are interconnected and mutually reinforcing. Addressing them requires an integrated, multidisciplinary approach that concurrently advances human exposure assessment, mechanistic understanding, and intervention development.

Figure 2.

An integrated, evidence-grading translational framework addresses knowledge gaps in the microplastic-food allergy axis. The framework is color-coded to reflect the flow from evidence gaps to actionable outputs: red boxes represent major translational hurdles; blue, purple, and green central panels correspond to the three interdependent research pillars; and beige panels depict final translational outputs. Arrows indicate the bidirectional and iterative flow of information between pillars.

Note: This figure was generated with the assistance of ChatCNS Extend (https://www.chatcns.com/extend) and has been reviewed and validated by the authors for scientific accuracy.

Abbreviations: FA, food allergy; MP, microplastic; FMT, fecal microbiota transplantation; SCFA, short-chain fatty acid; Th2, T helper type 2 cell; Treg, regulatory T cell.

Future Research Directions: An Integrated Roadmap

To systematically bridge the identified translational gaps, we propose an iterative, evidence-driven research framework structured around three pillars, as conceptually detailed in Figure 2. These proposed directions serve as a strategic guide to stimulate hypothesis-driven investigation rather than as rigid directives. They reflect the current state of the field, where mechanistic plausibility currently outpaces epidemiological validation, and are designed to offer a systematic pathway for converting preclinical insights into actionable public health evidence.

Human Validation and Causal Inference

The most pressing priority is to ascertain whether MP exposure precedes and predicts FA onset in human populations. Establishing reliable internal dose metrics necessitates prospective birth cohorts that incorporate advanced, polymer-specific biomonitoring, utilizing methods such as pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS) on samples like placenta, meconium, stool, and blood.^36,54 Such studies must integrate comprehensive dietary exposure assessment, longitudinal multi-omics profiling (metagenomics, metabolomics, and immunophenotyping), and rigorous clinical phenotyping of FA outcomes.^55,57 Crucially, we advocate for depositing multi-omics data in public repositories aligned with FAIR principles to accelerate discovery and validation.⁵⁸ This pillar directly addresses the dose-relevance dilemma and the causality vacuum that currently impede definitive human risk characterization.^10,20

Mechanistic Precision and Exposome Complexity

Translating hazard identification into nuanced risk assessment requires moving beyond pristine, monodisperse polymers to environmentally relevant MP mixtures. Systematic comparative studies are essential to evaluate how polymer type (PS, PVC, PE, PET), size, shape, surface chemistry, and weathering differentially influence gut barrier integrity, immune activation, and microbiota composition.^17,23,24 The “Trojan horse” effect, where MPs adsorb and concentrate co-pollutants such as heavy metals, antibiotics, and persistent organic pollutants, demands investigation in FA-relevant models. Emerging evidence suggests that co-exposure may produce synergistic toxicity exceeding that of either pollutant alone.^25,35,49 Key research priorities include: (i) the tryptophan–AhR axis, examining whether MP-induced dysbiosis reduces AhR ligand production and compromises IL-22-mediated barrier function;^26,27 (ii) direct innate immune activation via TLR4 and NLRP3 engagement;^22,23 (iii) bile acid signaling disruption and its consequences for mucosal immunity;^29,50 and (iv) epigenetic reprogramming during early-life developmental windows, a hypothesis grounded in the developmental origins of health and disease concept.⁵¹ Critically, research must investigate how the food matrix—comprising lipids, fibers, and proteins—modulates MP bioaccessibility, systemic absorption, and biological impact, as the near-universal use of “naked” MPs in preclinical studies represents a significant gap in physiological relevance.^47,52

Intervention and Resilience Building

While contingent on evidence generated from Pillars I and II, this pillar outlines a translational endpoint: the development of evidence-based strategies to counteract MP-associated health risks. Preliminary findings suggest that specific probiotic strains may mitigate MP-induced immune dysregulation in animal models; however, whether such interventions can counteract real-world MP exposure in humans remains speculative.⁵⁶ Nutritional strategies, such as promoting diverse, fiber-rich diets to support endogenous SCFA production, represent a well-established and low-risk approach for overall metabolic and immune health.^40,59 Further research is needed to determine whether specific prebiotic fibers (eg, inulin, fructo-oligosaccharides), polyphenols, and ω-3 polyunsaturated fatty acids can enhance gut barrier resilience and counteract MP-induced dysbiosis.^60,61 A critical unanswered question is whether MPs in the gut lumen interfere with the colonization, survival, or metabolic function of administered probiotics or microbial metabolites—a fundamental unknown that must inform any future therapeutic development.^62,63

In summary, bridging the translational gap necessitates a paradigm shift from pristine-particle toxicology to exposome-aware, interdisciplinary research that integrates advanced biomonitoring, longitudinal multi-omics, and complex mixture toxicology. The three-pillar roadmap outlined above offers a framework to advance the Plasticene Paradigm from a mechanistically coherent narrative toward a more evidence-based foundation that may, with further validation, inform future public health considerations.

Clinical and Public Health Implications

Although conclusive human evidence has yet to emerge, the consistency of preclinical findings, together with the widespread and persistent nature of MP contamination, provides a reasonable basis for a precautionary, risk-informed position.¹⁰ Clinical Practice: Gastroenterologists and pediatricians can counsel at-risk families on pragmatic strategies for exposure reduction. These include minimizing the use of plastic containers for food heating and storage, preferring fresh over ultra-processed foods, and using filtered tap water.³⁶ It should be noted that direct evidence specifically linking these behavioral changes to reduced internal MP exposure in humans is currently limited. Therefore, these recommendations are based on the precautionary principle and indirect evidence derived from studies on exposure sources.^10,36 Concurrently, advocating for microbiome-supportive, high-fiber diets offers a low-risk, beneficial adjunct with merits extending beyond merely counteracting MP effects. The advantages of such diets for metabolic and immune health are well-established,^40,59 and their fundamental role in shaping gut microbial ecology and producing key metabolites like SCFAs is now well-understood.⁶⁴

Health Equity Considerations: MP exposure varies significantly across different populations. Individuals with lower socioeconomic status often consume more ultra-processed and plastic-packaged foods, rely more heavily on bottled water, and live in areas with inadequate waste management infrastructure.^20,38 Consequently, these disadvantaged communities may experience a disproportionately higher burden of MP exposure, compounded by limited access to healthier alternatives like fresh produce or filtered water. Therefore, public health interventions should focus on structural solutions, such as enhancing access to safe tap water, regulating food packaging in more affordable food outlets, and investing in community-level plastic waste reduction initiatives. Prioritizing these systemic changes over individual behavioral recommendations is crucial to avoid exacerbating existing health inequities.

Public Health Policy: The biologically plausible mechanisms discussed here provide additional health-based justification for urgent environmental actions already warranted ecologically. Policies focused on reducing primary plastic production, enhancing waste management, regulating food-contact materials, and accelerating the transition to a circular economy represent the most fundamental and effective primary prevention strategy for this potential emerging health risk.^25,26 These actions offer clear co-benefits for both planetary and human health.

Conclusions

The Plasticene Paradigm provides a coherent framework for investigating whether dietary microplastic exposure contributes to food allergy through gut microbiota-dependent mechanisms. The available evidence, which is predominantly derived from preclinical models and is most robust under controlled, high-dose conditions, establishes biological plausibility rather than definitive causal proof. It justifies elevated concern rather than immediate, definitive action. Direct human evidence remains scarce and largely associative, and a substantial translational gap persists, characterized by ongoing gaps in causality, dose relevance, exposure complexity, and analytical capacity.

To bridge this divide, we have proposed an integrated three-pillar research agenda, detailed in Future Research Directions: An Integrated Road Figure. For researchers, this agenda prioritizes exposome-aware studies that incorporate early-life exposure assessment and food-matrix interactions. For policymakers, the plausible mechanisms reinforce the urgency of environmental interventions grounded in the precautionary principle. However, such actions are currently justified by ecological and planetary health considerations and by the inherent prudence of reducing widespread plastic contamination, rather than by an established human health risk. For clinicians, pragmatic advice on exposure reduction and microbiome support may be offered, but this must be accompanied by clear communication regarding the current evidence limitations and the understanding that these recommendations are provisional, rather than evidence-based clinical guidelines.

The Plasticene Paradigm, while mechanistically coherent, currently stands as a hypothesis rather than an established causal model. Transforming it into a rigorously tested framework capable of informing future risk assessments necessitates concerted interdisciplinary efforts. Until such evidence materializes, the paradigm should be regarded as a testable hypothesis. It has already yielded coherent preclinical data and a distinct research agenda, yet its applicability to human health remains an open and urgent question.

Funding Statement

This work was supported by: 1) Research Initiation Fund of Longgang District Maternity and Child Healthcare Hospital (Y2024011); 2) Key Medical Disciplines in Longgang District.

Declaration on the Use of Artificial Intelligence Tools for Figure Generation

We hereby declare that the conceptual illustrations presented in Figures 1 and 2 of this manuscript were generated with the assistance of an artificial intelligence tool. 1) AI Tool Information: Tool Name: ChatCNS Extend (AI-assisted conceptual illustration tool) Access URL: https://www.chatcns.com/extend. Version: 2026 version (web-based, accessed on July 2026). 2) Authors’ Confirmation (in compliance with journal policy): Originality and accuracy: The authors confirm the originality and scientific accuracy of the content presented in these images. The authors have reviewed, edited, and validated the mechanistic pathways and diagrams to ensure they accurately reflect the scientific literature and concepts cited in the manuscript. Terms of use: The authors have carefully checked the terms of use for ChatCNS Extend and confirm its suitability for publication in this journal. Publication rights: The authors confirm that they have the right to publish the images generated and have obtained any permissions required by the tool provider. Content responsibility: The authors take full responsibility for the integrity of the whole content, including the scientific correctness of the molecular pathways and the accuracy of the cited references. 3) Data Availability: Per the editorial guidelines, all versions of the images and the complete records of the prompts used for generating these figures have been retained by the authors and are available for sharing with the editorial office or reviewers upon reasonable request.

Data Sharing Statement

All data supporting this article are derived from publicly available published studies. No new datasets were generated or analyzed in this work.

Ethics Approval and Consent to Participate

Not applicable. This article is a critical commentary and synthesis of previously published literature and does not involve any direct human or animal subjects and thus ethics approval was not required.

Author Contributions

Lindong Shi: Conceptualization, Project administration, Resources, Validation, Writing – original draft. Peiqin Wang: Conceptualization, Resources, Visualization, Writing – original draft. Bin Wu: Data curation, Supervision, Writing – review & editing. Congfu Huang: Conceptualization, Project administration, Formal analysis, Resources, Writing – original draft, Writing – review & editing. All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.