The microbiota at the interface of environmental toxicants and the brain

SUMMARY

Throughout life, humans are exposed to a diverse array of xenobiotics originating from diet, pharmaceuticals, and environmental contaminants. Positioned at the interface between the host and external environment, the gut microbiota are uniquely situated to both sense and modify these exposure effects prior to systemic circulation and their host targets. Growing evidence indicates that the microbiota play critical roles in shaping xenobiotic fate through both direct metabolic transformation and modulation of host detoxification pathways, barrier integrity, and immune signaling. In this review, we summarize the impacts of disease-relevant environmental neurotoxicants on both the brain and microbial composition. We further integrate emerging mechanistic insights illustrating how microbiota-dependent processes can influence host toxicant responses and detoxification capacity, ultimately modifying exposure outcomes. Collectively, these findings position the gut microbiota as central mediators between environmental exposures and neurological health, providing a framework to better understand potential risk-modifying relationships.

INTRODUCTION

Human health is shaped not only by one’s genetic background but also by the totality of environmental exposures experienced across the lifespan, collectively referred to as the exposome. These exposures include diet, infections, psychosocial stress, and chemical agents (e.g. xenobiotics) that enter the body through air, food, water, and pharmaceutical use.^1,2 Xenobiotics encompass a wide spectrum of compounds, including environmental toxicants such as pesticides, heavy metals, and industrial pollutants. Growing epidemiological and experimental evidence demonstrates associations between such exposures and increased risks and pathologies of various gastrointestinal (GI) and neurological disorders^3–7 (Figure 1). The impact of toxicant exposure depends not only on the compound’s intrinsic properties, but also on the host systems that detect, metabolize, and respond to these external events.

Figure 1.

Outline of microbiota interactions with environmental neurotoxicants.

Humans and other animals are colonized by a community of microbes that inhabit environmentally-exposed surfaces, such as the GI tract, skin, oral cavity, and airway. These microbes are intimately intertwined with host physiology, modulating metabolism, immunity, and neurological functions.⁸ Anatomically positioned at the host-environment interface, the microbiota are poised to both respond to and exert effects on toxicant exposures. Rather than solely recording exposure history through shifts in composition, microbial communities have the capacity to metabolize, buffer, or amplify chemical signals, directly and indirectly host outcomes to toxicants.⁹ The microbiome contributes to systemic processes, including host metabolism, barrier permeability and immune homeostasis, that modify toxicant absorption, distribution, metabolism, and excretion. In parallel, microbes may directly metabolize xenobiotics into compounds with distinct properties,¹⁰ shaping toxicological outcomes. Exposures can disrupt microbial community structure and function, potentially leading to additional effects on host physiology.¹¹ Such reciprocal interactions highlight the microbiome as both a target of environmental toxicants and an active participant in shaping host responses. From this holistic perspective, the microbiome may be understood as a biological mediator of environmental toxicant exposures that impact the host.

While many studies profile microbiome composition throughout toxicant exposure and demonstrate impacts to the community, emerging data have experimentally defined microbial contributions to particular neurotoxic responses.^12–14 Microbiome manipulations, including probiotic supplementation, antibiotic treatments, and gnotobiotic models can test these contributions by assessing specific communities and/or members to the susceptibility or resilience in the face of neurotoxicant exposure.^15–18 In this review, we describe the capacity for the microbiome to directly and indirectly shape the outcome of disease-relevant environmental exposures. With a focus on neurotoxicants, other xenobiotic exposures, e.g. dietary inputs (including xenobiotics such as coloring agents and preservatives), constitute an extensive field in itself and will not be covered here.^19,20 In total, we propose the gut microbiome as a central modulator of neurotoxicant impacts on the brain, offering new avenues to understand and mitigate environmentally-driven neurological diseases.

ENVIRONMENTAL TOXICANTS IMPACT THE BRAIN AND MICROBIOME

In the last several decades, exposure to environmental contaminants and xenobiotics has continued to gain attention as risk factors for neurological disease and disorders. In turn, a suite of environmental chemicals, from pesticides to heavy metals, have been associated with specific neurodegenerative, neurodevelopmental, and neuropsychiatric conditions^5–7 (Table 1).

Table 1.

Select environmental neurotoxicants and their effects on CNS and microbiome

Chemical Category	Associated Disorders and Pathology		References
	Central Nervous System	Microbiome composition
PESTICIDES
Organochlorine Insecticides
Examples: Dichlorodiphenyltrichloroethane (DDT), Dichlorodiphenyldichloroethylene (DDE; metabolite of DDT), β-hexachlorocyclohexane (BHCH), Dieldrin, Heptachlor	PD: Elevated concentrations of Dieldrin, Heptachlor, ß-HCH, and DDE in the brains and serum, alterations to dopamine handling, excess species, accumulation of α-synuclein AD: Elevated levels of serum DDE, elevations in amyloid precursor protein and amyloid beta ND: Deficits in psychomotor development, as well as general cognition, memory, and executive function	Increase in Alloprevotella, decreased Lachnospiracheae	28–30,53,218–223
Pyrethroid Insecticides
Examples: Cypermethrin, Deltamethrin, Esfenvalerate, Permethrin	PD: Alteration to dopamine transporters, loss of dopamine and dopamine neurons, increased risk of PD with variant of the MHC-II HLA-DRA gene, activation of microglia, increased oxidative stress, and accumulation of α-synuclein ND: Deficits in social and language development, anxiety, impulsivity, IQ, and an increased risk of ADHD and ASD; Elevations in dopamine transporter and D1 receptor in nucleus accumbens	Increase in Prevotella sp., Enterobacteriaceae and Lactobacillus, decreased Bacteroidetes and Bacteroides-Prevotella-Porphyromonas sp.	21,31,34–37,100,198,224–231
Organophosphate Insecticides
Examples: Chlorpyrifos	PD: Declined dopamine uptake, increase in dopamine turnover ND: Impaired cognition, memory and motor function, higher risk of ADHD	Increase in Oscillospiraceae, Helicobacter, Colidextrobacter, Desulfovibrioceae Lactobacillus, Allobaculum, Roseburia, Butyricicoccus and Alistipes; decrease Lactobacillus, Akkermansia, Blautia, Bifidobacterium and Faecalibaculum	132 133,232,233
Rotenone	PD: Loss of dopamine and dopaminergic neurons; α-synuclein aggregation; inhibition of mitochondrial complex I and reduction in ATP	Increase in Akkermansia sp, Lactobacillus sp, Bifidobacteria sp, Streptococcus sp, and Escherichia coli; decrease in Lachnospiraceae and Clostridia spp.	91,93,99,234
Paraquat	PD: Alteration in dopamine metabolism, mitochondrial dysfunction, increased alphasynuclein expression	Increase in Akkermansia	92,235–237
Glyphosate	PD: Parkinsonism including resting tremor and limb rigidity, reduced accumbal D1-dopamine receptors and striatal extracellular dopamine levels and release AD: Increase in amyloid beta. Plaque load and phosphorylated tau	Increase in Ruminococcus, Prevotellaceae, Prevotella; decrease in Corynebacterium, Lactobacillus, Bacteroidetes	76–81,238–240
HEAVY METALS
Examples: Copper (Cu), Lead (Pb), Manganese (Mn), Mercury (Hg), Zinc (Zn)	PD: Elevated brain levels of Mn and Cu, disruption of dopamine neuron function, mitochondrial inhibition, reactive species generation ND: Pb and MeHg exposure associated with deficits in cognitive function, attention, processing speed, memory, and executive function; disrupt formation of dendritic spines, neuronal plasticity, and neurotransmission	Mn exposure increased Bifidobacterium and Akkermansia (females) and reductions in Clostridium (males) Adult exposure to Pb in drinking water increased Bacteroidota (fecal), decreased Bacteroidota (caecum) Perinatal exposure to Pb in drinking water reduced Bacteroidota Exposure to Hg in drinking water resulted in increased Oscillospira Zn-deficient diet leads to microbial divergence	7,38–46,48–51,94,101,241–251
HALOGENATED INDUSTRIAL COMPOUNDS
Examples: Per- and Polyfluoroalkyl Substances (PFAS), Polychlorinated Biphenyls (PCBs), Tricholorethylene (TCE)	PD: Elevated serum levels of PCBs, reduction in expression of the dopamine transporter (DAT) and the vesicular monoamine transporter 2 (VMAT2) TCE Degeneration of the nigrostriatal dopamine pathway, increased microglial activation, accumulation of phosphorylated α-synuclein ND: Elevated PCBs associated with impairments in cognitive development, attention, ADHD, ASD, disruption of neuronal differentiation, migration, impairment of neurotransmission, and thyroid hormone function PFAS exposure shows diminished executive function, cognition, language, motor development, increase in inattention, hyperactivity.	PCBs increased Akkermansia Prenatal PCBs reduced Muribaculaceae and Alistipes in offspring, impaired gut barrier integrity and elevated inflammatory responses TCE increased Akkermansia and Bifidobacteria	52,54–66,74,95,196,252
PLASTICIZERS
Examples: Bisphenol A (BPA), Phthalates	ND: Phthalates exposure associated autism and autism behaviors, reduction in IQ, psychomotor development, increased behavioral problems, impaired language development, working memory BPA associated with social impairment (females), reductions in IQ, working memory, and verbal comprehension (males)	Phthalates lead to increased Alloprevotella and decreased Bifidobacterium, Dorea, and Faecalibacterium BPA alters Akkermansia abundance	67–71,96,97,104

Abbreviations AD: Alzheimer’s disease, ADHD: attention-deficit/hyperactivity disorder, ASD: autism spectrum disorder, IQ: intelligence quotient, ND: Neurodevelopment, PD: Parkinson’s disease,

Environmental neurotoxicants can be broadly categorized based on whether they directly target neuronal signaling machinery or exert neurotoxicity through indirect systemic pathways. A prominent example of the former includes insecticides, a chemically diverse class of compounds that are specifically designed to disrupt conserved components of nervous system function. Although developed for selective toxicity toward invertebrate nervous systems, their shared evolutionary conservation of key neuronal targets, including ion channels, neurotransmitter receptors and neuronal enzymes,^21–24 renders mammalian nervous system function susceptible. Neuronal hyperexcitation is a shared neurotoxic mechanism among common-use insecticide classes, including pyrethroids (e.g. permethrin, deltamethrin), organochlorines (e.g. dichlorodiphenyltrichloroethane (DDT), dieldrin), and organophosphates (e.g. chlorpyrifos, malathion). For example, DDT directly inhibits neuronal sodium channels from closing and other organochlorine insecticides elicit hyperexcitation through direct inhibition of GABA_A receptors.^22,23 Whereas, pyrethroids can target both voltage-gated sodium channels and simultaneously inhibit GABA_A receptors.²¹ In contrast, organophosphate insecticides inhibit acetylcholinesterase, increasing the activity of the acetylcholine receptor. In the presence of an organophosphate, acetylcholinesterase is inhibited, and acetylcholine is allowed to accumulate in the synapse, leading to persistent activation of the acetylcholine receptors, neuronal hyperactivation, and eventual collapse of the acetylcholine response.²⁴

Given this intrinsic neurobiological activity, insecticides have been extensively associated with increased risk of neurological disease across both neurodegenerative and neurodevelopmental contexts. Human exposure to insecticides occurs predominantly through dietary intake and contaminated water, with additional inhalational and dermal exposure during application, as well as environmental residues. As a result, chronic low-dose exposure is widespread and largely involuntary. Epidemiological studies have linked long-term insecticide exposure to increased risk of neurodegenerative disorders, including Parkinson’s disease (PD) and Alzheimer’s disease (AD),^25–29 while developmental exposure through placental transfer and lactational exposure has been associated with neurodevelopmental dysfunctions.^30–32 Consistent with these observations, experimental models demonstrate that insecticide exposure can induce a broad spectrum of neurological phenotypes, including dopaminergic neurodegeneration, cognitive impairments, and anxiety- and depressive-like behaviors.³³ Despite acting through distinct mechanisms of action, diverse pesticides including rotenone, an insecticide and piscicide, and paraquat, an herbicide, can reproduce key neurodegenerative pathologies in animal models and have therefore been widely used to study environmentally induced neurological dysfunction.^34–37

Other relevant neurotoxicants, including heavy metals (e.g. lead, cadmium, mercury), halogenated industrial compounds (e.g. per- and poly-fluoroalkyl substances (PFAS), trichloroethylene), and plasticizers (e.g. bisphenol A) all have unique mechanisms of action that are linked to their associations with an array of neurological diseases. For instance, heavy metal exposure increases oxidative stress, impairs mitochondrial function, and outcompetes essential metals (e.g. Ca, Zn, Fe) as cofactors in central enzymes, leading to cellular damage and neurological deficits.^38–51 Although the mechanisms of PFAS and related halogenated compounds remain incompletely understood, experimental models consistently demonstrate increased neuroinflammation and glial activation, as well as synaptic and mitochondrial dysregulation.^52–66 Similarly, while the endocrine disruption effects of BPA are well-established, how these impact neurological functions are largely undescribed, despite epidemiological associations.^67–71 Determination of clear cellular and molecular targets and mechanisms of neurotoxicity for each of these compounds or compound classes has proved elusive. While pesticides are manufactured to target and disrupt specific biological processes, industrial compounds were manufactured to be used in non-biological capacities, making identification of cellular and systems-level targets more complex. Nonetheless, given their persistence and prevalence in the environment, understanding their associations with neurological dysfunctions are essential.^72–74 Yet the neurological consequences of environmental exposures may not be determined solely by the intrinsic properties of the toxicant or its direct interactions with host tissues. Increasing evidence suggests that environmental toxicants also interact extensively with the gut microbiome, raising the possibility that microbial responses represent an additional layer of susceptibility influencing neurotoxic outcomes. This concept is exemplified by glyphosate, whose herbicidal activity targets the shikimate pathway, a metabolic pathway absent in mammals but present in many gut bacteria. Because aromatic amino acids generated through this pathway contribute to the production of several neurotransmitters, microbial perturbations induced by glyphosate may have consequences not limited to the gut.^75–77 Consistent with this possibility, glyphosate exposure has been associated with alterations in brain neurotransmitter levels and behavioral outcomes in experimental models.^78–81 Consistent with a microbiota-dependent contribution, recent work demonstrated that transplantation of glyphosate-remodeled microbial communities was sufficient to recapitulate aspects of the social behavioral impairments observed following exposure, providing preliminary evidence that exposure-associated microbiome changes may themselves contribute to neurological outcomes.⁸² Thus, the gut microbiome is increasingly recognized as an active participant in exposure biology, capable of sensing, transforming, and responding to xenobiotics in ways that may ultimately influence host susceptibility to neurotoxic outcomes.

Neurologically active environmental toxicants may be encountered through ingestion, inhalation, and dermal exposure, resulting in interactions with microbial communities present on these bodily surfaces, including the gastrointestinal tract, respiratory tract, and skin. Across chemically diverse toxicants and routes of exposure, extensive literature consistently demonstrates alterations in gut microbial community composition and metabolic activity following exposure.^{11,33,83–87} (Table 1) Within the gastrointestinal tract, such direct interactions between environmental toxicants and the microbiota can impact microbial metabolism and/or exert antimicrobial effects, subsequently shaping community composition.^10,33,85 In addition, toxicant impacts that systemically impact host neuronal and hormonal physiologies can in turn alter the local GI environment.⁸⁸ This may affect microbially accessible nutrients and other aspects of intestinal ecology, such as oxygen content, osmolarity, and/or intestinal motility, contributing to shifts in microbiome composition.^88–90

The specific taxonomic shifts reported within the gut microbiome can be inconsistent across studies, with the same exposure associated with opposing directional changes in individual taxa depending on exposure model, dose, timing, existing microbial community, and host genetic background (Table 1). Rather than undermining the biological relevance of these findings, such variability highlights the limitations of interpreting microbiome responses solely at the level of individual taxa. Instead, these observations support a broader ecological perspective in which diverse toxicant exposures perturb microbial community structure and collective functional capacity. Nevertheless, some bacteria are more consistently shown to be affected by xenobiotic exposure. These examples include Akkermansia (pesticides,^91–93 heavy metal,⁹⁴ industrial compounds,^14,95 plasticizers,^96,97 neurotoxicant⁹⁸), Lactobacillus (pesticides,^{76,77,93,99,100} heavy metal,^94,101 neurotoxicant^102,103) and Bifidobacterium (pesticides,^76,93,99 heavy metal,⁹⁴ industrial compounds,⁹⁵ plasticizers¹⁰⁴). Although the functional significance of these recurrent taxonomic shifts remains unclear, their repeated perturbation across chemically distinct exposures reinforces the concept that xenobiotics disrupt broader microbial ecological networks rather than isolated organisms. Viewed through this lens, the gut microbiome function less as a static collection of discrete taxa and more as a dynamic metabolic ecosystem whose emergent properties influence host susceptibility to environmental exposures.

The gut microbial community is highly sensitive to perturbations from environmental exposures, and such disturbances may result in a feed-forward loop that amplifies toxicological outcomes. Exposure-induced alterations in microbiome composition and function can influence host physiology through changes in immune, metabolic, and neuroactive signaling pathways.¹¹ These observations align with a substantial body of work establishing the gut–brain axis as a key pathway through which microbiota-derived signals influence central nervous system function and vulnerability to neurological dysfunction.^105,106 This bidirectional communication network integrates microbial metabolites, immune signaling, endocrine pathways, and neural circuits linking the gastrointestinal tract and brain.^107–109 As such, understanding how specific exposures alter the microbial community is critical for assessing longer-term compound-related brain health impacts. While numerous neurological diseases are beginning to be associated with distinct microbiome characteristics, the extent to which environmental toxicants contribute to the establishment of these disease-associated microbial states remains largely unresolved. Importantly, however, microbiome contributions to toxicant responses are unlikely to depend solely on persistent compositional changes. It is clear that the microbiome plays key roles in shaping the host susceptibility to neurotoxicants prior to any prolonged compositional shifts within the community, making their role in exposures and subsequent vulnerabilities much more acute.

MICROBIOME-INTERACTIONS WITH XENOBIOTICS: PROPOSED MECHANISMS

With its vast genetic and metabolic diversity, emerging evidence positions the gut microbiota as a dynamic community at the host-environment interface, where microbial activities directly and indirectly shape xenobiotic biotransformation, host signaling, and systemic responses to environmental challenges.^10,11,110 While the liver is traditionally considered the central organ coordinating xenobiotic metabolism and detoxification, growing data implicate the gut microbiota as a critical, albeit underappreciated, mediator of the fate, bioavailability and toxicity of environmental exposures.^11,111,112 Rather than serving solely as passive targets of environmental perturbation, gut microbes encode a vast repertoire of metabolic enzymes capable of catalyzing reactions analogous to classical hepatic xenobiotic metabolism. These microbial activities extend beyond direct chemical modification to include indirect regulation of host detoxification pathways, immune signaling, and barrier integrity (Figure 2). To integrate and extend these findings, we highlight current mechanistic knowledge on how microbiota-dependent processes can either exacerbate or mitigate the neurotoxic effects of environmental xenobiotics on the host.

Figure 2.

Select mechanisms of microbiome-dependent processes that influence neurotoxic exposures.

Direct microbial interactions with environmental toxicants

Among the most immediate mechanisms by which the microbiota may influence host outcomes to xenobiotic exposure is through direct chemical transformation. The microbiota possesses extensive genetic and enzymatic capacity to catalyze a plethora of metabolic reactions that modify exogenous compounds, including reduction, hydrolysis, and lyase-mediated transformations.¹⁰ These reactions are mediated by diverse microbial enzymes, often in a strain- and xenobiotic-specific manner, and can substantially alter the bioavailability, persistence, and systemic distribution of xenobiotics before they enter host circulation. Importantly, microbial metabolism may either detoxify compounds into less bioactive forms or conversely generate metabolites with enhanced biological activity and toxicity, thereby fundamentally shaping xenobiotic pharmacokinetics and host exposure outcomes. Importantly, such biotransformation can significantly alter the pharmacokinetics, toxicity, and therapeutic efficacy of compounds before they are absorbed or enter systemic circulation.¹¹³ Although many mechanistic insights derive from pharmaceutical metabolism, these same principles are increasingly recognized to extend to environmentally relevant xenobiotics.

Toxification & Detoxification

The gut microbiota is capable of transforming xenobiotics into metabolites with altered bioactivity, toxicity, and bioavailability prior to host absorption. Much of the mechanistic understanding of microbiota-mediated xenobiotic metabolism initially emerged from pharmaceutical studies, as microbial enzymes can pharmacologically activate inert prodrugs into therapeutically active metabolites. One well-established example is the microbial activation of sulfasalazine, an antibiotic prodrug, by microbial azoreductases encoded by several colonic bacteria, generating the therapeutically active metabolite.¹¹⁴ Conversely, microbial metabolism can also reduce xenobiotic toxicity by diminishing their efficacy, modifying their elimination, or converting compounds into less bioactive forms. For instance, digoxin, a cardiac drug used for arrhythmia, is inactivated by enzymatic activity of strains expressing cardiac glycoside reductase (cgr) such as Eggerthella lenta.^115–117 Structure-function prediction suggests this species can broadly inactivate cardiac glycosides with similar structures,¹¹⁶ demonstrating potential for a breadth of functional activity against these environmentally-derived toxins. Similarly, levodopa (L-DOPA), the primary therapeutic for PD, is susceptible to multiple microbial metabolic pathways that limit its availability. L-DOPA can be metabolized to dopamine, by decarboxylation, or dihydroxyphenyl organic acids, by deamination, depending on the bacterial species present, potentially leading to the need for increased therapeutic dosing.^118–121 Together, these studies demonstrate that microbial metabolism can substantially influence xenobiotic bioavailability, pharmacokinetics and therapeutic response in a compound-specific manner.

Comparable principles extend to environmentally-relevant neurotoxicants, where microbial metabolism can similarly act to increase or reduce toxic potential through direct metabolic transformation. Mercury metabolism provides one of the clearest demonstrations that microbiota-dependent xenobiotic metabolism can operate bidirectionally. Sulfur-reducing bacteria can methylate inorganic mercury into methylmercury (MeHg),¹²² a more bioavailable and neurotoxic form that readily accumulates in tissues, including the brain.¹²³ Conversely, microbial detoxification pathways can reduce MeHg burden through demethylation reactions. Transgenic Drosophila expressing bacterial-derived organomercury lyase (MerB) markedly ameliorated MeHg-induced toxicity, demonstrating that microbial-like metabolism directly alters host toxicokinetics.¹²⁴ In humans, microbial demethylation activity in cultured stool samples correlates with individual mercury elimination rates. While germ-free mice are defective in this process, transplantation of human stool microbiota partially restores impaired MeHg clearance. Microbiome restoration correlated with recovery of MeHg elimination, while metagenomic analyses identified candidate taxa associated with elimination kinetics, including Alistipes onderdonkii, although mono-colonization experiments suggested that community-level interactions rather than individual taxa alone are likely required.¹²⁵ More recently, an engineered probiotic expressing both MerB and mercuric reductase (MerA) significantly reduced MeHg accumulation across multiple tissues, including the maternal and fetal brain reducing its neurotoxicity.¹²⁶ Collectively, these findings demonstrate that microbiome-mediated xenobiotic metabolism can directly shape systemic distribution and neurotoxic burden. These data identify microbial metabolism as a potentially modifiable determinant of host susceptibility to environmental exposures. However, whether microbiome-targeted interventions can meaningfully reduce neurological outcomes following toxicant exposure remains largely untested and represents an important avenue for future investigation.

Similar to neurotoxic metals, microbial detoxification has also been documented for other environmental toxicants. Chlorpyrifos, an organophosphate pesticide, undergoes microbial degradation by several bacterial species, including Alcaligenes faecalis,^127,128 mediated by organophosphorus hydrolases encoded by the opd operon.¹²⁹ Such microbial detoxification pathways are already leveraged in environmental bioremediation strategies aimed at reducing pollutant burden through microbial metabolism.¹³⁰ Analogous detoxification mechanisms mediated by gut-resident microbes are not yet characterized. However, emerging evidence suggests that gut-resident microbes may similarly contribute to organophosphate metabolism. For example, Lactobacillus brevis strains isolated from kimchi encode OpdB homologs. Structural characterization further identified conserved catalytic motifs and residues necessary for enzymatic activity, highlighting the mechanistic specificity underlying microbial xenobiotic metabolism.¹³¹ Interestingly, chlorpyrifos exposure of ex vivo cecal microbiota was found to increase in Lactobacillus, among other genera,¹³² raising the possibility that organophosphate exposure may directly select for microbes with xenobiotic-metabolizing capacity. While similar microbial increases were not observed in vivo following exposure, environmentally relevant chlorpyrifos exposure in mice nevertheless reproduced metabolic phenotypes associated with human epidemiological observations and implicated gut microbiota disruption as a contributing factor.¹³³ It is nonetheless intriguing to consider that chlorpyrifos and other organophosphate compounds may directly select for specific microbes capable of metabolizing the toxicant. Although organophosphate exposure is associated with adverse neurological outcomes,¹³⁴ the extent to which microbiota-mediated metabolism modifies host toxicokinetics and neurotoxic susceptibility remains unknown. Resolving these interactions will be important for determining whether gut microbial communities contribute meaningfully to host defense against environmentally relevant neurotoxicants.

Several high-throughput screening approaches have begun to systematically define the metabolic capacity of the gut microbiome toward xenobiotics, reinforcing that microbial xenobiotic metabolism is widespread, enzyme-driven, and specialized at the strain level. Studies demonstrate that the metabolic fate of a parent compound is not governed solely by microbial taxonomy but rather reflects the underlying repertoire of xenobiotic-transforming genes encoded within the microbiome, which collectively define the metabolic potential for downstream biotransformation.^135,136 However, despite this progress, linking individual chemical transformations to discrete gene products remains challenging, in part due to functional redundancy and the widespread conservation of core enzymatic reaction chemistries across phylogenetically diverse taxa. To overcome this limitation, gain-of-function screening approaches have employed heterologous expression of metagenomic DNA fragments to identify microbiome-derived enzymes capable of driving xenobiotic transformations. This approach enables direct assignment of metabolic activity to specific gene products and further reveals that xenobiotic-transforming enzymes span a continuum of specificity, ranging from highly selective to broadly cross-reactive activities across chemically related substrates.¹³⁵ Importantly, the presence of these genes alone does not necessarily predict metabolic output, as strain-specific regulatory and expression contexts can substantially influence whether encoded xenobiotic-transforming activities are functionally deployed under exposure conditions.¹³⁷ Together, these findings establish a functional framework for resolving microbial enzyme-level determinants of microbial xenobiotic metabolism and set the stage for understanding how such activities scale to community-level metabolic outcomes. While these methods have largely been applied to common pharmaceutical agents, they represent a foundation to understand microbial processes that may act on environmental toxicants.

Alongside individual enzymatic activities, xenobiotic metabolism is not solely a property of isolated bacterial strains but can also emerge from higher-order community interactions. In synthetic microbial communities, drug-sensitive species were protected through cross-protection mechanisms mediated by microbial biotransformation and bioaccumulation, whereas stronger perturbations promoted cross-sensitization and collapse of community resilience.¹³⁷ While substantial advances have been made in mapping microbial metabolism of pharmaceuticals and dietary xenobiotics,^135–137 comparable mechanistic frameworks for environmental toxicants remain underdeveloped, representing a critical gap given the neurotoxic relevance of many environmental exposures.

One study using defined gut microbial communities nevertheless demonstrate that environmental xenobiotics, like pesticides and halogenated industrial compounds, can broadly disrupt microbiome metabolic function, including alterations in drug metabolism, SCFA production, and RNA degradation. These functional disturbances occur alongside shifts in microbial community composition, suggesting that xenobiotic-induced restructuring of the microbiome may underlie broader metabolic dysfunction^138,139. However, as these experiments were done using simplified human microbiome model, the causal relationships linking compositional changes, microbial enzymatic capacities, and downstream host toxicological outcomes remain unresolved. Systematically defining microbiome-encoded metabolic capacity toward environmental toxicants, together with the community interactions that shape these responses, will therefore be essential for understanding how inter-individual microbial variation contributes to differential toxicological susceptibility and neurological outcomes. While these high-throughput approaches provide powerful frameworks to systematically map microbiome–xenobiotic interactions, they are largely performed under controlled in vitro settings that cannot fully recapitulate the ecological and physiological complexity of the gastrointestinal environment.¹⁴⁰ Integrating these data-driven screening platforms with in vivo validation, as has been implemented in some studies,¹³⁶ will therefore be essential to establish microbiome-dependent metabolic pathways that influence host toxicological and neurotoxic risks.

Sequestration

Alongside enzymatic biotransformation, gut microbes can also physically sequester xenobiotics, thereby influencing their bioavailability and systemic distribution, without chemical modification of the parent compound. This broadens microbiome-dependent xenobiotic handling to include mechanisms other than direct metabolism, positioning microbes as dynamic reservoirs that buffer, concentrate, or spatially compartmentalize environmental toxicants.

Heavy metal studies, including neurotoxic cadmium and lead, illustrate that sequestration can arise through two primary mechanisms: adsorption to the bacterial cell surface and intracellular accumulation following uptake.¹⁴¹ Surface-binding sequestration is frequently mediated by extracellular structures such as exopolysaccharides (EPS), secreted by bacteria such as lactic acid bacteria, which provide negatively charged functional matrices that coordinate divalent metal ions and promote extracellular immobilization at the cell envelope.¹⁴² In parallel, intracellular accumulation reflects uptake-dependent retention within the bacterial cytoplasm. These processes are not mutually exclusive and can occur simultaneously, as observed in cadmium-binding Lactobacillus strains,¹⁴³ where both surface-associated and intracellular pools contribute to overall metal retention.

Similar sequestration principles have also been reported for other environmental pollutants. Bacteroides uniformis bioaccumulates PFAS through a transporter-dependent process that sequesters these compounds intracellularly, which translated in vivo as seen from increased fecal excretion in mice.¹⁴⁴ The efflux pump utilized by B. uniformis, TolC, is notoriously promiscuous in its specificity, including not only PFAS but also antibiotic drugs and pesticides, making it plausible that other environmental pollutants are acted on via similar mechanisms.¹⁴⁵ Likewise, Lactiplantibacillus plantarum RS60 was shown to bind and sequester the pesticide cypermethrin through interactions involving EPS, peptidoglycans, and multiple bacterial surface functional groups, resulting in reduced cypermethrin residues in a fecal fermentation model.¹⁴⁶ Collectively, these findings suggest that physical sequestration mechanisms by microbes can alter toxicant retention, elimination, and host exposure dynamics. Although the consequences of microbiota-mediated sequestration for neurological outcomes remain largely unexplored, changes in bioavailability and systemic distribution could influence the amount of toxicant reaching peripheral organs and the central nervous system. Thus, even in the absence of direct chemical transformation, microbial sequestration represents a plausible mechanism through which the gut microbiota modifies host susceptibility to environmental exposures.

Reactivation

In addition to primary toxification and detoxification reactions, gut microbes can also reverse host detoxification pathways through xenobiotic reactivation. Reactivation frequently occurs through the enterohepatic circulation, wherein compounds that have undergone detoxifying conjugation reactions in the liver to create more water-soluble forms are excreted into the intestine. There, the conjugated xenobiotics can be enzymatically deconjugated by microbial enzymes, in some cases recreating the active form, and allowing the unconjugated form to be reabsorbed.^147,148 In this context, microbial metabolism effectively counteracts host detoxification processes, prolonging systemic exposure and altering xenobiotic clearance kinetics. A well-characterized example involves microbiome-derived β-glucuronidases, which reactivate glucuronidated metabolites such as the chemotherapeutic irinotecan metabolite SN-38, thereby contributing to intestinal toxicity.^149–151 Reactivation studies further highlight a recurring feature of microbiome-mediated xenobiotic metabolism: conserved enzymatic functions can display substantial taxa-specific differences in catalytic activity and substrate specificity.¹⁵² Reactivation processes have not yet been described for neurotoxic pollutants, however this general mechanism is likely to occur.

In essence, whether the physiological outcome is reduced, sustained, or heightened toxicity, xenobiotic handling by the gut microbiota emerges from a continuum of enzymatic and non-enzymatic processes, including hydrolysis, reduction, lyase, transferase, and radical-mediated reactions, as well as sequestration and reactivation events that collectively reshape xenobiotic structure, bioavailability, and biological fate.¹⁰ Together, these mechanisms underscore the complexity of gut microbial contributions and reinforce that xenobiotic handling is governed by both microbial genetic capacity and enzymatic activity within a broader metabolic context. While these principles are well characterized in pharmaceuticals, their extension to environmental pollutants, and neurotoxicants specifically, remains comparatively underexplored, despite the clear relevance of these exposures to neurological disease risk. Addressing this gap will be essential to further define how broadly microbiome-encoded metabolic frameworks apply across chemically diverse xenobiotics, and whether environmental toxicants are subject to analogous microbiome-driven transformations. Importantly, these and other approaches established in pharmaceutical microbiome research provide a useful conceptual and methodological framework for interrogating these interactions. However, they require adaptation and validation in the context of environmental exposures. Ultimately, resolving this will require in vivo studies to determine how microbiome-encoded metabolic, sequestration, and recycling processes translate into host toxicokinetics and neurotoxic outcomes.

Indirect interactions by the gut microbiota

Indirect microbiota–host interactions represent a higher-order regulatory layer in xenobiotic biology, whereby microbial communities do not directly transform chemicals but instead reprogram host physiological, metabolic, and immunological states that collectively determine xenobiotic disposition, toxicity, and tissue susceptibility. In this framework, the microbiota functions as a systems-level modulator of host exposure outcomes, shaping not only peripheral detoxification but also vulnerability of distant organs, including the central nervous system. Comparisons between germ-free and conventionally colonized animals demonstrate that the microbiota is a fundamental determinant of baseline host metabolic tone.^153–155 Germ-free animals exhibit broad alterations in xenobiotic-processing capacity, barrier function, and immune signaling, underscoring the microbiota as a key regulator of systemic homeostasis. These effects collectively influence xenobiotic toxicokinetics and toxicodynamics, reinforcing that exposure outcomes cannot be interpreted independently of microbial context. For clarity, indirect mechanisms are discussed in three categories; however, these processes are highly interconnected and operate in parallel.

Altered expression of xenobiotic processing genes

One of the most extensively studied indirect mechanisms by which the microbiota influences host detoxification capacity is through regulation of enzymatic machinery encoded by xenobiotic-processing genes. Cytochrome P450 enzymes (CYPs) represent a central node in this system,¹⁴⁷ controlled by xenobiotic-sensing nuclear receptors including pregnane X receptor (PXR) and constitutive androstane receptor (CAR).¹⁵⁶ As major determinants of xenobiotic biotransformation pathways, CYPs critically shape how environmental chemicals are metabolized and cleared by the host. Germ-free models consistently show altered hepatic and intestinal expression of CYPs, transferases, reductases and xenobiotic-sensing receptors.^157–160 Conventionalization partially restores expression of some genes, implicating dynamic microbiota-dependent signaling in host metabolic calibration.¹⁶¹

Notably, microbiota-dependent regulation of xenobiotic-processing pathways appears highly tissue- and region-specific. In germ-free mice, nuclear receptor expression was altered across tissues, with aryl hydrocarbon receptor (AhR) and CAR increased in the liver but not the intestine, whereas PXR upregulation was restricted only to the jejunum.¹⁵⁹ Similarly, mono-colonization with Lactobacillus plantarum and Escherichia coli Nissle 1917 restored expression of hepatic Cyp1a2 but not Cyp3a11,¹⁶² further supporting species-specific regulation of host detoxification programs. Together, these findings demonstrate the value of reductionist gnotobiotic approaches for resolving how specific microbial taxa fine-tune baseline host detoxification capacity in liver and gut. Whether comparable microbiota-dependent regulation of xenobiotic-processing pathways occurs within the central nervous system remains largely unresolved. Although CYP expression is substantially lower in the brain than in hepatic tissues,¹⁶³ microbiota-dependent modulation of local detoxification machinery could nevertheless influence regional toxicant handling and neurotoxic susceptibility, in parallel to modulating systemic response pathways. Determining whether germ-free or gnotobiotic states alter CNS xenobiotic-processing capacity, therefore, represents an important and largely unexplored avenue for future investigation.

Functionally, these baseline transcriptional changes translate into altered xenobiotic metabolism regulating systemic exposure. Many of the CYP enzymes whose expression is altered in germ-free models are known to participate in the metabolism of environmentally relevant toxicants, including pesticides,^164,165 halogenated industrial compounds^166–168 and plasticizers.¹⁶⁹ While direct evidence linking microbiota-dependent CYP regulation to altered neurotoxicant metabolism remains limited, these observations provide a mechanistic basis by which microbial status could modify host toxicokinetics. Similar principles extend beyond CYP-dependent metabolism to other host detoxification systems. Germ-free mice exposed to the neurotoxic metals cadmium or lead display increased metal residues in stool and periphery, accompanied by altered expression of detoxification genes including key metallothioneins, which sequester toxic metals,¹³ Although these studies did not directly assess toxicant accumulation within the brain, some environmental neurotoxicants readily cross the blood–brain barrier and accumulate in neural tissue.^123,170 Consequently, microbiota-dependent alterations in systemic toxicokinetics may indirectly influence CNS exposure by modulating the circulating pool of bioavailable toxicants. Collectively, these data demonstrate that microbiota-dependent regulation of host metabolic programming reshapes systemic toxicological responses and may ultimately contribute to variability in neurotoxic outcomes.

Host barrier integrity

The gut microbiota and its metabolites are key regulators of intestinal and blood-brain-barrier integrity, thereby influencing xenobiotic absorption, systemic distribution, and access to the central nervous system.^171–173 At the intestinal interface, the mucus layer constitutes the first physical and biochemical barrier separating luminal contents from the epithelium, and its composition and turnover are dynamically shaped by microbial activity.^174,175 Moreover, microbiome-derived signals dynamically regulate the expression, localization, and assembly of tight junction proteins, including claudins, occludin, and zonula occludens, in both the intestine and the brain, establishing barrier integrity as an active and reversible process responsive to microbial activity.^{172,176–178} While certain xenobiotics can bypass the biological barriers,^{123,170,179,180} microbiota-dependent alterations in barrier permeability may further modulate the magnitude and tissue distribution upon xenobiotic exposure.

Although many xenobiotics can directly impair epithelial and endothelial barrier integrity independent of the microbiota, microbial regulation of baseline barrier homeostasis may influence the downstream consequences of such damage. This may be particularly relevant for orally ingested toxicants, which must first cross the intestinal epithelium before entering systemic circulation. Increased intestinal permeability could therefore enhance absorption and xenobiotic uptake and exacerbate systemic or neural toxicity through enhanced distribution into the CNS. Consistent with this, antibiotic-induced microbiota depletion increases lead accumulation in host tissues, including the brain, while simultaneously worsening gut barrier damage. These effects were partially reversed by selective probiotic supplementation, including Faecalibacterium prausnitzii and Oscillibacter ruminantium, supporting a microbiota-dependent contribution to barrier maintenance and xenobiotic disposition.¹⁷ Although blood–brain barrier integrity was not directly assessed in this study, the partial reduction of brain lead accumulation following probiotic supplementation raises the possibility that microbiota-dependent barrier regulation may also influence CNS toxicant exposure. Supporting this concept, prebiotic inulin supplementation in another study partially restored tight junction protein expression following pesticide-induced barrier disruption,¹⁸ further implicating microbiota-dependent signaling in the maintenance of epithelial and endothelial barrier integrity. More broadly, disruption of epithelial and endothelial barriers may represent a convergent mechanism through which diverse xenobiotics and environmental neurotoxicants gain enhanced access to peripheral tissues including the brain. Determining whether microbiota-targeted interventions can mitigate these processes, while directly integrating barrier integrity, toxicokinetics, and neurological outcomes, will therefore be essential to establish links between microbial barrier regulation and neurotoxic susceptibility.

Immune System

Xenobiotic exposure elicits immune responses that critically shape host inflammatory landscape, influencing both sensitivity and severity of toxicological outcomes.¹⁸¹ The gut microbiota is a major governor of host immune system development and function, with microbial signals required for appropriate immune cell maturation and activation.^182,183 Germ-free animals exhibit impaired immune maturation that can be restored following colonization with defined commensal taxa, demonstrating a causal role for the microbiota in immune programming.^184–187 While a comprehensive overview of microbiota–immune interactions is outside the scope of this review,^182,188 these observations collectively suggest that microbiota-dependent immune calibration may substantially contribute to inter-individual variability in neuroinflammatory outcomes elicited by toxicant exposure. Conversely, immune activation can itself reshape microbial community structure,¹⁸⁸ establishing bidirectional host–microbiota feedback loops that further influence xenobiotic responses.

In addition to baseline immune programming, microbiota-derived metabolic activity can directly shape immune effector cell function. In this context, for example, the microbiota act as a key determinant of exposure-induced immune activation. A clear example of this principle is provided by mucosal-associated invariant T (MAIT) cells, which function as innate-like lymphocytes which can be activated by metabolites of riboflavin and folate, derived from microbial metabolism or diet.^189,190 In vitro studies using representative commensal bacterial strains have demonstrated that exposure to chlorpyrifos and glyphosate can alter the immunomodulatory capacity of these bacteria, leading to increased TNF and IFNγ production by MAIT cells. These effects were accompanied by altered folate production levels, indicating that xenobiotic-induced perturbation of microbial metabolic output can translate into functional reprogramming of immune effector cell activation.¹⁹¹ Importantly, this demonstrates that microbial responses to environmental chemicals can propagate beyond compositional changes to directly influence defined immune cell activation states, rather than reflecting only broad or non-specific inflammatory signaling. Such immune recalibration is expected to influence downstream cytokine cascades and tissue-level inflammatory responses, as commonly observed upon toxicant exposure,^192,193 thereby shaping susceptibility to exposure-induced damage across both peripheral and central compartments.

At a higher level of immune organization, microbiota-dependent modulation of innate immune signaling pathways further shapes host responses to environmental exposures. For example, supplementation with Bacteroides ovatus during organochlorine pesticide exposure has been shown to reduce brain TLR4 and MyD88 expression, alongside alterations in microbial metabolite profiles.¹⁹⁴ Although this finding links microbial intervention to modulation of both peripheral and central immune signaling under toxicant exposure, the downstream consequences on neurophysiology and toxicity remain to be fully defined. Nevertheless, it supports the broader concept that gut microbial activity can regulate immune activation thresholds and shape systemic inflammatory signaling pathways that extend to the brain.

Collectively, these observations suggest that microbiota-dependent modulation of immune responses operates across multiple organizational levels, ranging from defined immune effector cell activation to broader systemic immune signaling cascades. Such immune recalibration may therefore represent a key intermediate axis through which environmental xenobiotics shape inter-individual variability in inflammatory susceptibility and neuroimmune outcomes, with immune dysregulation recognized as a hallmark of neurodegenerative pathology and a potential mediator of environmentally induced neurotoxicity.¹⁹⁵ Importantly, while these studies demonstrate clear links between microbiota activity and immune modulation under xenobiotic exposure, the extent to which these immune alterations causally determine neurophysiological and neurotoxic outcomes remains incompletely defined. Further mechanistic work integrating immune cell profiling, microbial metabolic mapping, and in vivo exposure models will therefore be essential to determine how microbiota-dependent immune calibration shapes neurotoxic susceptibility and long-term neurological outcomes following environmental toxicant exposures.

Cross-Talk Between Microbiota-Mediated Mechanisms

Rather than functioning as isolated pathways, microbiota-mediated effects on xenobiotic responses emerge from extensive cross-talk between host metabolic, barrier, and immune mechanisms, which are jointly shaped by microbial composition and activity.^196,197 Because these pathways are highly interconnected, distinguishing whether observed toxicological outcomes arise directly from xenobiotic exposure, indirectly through microbiota disruption, or secondarily through downstream host responses remains challenging. This complexity is particularly evident in studies where multiple microbiota-dependent host systems are simultaneously perturbed upon xenobiotic exposures. For example, in rodent models of Gulf War chemical exposure, where toxicant administration was associated with concurrent alterations in gut microbiota composition, intestinal tight junction expression, systemic endotoxemia, and inflammatory signaling within both intestinal and brain tissues¹⁹⁸. Antibiotic-mediated microbiota depletion altered several of these exposure-associated outcomes, indicating that perturbation of the microbial ecosystem can modify the host response to toxicant exposure. However, given the pleiotropic effects of antibiotics on host physiology other than solely microbiota depletion, these findings do not resolve the causal link between microbial, barrier, and immune dysfunction. Instead, they highlight the extensive interdependence of these systems during relevant environmental chemical exposure. Similar mechanistic complexity is observed where combined exposure of mice to polystyrene microplastics and antibiotics resulted in disrupted gut microbiota composition, impaired intestinal barrier integrity, and altered intestinal cytokine profiles.¹⁹⁹ These changes were accompanied by deficits in brain function, including impaired learning and memory, as well as increased cytokine levels in hippocampus. Interestingly, FMT from control mice partially alleviated the co-exposure–induced neurobehavioral and immune abnormalities, but failed to fully restore intestinal barrier integrity, underscoring both the contribution of the microbiota to systemic and neuroimmune outcomes and the difficulty of disentangling interacting host pathways across compartments.

Although studies dissecting the full integration of microbiota-mediated host metabolic, transcriptomic, barrier, and immune functions remain limited in the context of environmental exposures, existing studies do provide valuable insights that these processes converge on shared host regulatory pathways that coordinate xenobiotic metabolism and epithelial homeostasis. Several nuclear receptors involved in xenobiotic sensing and metabolic regulation are themselves influenced by the gut microbiota.^200,201 In particular, the bile acid–activated nuclear receptor FXR is modulated by specific microbial taxa, including Akkermansia muciniphila and Bifidobacterium bifidum, and links microbial bile acid metabolism to the regulation of CYP enzymes and intestinal barrier permeability.^202–204 The relevance of this regulatory axis includes not only intestinal homeostasis but also systemic xenobiotic disposition along the gut–liver–brain axis.²⁰⁵ In parallel, nuclear receptor-mediated bile acid signaling contributes to enterohepatic circulation, hepatic and intestinal detoxification pathways, and systemic metabolic signaling, collectively shaping the distribution and clearance of xenobiotics.^112,206 Microbiota-associated modulation of xenobiotic-transforming enzymes, including microbial CYP-like activities, may further influence the balance between detoxification and bioactivation prior to systemic dissemination, thereby determining the effective toxicant burden reaching neural tissues.

This regulatory integration example is further supported by functional studies showing that administration of specific Lactobacillus plantarum reduces cadmium accumulation, an effect associated with enhanced bile acid metabolism and altered expression of bile acid–related genes (Cyp7a1 and Cyp8b1). Functional evidence supports the involvement of this bile acid–FXR axis in microbiota-dependent xenobiotic handling. Administration of Lactobacillus plantarum reduces cadmium accumulation and increases fecal excretion, accompanied by altered expression of bile acid–related genes (Cyp7a1 and Cyp8b1). These effects are attenuated by pharmacological activation of FXR and abolished following antibiotic treatment, indicating that microbiota-driven modulation of bile acid signaling contributes to xenobiotic disposition through an FXR-linked regulatory network.²⁰⁷ Collectively, these findings position FXR-linked signaling as a potential integration point through which microbiota-derived signals influence xenobiotic metabolism, systemic disposition, and host epithelial homeostasis. Given the role of these processes in determining the effective toxicant burden reaching peripheral tissues and the central nervous system, further mechanistic studies integrating microbial signaling, toxicokinetics, barrier physiology, and neurofunctional outcomes will be required to establish how microbiota-dependent regulatory networks contribute to neuronal dysfunction following environmental exposure.

Collectively, research on the microbiota–gut–brain axis reinforces that microbiota-dependent influences on xenobiotic responses include not only direct chemical transformation but also indirect interactions such as coordinated modulation of host metabolic, barrier, immune, and neurophysiological pathways. Germ-free and gnotobiotic models have been instrumental in establishing causal roles for the microbiota in shaping host xenobiotic handling and other relevant physiologies. However, resolving the indirect mechanisms underlying these interactions remains challenging, as many observed phenotypes arise from tightly interconnected host–microbiome processes in which direct microbial metabolism, host signaling, and systemic physiological responses occur simultaneously. Emerging quantitative and systems-level approaches are beginning to address this complexity. Recent studies integrating gnotobiotic models with pharmacokinetic modeling have demonstrated that microbiome-specific enzymatic activity can be quantitatively separated from host metabolism to predict systemic drug and metabolite exposure.²⁰⁸ Such frameworks provide a powerful strategy to disentangle overlapping host–microbiome contributions to xenobiotic disposition and may ultimately clarify how microbial metabolism and host regulatory pathways jointly shape systemic and neurological exposure profiles.

Moving forward, integrative experimental designs combining gnotobiotic systems, targeted microbial and host multi-omics, toxicokinetic modeling, and stepwise mechanistic interrogation will be essential to resolve the hierarchical sequence of microbiota-mediated events underlying xenobiotic responses. Establishing these frameworks will be critical for understanding how inter-individual variation in microbiome composition and function contributes to susceptibility to environmental toxicants and their downstream neurotoxic consequences.

Future Outlook and Directions

A central challenge in the field is moving beyond association to contributions. Specifically, determining whether and how the gut microbiota is required for translating environmental exposures into neurological impairments. Although environmental toxicant exposures are widely recognized as pervasive and significant risks for neurological diseases, the extent to which these effects are mediated through microbiota-dependent mechanisms remains unclear. While pesticides and heavy metals are well-established to drive neurological outcomes, others such as microplastics are only emerging. Similarly, diseases such as PD have demonstrated links to toxicant exposures, while others, including neuropsychiatric disorders, have more limited associations. These differences across toxicant and disease susceptibility represent the complexity of modeling the entirety of the exposome throughout the life course alongside pathologies that may be quiescent for many years following exposure. This includes core variables like dose and route of exposure, as well as the duration and the age at exposure. The microbiome represents an additional and dynamic layer in understanding exposure outcomes. The complexity of this system makes it essential to carefully consider microbiome-focused experimental design when teasing apart the microbial influence of host xenobiotic handling and its extended impact on the brain.

Many studies have demonstrated that diverse environmental exposures including pesticides and other environmental pollutants can impact the composition of the gut microbiome.^11,20,112 However, the mechanistic contributions of the gut microbiota to exposure outcomes itself are less clear. The emerging data to date demonstrate that the gut microbiome does not merely respond to an exposure; it interprets it. In other words, through both direct metabolic transformation and indirect modulation of host physiology, the microbiome can influence the properties of the toxicant or the host, altering the outcomes of the exposure itself.

Understanding if and how environmental inputs reshape the microbiome composition is an important first step. However, the field must expand upon solely descriptive taxonomic changes following exposures. Population-scale and longitudinal microbiome profiling integrated with exposure history may identify microbial community configurations associated with neurotoxicant susceptibility. Integrating microbiome composition, toxicant exposure, and subsequent risk of neurological disease can further refine the associations to taxa or communities that are predicted to modulate resistance or susceptibility to toxicant-induced disease. Combining these data with gnotobiotic, probiotic, microbial metabolite supplementation, and fecal microbiota transplantation animal experiments will be essential for establishing microbial contributions. For example, colonization of germ-free animals with candidate taxa or defined microbial consortia could identify organisms and functions that modify toxicant metabolism, detoxification capacity, or neurological vulnerability. Probiotic or microbiome-targeted interventions may further reveal whether exposure-associated phenotypes can be prevented, reversed, or overridden through manipulation of the microbial community, thereby establishing the therapeutic potential of microbiome-directed strategies. Conversely, transplantation of toxicant-remodeled microbiota into exposure-naïve recipients could determine whether exposure-associated microbial communities are sufficient to alter host susceptibility to subsequent neurotoxicant challenge or reproduce aspects of the neurological phenotype. Together, these approaches will help establish causal relationships between environmental exposures, microbiome function, and neurotoxic outcomes. Resolving these questions will be critical for determining whether the gut microbiota functions merely as a biomarker of exposure or as an active and therapeutically tractable regulator of neurotoxic resistance and susceptibility.

Given the data that certain microbes can facilitate or limit xenobiotic metabolism in various ways, such experiments are critical for addressing the key gap of whether one’s existing microbiome composition and functional capacity constitute a risk factor for future toxicant-mediated disease. This requires the conceptual reframing of indigenous microbes as both sensors and modifiers of external impacts of environmental exposures. Importantly, future work must use descriptive taxonomic associations as a step towards understanding the microbiome as a functional metabolic community, in which collective enzymatic capacity, ecological interactions, and metabolite exchange networks may be more informative than the presence or absence of individual taxa alone. In addition, the microbial community which arises post-exposure may itself result in modified physiological states that persist after the initial toxicant encounter. Determining whether such exposure-remodeled communities actively contribute to host vulnerability or resilience will be essential for understanding how environmental exposures produce long-term neurological consequences.

The timing of environmental exposure during and across the life course is as critical as the type of chemical exposed. Neurodevelopment is characterized by sensitive windows during which environmental perturbations can exert disproportionate and lasting effects on brain structure and function.²⁰⁹ In parallel, early life represents a critical period for the establishment of microbe-derived metabolic, physiological and neuroactive signaling pathways.^210,211 Perturbations during these convergent developmental windows may produce enduring alterations in host–microbiome interactions, amplifying susceptibility to neurodevelopmental and neuropsychiatric disorders later in life. Integrating developmental timing into microbiome–toxicant research will thus be essential for understanding how early-life exposures translate into long-term neurological risk.

One additional challenge is the inherent variability of the gut microbiome composition, particularly within the human population.^212–214 Notably, studies of traditional hunter-gatherer populations have revealed unexpectedly high interpersonal microbiome diversity despite shared environments, dietary practices, and close familial relationships,²¹⁴ highlighting the complexity of defining common microbiome responses to environmental exposures. Inter- and intra-individual differences and functional redundancy among microbial taxa may limit shared responses within human studies. Experimental gnotobiotic animal models, with defined microbial communities, continue to provide exquisite control for microbial composition and function. These can provide a singular baseline to understand both compositional shifts and contributions of individual microbial taxa to exposure outcomes. Additional elements, such as the taxonomic resolution of microbiome analyses (e.g., phylum versus genus level), inclusion of microbes in other anatomical sites,^215–217 the timing of the exposure across the life course, and the need to study real-world mixtures of xenobiotics representing the holistic exposome, rather than single compounds, further complicate interpretation and translational relevance. Although the gastrointestinal microbiome has received the greatest attention, environmental toxicants first encounter microbial communities at multiple anatomical interfaces, including the skin and respiratory tract. These microbial ecosystems may independently, or in concert with the gut microbiota, influence toxicant transformation, absorption, and host responses, yet their contribution to neurological outcomes remains largely unexplored. Expanding investigations to body sites outside of the gut will therefore be important for developing a more comprehensive understanding of microbiome–environment interactions across the exposome.

Despite these challenges, emerging data have begun to reveal numerous ways in which native microbes can modify the outcomes of an exposure, particularly those with neurologically relevant toxicity. These effects arise through both direct mechanisms, such as microbial biotransformation of xenobiotics, and indirect mechanisms, including regulation of host gene expression, barrier function, and immune system. To move the field past correlative observations, future research must prioritize mechanistic, hypothesis-driven, translationally-relevant approaches. Combining in vitro and in vivo models, gnotobiotic systems, targeted microbial and host omics, pharmacokinetic modeling, and stepwise mechanistic interrogation can provide a powerful framework to disentangle host and microbial contributions. Importantly, future studies must better reflect real-world exposure paradigms relevant to human health risk assessment, as many existing experimental studies rely on acute or comparatively high-dose exposures that may not accurately represent environmentally encountered conditions. This includes investigating chronic low-dose exposures that approximate environmentally encountered concentrations currently considered safe, incorporating realistic exposure routes such as food, water, and inhalation, and examining complex mixtures of xenobiotics representative of the broader exposome rather than isolated compounds alone. Defining how microbiota-dependent processes alter susceptibility thresholds under these conditions will be essential for understanding inter-individual variability in toxicant responses and may ultimately influence future toxicological evaluation frameworks. Such integrative strategies are essential to advance our understanding of the gut microbiota as a mediator of the xenobiotic-microbiota–brain interface which ultimately may be key to predict inter-individual variability in disease risk following an exposure. These approaches may ultimately inform microbiome-targeted therapeutic avenue aimed at modifying toxicant susceptibility in high-risk populations. For instance, the use of probiotic or microbial metabolites that preferentially increase detoxification pathways as a prophylactic in at-risk occupations.

Overall, addressing these complexities with both integrative and reductionist approaches will be critical to move from descriptive observations toward mechanistic models of how the native gut microbiota shapes xenobiotic metabolism and neurotoxicity (Figure 3). Ultimately, resolving how microbial metabolic capacity, host physiology, and environmental exposures interact across the xenobiotic-microbiota–brain axis will be essential for developing predictive mechanistic frameworks linking the microbiome to xenobiotic susceptibility and neurological dysfunction risk.

Figure 3.

Future considerations for studies defining contributions of the microbiome to environmental exposures.

RESOURCE AVAILABILITY

Lead contact

Further information and requests for resources should be directed to and will be fulfilled by the lead contact, Timothy Sampson (trsamps@emory.edu).

Materials availability

This study did not generate new materials.

Data and code availability

This study did not generate new data or code.