Arsenic (As)

Overview

Arsenic is a metalloid toxin that shapes microbial pathogenesis by altering gut microbiota composition and function and by exerting selective pressure for metal-resistant organisms. Chronic ingestion of contaminated water and food leads to variable disease outcomes, partly attributable to differences in the microbiome. The principal host niches for arsenic–microbe interaction are the gastrointestinal tract (where arsenicals contact a dense microbial community), reducing the abundance of commensals such as Bifidobacterium and butyrate-producing Firmicutes.^[1] These changes not only diminish barrier-protective metabolites but also select for multidrug-resistant organisms, thereby increasing the risk of difficult-to-treat infections. Another host niche is the systemic circulation (where arsenic can modulate immune cells). The most actionable leverage point is exposure mitigation coupled with emerging microbiome-targeted interventions that reduce arsenic absorption. This dual strategy can prevent arsenic-driven dysbiosis and downstream pathologies.

Chemical speciation across host niches

In oxygenated, acidic gastric fluid, arsenic exists mainly as pentavalent arsenate (As(V)) oxyanions (H₂AsO₄⁻/HAsO₄²⁻). A shift to mildly reducing conditions (as in the anaerobic colon) favors the formation of trivalent arsenite (As(III)) as uncharged arsenous acid (H₃AsO₃). This redox-dependent speciation governs bioavailability: arsenate, being an analog of phosphate, requires transporters for uptake, whereas arsenite (more mobile) can pass via aquaglyceroporins. For example, in the neutral small intestine As(V) competes with phosphate for the Pst/Pit uptake systems, but As(III) readily permeates through glycerol channels like GlpF. Gut bacteria further alter arsenic speciation by methylation and thiolation – generating monomethylarsonous acid (MMA(III)), dimethylarsinic acid (DMA(V)), and thioarsenicals – which can increase toxicity or volatility. These transformations change which importers or detox pathways are engaged and thus arsenic’s distribution across host niches.

Microbial acquisition, regulation, and buffering

Pathogens acquire arsenic inadvertently and must buffer its toxicity via specialized systems. Arsenate (As(V)) enters bacterial cells through phosphate transporters (e.g. pst operon) due to its chemical mimicry, and arsenite (As(III)) diffuses through aquaglyceroporin channels meant for glycerol. Once inside, arsenic triggers regulatory responses: ArsR family repressors sense As(III) and dissociate from DNA, inducing the ars operon. A canonical arsenic-resistance operon encodes an arsenate reductase (ArsC) that converts As(V) to As(III) and efflux pumps that expel As(III) from the cell. For example, Staphylococcus plasmid pI258 and Escherichia coli R773 each carry arsRBC modules, where ArsC reduces arsenate and ArsB (or Acr3) pumps out arsenite. Some systems include a metallochaperone ArsD, which transfers As(III) to the ArsA ATPase efflux pump, increasing efflux efficiency. These import, regulation, and efflux mechanisms act in concert to detoxify arsenic, allowing microbes to survive in arsenic-rich environments albeit with a metabolic burden.

Metal toolkit

Nutritional immunity and host sequestration

Although arsenic is not needed for microbial nutrition, the host still limits its bioavailability to protect itself and microbiota. Host proteins bind and compartmentalize arsenic, effectively sequestering it in less reactive forms. Metallothioneins – small, cysteine-rich proteins – are strongly induced by arsenic and bind As(III) with high affinity, reducing the pool of free arsenic that could disrupt microbial enzymes. Arsenic in blood partitions predominantly into red blood cells (∼90–99%), where it binds to hemoglobin at cysteine residues. This RBC binding traps arsenic in a less toxic, protein-bound state and limits exposure to peripheral tissues and pathogens.. Similarly, serum albumin binds arsenic trioxide and arsenate, blunting spikes of free arsenic in circulation.The blood–brain barrier further prevents arsenic from entering the central nervous system, guarding that niche from arsenic’s effects. By sequestering arsenic in these ways, the host’s “nutritional immunity” inadvertently shields microbes as well – preventing arsenic from widely killing commensals or invading pathogens, but also denying pathogens any possible benefit from arsenic.

Host sequestration map

Metallophores and community competition

Metals often drive microbial competition via chelators, but arsenic’s role is unique: some microbes use arsenic compounds as chemical weapons rather than nutrients. Certain bacteria secrete or generate arsenicals that reshape the local microbial community. For example, soil and gut bacteria with the arsM gene enzymatically methylate arsenite to produce monomethylarsonous acid (MAs(III)), a highly toxic organoarsenical with antibiotic-like properties. This secreted MAs(III) can inhibit neighboring microbes, giving the producer a competitive edge in arsenic-rich niches (C). In response, other bacteria have evolved capture and detox systems for these arsenicals: e.g. some carry ArsI (an C–As bond lyase) to degrade MAs(III) or ArsH enzymes to oxidize it to less toxic pentavalent forms. Host factors during inflammation may also influence arsenic competition – for instance, host neutrophils releasing reactive oxygen and sulfur species could convert arsenite to less available forms or precipitate it with H₂S, indirectly benefiting arsenic-sensitive commensals (D). Overall, arsenic “metallophores” are not true nutrient-scavenging molecules but rather toxic intermediates; their production and detoxification shape community structure by selectively eliminating organisms that lack resistance.

Metallophores and capture

Mismetallation and cross-metal crosstalk

When arsenic levels rise relative to essential nutrients, enzymes can mis-bind arsenic in place of the correct metals or substrates, leading to malfunctions. For example, arsenate (As(V)) competes with phosphate in many biochemical reactions; it can mistakenly substitute for phosphate in kinases and ATP synthesis. This “wrong-metal” incorporation yields unstable ADP–arsenate instead of ATP, causing rapid hydrolysis of high-energy bonds and effectively uncoupling oxidative phosphorylation. Likewise, arsenite (As(III)) binds to vicinal sulfhydryl groups in proteins – notably the lipoic acid cofactor of pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase – thereby inactivating these key metabolic enzymes. The result is inhibition of the TCA cycle and a shift to anaerobic metabolism (e.g. pyruvate is shunted to lactate). Arsenic can also perturb regulatory metals: it interacts with zinc-binding sites in transcription factors, such as the zinc-finger domains of GATA-1, displacing Zn and causing loss of DNA-binding activity. These mismetallation effects explain some arsenic toxicities (e.g. impaired gluconeogenesis and hematopoiesis) and inform combination strategies – for instance, ensuring adequate dietary phosphate and zinc may reduce arsenic’s ability to hijack those sites, and using thiol-chelating drugs can preferentially bind arsenite to protect enzyme thiols. Recognizing which enzymes are “at risk” guides us in devising interventions to prevent arsenic from usurping critical biochemical pathways.

Mismetallation map

Virulence pathway mapping

Arsenic exposure can modulate pathogen virulence and host susceptibility pathways. In Helicobacter pylori infection, co-exposure to arsenic dramatically intensifies gastric injury: arsenic supports a heightened inflammatory response (upregulating oxidative stress markers Nrf2, HO-1 and cytokine IL-18) that drives tight-junction loss and epithelial barrier disruption. This synergy translates to more severe gastritis and ulceration than H. pylori alone. Targeting arsenic – by removing it from drinking water or using arsenic chelators – reduces the additive oxidative damage and preserves gastric barrier function, thereby attenuating H. pylori’s virulence impact. Another example: enteric pathogens carrying arsenic-resistance genes have a fitness advantage in arsenic-rich hosts. In Yersinia spp., an ars operon on a virulence plasmid was associated with survival inside macrophages, presumably by detoxifying arsenic that immune cells might unleash. Disabling such resistance (e.g. via ArsC or ArsB inhibitors) could make these pathogens more susceptible to host arsenic stress and reduce their persistence. Overall, arsenic’s presence can exacerbate certain virulence pathways (like H. pylori-induced barrier dysfunction), and interventions that remove arsenic or block microbial arsenic defenses can indirectly reduce pathogenesis.

Virulence targets to MBTIs

Exposure to microbiome outcomes

At real-world exposure levels, distinctive microbiome alterations emerge. At low-level chronic exposure (e.g. drinking water ~10–50 μg As/L), human studies report subtle but measurable shifts: infants with moderate arsenic in urine had enrichment of certain Firmicutes and depletion of beneficial genera like Bifidobacterium (A)nature.com, while adults show decreased gut alpha-diversity and early metabolic disturbances in stool (B). At higher exposures (100+ μg/L), more pronounced dysbiosis occurs: long-term arsenic-exposed populations in West Bengal and Nepal exhibit significantly reduced microbial diversity and a community profile skewed toward arsenic-tolerant taxa. For instance, arsenic-volatilizing bacteria such as Desulfovibrio and opportunists like certain Bacillus spp. become overrepresented, whereas commensal Bacteroides and butyrate-producing Firmicutes decline. Mouse models mirror these findings, showing perturbed microbial metabolism (short-chain fatty acid profiles) and barrier function at doses equivalent to human environmental exposure. The most consistent signal across studies is a loss of beneficial anaerobes (e.g. SCFA-producers) and an expansion of arsenic-resistance gene carriers in the gut microbiome of arsenic-exposed hosts. These changes correlate with functional consequences such as increased intestinal permeability and systemic inflammation. Notably, upon reduction of arsenic exposure, partial microbiome recovery has been observed, suggesting these selection effects, while significant, might be reversible if interventions occur before irreversible host damage.

Exposure thresholds to selection signals

Antimicrobial resistance co-selection

Chronic arsenic exposure in the environment exerts a selection pressure that co-selects for antimicrobial resistance (AMR) in microbiomes. Long-term arsenic in drinking water has been linked to higher carriage of multi-drug-resistant gut bacteria in human populations. In Bangladesh, for example, children consuming high-arsenic well water (>100 μg/L) showed significantly higher prevalence of arsenic-resistant Escherichia coli that were concurrently resistant to multiple antibiotics, including third-generation cephalosporins and fluoroquinolones, compared to children in low-arsenic areas. The mechanism involves co-location of ars operons with antibiotic resistance genes on plasmids and transposons – exposure to arsenic selects for bacteria harboring these genetic elements, and those elements often carry AMR determinants as well. Moreover, arsenic can induce global stress responses (e.g. efflux pumps, oxidative stress regulons) that also reduce antibiotic susceptibility. This co-selection persists even after arsenic exposure decreases: once multi-resistant, bacteria remain in the community and can spread their plasmids. In agricultural contexts, historical use of arsenical feed additives similarly enriched soil and animal microbiomes with both ars genes and AMR genes. Thus, arsenic pollution contributes to an expansion of the resistome in exposed microbiomes. Importantly, interventions like improving water quality have the potential to gradually diminish this co-selected AMR burden, but the persistence of resistance genes means benefits may lag (resistance can remain stable in absence of arsenic for some time). Recognizing arsenic as an AMR co-selector highlights the need to address heavy metal exposures as part of antimicrobial resistance control strategies.

AMR co-selection signals

Assays and decision use

Measuring arsenic exposure and its microbiome impact is crucial for clinical decision-making. Each assay has interpretation nuances – e.g. high urinary arsenic with low hair arsenic suggests recent acute exposure, whereas high hair arsenic indicates chronic exposure even if current urine is low. By combining these assays, clinicians and researchers can make informed decisions: when to initiate chelation, whether to advise microbiome-supportive therapy (like probiotics or prebiotics), and how aggressively to pursue environmental remediation. Establishing a threshold (such as urine arsenic >50 μg/L or finding arsenic-resistant gut bacteria) provides a concrete trigger for action in patient management.

Assays to decision use

Body-site biogeography

Arsenic’s interaction with host and microbiota varies by body site, which has clinical implications for monitoring. The major microbiome impact zones are the GI tract (stomach and colon) and, indirectly, systemic compartments affecting immunity. Monitoring should focus on GI symptoms and using site-specific biomarkers (e.g. urine arsenic for systemic exposure, stool tests for gut effect) to catch arsenic’s impact early.

Site to interaction of interest

MBTIs and clinical strategies

Microbiome-based therapeutics (MBTIs) are emerging as adjuncts to traditional arsenic detoxification strategies. Use probiotics to alter arsenic handling: A prime example is the use of probiotic yogurt containing Lactobacillus spp., which was shown to bind dietary arsenic in the gut and reduce arsenic absorption by up to 78% in a human trial. By incorporating such probiotics, we can alter the gut “toolkit” – more arsenic is sequestered in the intestine and excreted, thereby sparing the host and its microbiome from toxicity. This can be paired with conventional measures like providing arsenic-free water; together, safe water plus probiotic supplementation yielded improved outcomes in exposed populations. Modulate the diet to support arsenic-detoxifying microbes: Increasing dietary fiber (prebiotics) can foster gut commensals (like Faecalibacterium and certain Bifidobacterium) that help repair the intestinal barrier and may co-metabolize arsenic into less toxic forms. Such a diet, rich in whole grains and fermentable fibers, is recommended when arsenic exposure is identified, as it can mitigate dysbiosis and inflammation. Combine cross-metal strategies: Because arsenic interacts with other metals, interventions like zinc or selenium supplementation can be used alongside microbiome therapy. For instance, selenium can form seleno-arsenic complexes that are excreted, and adequate zinc might protect zinc-dependent gut enzymes from arsenic. These supplements, when paired with probiotics, address both metal and microbiome aspects of arsenic pathology. When to combine and cautions: MBTIs are best deployed early – e.g. initiating a probiotic regimen as soon as arsenic exposure is discovered, rather than waiting for severe dysbiosis. In severe cases, traditional chelation (e.g. dimercaprol) is necessary; probiotics can be given during and after chelation to help restore the microbiome. One caution is to ensure probiotics used are themselves arsenic-resistant or effective at binding arsenic, otherwise high arsenic could kill the beneficial microbes (lab studies show some strains of Lactobacillus tolerate arsenic well). Additionally, any intervention must consider co-selection of resistance – e.g. using antibiotics in an arsenic-exposed patient might wipe out susceptible flora and leave behind arsenic/antibiotic-resistant strains, so antibiotic stewardship is critical. Microbiome-targeted interventions such as fecal microbiota transplantation (FMT) are still experimental for arsenic toxicity, but conceivably, an FMT from a healthy donor with a robust arsenic-metabolizing microbiome could help an exposed individual; this would be considered if conventional measures fail. Clinically, the strategy is: remove or bind the arsenic (filters, chelators, probiotics), repair and protect the gut (diet, commensals), and bolster the host’s nutrient status to handle arsenic. By doing so, we expect to see improved microbial diversity, reduced arsenic in tissues, and better health outcomes. These MBTIs, combined with standard interventions, form an integrated approach to arsenic exposure management.

Intervention to expected microbial effect

Knowledge gaps and priorities

Several uncertainties limit translation of arsenic–microbiome science into clinical practice. First, the identity of gut microbes that actively methylate or reduce arsenic in vivo remains poorly defined, despite strong in vitro evidence. Second, the durability of arsenic-induced dysbiosis is unclear: whether communities rebound after exposure removal, and on what time scale, has not been established. Third, it is not known whether host immune cells deliberately use arsenic metabolites in defense, a concept suggested by As3mt activity in immune subsets but lacking direct proof. Finally, intervention efficacy is uncertain. While small studies show probiotics and micronutrients can mitigate arsenic uptake, large-scale randomized trials are lacking. Priority directions include longitudinal cohort studies in exposed populations, linking arsenic speciation to microbiome changes and health outcomes; randomized probiotic or synbiotic trials measuring arsenic levels, microbial diversity, and barrier function; and mechanistic experiments using germ-free animals and gut simulators to map microbial pathways of arsenic metabolism. Improved analytical tools, such as isotopic tracing, will also be critical. Collectively, these efforts will clarify which microbes drive arsenic fate in the gut and guide microbiome-based interventions to protect vulnerable communities.

Update History

References

1. Arsenic disturbs the gut microbiome of individuals in a disadvantaged community in Nepal.. Brabec JL, Wright J, Ly T, Wong HT, McClimans CJ, Tokarev V, Lamendella R, Sherchand S, Shrestha D, Uprety S, Dangol B, Tandukar S, Sherchand JB, Sherchan SP.. (Heliyon. 2020;6:e03313.)