"Never get involved in a land war in Asia" is, according to some, a well-known piece of advice, right up there with "Never go in against a Sicilian when death is on the line." For those unfamiliar with these quotes, they come from the classic movie The Princess Bride, in which Vizzini (a Sicilian) engages in a battle of wits involving two cups of wine, one of which may contain the fictional poison iocaine.
If you haven't seen this movie, please stop reading here and watch it before continuing, as we're about to spoil the famous scene… (I'll wait). In the end, Westley (our hero) ensured his victory by poisoning both cups of wine, knowing it didn’t matter which cup his opponent chose. He had built up an immunity to the poison by repeatedly taking small doses and could safely drink it.
In the real world, complex multicellular organisms have much more limited physiological adaptability. While immunity can be developed to certain poisons through repeated exposure, tolerance does not always build from sub-lethal doses. More often, chronic exposure to a toxin can lead to long-term diseases rather than increased resistance.
Microbes, on the other hand, are more flexible and adaptable at the cellular level, allowing them to survive and thrive in harsh environments with significant toxic pollution.
While the word detoxification may conjure up images of strange diets or odd juice combinations, its true biological meaning refers to the process of transforming harmful substances into inert compounds or removing them from the environment through other means —a task at which microbes excel.
This blog explores how microbes can process and neutralize some of the most hazardous substances imaginable—often for the better, but sometimes for the worse.
Microbes: Nature's Little Recyclers
While many biological waste products—such as carrion, dead plants, and other detritus—are not typically considered toxic, their accumulation in the environment can be ruinous if they are not recycled down to their basic components quickly enough. The good news is that much of this material remains rich in energy, providing a strong incentive for a diverse array of species to break it down. For a more in-depth discussion of this topic and what happens when it fails, please refer to our previous blog.
Environmental Detoxification
Microbial Soil Detoxification
Spilled hydrocarbons and other industrial chemicals tend to be persistent pollutants of soil near sites where they are produced and/or used.
Soil microbes play a crucial role in decomposing organic matter, including dead plants and animals. However, some of the materials these microbes break down also include harmful substances, such as pesticides, herbicides, and synthetic hydrocarbon residues. One famous taxon of bacteria, the Pseudomonads, is known for its ability to degrade polycyclic aromatic hydrocarbons (PAHs), which are toxic pollutants commonly found in oil and other chemically-contaminated soils1. Due to their hydrophobic nature, these substances are prone to accumulating in environments and food chains, where they can bioaccumulate in species higher up the chain, leading to cancer, reproductive harm, and other diseases. This hydrophobic characteristic also makes their breakdown more challenging.
A more recent challenge is the breakdown of per- and polyfluoroalkyl substances (PFAS), also known as "forever chemicals," which have proven to be even more difficult to degrade than PAHs. PFAS2 have been industrially desirable due to the strength and stability of the C–F bond, but this same strength and stability makes these chemicals extremely difficult to degrade in the natural environment. Additionally, breaking this bond inherently releases free fluorine, which is highly toxic. As a result, any species employed to degrade PFAS must not only possess the molecular machinery to break this challenging chemical bond but also have a method for handling the harmful breakdown products it generates. Monitoring soil microbial communities in PFAS-contaminated sites can provide valuable insight into potential bioremediation strategies.
Water and Wastewater Detoxification
Spilled oil in the ocean from illegal discharges and accidents involving tanker ships can be an environmental disaster requiring immediate response to mitigate the damage.
Water microbes play critical roles in maintaining the cleanliness of our oceans and freshwater, effectively breaking down many pollutants. Wastewater microbes also play a vital role in breaking down various compounds as part of wastewater treatment, ensuring it can be safely discharged into the environment. In oceans, Alcanivorax bacteria have proven to be highly effective consumers and degraders of hydrocarbon pollution, capable of breaking down everything from crude oil spills to plastic garbage.3 In freshwater, especially in potential drinking water sources deep underground, contamination with toxic minerals is a great concern. One potential contaminant that presents obvious dangers is dissolved uranium. Uranium in its more oxidized state—uranium (VI)— easily dissolves in groundwater, posing a clear threat if that water is used for drinking, agriculture, or other applications.
One potential method to mitigate this issue is bioremediation with microbes capable of reducing the highly soluble uranium (VI) to the much less soluble uranium (IV). Many microbial species can carry out this reaction under different conditions (such as varying water temperatures), and the resulting lower-solubility uranium simply precipitates out of the water, becoming part of the sediment and posing no further harm.
While spilled oil produces an attractive rainbow as it goes down the drain, this same oil becomes a nightmare as it makes its way through wastewater treatment and can cause tremendous harm if significant amounts of it are released into the environment with wastewater discharge.
Microbes play a critical role in processing wastewater for safe discharge into the environment. At a scale visible to the naked eye, microbial populations influence the formation of foams and can also create filamentous bulk and biofilms4 —properties that can significantly impact the operation of wastewater treatment plant equipment and even render a facility inoperable.
On a microscopic and chemical level, nitrogenous compounds like ammonia and nitrogen oxides must be removed from water by breaking them down into nitrogen gas through microbial processes. Both the nitrification pathway (breakdown of ammonia) and denitrification pathway (breakdown of nitrogen oxides) require significant inputs of energy, oxygen, and organic carbon material to function.5
Additionally, the hydrocarbon and fluorocarbon pollutants mentioned earlier remain an ongoing concern and may require continued monitoring and intervention. This area of study is still evolving, but fungi have been suggested as a potentially important bioremediatory tool for PAH-contaminated wastewater.6 Reliable water microbiology tools can aid in these efforts by facilitating accurate monitoring and assessment of microbial communities in affected environments.
Microbial Detoxification within the Animal Body: For Better or for Worse
For Better: Dietary Detox and the Expansion of Food Options
The desert woodrat hiding among cactus leaves and the creosote bush with its characteristic small leaves and fuzzy seeds.
Larrea tridentata, better known as the creosote bush and greasewood, is a highly predominant species of many southwestern deserts in North America. Local indigenous peoples have historically used preparations of this plant to treat a wide range of conditions, as it contains multiple antimicrobial and pharmacologically-active compounds.7 This property likely contributes to the plant's biological success, as most animals attempting to feed on creosote bush will suffer ill effects due to an overdose of these pharmacologically active compounds.
A notable exception is the desert woodrat (Neotoma lepida), which has subpopulations that specialize in consuming this plant. Experiments conducted by the University of Utah showed that transplanting the gut microbiome of a creosote bush-consuming desert woodrat to one that does not consume the plant protected it from the ill effects of the diet. Conversely, disrupting the microbiome of a desert woodrat that could tolerate consuming creosote bush made it susceptible to the toxic effects of the compounds8. These observations provided definitive evidence that the gut microbial community was both necessary and sufficient to confer creosote bush toxins and allow for its consumption.
Cassava provides a major source of calories in many parts of the world, but some varieties of this plant contain dangerous cyanide-producing compounds.
Manihot esculenta, more commonly known as cassava or yucca, is another hardy plant that thrives in harsh growing conditions often found in regions with high food insecurity. Its starchy root may provide the only reliable food source in some underdeveloped regions of the world, such as the Congo in Central Africa. One survival strategy adopted by cassava, much like the creosote bush, is the build-up of compounds within its tissues (including the starchy roots) that release cyanide when digested by animals. While the immediate toxicity of cyanide is well-known, chronic exposure to sub-lethal doses—unlike the fictional iocaine—does not lead to tolerance. Instead, it can cause a debilitating neurological disease known as konzo. Because the production of cyanide from cassava is dependent on the digestive process, the involvement of the microbiome in cassava toxicity would seem quite plausible. Pandas are already known to employ an adaptation of their gut microbiome to process similar toxins from their bamboo diet.9 Matthew Bramble et al., in a 2021 Nature Communications paper, demonstrated that differences in the gut microbiome of humans consuming cassava were linked to their risk of developing konzo.10
For Worse: Microbial Degradation of Chemotherapeutics
Many chemotherapeutics, especially older ones, are toxins by design—their usefulness as pharmaceuticals lies in their ability to be much more toxic to rapidly dividing (cancerous) cells than to healthy cells with tightly regulated replication cycles. In a 2017 Science publication, researchers sought to understand why colon cancer cells that were normally susceptible to gemcitabine and would die in its presence became resistant when cultured alongside human skin cells derived from plastic surgery patients. To the surprise of the authors, the skin cells were merely bystanders in this deadly process. It was the bacteria Mycoplasma hyorhinis, a common contaminant in the skin cell cultures, that protected the cancer cells by metabolizing the gemcitabine11 into an inactive form. The authors also demonstrated that while Mycoplasma were protective in their initial studies (with Mycoplasma resistant to many standard cell culture methods used to prevent bacterial contamination, often earning the nickname "the fifth horseman of the apocalypse" among cell culturists), a variety of gut microbes were capable of detoxifying gemcitabine. These gut microbes appeared to be colonizing and protecting tumors from treatment with the drug.
Effective treatments for pancreatic cancer have continued to prove elusive despite significant efforts and resources being dedicated to the challenge. One reason for this is that chemotherapeutics that appear effective against cancer cells in a dish often prove ineffective when applied to actual patients (gemcitabine being one such drug). In a recent publication from Mount Sinai School of Medicine, it was shown that patients treated with antibiotics within a month prior to starting gemcitabine therapy for pancreatic cancer exhibited improved survival.12
The Future of Microbial Detoxification
Microbial breakdown and/or neutralization of unwanted or harmful substances has been a long-standing natural process, predating mankind. Modern biotechnology is able to harness this process, directing and encouraging it where it is needed most—whether at the site of pollution or where unwanted waste materials are accumulating. However, this process can sometimes occur to our detriment, such as when microbes break down an intentionally introduced toxin designed to control a biological threat (like a tumor). In such cases, controlling the microbes mediating this process could enhance the efficacy of cancer and other treatments once identified as an issue.
The diversity of enzymes and metabolic processes able to be carried out by microbes far exceeds what multicellular organisms are capable of. By harnessing the power of protein engineering and synthetic biology, humans will be able to take this process even further. This could help clean polluted environments, reduce energy consumption during wastewater treatment, and potentially even enable the safe consumption of food that would otherwise be unusable—advancements that could play a critical role in facilitating human space exploration.
Continuing to understand and harness these natural processes, while building upon them using current and future biotechnological methods, will remain a major area of interest and a critical sector of the bioeconomy. The increased utilization of microbial degradation of pollutants is almost certain to play a key role in moving towards a cleaner, more sustainable future for the planet. Additionally, the interplay between microbes and cancer treatment—particularly regarding the immune response and interactions with chemotherapeutics—is an active area of research, with new discoveries emerging almost daily. Gaining a deeper understanding of this hidden aspect of cancer biology is likely to provide valuable insights for developing and improving treatments for cancer patients.
Citations
- https://www.sciencedirect.com/science/article/abs/pii/S0048969722071108
- https://link.springer.com/article/10.1186/s44315-024-00017-3
- https://link.springer.com/article/10.1023/A:1020586312170
- https://www.sciencedirect.com/science/article/pii/S0960852419317213
- https://onlinelibrary.wiley.com/doi/abs/10.1002/jobm.202100376
- https://www.mdpi.com/1420-3049/27/17/5393
- https://onlinelibrary.wiley.com/doi/abs/10.1111/ele.12329
- https://journals.asm.org/doi/10.1128/msphere.00229-18
- https://www.nature.com/articles/s41467-021-25694-1
- https://www.science.org/doi/full/10.1126/science.aah5043
- https://academic.oup.com/jncics/advance-article/doi/10.1093/jncics/pkaf024/8029668
- https://journals.asm.org/doi/full/10.1128/jb.182.8.2059-2067.2000