Environmental Toxins, Drug Metabolism, and the Microbiome

Environmental toxins are ubiquitous in our modern world, and high levels of exposure are associated with several chronic diseases. While we typically think of the liver as the primary site of detoxification, the gut and its associated microbes play an incredibly important role in determining the toxicity of compounds. Read on to learn how the gut influences toxin and drug absorption, metabolism, and more.

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As we come to understand more and more about the microbiota, we find that it is increasingly connected to our physiology. I’ve written a series of blog posts on the microbiome, including its connections to skin, allergies, thyroid, autoimmune disease, brain health, food cravings, bone health, ocular health, and even its involvement in human evolution. In this next article in the series, I’ll tackle the role that the gut microbiota plays in detoxification and, in some cases, toxification.

Why We Need to Detoxify

Chemicals in the environment have also been shown to play a role in mental health issues, neurodegenerative disease, kidney and liver disease, autoimmunity, and cancer (1, 2, 3, 4, 5, 6, 7). Environmental toxins are also at least partly responsible for the growing epidemic of obesity and diabetes (8, 9, 10, 11).

A well-functioning detoxification system is clearly important for maintaining our health in the modern environment. Pollutants, hormones, heavy metals, food toxins, pathogens, and cellular waste all require specific processes to remove them from the body. In previous articles, I covered the basics of detoxification, including steps for reducing exposure and increasing detoxification and environmental toxins: the elephant in the room? Here, we’ll skip the basics and focus on the involvement of the gut and gut microbiota.

Gut microbes are the true first line of defense against toxins

The Gut as a Detoxification Organ

You may recall learning that there are three primary phases of detoxification:

Phase I: cytochrome P450 and other enzymes introduce polar groups via oxidation, reduction, or hydrolysis

Phase II: conjugation via processes like methylation, acetylation, or sulfonation

Phase III: further modification and excretion

The Gut as “Phase 0.5” Detoxification

Phase I cytochrome P450 is often referred to as the “first line of defense” against environmental toxins. However, this is really an inaccurate view of detoxification. Epithelial barriers, such as those of the gut, mouth, skin, and lungs, and the microbes associated with these mucosal surfaces, are the true first line of defense against toxins. Not only do they directly alter the chemical structure of compounds, but they also influence barrier function and thus affect chemical absorption.

Substances encountered through oral exposure must pass through the gut before making their way to the liver via the portal vein. Only after passage through the liver do compounds make it into general systemic circulation. In this way, we can really think of the gastrointestinal tract and gut microbiota as the site of “Phase 0.5” detoxification, occurring before ingested substances reach the liver. The gut also plays a role in phase II detoxification, as I’ll discuss in more detail later on.

Microbes: Not All Good

It’s important to note that microbial–toxin interactions are not always beneficial for the human host. In many cases, the microbiome helps to detoxify, but in others, microbes can enhance the toxicity of various compounds. This effect seems to be exacerbated in the context of microbial dysbiosis. Aspects of environmental toxin processing that can be affected by microbes include absorption, distribution, metabolism, and excretion (12). They do this in several ways, which I’ll discuss in the next several sections.

Microbes Directly Alter Chemical Activity

The first way that microbes affect toxin exposure is by directly altering chemical structure and activity.

Environmental Pollutants

Polycyclic aromatic hydrocarbons (PAH) are known to be potent carcinogens. Exposure through the oral route is most common through consumption of grilled meats on charcoal grills and from contaminated soils on unwashed vegetables (13, 14). In vitro studies have demonstrated that gut microbes are capable of converting PAH into bioactive estrogenic metabolites (15). Without these microbes, most PAH would pass harmlessly through the intestine unabsorbed. It is only through microbial metabolism that PAH become harmful.

Heavy Metals

Gut microbes were also found to thiolate and methylate arsenic in both human and mouse models (16, 17, 18). The resulting arsenic metabolites are much more toxic than inorganic arsenic. Intriguingly, a microbiome associated with a Western-type diet was shown to have an increased capacity to produce toxic methylated arsenic species compared to a high-fiber diet. These toxic arsenic species were also able to pass more easily across an epithelial barrier (19).

Dietary Compounds

In addition to toxifying heavy metals, microbes can also turn harmless dietary compounds into potentially toxic metabolites. You may be familiar with trimethylamine-N-oxide, or TMAO, which is produced via the microbial metabolism of choline to trimethylamine (TMA) and subsequent oxidation in the liver. Several studies have indicated that TMAO may increase risk of cardiovascular events (20, 21). However, as I’ve suggested before, serum TMAO will only be formed in significant quantities if the bacteria that convert exogenous substances to TMA are present (22). Additionally, a compound found in extra virgin olive oil has been shown to inhibit TMA formation in vitro, suggesting yet again that dietary context matters (23).

Microbes also detoxify dietary compounds. For example, many plant foods contain oxalate, a chelator that binds to calcium, magnesium, and other mineral cations. High oxalate levels can result in hyperoxaluria, kidney stones, and renal failure (24). Mammals lack enzymes to detoxify oxalate, and thus rely on microbial transformation of oxalate by microbes such as Oxalobacter formigenes (25).

Microbial Metabolites Compete for Detoxification and Absorption Pathways

Metabolites produced by the gut microbiota may also compete for host enzymes in detoxification pathways. One study found that individuals with high urinary levels of p-cresol sulfate had low urinary levels of acetaminophen sulfate after acetaminophen dosing. The authors concluded that the microbial metabolite p-cresol competes for sulfonation enzymes, reducing the capacity for sulfonation of acetaminophen (26).

It has also been hypothesized that microbial metabolites compete with toxins or drugs in absorption pathways. For instance, primary bile acids may compete for the same intestinal transporters that enable statin absorption. Thus, increased microbial bile acid metabolism would increase the amount of statin that could be absorbed (27). This likely occurs for many drugs and environmental toxins in ways that have yet to be discovered.

The Gut Microbiome Affects Phase I and Phase II Enzymes

The gut microbiota can also indirectly affect expression of detoxification enzymes. Claus et al. showed that the expression of several phase I cytochrome P450 enzymes were significantly reduced in germ-free mice compared to mice “conventionalized” with a gut microbiota (28). Another study found that germ-free rats were found to have higher levels of phase II hepatic sulfotransferases and several colonic phase I and II enzymes compared to conventionalized mice (29).

Diet also plays a role in shaping the gut microbiome-detoxification relationship. Short chain fatty acids, produced from the bacterial fermentation of dietary fiber, have been shown to increase in vitro colonocyte expression of phase II enzyme glutathione S transferase (GST) (30, 31). Additionally, animal studies suggest that gut microbes may play a role in the ability of the polyphenols quercetin and catechin to influence liver or gut levels of phase II enzymes (32).

The Gut Microbiome and Enterohepatic Circulation

After phase I detoxification in the liver, many environmental toxins are excreted in bile and undergo phase II metabolism in the gut. The gut microbiome encodes several phase II enzymes with the capacity for methylation, hydroxylation, sulfonylation, and other modifications. After modification, these compounds are often reabsorbed. This enterohepatic circulation may lead to increased time that a compound remains in the body, so reducing enterohepatic circulation may reduce toxicity. For example, excretion of the flame retardant PBDE-47 was shown to be increased following administration of a nonabsorbable fat which decreases enterohepatic circulation (33).

β-glucoronidase is a phase II enzyme that is highly important in enterohepatic cycling and is responsible for the activation of foodborne carcinogens in the gut (34). Genes related to β-glucoronidases have been shown to be enriched in an obesity-associated microbiome (35), and it has been hypothesized that increased β-glucoronidase activity and increased enterohepatic cycling of toxins may play a role in the pathophysiology of obesity or diabetes (12).

Gut Microbes & Drug Metabolism

Drugs also need to be metabolized and detoxified. Nearly a century ago, research groups discovered that gut microbes play a role in drug metabolism (35). Today, more than 50 drugs have been shown to be metabolized by gut bacteria (36, 37). Indeed, the “first pass effect,” or the extent to which a drug is metabolized by intestinal, hepatic, and microbial enzymes, is ultimately what determines the bioavailability of a drug (how much reaches circulation) and is subject to considerable variability depending on the presence or absence of certain microbes and enzymes.

Drug development is increasingly moving towards an integrated assessment of environmental and host factors, including the microbiome (35). For example, prodrugs that contain azo bonds take advantage of microbial azoreductases that render the drug bioactive upon reaching the gut (38). There is also increasing interest in using patient metabolite profiles to predict the efficacy of a pharmaceutical intervention, a field known as “pharmacometabolomics.” Advances in technology will likely make this a clinical reality in the very near future.

Intestinal Permeability Overburdens Detoxification Systems

Microbes can also impact detoxification processes by influencing gut barrier function. Microbial dysbiosis has been shown to lead to increased intestinal permeability (39). When this occurs, large proteins, food toxins, pathogens, and bacterial components “leak” into the portal vein. The liver is then burdened with these incoming toxins and must attempt to process them before they reach systemic circulation.

The presence of these endotoxins in the blood and the associated inflammation is likely involved in the pathogenesis of liver disease (40, 41, 42). In animal models, endotoxin has been shown to reduce expression of liver enzymes such as microsomal epoxide hydrolase (mEH) and GST (43), effectively reducing detoxification capacity.

The Skin Microbiome and Environmental Toxins

All mucosal surfaces serve as a potential route of exposure to environmental toxins. The skin microbiome, like the gut microbiome, has a collective metabolic potential that far exceeds that of the human host. While not as much is known about the role of skin microbes in toxification and detoxification, preliminary evidence suggests that the skin microbiome plays a similar role. As we come to understand more about the skin microbiome, it’s likely that more microbe–toxin interactions will be discovered.

One interaction that is known is that of skin microbes and PAH. Like gut microbes, skin microbes are able to metabolize PAH into bioactive estrogenic benzo[ɑ]pyrene (44). Commensal microbes may further metabolize benzo[ɑ]pyrene into several genotoxic and cytotoxic compounds (45).  Skin exposure to PAH may be even more common than oral exposure, as the most frequent sources of PAH are consumer products such as cosmetics and contaminated air.

How Environmental Toxins Harm the Microbiota

We’ve now discussed several ways that microbiota can affect the absorption, disposition, metabolism, and excretion of environmental toxins. On the flip side, environmental toxins also alter microbial communities in ways that may harm host health. The following toxins have well-established detrimental effects on the composition of the microbiota:

• Antibiotics (46, 47)
• Chlorinated water (48, 49)
• Immunizations (50)
• Pesticides (51, 52)
• Heavy metals (53, 54)

In other words, toxins may cause microbial dysbiosis, which may, in turn, increase the toxicity of environmental pollutants and their ability to be absorbed by the host.

So, what’s the takeaway? In order to protect ourselves and our patients against environmental toxins in the modern environment, we should:

1. Reduce exposure as much as possible
2. Support detoxification pathways
3. Cultivate a healthy gut microbiota

By taking these steps, we can reduce our risk of the many modern chronic inflammatory diseases associated with environmental toxins.