The gut microbiota: a major player in the toxicity of environmental pollutants?

Abstract

Exposure to environmental chemicals has been linked to various health disorders, including obesity, type 2 diabetes, cancer and dysregulation of the immune and reproductive systems, whereas the gastrointestinal microbiota critically contributes to a variety of host metabolic and immune functions. We aimed to evaluate the bidirectional relationship between gut bacteria and environmental pollutants and to assess the toxicological relevance of the bacteria-xenobiotic interplay for the host. We examined studies using isolated bacteria, faecal or caecal suspensions-germ-free or antibiotic-treated animals-as well as animals reassociated with a microbiota exposed to environmental chemicals. The literature indicates that gut microbes have an extensive capacity to metabolise environmental chemicals that can be classified in five core enzymatic families (azoreductases, nitroreductases, β-glucuronidases, sulfatases and β-lyases) unequivocally involved in the metabolism of >30 environmental contaminants. There is clear evidence that bacteria-dependent metabolism of pollutants modulates the toxicity for the host. Conversely, environmental contaminants from various chemical families have been shown to alter the composition and/or the metabolic activity of the gastrointestinal bacteria, which may be an important factor contributing to shape an individual's microbiotype. The physiological consequences of these alterations have not been studied in details but pollutant-induced alterations of the gut bacteria are likely to contribute to their toxicity. In conclusion, there is a body of evidence suggesting that gut microbiota are a major, yet underestimated element that must be considered to fully evaluate the toxicity of environmental contaminants.

Figure 1

Environmental chemicals and the GI microbiota interact via multiple mechanisms. (a) Environmental chemicals that are poorly absorbed after ingestion are swept to the distal small intestine and caecum by peristalsis, and those that partition across the intestinal wall from the blood may be directly metabolised by the GI microbiota. (b) Most xenobiotics are non-polar and therefore readily absorbed from the GI tract, then transported by the portal blood to the liver for detoxification. The liver tends to oxidise xenobiotics, forming conjugates with glucuronic acid, sulfate, or glutathione that can be excreted in the bile and enter the intestine where microbiota metabolism can take place. The GI microbiota generally deconjugates and reduces the hepatic xenobiotic metabolites, resulting in the formation of non-polar molecules of lower molecular weight, which are readily reabsorbed. Microbiota-mediated deconjugation of metabolites previously conjugated by the liver may regenerate the original xenobiotic or form new toxic metabolites. (c) Environmental chemicals can also interfere with the composition of the GI microbiota, which may lead to detrimental consequences for the host. (d) Pollutants can also change the metabolic activity of the GI microbiota, which may affect the activity of endogenous metabolites or the toxicity of other xenobiotics that depend on gut bacteria for their metabolism.

Figure 2

Examples of GI-bacteria-mediated transformations of environmental xenobiotics.

Figure 3

Xenobiotic-metabolising enzymes of the GI microbiota: (i) The reductive cleavage of azo (N=N) bonds is performed by bacterial azoreductases. Three groups of azoreductases have been described: flavin-dependent NADH preferred azoreductases, flavin-dependent NADPH preferred azoreductases and flavin-free NADPH preferred azoreductases. (ii) Bacterial nitroreductases reduce nitro (–NO₂) functional groups to the corresponding amines. Two types of bacterial nitroreductases have been described: type 1 nitroreductases are oxygen-insensitive and catalyse the sequential reduction of nitro groups through the addition of electron pairs from NAD(P)H to produce the nitroso, hydroxylamino and amino derivatives. Type 2 nitroreductases are oxygen-sensitive and catalyse the single-electron reduction of the nitro group to produce a nitro anion radical. (iii) Endogenous sulfate esters are hydrolysed in the GI tract by sulfatases of bacterial origin. (iv) Glutathione conjugates of xenobiotics are also extensively excreted in the bile. They are degradated by various mammalian enzymes (γ-glutamyl transpeptidase and carboxypeptidase), resulting in the formation of cysteine conjugates. These cysteine conjugates may reach part of the GI tract that contain ß-lyase activity and be converted to their corresponding thiol. (v) ß-glucuronidases are present throughout the GI tract and play a role in the hydrolysis of xenobiotic glucuronides, the largest class of xenobiotic conjugates excreted in bile. The intestinal microorganisms are thought to be the major source of ß-glucuronidase because hydrolysis of many xenobiotic glucuronides is dramatically reduced (>90%) in GF or antibiotic-treated rats.