Xenobiotics

Microbial xenobiotic metabolism; microbiota; microbiomes, gut microbiota; 

Xenobiotics (singular: xenobiotic; from the Greek xénos = foreign, bíos = life) are chemical substances that are foreign to an organism. These include, for example, pharmaceuticals, pesticides, personal care products, industrial chemicals, and environmental pollutants (Gjorgjievska K et al. 2026). The term “xenobiotic” describes their foreign nature, not their toxicity: a xenobiotic is not necessarily toxic.

Xenobiotics can be absorbed, distributed, metabolized, and excreted. The human gut microbiota plays a crucial role in the metabolism of absorbed xenobiotics by converting ingested food components, industrial chemicals, and pharmaceuticals into metabolites, thereby altering their efficacy, toxicity, and duration of residence in the body are thereby altered (Koppel N et al. 2017). The chemical processes involved in xenobiotic metabolism by gut microbes often differ from those of host enzymes but have not yet been extensively studied.

The effectiveness of drugs varies significantly from person to person. The gut microbiota plays an important role in this variability. The commensal microbiota living in the human gut encodes several enzymes that chemically modify systemically administered and orally ingested drugs; such modifications can lead to activation, inactivation, toxication, altered stability, reduced bioavailability, and rapid excretion. (Pant A et al. 2023). On the other hand, therapeutic active ingredients or even xenobiotics can influence the composition of the gut microbiome and the functions encoded by microorganisms. These changes, in turn, can affect the chemical transformations of the active ingredients and thus also their efficacy (Pant A et al. 2023).

One example is the long-established relationship between antibiotics and weight gain. Since the 1940s, tetracyclines have been associated with weight gain in human infants and children. Significant weight gain has also been documented in adults following various courses of antibiotic therapy.

Xenobiotics are often difficult or impossible to break down biologically. For the human body—including the skin, which acts as a biochemical and molecular barrier—the glutathione detoxification system plays a special role in the breakdown of xenobiotics. The glutathione detoxification system includes cysteine, glutathione synthetases, reduced glutathione, glutathione S-transferases, as well as glutathione peroxidases and glutathione reductases. The “glutathione defense system” also plays a major role in insects, for example, in inactivating xenobiotics, such as in the development of resistance to insecticides. Similarly, keratinocytes are able to use this system to render chemical warfare agents harmless, for example.

The biotransformation of xenobiotics often occurs in the liver: Phase I reactions modify functional groups, while Phase II reactions conjugate the substance or its metabolites to endogenous molecules. This often facilitates excretion (Guengerich FP 2012). In some cases, however, the transformation actually results in the formation of more potent or toxic products (bioactivation; Nakov R et al. 2020).

A molecular understanding of microbial xenobiotic metabolism in the gut will serve as a guide for personalized medicine and nutrition in the future, support toxicological risk assessment, and improve drug research and development.

1. Gjorgjievska K et al. (2026) Xenobiotic-Induced Liver Toxicity. Pril (Macedonian Academy of Sciences and Arts, Section of Medical Sciences) 47(2):111–124.
2. Guengerich FP (2012) Metabolism of xenobiotics in the human environment. Chem Res Toxicol. 25:1800–1802.
3. IUPAC: Compendium of Chemical Terminology, entry “xenobiotic,” DOI: 10.1351/goldbook.XT06755.
4. Koppel N et al. (2017) Chemical transformation of xenobiotics by the human gut microbiota. *Science* 356(6344): eaag2770.
5. Nakov R et al. (2020) Chemical Metabolism of Xenobiotics by Gut Microbiota. Curr Drug Metab. 21:260–269.
6. Pant A et al. (2023) Human Gut Microbiota and Drug Metabolism. Microb Ecol 86: 97-111.