Although the contribution of human genetic polymorphisms to the prevention and treatment of human disease has been widely investigated, the role of genes encoded by the microbiota in therapeutic outcomes remains underexplored. A recent review, led by Prof. Peter Turnbaugh from the Department of Microbiology & Immunology at University of California San Francisco (USA), discusses several mechanisms that link the gut microbiota with xenobiotic metabolism, and explores how this knowledge can be applied to improve the treatment of human disease.
The structure and function of the gut microbiota is shaped by several factors including dietary compounds, drugs, age, geography, and even human genetics. Although in the last decade the human gut microbiome has been associated with many diseases, mechanisms by which it affects the metabolism of xenobiotics remains underexplored. Gut microbiota produce metabolites that might affect the appropriate function of the homeostatic systems (nervous, endocrine or immune); moreove, gut microbial communities can biotransform xenobiotics, including drugs, dietary compounds and environmental toxins.
Gut microbiota can affect metabolism and bioavailability of both drugs and their metabolites through direct or indirect mechanisms. Direct mechanisms include the biotransformation of drugs or their metabolites into active, inactive or toxic products. Besides this, xenobiotics may also shape the composition of the gut microbiota through antimicrobial activity or by encouraging selective bacterial growth. Indirect mechanisms involve modulation of host pathways that are involved in metabolism and transport. On the other hand, the gut microbiota may metabolize oral drugs and dietary compounds prior to their absorption, thus affecting first-pass metabolism and decreasing their concentration before reaching systemic circulation and target tissues. Major reaction types catalysed by the gut microbiota include reduction and hydrolysis, which may reflect the metabolic demands of the gut microbiota. The microbial metabolism of pharmaceuticals can lead to their activation (e.g., sulfasalazine and prontosil), inactivation (e.g., digoxin and methotrexate) or result in the production of toxic metabolites (e.g., anti-cancer drug metabolite SN-38 glucuronide and metabolites derived from the hydrolysis of glucuronidated non-steroidal anti-inflammatory drugs). These examples show the impact of microbial metabolism on the side effects of drug therapy through interference with host pathways that are involved in drug detoxification.
Studies in mice have shown that the microbiota can affect the expression of several host genes that are involved in drug metabolism and transport, not only in gut tissues but also in the liver. In addition, gut microbiota can change the serum metabolome in the host. Host-microbial interactions may also influence drug efficacy through microbial metabolite competition with drugs for host xenobiotic metabolism enzymes. For instance, the microbial metabolite p-cresol, which is an end product of tyrosine and phenylalanine metabolism, inhibits the conversion of acetaminophen (also known as paracetamol, the active form) to acetaminophen sulphate (the inactive form).
Beyond influencing drugs, the gut microbiota can also metabolize several xenobiotic compounds found in our diet, thus affecting the health-promoting potential of the foods that we usually eat. Many diet-derived bioactive compounds require metabolism by the gut microbiota for activation and/or absorption and include, among others, dietary polyphenols and phytoestrogens. However, microbial biotransformation may exacerbate the effect of harmful compounds that are derived from the diet, such as heterocyclic amines formed during the charring of meat and choline-containing compounds that are metabolized by gut microbiota to form trimethylamine (TMA), which is transformed to TMA N-oxide (TMAO)—a reported risk factor for cardiovascular disease (CVD).
Taking all these data together, the researchers conclude the review by pointing out the main translational implications of microbiome research in pharmacology:
- Using gut microbiota species or strains, genes, enzymes or metabolites to find biomarkers in order to develop co-therapies that target the microbiota or to identify novel drugs.
- Using molecules to inhibit the activity of bacterial enzymes in the gut to decrease drug toxicity or increase drug bioavailability.
- Using microbial species, strains, genes, enzymes or metabolites for diagnostics.
To sum up, research into the microbial and molecular mechanisms involved in xenobiotic metabolism could have immediate translational implications for human health and would allow development of microbiome-based diagnostics and co-therapies.
Spanogiannopoulos P, Bess EN, Carmody RN, Turnbaugh PJ. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat Rev Microbiol. 2016; 14(5):273-87.