acetaminophen (Tylenol) metabolism, with microbial excretion patterns partly determining whether an individual is a weak or strong “sulfater.” Sulfation is one of two main pathways of acetaminophen metabolism, with weak sulfaters being poor metabolizers. Nicholson explained that Clostridium and other microbes produce 4-cresol, a structural analog to acetaminophen that saturates the sulfation system, making for a weak sulfater. Moreover, 4-cresol does not compete for sulfation only with acetaminophen, but with all hydroxylated drugs. Nicholson said, “It affects hundreds of different compounds…. One gut microbial enzyme actually has amazing effects on the metabolism disposition and potentially toxicity in a very large number of drugs.”
Interestingly, Nicholson noted, autistic children cannot sulfate acetaminophen (Alberti et al., 1999). In fact, according to Nicholson, the ability to sulfate acetaminophen is one of the most statistically significant tests for autism. Again, there is evidence of a microbial connection. Finegood et al. (2002) demonstrated abnormal Clostridium in children with autism. Altieri et al. (2011) showed that children with autism have much higher levels of microbially produced cresol than normal children. Yap et al. (2010a) reported that even non-autistic siblings of children with autism have higher levels of cresol than non-autistic siblings of children without autism.
The competition between 4-cresol and acetaminophen is just one of many types of microbiome-drug interactions. Other interactions include primary metabolism of orally administered drugs (as the first genomes that oral drugs interact with are microbial, not human, genomes), induction of enzymes that metabolize drugs, and changes in bioavailability (e.g., by changing local pH and the ionization state of drugs).
“There is now an enormous amount of interest in the pharmaceutical industry in the modulated microbiome for changing the way that drugs work,” Nicholson remarked. In fact, there is a great deal of interest in drug-targeting the microbiome itself (Jia et al., 2008). Wallace et al. (2010) showed that drugging the microbiome can alleviate the toxicity associated with the common colon cancer drug CPT-11.
Population Metabolic Phenotyping and Disease Risk
In addition to its potential role in personalized medicine, metabolic phenotyping has potential applicability at the population level. Holmes et al. (2008b) introduced the concept of metabolome-wide association studies (MWAS), the metabolic equivalent of GWAS, and showed significant geographic variation in metabolic phenotypes. The same variation has also been associated with varying risks of cardiovascular and other diseases (Yap et al., 2010b).