The
drug nitisinone (NTBC) is used to treat
tyrosinemia type I, and more recently has been also used for the treatment of another disorder of
tyrosine metabolism,
alkaptonuria. While studying the dose effects of NTBC treatment on
alkaptonuria, untargeted metabolomics revealed perturbations in a completely separate pathway, that of
tryptophan metabolism. Significant elevations in several indolic compounds associated with the indolepyruvate pathway of
tryptophan metabolism were present in NTBC-treated patient sera and correlated with elevations of an intermediate of
tyrosine metabolism. Indolic compounds of this pathway have long been associated with commensal bacterial and plant metabolism. These exogenous sources of
indoles have been more recently implicated in affecting mammalian cell function and disease. We studied the correlation of these indolic compounds in other disorders of
tyrosine metabolism including
tyrosinemia types I and II as well as transient
tyrosinemia, and demonstrated that
4-hydroxyphenylpyruvate (4-HPP) was directly responsible for the promotion of this pathway. We then investigated the regulation of the indolepyruvate pathway and the role of 4-HPP further in both mammalian cells and intestinal microbial cultures. We demonstrated that several of the indolic products, including indolepyruvate and indolelactate, were in fact generated by human cell metabolism, while the downstream
indole metabolite,
indolecarboxaldehyde, was produced exclusively by microbial cultures of human gut flora. This study describes a symbiotic perturbation in host and microbiome
tryptophan metabolism in response to elevations related to defects of
tyrosine metabolism and concomitant
drug treatment.