7 CONCLUSIONS AND PERSPECTIVES
Gut microbiota increasingly appears in our field of view whether as a
pathogeny or remedy in recent decades. It interacts with almost whatever
enters the intestinal tract and directly or indirectly influences fates
of xenobiotics. Oral drugs are especially within the scope of gut
microbial action with their therapeutic and toxic outcomes largely
determined by it. In drug-related hepatotoxicity and gastrointestinal
toxicity, gut microbiota acts more like a metabolic role with some drugs
exhibiting attenuated toxicity after gut microbial metabolism while some
in contrast. Within the process, microbial
βglucuronidase plays a crucial
role. βglucuronidase is a hydrolase extensively distributed in
mammalian tissues, body fluids, and microbiota. A wide range of toxic
drugs undergo detoxification in the liver by UGTs but the glucuronic
acid conjugated metabolites are reabsorbed in the gut where gut
microbial βglucuronidase transforms the metabolites back into their
toxic prototype. Inhibition of βglucuronidase activity has been
demonstrated effective in alleviating drug toxicities and it presents as
an attractive target for the development of novel therapeutics. Some
natural products such as quercetin can not only generate protective
metabolites by gut microbiota but also function as βglucuronidase
inhibitors. However, the clinical utilization of currently discovered
βglucuronidase inhibitors is limited by poor pharmacokinetic profile
(Awolade et al., 2020). Still and all, βglucuronidase may serve as a
potent target in respiting drug toxicity. Besides, the use of
antibiotics and pre-/probiotics is also effective in coping with drug
toxicity. Although gut microbiota are highly dynamic, the diminishing of
opportunistic microbiota and supplementation of beneficial ones are
truly effective in attenuating relevant diseases as well as drug
toxicity. It is worth noting that antibiotics also cause severe
neurotoxicity which is associated with gut microbiota. Propionic acid is
an important factor that contributes to autistic symptoms in children
with antibiotics usage and it can be decreased by modulating gut
microbiota. It also hints us that utilization of antibiotics is a
double-edged sword: for one thing, targeting gut microbiota by using
antibiotics has become a rising field in liver disease treatment; for
another, neurotoxicity of antibiotics mediated by gut microbiota should
beware. On the whole, gut microbiota is a common target for some drugs
that cause hepatotoxicity, gastrointestinal toxicity, and neurotoxicity.
Moreover, we come to a hypothesis that drugs capable of inducing gut
dysbiosis tend to more or less impact the gut-connected organs as
evidenced by the drug-induced HE, which means there is an underlying
link among the gut, liver, brain, and possible other organs in
drug-induced toxicity.
Table
1 Drugs with toxicity modulated by gut microbiota and intervening
strategies