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