Abstract
Gut microbiota has been demonstrated to have a vast influence on human health in recent decades and its role in initiating, aggravating, or ameliorating diseases is emerging. Therapeutic strategies have therefore increasingly developed by targeting gut microbial modulation. Recently, its contribution to heterogeneous toxicological responses is also gaining attention, especially in drug-induced toxicity. Oral drugs interact directly with gut microbiota within the gastrointestinal tract and a number of them elicit toxicity mediated by intestinal microbiota. Present studies focus more on the unidirectional influence of how xenobiotics disturb intestinal microbial composition and function and consequently induce altered homeostasis. However, interactions between gut microbiota and xenobiotics are bidirectional and the impact of gut microbiota on xenobiotics especially on drugs should not be neglected. Thus, in this review, we intend to focus on how gut microbiota modulates drug toxicity by highlighting gut microbiota, microbial enzyme, and metabolites to proffer references for seeking common countermeasures in coping with drug toxicity by targeting gut microbiota. Moreover, we give 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 hepatic encephalopathy, indicating an underlying link among the gut, liver, brain, and other possible organs in drug-induced toxicity.
Key words:gut-liver axis; gut-brain axis; gut microbiota; hepatotoxicity; gastrointestinal toxicity; neurotoxicity.
Abbreviations : 4-HPA, 4-hydroxyphenylacetic acid; 5-FU, 5-fluorouracil; AChE, acetylcholinesterase; AFB1, aflatoxins B1; APAP, acetaminophen; ASD, autism spectrum disorders; BBB, blood brain barrier; CYPs, cytochrome 450 enzymes; DOPA, 3,4-dihydroxyphenylacetic acid; FGF, fibroblast growth factor; FMT, fecal microbiota transplantation; FXR, farnesoid X receptor; GABA, γ-aminobutyric acid; GSH, glutathione; HE, hepatic encephalopathy; LPS, lipopolysaccharide; MMF, mycophenolate mofetil; MPA, mycophenolic acid; MPAG, mycophenolic acid glucuronide; MTX, methotrexate; NAFLD, non-alcoholic liver disease; NAPQI, N-acetyl-p-benzoquinone imine; Nrf-2, nuclear factor erythroid 2-related factor 2; PPD, 1-phenyl-1,2-propanedione; SCFAs, short-chain fatty acids; SN-38, SN-38 glucuronide; TLR, toll-like receptor; UGTs, UDP-glucuronosyltransferases.
1 INTRODUCTION
The microbiota has gained enough attention wherever in liver, brain, and other diseases in recent decades. Indeed, it is comparable with the liver in weight and outnumbers human cells by magnitudes (Qin et al., 2010), indicating its great potential in regulating human health and diseases. Presented as an integral microorganism system, microbiota resides in almost every niche of the human body and is mainly colonized in the skin, airways, urogenital, eyes, and gastrointestinal tract. Among the habitats of microbiota, gut harbors the majority of it, comprised of bacteria, archaea, fungi, viruses, and diverse other microorganisms (Leung et al., 2016). The prokaryote is the most abundant constituent of intestinal microbial microorganisms which can be classified into 11 phyla, with Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes comprising over 90% of the gut microbiome. Some of the phyla have determinant significance in homeostasis maintenance, for instance, the Firmicutes /Bacteroidetes ratio is bound up with obesity (Koliada et al., 2017). Specific gut microbiota may secrete particular enzymes such as α-Rhamnosidase, β-Glucuronidase, and β-Glucosidase (Gong et al., 2020) and produces metabolites including lipids, short-chain fatty acids (SCFAs), bile acids, vitamins, and amino acids (Fiori et al., 2020), which also are extensively engaged in disease pathogenesis. Since gut microbiota has been perceived as an important modulator of human health, numerous strategies including the use of germ-free animals, antibiotics and fecal microbiota transplantation (FMT) have been developed by targeting it, pushing it as a burgeoning area in physiological and pathological researches. Unsurprisingly, intestinal microbiota has been discovered to be implicated in ailments of the brain (Dinan and Cryan, 2017; Quigley, 2017), liver (Tilg et al., 2016), kidney (Mahmoodpoor et al., 2017), gastrointestinal tract (Gorkiewicz and Moschen, 2018; Nishida et al., 2018), and other parts of the human body and therapies including pre-/pro-/synbiotics supplementation, antibiotics treatment, diet intervention, and FMT have been implemented both in animal experiments and human trails. The intertwining of the gut with other organs derives many terms that connecting both, including the gut-liver/brain/kidney axis, each of which contains distinctive pathways but also interosculates in some. In other words, the gut serves as a bridge that connects other organs with the gut-liver-brain axis and gut-liver-kidney axis already put forward as key modulators in hepatic encephalopathy (HE) (Mancini et al., 2018) and chronic kidney disease (Yang et al., 2018a) pathogenesis respectively.
A plethora of marketed drugs have been reported with severe toxicity that confines their clinical application and some of them are compelled to withdraw from the market for unbearable toxicity. Since most drugs are orally administered, which means a majority of them especially those with low bioavailability are subject to gut microbiota (Dey, 2019), it is now proved to play a pivotal role in drug metabolism (Li et al., 2016; Walsh et al., 2018), pharmacokinetics (Zhang et al., 2018), and efficacy (Klaassen and Cui, 2015). The emerging of gut microbiota also provides a new perspective into understanding drug toxicity and manipulation of gut microbiota has been demonstrated with palliative effect in drug toxicity including hepatotoxicity, neurotoxicity, and gastrointestinal toxicity. Nowadays, evidence-based medicine highlights pharmacogenetics in deciphering and tackling variations of drug responses in patients (Relling and Evans, 2015) and since microbiota expresses tremendously more gene than the human host, gut microbial contribution to drug metabolism and toxicity also should be emphasized (Zimmermann et al., 2019).
Herein, we intend to give a brief introduction to gut-liver/brain axis first and then focus on drug hepatotoxicity, gastrointestinal toxicity, and neurotoxicity mediated by gut microbiota for the sake of connecting gut, liver and brain highlighting gut microbial function in modulating drug toxicity. Because each drug exhibits different metabolic characteristics that are pertinent to toxicity, this review is structured by drugs. Then, we elaborate the link of gut-liver-brain axis in HE and give some examples of drugs and chemicals that induce HE via gut-liver-brain axis. Finally, we summarize common targets by which gut microbiota impact drug toxicity and give our perspectives on future research directions of it.