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.