6 CONNECTING THE DOTS: GUT-LIVER-BRAIN AIXS IN DRUG TOXICITY
Patients with chronic liver diseases
and cirrhosis often present with global mucosal immune impairment and it
can progress with advancing degrees of cirrhosis and further induces HE
(Bajaj and Khoruts, 2020). HE is a major complication of liver diseases
that can be initiated by a wide spectrum of factors including systemic
inflammation, liver cirrhosis, microbiota alteration, skeletal muscle
disability, and medications (Bajaj, 2018). As we mentioned above,
ammonia is a significant contributor to HE: normally, the ammonia in the
gut lumen is transferred into the liver where it is metabolized into
urea via urea cycle but when the host undergoes hyperammonemia or liver
diseases, it enters the brain and causes aberrantly functioning neurons
(Fig.2) (Wijdicks, 2016). It is a representative example of how the gut,
liver, and brain are functionally connected and modulations of gut
microbiota by supplementing prebiotics (lactulose) and probiotics,
administering antibiotics (rifaximin), altering the dietary structure,
and FMT are emerging in HE treatment (Amodio et al., 2014; Campion et
al., 2019; Weir, 2020). What accords with the theme here is that HE can
be triggered by medications. Although alterations in the brain caused by
APAP have long been considered secondary effects of acute liver injury,
recently it is found to be a cannabinoid system modulator and cause “in
situ” toxicity in the brain especially at high doses (Ghanem et al.,
2016). Acute APAP intoxication disturbs neurotransmitters including
GABA, glutamate, dopamine, serotonin, norepinephrine, and acetylcholine,
increases oxidative stress and reactive astrogliosis in the brain, and
consequently induces HE (Saad et al., 2018; Vigo et al., 2019). And
similar to the case in antibiotics, maternal use of APAP also induces
neurofunctional impairments in the progeny (Klein et al., 2020). In
addition to the fact that APAP also distributes and is metabolized in
the brain which directly affects brain function, the gut-brain axis may
play a part therein, and the liver may be an important mediator. Carbon
tetrachloride (CCl4) is one of the most commonly used
chemicals in establishing liver injury models in animals. It is reported
that CCl4 also can be utilized to establish HE model in
rats and the CCl4-treated rats showed HE symptoms of
impaired spontaneous movement, cachexia, somnolence, and brain
histological alterations (Wang et al., 2017). FMT improved hepatic
necrosis, intestinal mucosal barrier damage, behaviors, HE grade, and
spatial learning capability of these rats (Wang et al., 2017), revealing
that the gut microbiota can be a common target in treating liver and
brain diseases. Besides, drugs such as 5-FU that induce hyperammonemia
also may cause severe HE and should be given special attention in
clinical use (Chahin et al., 2020). Theoretically, drugs eliciting
hepatotoxicity or inducing hyperammonemia are potential in causing HE.
Besides mechanisms mentioned in drug hepatotoxicity, possible mechanisms
involved therein may include enhancing ammonia-producing microbiota,
altering neurotransmitters, and increasing gut permeability. Extendedly
speaking, drugs that induce gut dysbiosis tend to more or less impact
the organs connected by the gut. The gut-liver-brain axis may explain
the multi-facet toxicity property of some drugs, foresee probable
toxicological responses in other organs besides conventional ones, and
offer countermeasures in coping with them.