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.