5 GUT MICROBIOTA-MEDIATED DRUG NEUROTOXICITY
The intestinal microbiota produces vast amounts of metabolites some of which exert neurotoxicity, such as D-lactic acid and ammonia (Galland, 2014). Ammonia is a key factor contributing to hepatic encephalopathy which is accumulated in the brain when the liver undergoes dysfunction (Wijdicks, 2016), and modulation of gut microbiota has been demonstrated effective in decreasing ammonia production and subsequently alleviating encephalopathy (Shen et al., 2015). Moreover, the intestinal microbiota is also indirectly engaged in neurotoxicity of xenobiotics including environmental neurotoxicants, metals, drugs, and pesticides (Dempsey et al., 2019) of which neurotoxicity is the most frequently encountered adverse effect in antibiotic exposure representing in multiple ways including headache, delirium, psychosis, and seizure (Bangert and Hasbun, 2019; Champagne-Jorgensen et al., 2019) (Fig.5). While some absorbable antibiotics enter the brain through blood brain barrier (BBB) and cause direct damage, most non-absorbable antibiotics such as neomycin and vancomycin also induce impairments in nervous system and behavior, suggesting a pivotal of the gut-brain axis plays therein (Fröhlich et al., 2016). With antibiotic treatment proven efficient in a variety of microbiota-implicated diseases, tackling antibiotics-induced neurotoxicity seems more troublesome, especially with its mechanisms remaining ambiguous. Besides antibiotics, anesthetics and psychotropic drugs are also found to exert neurotoxicity with intestinal microbiome involved and they will also be discussed afterward.