Fig.5 Drugs with neurotoxicity modulated by gut microbiota and possible mechanisms. Abbreviations: GABA, γ-amino butyric acid; SCFAs, short-chain fatty acids.
5.1 Antibiotics
Neurological disorders are usually seen in antibiotics-exposed children who are represented with autism spectrum disorders (ASD). Bacteria overgrowth and especially an abundance of Bacteroidetes andClostridium phyla are closely related to ASD, with the former one specializing in producing propionate and LPS and the latter one propionate. Such opportunistic pathogenic microbiome like clostridial spores are often resistant to most antibiotics and since antibiotics eliminate the majority of intestinal bacteria, it consequently leaves pathogenic bacteria a higher proportion which may be one of the mechanisms that antibiotics induce autism in children (Finegold, 2008). Indeed, both propionic acid and clindamycin administrations induced neurotoxicity in the rodent model and the clindamycin-induced neurotoxicity might be partly attributed to an overgrowth of propionic acid-producing bacteria (El-Ansary et al., 2013). Additionally, both of them depleted Mg2+ and GABA and increased Na+/Mg2+ and glutamate/GABA ratios in the brain which could be restored by replenishing probiotics such asBifidobacteria , Lactobacilli and ProtexinR (Al-Orf et al., 2018; El-Ansary et al., 2018). An experiment conducted in mice of late gestation suggested that a low dose of exposure to penicillin induced gender-specific aberrant behaviors in fetus mice with male mice displaying more anxiety-like behaviors which were associated with altered expression of arginine vasopressin receptor 1A/B (AVPR1A/B) and oxytocin receptor (OXTR), imbalanced forkhead box P3-positive (FOXP+) Treg cells and gut microbial dysbiosis (Champagne-Jorgensen et al., 2020). A similar study conducted in perinatal mice revealed that long-term administration of low-dose penicillin led to changes in gut microbiota, intestinal barrier function, BBB integrity, cytokines expression, and behavior while supplementation of Lactobacillus rhamnosus JB-1 showed partial preventive effects against these symptoms (Leclercq et al., 2017). Disturbance of gut microbiots by antibiotics in an early age tends to alter neurodevelopment which may lead to functional bowel disorders later in life (Caputi et al., 2017). Another study also found that amoxicillin abuse caused gut microbiota dysbiosis and histopathological and neurobehavioral alterations in adult mice, which may explain the rising trend of neuropsychiatric diseases in antibiotics abusing countries (Helaly et al., 2019). Comparing the studies and findings, we find that antibiotic exposure leads to neurotoxicity in fetuses with a low dosage while antibiotic abuse in adults may also induce nerve injury, urging for prudent usage of antibiotics. Besides, ampicillin was also discovered to confer neurotoxicity with modulation of gut microbiota effective in attenuating it. The neurotoxic effect of ampicillin was linked with an increase in lipid peroxidation and a decrease in GSH and potassium levels, and alteration in neurotransmitters which could be reversed by diet intervention, partly due to restored gut microbiota (El-Ansary et al., 2015; Bhat et al., 2016). Antibiotics have been used as a valuable tool in microbiota-related studies but their neurotoxicity has been long neglected in the process (Champagne-Jorgensen et al., 2019). While the direct nerve damage caused by absorbable antibiotics is widely recognized, neurotoxicity of non-absorbable antibiotics seems unintelligible. Given the emerging importance of microbiota-gut-brain axis, it is reasonable to connect antibiotic neurotoxicity with gut microbiota, which has been demonstrated by some researches mentioned above. However, these phenomenon-based studies fail to decipher incisive interactions between antibiotics and neurotoxicity and it can be improved with the uncovering mechanisms of gut-brain axis.
5.2 Anesthetics and psychiatric drugs
Besides antibiotics, some anesthetic agents also induce neurological injuries in neonates. Evidence suggests that inhaled isoflurane is neurotoxic to developing brains of neonatal rodents which may be associated with disturbed gut microbial composition (Wang et al., 2019b). The isoflurane inhaled rats displayed gut dysbiosis with an abundance of Firmicutes , Proteobacteria ,Clostridia , Clostridiales , and Lachnospiraceaesignificantly increased and Bacteroidetes, Actinobacteria, Bacteroidia, and Bacteroidaceae decreased. However, it is a preliminary study connecting anesthetic neurotoxicity to intestinal microbiota and further research should be conducted. What is similar herein is volatilized cocaine whose cause of brain functional and emotional disorder was partly attributed to gut dysbiosis (Scorza et al., 2019).
5.3 Substances other than drugs
Some environmental toxicants especially pesticides represented by organophosphates affect the central nervous system badly and their interactions with gut microbiota have been elaborately elucidated with epithelial permeability, bacterial translocation, and other intestinal microbial factors found to contribute to their neurotoxicity (Roman et al., 2019). Acetylcholinesterase (AChE) inhibition is a common cause of neurotoxicity of these kinds of chemicals but with gut microbiota emerging, alterations in intestinal neurotransmitters and metabolites are also frequently found to contribute to neurotoxicity of them (Lin et al., 2020). Gut microbial metabolism also plays an instrumental role in organophosphates as neurotoxicity of chlorpyrifos was exacerbated after transformation to chlorpyrifos-oxon by gut-derived Lactobacillus plantarum , and could be attenuated with antibiotics and probiotics treatments (Daisley et al., 2018). Rotenone, another kind of pesticides, was used to establish a PD model in animals and it was found that probiotics could rescue dopaminergic neurons in the PD model by promoting butyrate production (Srivastav et al., 2019). Moreover, prebiotics like fructo- and xylo-oligosaccharides also conferred protective effects against neurotoxic chemicals by restoring the activity of AChE and improving levels of dopamine in the maternal cortex (Krishna and Muralidhara, 2018). These researches and discoveries may proffer references for mechanistic investigations of drug-related neurotoxicity.