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.