The role of gut microbiota dysbiosis in drug-induced brain injury: mechanisms and therapeutic implications

Abstract

Drug-induced brain injury (DIBI) results from toxicity, interactions or misuse and is increasingly linked to gut-microbiota dysbiosis operating via the gut-brain axis. Disturbed microbial balance drives three core mechanisms-oxidative stress, neuroinflammation and metabolic dysfunction-leading to blood-brain barrier leakage, neuronal loss and cognitive impairment; antibiotics, antineoplastics and psychoactive drugs further promote bacterial translocation and systemic inflammation. Microbial metabolites and neurotransmitters also mediate post-injury anxiety and depression. Restoring microbial equilibrium with probiotics, prebiotics or microbiota transplantation attenuates these pathways and offers a promising therapeutic strategy for DIBI.

Keywords: blood-brain barrier; drug-induced brain injury; gut microbiota; gut-brain axis; neuroinflammation.

FIGURE 1

The Impact of Intestinal Dysbiosis on Brain Injury. Beneficial microbes strengthen tight-junction proteins and secrete short-chain fatty acids that protect the blood–brain barrier, whereas harmful microbes and their cytokines (TNF-α, IL-6, IL-1β) disrupt these junctions, fueling gut and brain inflammation and ultimately increasing neuronal injury.

FIGURE 2

Mechanisms of Drug-Induced Brain Injury via Gut Dysbiosis. Oxidative Stress: ROS generated during drug metabolism can damage cellular membranes and DNA. This damage is exacerbated by an imbalanced gut microbiota. The imbalance reduces the production of beneficial metabolites such as SCFAs while increasing the release of harmful substances. This process impairs the integrity of the BBB and induces neuronal apoptosis. Metabolic Disturbances: Drugs can interfere with host metabolic processes, leading to the accumulation of neurotoxic substances and imbalances in energy metabolism. These changes may contribute to cognitive dysfunction and neurodegenerative disorders. Neuroinflammatory Responses: Gut dysbiosis facilitates the translocation of bacterial components such as LPS, and metabolites into the systemic circulation. This activates the immune system and leads to the release of pro-inflammatory cytokines, which further compromise the integrity of the BBB and exacerbate inflammation in the central nervous system. Additionally, the gut microbiota indirectly modulates brain function by regulating the autonomic nervous system and neuroendocrine pathways, such as influencing the synthesis of neurotransmitters like GABA and serotonin. This further aggravates cerebral damage.

FIGURE 3

Disruption of the Gut-Brain Axis by Drugs. This diagram illustrates how drugs, impact neuroinflammation, neurotransmitter synthesis, and mitochondrial function, thereby influencing the gut-brain axis. These effects can lead to intestinal barrier damage, allowing bacteria, endotoxins, and other substances to enter the bloodstream. This triggers systemic inflammatory responses and disrupts host RNA gene expression, both of which affect the brain via the gut-brain axis. Meanwhile, activation of the gut-brain axis through signaling pathways like TLRs can activate immune response genes, potentially causing brain injury. In turn, brain injury can exacerbate systemic inflammatory responses, creating a complex interplay between the gut and brain.