Dysbiosis triggers systemic inflammation through several mechanisms. Beneficial gut bacteria produce anti-inflammatory metabolites such as short-chain fatty acids (Intestinal Microbes, 2014), which maintain intestinal barrier integrity and modulate immune responses. Although the activation of TLR-4 on the intestinal epithelium by lipopolysaccharides from gut commensals has been considered part of homeostatic processes for decades, pathogenic bacteria can activate toll-like receptors (TLRs) on intestinal epithelial cells and immune cells, initiating pro-inflammatory signaling cascades (Xia et al., 2021). This leads to increased production of pro-inflammatory cytokines like TNF-α, IL-6, and IL-1β, which can cross the blood-brain barrier (BBB) and exacerbate neuroinflammation (TNF-α, 2004). Neuroinflammation is a key contributor to various brain injuries, including traumatic brain injury, stroke, and neurodegenerative diseases (Liu et al., 2023).

The gut microbiota interacts with the central nervous system through the gut-brain axis, a bidirectional communication network involving neural, endocrine, and immune pathways (Schaible et al., 2025). Gut bacteria can influence BBB permeability by modulating the expression of tight junction proteins such as claudin and occludin (Ma et al., 2022). They also produce and metabolize neurotransmitters like serotonin, dopamine, and gamma-aminobutyric acid (GABA), which affect cognitive function, mood, and behavior (Borrego-Ruiz and Borrego, 2025). Dysbiosis alters this neuroendocrine regulation, potentially leading to cognitive dysfunction, mood disorders, and delayed recovery from brain injury (Ashique et al., 2024). Studies have shown that probiotic intake may help maintain the integrity of the gut and BBB, thereby improving these neurodegenerative diseases (Neuroimmunology, 2003).

A balanced gut microbiota is essential for maintaining mental health (Appleton, 2018). Brain injury can disrupt the gut microbiota composition, leading to an overgrowth of harmful bacteria and a reduction in beneficial species. This microbial imbalance may contribute to psychological issues such as anxiety and depression, which are common complications of brain injury (Guha et al., 2023). These psychological factors can, in turn, affect patient compliance with rehabilitation programs and overall recovery outcomes (Zhang et al., 2025).

The interaction between gut microbiota dysbiosis and brain injury represents a complex and dynamic relationship that warrants further investigation. Future research should focus on elucidating the specific microbial species and metabolic pathways involved in these mechanisms. Additionally, clinical studies are needed to evaluate the efficacy of interventions targeting intestinal microecology, such as probiotics, prebiotics, fecal microbiota transplantation, and dietary modifications, in promoting brain injury recovery. Understanding these aspects may lead to the development of innovative therapeutic strategies for neurological injuries, offering new hope for patients suffering from these conditions.

Drug metabolism generates free radicals, including reactive oxygen species (ROS) such as superoxide anions and hydroxyl radicals, which cause oxidative damage to cells. Cell membranes, rich in polyunsaturated fatty acids, undergo lipid peroxidation when exposed to free radicals. This disrupts membrane function and impairs transport mechanisms. Free radicals also damage DNA, causing strand breaks and base modifications, which can lead to cell death if not repaired (Jakubczyk et al., 2020).

In the nervous system, nerves are particularly vulnerable to oxidative stress due to their high metabolic activity and limited regenerative capacity (Michaelis et al., 2024). Accumulated free radicals can overwhelm neuronal antioxidant defenses, causing dysfunction and death (Chandimali et al., 2025). Chemotherapy drugs, for example, induce oxidative stress that directly harms nerve cells, contributing to neuropathies and cognitive impairments (Cauli, 2021).

Drugs can disrupt the gut microbiota balance, which alters microbial metabolite production, reducing beneficial short-chain fatty acids and increasing harmful substances (Garg and Mohajeri, 2024). The resulting impaired gut barrier function allows bacterial endotoxins into the bloodstream, activating immune cells and triggering inflammation, which further elevates ROS levels (Microbiome, 2009). This inflammatory response can become chronic, disrupting synaptic transmission and inducing neuronal apoptosis, ultimately contributing to brain injury (Dash et al., 2025).

Drugs have the potential to interfere with normal metabolic processes in the body. This interference can lead to abnormalities in various metabolites, including sugars, fats, and proteins (Bio-Regulation, 2017). Experimental studies have demonstrated that drug-induced gut microbiota dysbiosis can significantly alter the host’s metabolite profile, thereby affecting central nervous system (CNS) function. For instance, antibiotics (such as ciprofloxacin) and immunosuppressants (such as tacrolimus) increase the abundance of Clostridium spp. in the gut, leading to a 2.8-fold elevation in serum concentrations of the neurotoxic metabolite indoxyl sulfate (IS). IS can activate the microglial TLR4/ROS pathway, resulting in hippocampal neuronal apoptosis and a 35% decrease in cognitive function scores in animal models (Kwart et al., 2019a). On the other hand, antipsychotic drugs (such as olanzapine) cause a 40% reduction in the phylum Bacteroidetes, leading to a 60% decrease in the levels of neuroprotective short-chain fatty acids (SCFAs), particularly butyrate. Supplementation with butyrate effectively restores mitochondrial complex I activity and improves energy metabolism in the prefrontal cortex (as indicated by a 22% increase in glucose uptake on PET-CT) (Lu et al., 2021).

However, there remains a significant gap in direct causal evidence for DIBI in humans: prospective cohort studies confirming the causal chain between microbiota metabolite changes and neural injury are currently lacking, with existing evidence primarily derived from animal models or correlational clinical studies (e.g., a positive correlation between serum IS levels and white matter lesion volume in stroke patients [r = 0.68]) (Wang et al., 2022). Based on this, we propose a rate-limiting hypothesis—when CNS energy supply is compromised (e.g., due to mitochondrial dysfunction) and neurotoxic metabolites continue to accumulate, this may synergistically trigger neurological dysfunction (Figure 2). This hypothesis has received indirect support from preclinical models of Alzheimer’s disease (where butyrate deficiency increases Aβ deposition by 50% and IS infusion leads to a 30% decrease in synaptic density) (Kwart et al., 2019b), but further experimental validation is still needed in the context of DIBI.

Based on this rationale, it is further hypothesized that drug-induced metabolic disturbances, which can exacerbate the aforementioned shifts in metabolite profiles, may increase the risk of DIBI by enhancing neural vulnerability. This heightened vulnerability could render neurons more susceptible to the toxic effects of drugs or their metabolites, thereby contributing to the development or progression of brain injury. However, it is important to emphasize that this hypothesis requires further validation through rigorous experimental studies and clinical investigations to fully elucidate the underlying mechanisms and to develop effective therapeutic strategies (Microbiota in Neurological, 2015). Understanding the complex relationship between drug-induced metabolic disturbances and brain injury is essential for developing strategies to prevent and mitigate these adverse effects.

The BBB serves as a critical protective interface that prevents the entry of exogenous substances and endogenous toxins into the brain parenchyma (Alaqel et al., 2025). However, certain medications, such as antiviral and antituberculosis drugs, have been shown to compromise BBB integrity by penetrating this protective barrier and impairing its function (Hahn et al., 2017).

The gut microbiota plays a regulatory role in maintaining BBB integrity (Ma et al., 2022). When drugs disrupt the gut microbiota, it can lead to intestinal epithelium imbalance. This disruption facilitates the release of toxic metabolites and pro-inflammatory cytokines, which subsequently activate endothelial cells and damage the BBB (IL-1β, 2016).

Additionally, some drugs can interfere with the metabolic process of tryptophan, an amino acid with important neurological functions (Luo et al., 2024). This interference increases BBB permeability, allowing the translocation of gut microbiota, inflammatory factors, and neuroactive metabolites into the brain. The resulting disruption of immune homeostasis creates a toxic inflammatory environment that can alter brain morphology and contribute to various neurological diseases (Targeting the blood-brain, 2016; dysbiosis).

The autonomic nervous system regulates visceral organs, smooth muscles, and cardiac muscles to maintain internal stability (Valenza et al., 2025). Changes in the gut microbiota can significantly impact this system. Drugs like antibiotics and nonsteroidal anti-inflammatory drugs alter gut microbiota composition, disrupting the gut-autonomic nervous system equilibrium.

Gut microbes influence neuronal function by modifying neurotransmitter synthesis and release, such as GABA (Qu et al., 2024). Dysbiosis can disrupt GABA synthesis, hindering neural transmission and normal neuronal activity (Alzheimer’s disease, 2020). The gut microbiota may also regulate the autonomic nervous system through the gut-brain axis, affecting stress responses, emotions and potentially causing psychiatric disorders (Mallick et al., 2025).

Paul A. Muller et al. identified a group of vagal neurons projected to the distal gut that play an afferent role in the regulation of sympathetic activity by the gut microbiota, using chemogenomic manipulation, translational profiling, and anterograde tracing techniques. In addition, sensory nuclei in the brainstem were found to be activated in response to microbial absence, while efferent sympathetic glutamatergic neurons regulate gastrointestinal trafficking. These results suggest that the gut microbiota controls the activation of intestinal external sensory nerves through the gut-brain circuit dependently (Microbiota, 2024). The specific mechanism is shown in Figure 2.

The gut microbiome regulates neuroinflammation, neurotransmitter synthesis, mitochondrial function, and intestinal barrier integrity through the microbiome-gut-brain axis (Mahbub et al., 2024). Dysbiosis disrupts the intestinal barrier, increasing permeability (“leaky gut”) and allowing bacterial products (e.g., LPS) to enter systemic circulation (Shukla et al., 2025). This triggers primary inflammatory cascades, including myeloid cell activation (e.g., macrophages) and TREM-dependent neuroinflammation, ultimately contributing to neuronal damage (Zhao et al., 2023; TREM, 2021), as shown in Figure 3.

Off-target effects further exacerbate this process. For instance, microbial metabolites (e.g., SCFAs, trimethylamine N-oxide [TMAO]) modulate systemic immunity via TLR signaling and vagal neurotransmission, indirectly influencing BBB permeability and neuroinflammation (Eshleman et al., 2024; Luqman et al., 2024). Medications like antibiotics and NSAIDs disrupt microbial homeostasis (Cully, , 2019; Goyal et al., 2024), while dysbiosis-derived LPS activates peripheral immune responses, amplifying neuroinflammatory pathways (hypoxia, 2016). These secondary mechanisms link gut barrier dysfunction to neurodegenerative (e.g., Alzheimer’s disease) and neuropsychiatric disorders (e.g., depression) (El-Hakim et al., 2022).

Additionally, gut-immune interactions facilitate prion-like protein translocation (Dysbiosis, 2019), highlighting the interplay between primary barrier disruption and off-target CNS effects.

The gut microbiota regulates host physiology through primary RNA-mediated mechanisms, including non-coding RNAs (miRNAs, siRNAs) that modulate intestinal barrier function and inflammatory responses (Chen et al., 2021; Maazouzi et al., 2025; Liu et al., 2016). For example, fecal miRNAs from intestinal epithelial cells directly regulate bacterial gene expression, and their depletion exacerbates colitis (Liu et al., 2016).

Off-target systemic effects emerge when gut-derived RNAs or metabolites (e.g., four-ethylphenyl sulfate [4EPS]) enter circulation, cross the BBB, and alter microglial activity or synaptic plasticity (Metabolite alters brain, 2017). Microbial small RNAs may also indirectly influence neurorepair processes by modulating peripheral immunity (Bi et al., 2020) or epigenetic pathways (e.g., SCFA-mediated histone deacetylation) (Eshleman et al., 2024).

Diet and stress further shape these interactions, as microbiota composition dictates metabolite profiles (e.g., SCFAs, TMAO) with divergent effects on neuroinflammation (He et al., 2020; Hasan and Yang, 2019). While primary RNA regulation occurs locally in the gut, off-target CNS effects underscore the therapeutic potential of targeting gut-derived molecules (e.g., probiotics, miRNA mimics) (Cunningham et al., 2021).