AD is a progressive loss of memory, cognitive capabilities, speech, executive abilities, and language (Bayles et al., 2018). There are also changes in personality and behavior with the disease. AD decreases life span; the median survival rate of a person with AD is 5–9.3 years (Hegde et al., 2022; Kao et al., 2018). Many common neuropathological factors are linked with progressive AD. Neurofibrillary tangles are pathological, entangled structures in the cytoplasm of neuron cell bodies, dendrites, and axons (Metaxas and Kempf, 2016). Neuritic plaques are microscopic lesions in dendrites and terminal portions of axons. Neuritic plaques are also called senile plaques. Granulovacuolar degeneration (GVD) is a state where cells create microscopic vacuoles with granulated protoplasm (Funk et al., 2011). GVD lesions, found in regions such as the neocortex and amygdala, align with areas involved in stress and sleep regulation (Thal et al., 2011). In AD, GVD increases with disease severity, correlating with neurofibrillary lesions and memory decline, similar to β-amyloid plaques and tangles. However, the exact mechanism and the connection to Tau remain unclear (Funk et al., 2011). Reduced dendritic connections hinder neuron impulse transmission. Dopamine and cholinergic neurotransmitter deficiencies are common with all types of AD. Both white and gray matter are lost, best observed in the frontal and temporal lobes of the brain (Hegde et al., 2022; Kao et al., 2018). Increased ventricles and sulcal dilatation are a consequence of neuron degeneration within the brain. Reduced cerebral metabolism is a sign of pathological changes at the neuronal level (Wang Z. et al., 2025). When neurofibrillary tangles, neuritic plaques, and other injury occur in neurons within the brain, metabolic function is reduced (Wang Z. et al., 2025). Numerous clinical trials focusing on amyloid-beta (Aβ) and Tau proteins of AD within recent decades have been ineffective (Asher and Priefer, 2022). Existing drugs achieve little cognitive improvement and cannot halt disease progression (Bazzari et al., 2019). Because of the enigma of AD molecular mechanisms, there is an urgent need for alternative therapies acting on multiple biological pathways (Wu et al., 2024).

Amyloid plaques arise from the aggregation of Aβ peptides, particularly Aβ4₂, which is harmful due to its tendency to form plaques and resist dissolving (Jarrett et al., 1993). The peptides are generated when the amyloid precursor protein (APP) is cleaved by BACE1 and γ-secretase (Ashe, 2020). The amyloid cascade hypothesis, which came into being as a result of the work of Hardy and Higgins in 1992, has almost since then been the dominant purview in the field of AD. According to the hypothesis, accumulation of Aβ resulting from APP triggers tau hyperphosphorylation and consequent neurodegeneration (Ma et al., 2022). Tau, which is normally a microtubule-stabilizing protein, becomes pathogenic after being hyperphosphorylated, thereby compromising neuronal transport systems. The hypothesis has expanded to include vascular dysfunction, oxidative stress, microglial activation, and impaired proteolysis (Roda et al., 2022). Nevertheless, one singular hypothesis cannot fully justify the complex etiology or mechanisms underlying AD (Joe and Ringman, 2019). Toxic Aβ oligomers activate microglia and encourage the release of pro-inflammatory cytokines (De Felice et al., 2022). Moreover, the deposit of Aβ in the vascular system may lead to the development of cerebral amyloid angiopathy, which is frequently observed in AD and involves cerebrovascular pathology (Glenner and Wong, 1984).

Insulin, a hormone produced by the pancreas β-cells, regulates glucose metabolism. When the body's tissues become less responsive to insulin, a condition known as insulin resistance, it increases the risk of type 2 diabetes mellitus (T2DM), metabolic syndrome, fatty liver disease, and atherosclerosis (Arnold et al., 2018; Lee et al., 2022). Aging often worsens this resistance through chronic high insulin levels. Emerging research links insulin resistance to AD; for instance, diabetic rats induced with streptozotocin show AD-like brain changes, including Aβ and neuroinflammation (Clark et al., 2012). While the exact connection between AD and T2DM remains unclear, insulin resistance contributes to cognitive decline. Enhancing insulin signaling in the hippocampus has shown promise in improving memory and cognition in AD models (Biessels and Reagan, 2015). Tau hyperphosphorylation and Aβ accumulation are promoted by microglial and astrocytic actions. Aβ deposits give rise to microglia-mediated neuroinflammation (Thakur et al., 2023). While the BBB tries to limit systemic inflammation, it can be compromised by cytokines such as tumor necrosis factor (TNF-α) and IL-1β. Sustained glial activation drives neuroinflammation in a vicious cycle via reactive oxygen species (ROS), cytokines, and chemokines (Thakur et al., 2023). Astrocytes, key modulators of neuroinflammation, congregate around Aβ plaques, as described in both human and mouse models. They affect amyloidosis through their role in the synthesis and disposal of Aβ, as well as through interactions with other CNS cells (Frost and Li, 2017). In reaction to AD, astrocytes experience a shift in profile, one that is reactive and pro-inflammatory while losing homeostatic roles thus disrupting BBB integrity, ion and neurotransmitter buffering, and energy metabolism (Liddelow et al., 2017; Escartin et al., 2021). Reactive astrocytes also release neurotoxic saturated lipids through the APOJ and the C3 complement component, thus affecting neuronal network activity via C3aR signaling (Lian et al., 2015; Liddelow et al., 2017). Importantly, as the chief brain source of APOE, astrocytes, especially those expressing the APOE4 allele, promote Aβ aggregation, tau pathologies, BBB breakdown, and cerebrovascular dysfunctions (Wang M. et al., 2021).

There are still important questions concerning the role of the gut microbiome in astrocyte function in AD that have yet to be studied. Of interest are which species of microbes mediate MGBA-astrocyte signaling; which astrocytic molecular pathways are modulated by the MGBA; how the MGBA-regulated astrocytic pathways contribute to AD pathology; and whether the MGBA-astrocyte could be therapeutically targeted for our benefit. On the immune front, gut microbiota can increase systemic inflammation by releasing lipopolysaccharides (LPS) and proinflammatory cytokines, and they also produce amyloids, which may stimulate neural amyloid production via immune priming. Recognition of bacterial amyloids by toll-like receptor-2 (TLR2) activates immune cells, escalating inflammation (Mulak, 2021). In the gut, T cells maintain immune balance, differentiating into proinflammatory (Th1, Th17) or anti-inflammatory [Th2, regulatory T cells (Tregs)] subsets (Dressman and Elyaman, 2022).

AD, based on emerging research over the past two decades, may be associated with chronic stress, where prolonged exposure to adverse life events (such as MDD and anxiety) increases the risk of developing the disease (Huang et al., 2024). The HPA axis plays a key role in this connection; it is the central component that regulates the stress response by stimulating the release of glucocorticoids from the adrenal cortex (Mulak, 2021). Elevated glucocorticoid levels, along with decreased glucocorticoid receptor (GR) function in early AD, are linked to Aβ production and abnormal tau phosphorylation (Canet et al., 2019). Additionally, GR dysregulation impacts dyslipidemia and insulin resistance. Therefore, chronic stress-induced dysregulation of the HPA axis, potentially mediated by imbalances in gut microbiota, might be a crucial link between dysbiosis and the progression of AD (Figure 1).

A potential therapeutic approach for AD consists of the BAs, which are produced in the liver (Grant and DeMorrow, 2020). Although their largest involvement is in nutrient and metabolic regulation, around 10% of them might cross the BBB, as shown in animal studies with mechanistic details (Monteiro-Cardoso et al., 2021). A comparison of 119 patients suffering from AD with 267 controls found that alterations in serum BAs correlate with cerebrospinal fluid (CSF) Aβ1–42, tau, and p-tau. Higher concentrations of glycochenodeoxycholic acid, glycodeoxycholic acid, hyodeoxycholic acid, and certain bile acid ratios were associated with patient CSF tau and p-tau. Higher hyodeoxycholic acid and certain ratios were associated with lower CSF Aβ1–42. While these associations suggest a link between serum bile acids and AD pathology, a causal relationship has yet to be established (Nabizadeh et al., 2024). BAs act in the brain by interacting with key receptors on neurons and glial cells-Farnesoid X receptor (FXR), Takeda G protein receptor 5 (TGR5), GR, and sphingosine-1-phosphate receptor 2 (S1PR2; Kiriyama and Nochi, 2019; Figure 2). BAs may modulate gut microbiota through antimicrobial properties, with deconjugated BAs produced by bacterial bile salt hydrolases being much less toxic to gut bacteria. In animal models of neurodegenerative disease, activation of TGR5 receptor was neuroprotective, decreasing neuronal death and inflammatory response (Monteiro-Cardoso et al., 2021). S1PR2, located both in the liver and in the brain, activates the ERK and AKT pathways that regulate cell survival, inflammation, and stress response in the CNS. In the liver, S1PR2 activates pro-insulin signaling through enhancing insulin-degrading enzyme (IDE), thereby potentially alleviating insulin resistance associated with T2DM and AD based on animal mechanistic studies (Vettorazzi et al., 2017; Zangerolamo et al., 2022). Beyond directly influencing pathological changes in the AD brain, BAs may provide neuroprotective benefits by modulating the microbiota–gut–brain (MGB) axis, which supports memory function. GM also regulates BA synthesis; both antibiotic use and germ-free conditions suppress the expression of CYP7A1 and CYP27A1, key enzymes involved in BA production based on animal mechanistic studies (Chiang and Ferrell, 2019). Deconjugated BAs, which are less toxic to gut microbes, are reduced in AD, likely due to decreased BSH-secreting bacteria like Clostridium and Bifidobacterium, as observed in human associative studies (Mulak, 2021). While these findings support the hypothesis that restoring BA–microbiota interactions could influence AD symptoms, causal evidence in humans remains limited and warrants further investigation. Studies consistently show altered MGBA composition in AD patients, suggesting a possible role in disease onset and progression, as shown in Table 1. Confounding variables, such as diet and environmental exposures, complicate comparisons.

PD is the second-most common neurodegenerative disorder after AD. It acts from a lack of equilibrium between two neurotransmitters in the basal ganglia: dopamine (inhibitory) and acetylcholine (excitatory). In typical basal ganglia function, the actions of these neurotransmitters counterbalance each other to refine voluntary movement; however, in PD, the neurons producing dopamine slowly die out, causing an excess of acetylcholine to overstimulate the basal ganglia (Wang Q. et al., 2021). This leads to the major motor symptoms of tremor, bradykinesia, and rigidity, along with postural difficulties, which are classical for PD (Obeso et al., 2017). Affected individuals may show other non-motor symptoms, with some being GI-oriented and emerging years before the classical motor features (Cersosimo et al., 2013). Cognitive manifestations include depression, irritability, and anxiety, while GI manifestations encompass constipation, dysphagia, nausea, and prolonged intestinal transit time (Pfeiffer, 2003; Li et al., 2023). Most non-motor symptoms go unrecognized when this neurodegenerative disease begins in his prodromal form. Diagnosis and treatment usually begin after the disease shows motor symptoms. It has a complicated pathogenesis associated with environmental modifications, genetic predispositions, deregulated dopamine metabolism, neuroinflammation, oxidative stress, and mitochondrial dysfunction (Gökçe Çokal et al., 2017; Wang T. et al., 2020). However, the leading theory behind PD pathogenesis is the accumulation of alpha-synuclein aggregates within cells, which trigger neuroinflammation and neuronal apoptosis (Kim et al., 2019). Gut findings of alpha-synuclein abnormalities in early-stage PD are documented in patients having PD. Imaging studies further corroborate that PD may arise from the gut and subsequently spread into the brain (Horsager et al., 2021, 2022). Through the spinal cord, the brain communicates with all other body systems, including the endocrine system, which regulates body functions such as stress and mood via hormone secretion, and the immune system, which defends the body from pathogenic infection and promotes healing. These systems share signals through the vagus nerve, which carries information from the body's organs to the brain regions (Jackson et al., 2019; Li et al., 2023; Figure 3). Some epidemiological studies carried out in Denmark and Sweden have indicated that people who had undergone complete truncal vagotomies decades ago had a lower risk of developing PD later in life (Svensson et al., 2015; Liu et al., 2017). This points to the possibility of some disturbances in gut microbial position, thereby predisposing to PD.

The vagus nerve is the tenth cranial nerve. It has been so named from the Latin word meaning “wandering,” because it wanders widely through the body. It originates from either side of the medulla oblongata, exits through the jugular foramen, and descends the neck, chest, and abdomen (Liu and Forsythe, 2021). Along the way, the vagus nerve sends off branches to innervate and regulate almost all the visceral organs. Functionally, it is vital for the control of immune responses via neural signaling. Containing both motor and sensory fibers, the vagus nerve is also the main afferent pathway from the abdominal organs, lungs, liver, stomach, pancreas, and intestines to the brain. Sensory information from the abdominal organs traverses the vagus nerve to the nucleus of the solitary tract in the brainstem, with projections to several other areas of the CNS, including the cerebral cortex and medulla oblongata (Liu and Forsythe, 2021). At present, vagotomy is considered only for those patients who are resistant to pharmacological treatment or who are severely ill with complications, such as perforations or gastric outlet obstruction. In the past, it has also been employed in the treatment of biliary dyskinesia and chronic abdominal pain in neurological conditions (Crile, 1951; Liu and Forsythe, 2021).

In PD, the spread of the pathological alpha-synuclein from the gut to the brain is mediated along the vagus nerve. There are two major forms of vagotomy: truncal vagotomy, which severs all connections, and selective vagotomy, which maintains intestinal innervation (Wang Q. et al., 2021). Studies have noted that vagotomy can inhibit the misfolding of alpha-synuclein in enteric neurons and reduce the appearance of PD symptoms in animal models (Uemura et al., 2018; Kim et al., 2019).

The total vagotomy can be beneficial in reducing the chances of developing secondary PD, according to a cohort study done in Denmark (Svensson et al., 2015). On the other hand, there is a separate study in Sweden that has followed patients after vagotomy and pointed out no relation between vagotomy and PD risk (Liu et al., 2017). However, 5 years of follow-up indicated that within that period, after vagotomy, there is a reduced risk of PD, and very similar results were obtained in the 10-year follow-up. These findings provoke interesting primary questions as to the possible origins of PD-associated alpha-synuclein misfolding from within autonomic nerve fibers of the gut.

Selective or highly selective vagotomy may permit α-synuclein pathology from elsewhere in the GI tract to still reach the vagus nerve and, thereafter, the brainstem. Vagotomy in animal studies is said to disrupt the transfer of α-synuclein derived from the gut to the CNS, but human observational evidence is inconsistent, with some studies indicating no change in PD incidence and others suggesting a reduced risk following truncal vagotomy (Elfil et al., 2020). Currently, there is too immature an understanding of PD pathophysiology to make vagotomy a potential treatment method, and clarification through research is needed regarding the vagotomy-PD relationship. Therefore, no clinical role for vagotomy exists at present.

The composition of gut microbiota might vary whether PD has an early or late onset. In a study, Pasteurellaceae, Alcaligenaceae, and Fusobacteria were more common in early prodromal PD stages vs. Comamonas and Anaerotruncus, which were commonly detected in late-onset PD cases (Lin et al., 2018). Some gut pathogens, such as Aquabacterium, Peptococcus, and Sphingomonas, have been associated with motor complications in PD (Qian et al., 2018).

Weis et al. (2019) examined the impact of PD medications (levodopa and entacapone) on gut microbiota, finding marked changes in Peptoniphilus, Finegoldia, Faecalibacterium, Fusicatenibacter, Anaerococcus, Bifidobacterium, Enterococcus, and Ruminococcus. For other drugs such as MAO inhibitors, amantadine, and dopamine agonists, no indication was found for an effect on taxa abundance or microbial functions (Horsager et al., 2020). Palacios et al. (2021) reported lower Clostridium group IV in PD as well as no strongly associated taxa with levodopa (L-DOPA) use, although preliminary data suggest Clostridium cluster IV may be linked to short-term motor-symptom response to L-DOPA, which deserves a thorough controlled validation. Other studies have shown that the other PD drugs acted independently to shape different microbial profiles, which strengthens the rationale for disentangling drug effects from disease signatures (Hashish and Salama, 2023).

Aho et al. (2019) distinguished PD patients who are stable and those with rapid progression, with inconsistent taxa throughout methods and times but uniquely exiting enterotypes, accompanied by a decline in Prevotella for the rapid-progression cases. Group differences between PD and controls stayed after the removal of confounds such as deep-brain stimulation (DBS), but differed across studies. In general, replications of the PD-microbiome instances are often poorly developed, presumably as a result of confounding by usage of medication, geographical differences, sequencing methods, and analytical pipelines. Nevertheless, some microbial changes were reported consistently: decrease in Prevotellaceae, Prevotella, and P. copri (Scheperjans et al., 2015; Unger et al., 2016; Hopfner et al., 2017), and increase in Akkermansia/Verrucomicrobiaceae (Keshavarzian et al., 2015; Heintz-Buschart et al., 2018; Lin et al., 2018).

The most important GI symptom is constipation, which impacts almost 60% of people suffering with PD (Pavan et al., 2022). Research indicates that the severity of PD-related constipation helps diagnose the PD stage, with 67% sensitivity and 90% specificity (Hashish and Salama, 2023). References state that the dysbiosis is likely to be responsible for early stage PD GI-related problems, including constipation, with a notable increase in bacterial families that include Lactobacillaceae, Verrucomicrobiaceae, Bradyrhizobiaceae, Bifidobacterium, and Akkermansia (Baldini et al., 2020; Hashish and Salama, 2023). Among these groups, through greater severity of constipation, longer transit times, and harder stool, Akkermansia has been related to constipation (Lubomski et al., 2022b; Hashish and Salama, 2023). Patients suffering from PD and characterized by slowed transit of the intestine may consequently need to receive higher amounts of L-DOPA (Fasano et al., 2013; Weis et al., 2019). Such patients lack in terms of absorption of medicines, thus translating into efficacy problems because of the delays in transit. Constipation may also predispose bacteria to reach excessive populations, particularly Lactobacillus species that can execute tyrosine decarboxylation, L-DOPA by converting it into dopamine in the gut hence limiting its release into the bloodstream and causing motor fluctuations (Menozzi and Schapira, 2024). More doses of L-DOPA combined with decarboxylase inhibitors have to be repeated under this scenario, thus denoting a complicated interaction of PD medications with GI tract-related symptoms.

Most people who suffer from PD, may have experienced either the condition of small intestinal bacterial overgrowth (SIBO) or colonization by Helicobacter pylori (H. pylori; Gabrielli et al., 2011; Felice et al., 2016). SIBO could lead to symptoms like bloating, excessive gas, or impaired absorption of nutrients. A relationship between PD and SIBO was first established in 2021 by the symptom of constipation, indicating that aggravation in the severity of constipation might correlate with an increased risk for SIBO (Dănău et al., 2021). Relief from SIBO not only alleviates the GI discomfort, but it also helps in the amelioration of the motor fluctuations experienced by PD patients (Gabrielli et al., 2011; Fasano et al., 2013). Patients with PD and comorbid SIBO—as opposed to those without it—showed more severe dyskinesia which included prolonged rest time, delayed on-time and off-time. Another proof of this was that motor fluctuations in PD patients improved after SIBO eradication, hence providing more support of the association between SIBO and motor fluctuations (Lubomski et al., 2020). Interestingly, studies show multiple symptoms of PD improve with H. pylori antibiotic therapy due to increased absorption and bioavailability of L-DOPA (Pierantozzi et al., 2001). A trial, double-blind, placebo-controlled study pronounced that motor symptoms do improve from hypokinesia over the year since the eradication of H. pylori but worsen from flexor rigidity (Dobbs et al., 2010). Although the mechanisms remain unknown, researchers present their theory claiming that the thickening rigidity coexists with SIBO because of overgrowth by certain bacterial strains already present (Felice et al., 2016). The increasing evidence that altered gut microbiota correlate with non-motor features of PD rests on the premise of the need for more evidence to be generated for possible therapeutic strategies to be unveiled.

Evidence consistently points toward the role of gut microbiota in the persistent interaction upon L-DOPA treatment response. It has been seen that the efficacy of L-DOPA in antibiotic therapy was improved as gut microorganism influences drug metabolism and action (Hashim et al., 2014; Hashish and Salama, 2023; Hey et al., 2023). As one of the most important dopamine-replacement therapies for PD, L-DOPA is commonly given with carbidopa to improve bioavailability and avoid early conversion into dopamine before penetration into the brain (Gandhi and Saadabadi, 2025). Thus, an increasing amount of evidence suggested that the gut microbiome has taken a rather complex interest in influencing the response of the body to L-DOPA treatment. Such studies have shown that antibiotic administration might increase the effectiveness of L-DOPA therapy, indicating that gut microorganisms affect metabolism and the effectiveness of the drug (Hashim et al., 2014). Another important fact is that this L-DOPA is co-administered with carbidopa, another important dopamine-replacement therapy for PD, aiming to increase the bioavailability of the substance and prevent early conversion into dopamine prior to entering the brain (Gandhi and Saadabadi, 2025).

The research by Lubomski et al. (2022b) looked at how the administration of levodopa-carbidopa intestinal gel (LCIG) has effects on the gut microbiome in PD. The LCIG treatment involves a continuous infusion of a carboxymethylcellulose aqueous gel directly into the proximal jejunum via a percutaneous gastrojejunostomy tube, with delivery by a portable infusion pump (Olanow et al., 2014). When assessing alpha diversity (the diversity and evenness of microbial species within a single sample, representative of microbial richness and community balance), they found no marked changes attributable to LCIG. The LCIG application caused changes in the beta diversity (which assesses the differences in microbial community composition between samples, indicating how similar or dissimilar microbial communities are across individuals or time points). Changes in beta diversity reveal that while overall species richness and evenness among the individuals were stable, LCIG can redistribute the abundance of different taxa, thereby altering cohabitation structure and interrelations among microbial species. This pattern holds biological significance in PD in that it suggests that disease- or treatment-related effects may exert selective pressure on the microbial network in the gut without necessarily lowering the overall number of microbial species present, thereby exerting an influence on GBA signaling and L-DOPA metabolism. The acidic condition of LCIG may alter the chemical situation in the gut, which, finally, leads to hypergrowth of Escherichia/shigella, being acid-tolerant bacteria (Lubomski et al., 2022b). This observation of microbial shift may contribute to the excessive gut inflammation. Research is scarce on the effect of LCIG on the gut microbiota in PD individuals, and more studies are needed to substantiate findings on gut homeostasis.

Previously reported changes in the abundance of this family Prevotellaceae in advanced PD seem to have been expanded upon by Bedarf and associates, who have shown a dramatic decrease in the numbers of Prevotella copri in patients with early-stage PD (Bedarf et al., 2017). Since these species of Prevotella produce SCFAs like butyrate, their decrease may affect intestinal barrier function and immune health and thus be involved in the pathogenesis of PD (Hey et al., 2023). Notably, neither MAO inhibitors nor dopamine agonists appear to affect the composition and function of gut microbiota (Bedarf et al., 2017). However, emerging data suggest that different PD therapies exert differential effects on gut microbiota, as shown in Table 4. Since PD patients are frequently on multiple therapies, it will be important for future studies to determine the independent effect of these therapies on the gut microbiome and their potential roles in the progression and management of the disease.

ALS is a serious and progressive disease that damages both the upper and lower motor neurons, which are the nerve cells that control voluntary muscle movement. It usually begins between the ages of 50 and 70 and is slightly more common in men than women, with a male-to-female ratio of about 1.5–1 (Chiò et al., 2013). Worldwide, ALS affects about 1–2.6 people out of every 100,000 each year, and at any given time, around 4–8 out of every 100,000 people, especially those of Caucasian descent are living with the disease (Al-Chalabi and Hardiman, 2013; Chiò et al., 2013). Roughly 90% of ALS cases happen without a family history (sporadic ALS), while the remaining 10% are inherited (familial ALS). More than 50 genes have been linked to ALS, with the most common being C9ORF72, which causes up to 50% of inherited cases and 5–10% of sporadic ones. Other key genes include SOD1, TARDBP (which codes for TDP-43), and FUS (Renton et al., 2011). Interestingly, ALS and frontotemporal dementia (FTD) are closely related conditions and often share both genetic and disease mechanisms, especially in people with C9ORF72 mutations suggesting they may be part of the same disease spectrum (Parobkova and Matej, 2021). In addition to genetics, certain environmental exposures may increase the risk of developing ALS. These include smoking, military service, pesticide exposure, and heavy metals, with smoking raising the risk by about 40% (Al-Chalabi and Hardiman, 2013).

ALS can look very different from person to person in how it begins and how quickly it progresses. In about 70% of people, the first symptoms appear in the limbs usually starting with hand weakness (60%) or leg weakness (40%). Around 30% of patients start with bulbar symptoms, which affect the muscles used for speaking and swallowing, leading to problems like slurred speech (dysarthria), trouble swallowing (dysphagia), and twitching of the tongue muscles (Chiò et al., 2013). A small number (less than 5%) have respiratory-onset ALS, where breathing muscles weaken early, and these cases tend to be more severe.

The disease usually begins in one part of the body and spreads gradually, leading to increasing muscle weakness. On average, there's a delay of 10–16 months between the first symptoms and the official diagnosis (van den Bos et al., 2019). Once diagnosed, median survival is between 2 and 5 years, although patients with bulbar-onset ALS tend to decline more quickly.

ALS is mostly diagnosed based on clinical signs, using the revised El Escorial criteria, which require signs of both upper motor neuron (e.g., spasticity, brisk reflexes) and lower motor neuron damage (e.g., muscle wasting, twitching) in multiple body regions (Brotman et al., 2025). Electromyography (EMG) tests are crucial to show nerve damage and muscle denervation, while nerve conduction studies are used to rule out other diseases. MRI scans are also done to make sure there isn't another condition, such as a structural issue in the brain or spine (Kwan and Vullaganti, 2022). Despite all this, about 10–15% of ALS cases are initially misdiagnosed. Conditions that are often mistaken for ALS include multifocal motor neuropathy, cervical spine disorders, and inclusion body myositis (Kwan and Vullaganti, 2022).

The development of ALS is driven by several overlapping biological mechanisms that together cause motor neuron degeneration. One key process is glutamate excitotoxicity, where a buildup of glutamate at the synapse due to reduced function of the transporter EAAT2 (also known as GLT-1) leads to overstimulation of N-methyl-D-aspartate (NMDA) receptors. This causes excessive calcium to enter neurons, damaging mitochondria and triggering cell death (Arnold et al., 2024). Another central feature is the loss of protein balance, especially involving TDP-43, a protein that is abnormally located in the cytoplasm instead of the nucleus in about 97% of ALS cases. In this mislocated state, TDP-43 forms toxic clumps that interfere with RNA processing and disrupt essential cellular functions (Prasad et al., 2019). In patients with mutations in the C9ORF72 gene, the production of harmful dipeptide repeat proteins further disrupts communication between the nucleus and cytoplasm, impairing cell function. Neuroinflammation also plays a major role, with microglial cells releasing inflammatory molecules such as TNF-α, IL-6, and IL-1β, along with ROS, all of which intensify neuronal damage (Liu and Wang, 2017). In addition, astrocytes, which normally support neurons, become dysfunctional through a process called astrogliosis, which worsens glutamate imbalance and reduces neuronal support (Boillée et al., 2006). Other contributors include faulty axonal transport, resulting in buildup of neurofilaments and synaptic breakdown (Taylor et al., 2016), and genetic mutations—such as SOD1 (causing harmful protein accumulation), FUS (interfering with RNA handling), and TBK1 or OPTN (which impair the cell's waste disposal system known as autophagy; Goutman et al., 2022; Figure 4). Together, these processes create a toxic environment that progressively destroys motor neurons in ALS.

Recent studies have shown that the gut microbiome, the community of bacteria living in our digestive system may play an important role in the development and progression of ALS. People with ALS often have an imbalance in their gut bacteria, known as dysbiosis, with fewer helpful bacteria like Faecalibacterium prausnitzii and Bifidobacterium, and more potentially harmful ones such as E. coli and Dorea species (Brenner et al., 2018). This imbalance may speed up the disease in several ways. For example, reduced levels of SCFAs (like butyrate, which is normally made by good bacteria) can weaken the BBB, making the brain more vulnerable to harmful substances. At the same time, increased levels of inflammatory molecules, such as LPS from harmful bacteria, can lead to systemic-wide inflammation (Obrenovich et al., 2020). The gut microbiome also affects the immune system, with ALS patients showing increased Th17 immune cells and higher levels of IL-17, an inflammatory cytokine that may worsen the disease (Zang et al., 2023). Together, these findings support a strong connection between gut health and brain health in ALS.

MS is an autoimmune disease of the CNS, whose hallmark is the demyelination and consequent damage to the demyelinated axons. Demyelination causes a multitude of neurological symptoms, including loss of coordination of movement, ataxia, visual impairments, psychiatric abnormalities such as depression, and cognitive decline (Preiningerova et al., 2022). MS likely results from a combination of genetic and environmental factors (Preiningerova et al., 2022). It is normally diagnosed based on clinical symptomatology complemented by MRI with lesions of various stages, combined with biomarkers of immunologic activity in CSF, namely oligoclonal bands and elevated IgG index (Thompson et al., 2018). The experimental autoimmune encephalomyelitis (EAE) animal model of MS has proven the pathogenic function of myelin-reactive T cells in MS pathogenesis (Laaker et al., 2021). The triggers of activating self-reactive clones are still to be determined, but may be common infections, molecular mimicry, or inflammation signals from gut microbiota (Westall, 2006). Histological evidence has shown that the activated T cells cross the BBB, invade the CNS, and congregate around small venules to trigger localized inflammation (Kuhlmann et al., 2017). Over the decades, the EAE model, focused primarily on T cells, has been the model for MS pathogenesis and treatment studies (Preiningerova et al., 2022). Current treatments are largely the primary application of disease-modifying treatments, immunosuppressants, immunomodulators, and immune-reconstitution therapies, in addition to symptomatic treatments such as anticholinergics for urinary incontinence and pain medication for neuropathic pain (Dobson and Giovannoni, 2019). Patient-dependent conditions affecting the effectiveness of treatment or, quite possibly, affecting outcomes through the gut microbiota, however, are still to be established.

In patients with MS, it was found that the composition of their microbiota was relatively reduced from that of healthy individuals. Studies are not entirely consistent, but they mostly report an increase in Akkermansiaceae and Methanobacteriaceae, and a decrease in SCFA-producing Bacteroidetes and Clostridia clusters (Atarashi et al., 2011; Palm et al., 2015; Wang et al., 2019). While EAE models have offered valuable insight into adaptive immune responses, demyelination, and axonal damage in MS, they fall short in replicating the full spectrum of human MS pathology, particularly the disease's onset and heterogeneity (Figure 5).

GI symptoms, including anorectal dysfunction such as constipation and fecal incontinence, are commonly reported in MS, affecting approximately 40% of patients (Nusrat et al., 2012). Additionally, Minuk and Lewkonia (1986) have even reported familial clustering of Inflammatory Bowel Disease (IBD) and MS, suggesting that they have genetic or environmental risk factors in common. In the past few years, several studies have explored the differences in fecal gut microbiota between MS patients and healthy controls, revealing that gut microbial dysbiosis with both depletion and enrichment of certain gut microbiota in MS patients, as shown in Table 6. For example, Chen et al. (2016) reported increased levels of Pseudomonas, Mycoplasma, Haemophilus, Blautia, and Dorea, and reductions in ParaBacteroides, Adlercreutzia, and Prevotella in RRMS patients. Whether these changes are a cause or a consequence of the disease remains unclear. Increased levels of Methanobrevibacter and Akkermansia are increased, whereas those of Butyricimonas decreased in RRMS patients (Jangi et al., 2016).

In addition, differences in corresponding changes in expression levels of genes associated with dendritic cell maturation, interferon signaling, and NF-κB signaling pathways in circulating T cells and monocytes have been noted (Jangi et al., 2016). The relation between the variation in gut microbiota diversity and relapse risk in children with MS was found with testing by Tremlett et al. (2016); thus, the depletion of Fusobacteria correlated with the relapse risk of pediatric MS. Nevertheless, all those discoveries were performed on gut microbiota obtained from stool samples of MS patients in remission. A recent study has been done on changes in microbiota within small intestinal tissues from MS patients in the active phase. The authors reported an increased Firmicutes/Bacteroidetes ratio and Streptococcus abundance, with a reduction in Prevotella strains in patients with active MS when compared with healthy controls and patients with MS in remission (Cosorich et al., 2017). Moreover, the relative presence of Prevotella strains was inversely associated with Th17 cells in the small intestine, while positively related to disease activity (Cosorich et al., 2017). Although changes in gut microbiota have been reported, it remains uncertain whether these changes are a cause or a consequence of the disease.

MDD is characterized by constant depressed mood, anhedonia, altered sleep and appetite, fatigue, guilt, hopelessness, and suicidal tendencies (Arnaud et al., 2022). Over the years, a rising trend has been seen in the prevalence of depression since the time of observation (Cui et al., 2024). In 2018, MDD disease burden ranked third in the world according to the WHO, and by 2030, it is supposed to rise to the first (Malhi and Mann, 2018). A psychiatric disorder is formed due to the complex interplay of environmental factors and genetic vulnerability (Souza et al., 2023). The risks of developing several physical comorbidities like cardiovascular diseases, stroke, diabetes, and obesity along with social stigma are quite higher for MDD persons (Penninx et al., 2013). Some of these revolve around education, work, and relationships (Campbell et al., 2022). In case antidepressants are used in conjunction with psychotherapy, some patients can get better. Unfortunately, not all respond to treatment. As many as 30–50% of depressed patients respond only partially to antidepressants, leaving them with substantial residual symptoms (Davis et al., 2021). Additionally, 10–30% of patients of those who are resistant to the effects of antidepressants and thus non-responders to treatment. Differences in treatment response may be indicative of differences in etiologies and mechanisms, like neuroinflammation, changes in the neuroendocrine system, or alterations in the gut microbiome (Mousten et al., 2022). This greatly simplifies a complex process, but a map of the human microbiome may offer new opportunities for tracking therapeutic responses in depression.

Another study showed that both psychosocial as well as physical stressors influence the body's response through the HPA axis (Godoy et al., 2018). The HPA axis initiates a response in times of stress, stopping the activity through negative feedback, engaging the hippocampus and the paraventricular nucleus of the hypothalamus. A properly perceived stress situation calls for a rapid and vigorous response, along with a timely cessation of that response (McEwen and Akil, 2020). Dysfunction of the HPA axis is common in individuals with MDD and is capable of activating the axis that would alter gut microbiota and increase gut permeability (De Punder and Pruimboom, 2015).

MDD is also marked by systemic inflammation with high cytokines IL-6, TNF-α, and IL-1β (Troubat et al., 2021). The increased level of inflammatory cytokines is perhaps a result of dysbiosis of the gut microbiota, which may further weaken the integrity of the gut barrier. These stimuli will also stimulate brain microglia and trigger the NLRP3 inflammasome to release IL-1β and IL-18 (Troubat et al., 2021). The released mediators would also support neuroinflammation. Inflammation also shifts tryptophan metabolism away from serotonin to neurotoxic kynurenine pathway metabolites, like quinolinic acid, and disturbs neurotransmission and thus plays a role in depressive symptoms (Chen et al., 2021; Liang et al., 2024). Major depression is treated by various pharmacological and non-pharmacological interventions. Exercise and lifestyle modification exert substantial antidepressant effects, especially for mild MDD (Marx et al., 2023). Therefore, modulation of gut microbiota mechanisms might be the key to symptom relief of MDD.

Escherichia and Enterococcus produce serotonin, while Bifidobacterium and Lactobacillus synthesize GABA (Socała et al., 2021). Microbes like Coprococcus and Faecalibacterium also produce acetate, butyrate, and propionate, which are known to affect the immune, endocrine, and nervous systems (Valles-Colomer et al., 2019). Gut SCFAs promote serotonin synthesis in the gut and further communicate with the brain via the vagus nerve. Although SCFAs can cross the BBB, serotonin and GABA generally do not, unless barrier integrity is compromised, as seen in stress and depression models (Margolis et al., 2021). A translation from gut microbiota research to clinical settings is undermined by the complexity surrounding individual microbial profiles (Galland, 2014). Investigative efforts so far concerning enterotypes, such as alpha diversity, the Firmicutes-to-Bacteroidetes ratio, aim at the identification of an MDD-specific fecal signature (Valles-Colomer et al., 2019). Reduced Firmicutes proportion in MDD patients, as a suggestion for the establishment of an MDD biomarker, was reported by Jiang et al. (2015). This, however, was followed by systematic reviews showing inconsistent results and hence raised questions on replicability (Barandouzi et al., 2020). Most studies have shown that the GM of MDD patients differs from that of controls at the phylum, class, order, family, and genus levels, but with a particular emphasis on differences at the phylum, family, and genus levels (Table 7).

Higher relative abundance of proinflammatory bacteria like Eggerthella, Atopobium was found to be increased, and decreased relative abundance of Faecalibacterium in the subjects with MDD (Knudsen et al., 2021). Similarly, patients with MDD also had decreased relative abundance of the genera Coprococcus and Faecalibacterium compared to non-depressed individuals in a meta-analysis by Sanada et al. (2020). The meta-analytical study shows decreased abundance in the MDD patients when compared to controls in the bacterial families Veillonellaceae, Prevotellaceae, and Sutterellaceae, genera Coprococcus, Faecalibacterium, Ruminococcus, Bifidobacterium, Escherichia, and shows an increase in abundance in Actinomycetaceae family and Paraprevotella genus (Sanada et al., 2020). Interestingly, Faecalibacterium served as a primary butyrate-producing bacterium in the gut, being crucial for gut homeostasis and possibly alleviating depressive symptoms at least in animal models (Stilling et al., 2016).

BD is a chronic psychiatric condition characterized by alternating episodes of depression and elevated mood states, which may manifest as mania or hypomania. These episodes often alternate with periods of euthymia but can also occur in rapid succession or with mixed features. The disorder is classified into two main subtypes: bipolar I disorder (BP-I), defined by the presence of at least one full manic episode, and bipolar II disorder (BP-II), characterized by hypomanic episodes without progression to full mania (Grande et al., 2016). Longitudinal studies highlight the persistent and fluctuating nature of BD. Research indicates that individuals with BP-I remain symptomatic for nearly half of their illness course, with depressive symptoms being the most frequent and persistent, significantly outweighing manic/hypomanic and mixed episodes (Nierenberg et al., 2023). Subsyndromal symptoms are more prevalent than full-threshold episodes, while psychotic features occur infrequently and primarily during manic states. The illness trajectory is highly variable, marked by frequent shifts in symptom polarity, underscoring the chronic and recurrent nature of BD (Grande et al., 2016). Epidemiological data further demonstrate that over 90% of individuals with BD experience recurrent episodes, which contribute to progressive neurobiological changes, cognitive decline, and increased medical and psychiatric comorbidities (Nierenberg et al., 2023). Manic episodes are defined by at least 1 week of persistently elevated, expansive, or irritable mood accompanied by increased activity or energy, whereas hypomanic episodes present similar features without marked functional impairment or hospitalization. The presence of psychotic features necessitates classification as mania. The global burden of BD is substantial. The World Mental Health (WMH) survey, using the WHO Composite International Diagnostic Interview (CIDI 3.0), identified BD as one of the most disabling psychiatric conditions, with affected individuals averaging 41.2 days of role impairment per year 36.5 of which were directly attributed to BD (Alonso et al., 2011). These findings emphasize the critical need for early intervention, personalized treatment strategies, and ongoing research into the disorder's pathophysiology and long-term management (Grande et al., 2016; Nierenberg et al., 2023).

Biologically, people with BD, especially those who haven't started treatment, show noticeable changes in their gut microbiome. A study by Hu et al. (2019) found that these untreated patients had significantly less diverse gut bacteria (lower α-diversity) compared to healthy individuals. They also had unique bacterial compositions (Hu et al., 2019). These changes were found not only in untreated individuals but also in those who were being treated with the medication quetiapine. The study also looked closely at quetiapine, which was used to treat depressive episodes in BD. It was given on its own (monotherapy) at a dose of 200–300 mg daily for 4 weeks. All participants were confirmed to be experiencing a depressive episode using structured psychiatric interviews and rating scales like the HDRS-17 and MADRS. After treatment, there was a clear improvement in symptoms. Although quetiapine is not directly labeled as an antipsychotic in this study, the effects it had both metabolically and on gut bacteria are consistent with what is known about that class of drugs. Importantly, the study only explored quetiapine's use in bipolar depression and did not extend its findings to other mental health conditions (Hu et al., 2019).

On the genetic side, research by Heun and Maier (1993) showed that BP-II may be genetically different from BP-I and unipolar depression. In their family-based study, relatives of people with BP-II had a higher risk of also having BP-II, suggesting it tends to run specifically in families (Heun and Maier, 1993). In contrast, less severe mood disorders did not show this familial pattern, supporting the idea that BP-II is a distinct and genetically separate condition. Moreover, the pilot study by McIntyre et al. (2021) observed that patients with BD had lower gut microbial α-diversity compared to healthy individuals, indicating a less varied gut microbiome. They also found a higher presence of Clostridiaceae bacteria in BD patients, with Collinsella specifically enriched in individuals with BD-II compared to those with BD-I, suggesting that different BD subtypes may have distinct microbiome patterns (McIntyre et al., 2021). However, due to the study's small sample size and lack of consistent grouping based on diagnosis or diet, the results need further investigation. Similarly, Painold et al. (2019) reported notable changes in gut microbiota among BD patients. They found that microbial α-diversity decreased as the duration of illness increased, meaning that the variety of gut bacteria reduced over time in individuals with BD (Painold et al., 2019). Compared to healthy controls, BD patients had higher levels of Actinobacteria and Coriobacteria, while healthy individuals had more Ruminococcaceae and Faecalibacterium, which are generally considered beneficial. Among BD patients with elevated levels of the inflammatory marker IL-6, there were increases in Lactobacillales and Streptococcaceae, suggesting a connection between inflammation and gut microbiota changes. The study also linked specific bacterial groups to metabolic issues in BD. For instance, Clostridiaceae were more abundant in patients with high cholesterol, and Eubacterium was associated with markers of oxidative stress. Additionally, more severe depressive symptoms were correlated with an increased presence of Enterobacteriaceae, while comparatively healthier BD patients had more Clostridiaceae and Roseburia. These findings support the relevance of MGBA mechanisms in BD pathophysiology, implicating both immune and metabolic pathways as shown in Table 8, and are conceptually illustrated through the microbiota–immune–metabolic–brain axis model (Figure 6; Painold et al., 2019).

A cross-sectional study has found that taking atypical antipsychotics (AAPs) led to an increase in a group of gut bacteria called Lachnospiraceae and a decrease in Akkermansia, which is often linked to gut health (Flowers et al., 2017). While there was also an initial drop in Sutterella, this result was no longer significant after adjusting for age, body mass index (BMI), and gender. AAP use was also linked to a general decrease in gut microbial diversity, especially in women. In a related finding, A related study reported that people with BD had lower levels of Faecalibacterium, a beneficial bacterium known for producing butyrate a short-chain fatty acid important for gut health. Higher levels of this bacterium were associated with better physical wellbeing, mood, sleep quality, and lower anxiety (Evans et al., 2017). Moreover, another study also highlighted the important role of Faecalibacterium in producing butyrate (Tanca et al., 2017). Independently, Sasaki et al. (2018) tested the effects of small amounts of prebiotic fibers like indigestible dextrin, α-cyclodextrin, and dextran using a lab-based colon model and a small human trial. They found that these supplements increased the production of beneficial SCFAs like acetate and propionate without changing the overall diversity or makeup of gut bacteria. This suggests that low-dose prebiotics can boost gut health without disrupting the balance of the microbiome. Another study found that patients hospitalized for acute mania were 5.5 times more likely to have used systemic antibiotics in the preceding 3 days than controls (Yolken et al., 2016). This association suggests that bacterial infections, as evidenced by antibiotic use, may contribute to manic episodes through immune activation, highlighting infection prevention and treatment as potential targets. Complementary findings demonstrated that systemic immune activation via LPS in mice produced sustained reductions in novel object exploration for up to 24 h (Haba et al., 2012). These effects were independent of acute sickness and linked to impaired cognition and motivation, particularly continuous attention and curiosity, through prolonged central amygdala activation. Although not directly tied to BD prevention, the study illustrates how transient inflammation may result in lasting behavioral changes.

Disruptions to the gut microbiome during early development or the initial phases of psychiatric illness may influence the trajectory of mental disorders (Lavebratt et al., 2019) reported that early-life antibiotic exposure is linked to modestly increased risks for several childhood psychiatric disorders, including mood disorders, suggesting sensitive developmental windows for microbiome perturbations (Lavebratt et al., 2019). In first-episode psychosis, Schwarz et al. (2018) identified a distinct microbial signature with elevated Lactobacillus and decreased Veillonellaceae, correlating with greater symptom severity and poorer 12-month remission. These findings support the use of microbiome-targeted interventions early in life or illness to potentially mitigate progression of severe psychiatric conditions. Changes in the gut microbiome caused by antipsychotic medications particularly risperidone have been linked to weight gain and metabolic effects. In children receiving long-term risperidone, the ratio of Bacteroidetes to Firmicutes (two major bacterial groups in the gut) dropped significantly from 1.24 in psychiatric controls to just 0.20 in those who gained a lot of weight. This shift came with an increase in certain Firmicutes bacteria, especially Clostridium species and Erysipelotrichaceae. On the other hand, children whose weight stayed stable had higher levels of Collinsella aerofaciens (Bahr et al., 2015). Supporting this, Bahr et al. (2015) found that risperidone causes weight gain not only by affecting appetite but also by altering the gut microbiome in ways that reduce the body's ability to burn energy. In mice, risperidone treatment led to gut bacterial changes similar to those seen in obesity more Firmicutes, fewer Bacteroidetes and a 16% drop in resting energy expenditure, especially from anaerobic (non-oxygen-requiring) metabolism. Remarkably, this effect was transferable: when gut microbes or even just viral particles (phages) from risperidone-treated mice were transplanted into healthy mice, the recipients also experienced slower metabolism and weight gain. This suggests that risperidone's metabolic side effects are largely driven by changes in gut microbes, opening up the possibility of targeting the microbiome to prevent or reduce weight gain in patients taking this medication.

Anxiety disorders represent a group of persistent neuropsychiatric conditions affecting approximately 4.05% of the global population, with prevalence rising by over 55% since 1990 (Javaid et al., 2023). Despite the widespread use of serotonergic medications, benzodiazepines and cognitive behavioral therapy (CBT), therapeutic outcomes remain limited with less than 50% of patients reaching full remission and nearly one-third do not respond to conventional treatments (De Vries et al., 2016). Clinically, anxiety disorders encompass disorders such as generalized anxiety disorder (GAD), panic disorder, specific phobias, and social anxiety disorder (SAD), all marked by fear responses, behavioral avoidance, and heightened nervous arousal in perceived threatening situations (Wu et al., 2025). Yet, symptomatology is highly variable across individuals, shaped by underlying neurobiological factors. Evidence suggests a widely distributed neural circuit underpinning anxiety disorders, involving interconnected regions such as the amygdala, hippocampus, bed nucleus of the stria terminalis, insula, hypothalamus, anterior cingulate cortex and prefrontal cortex (Drzewiecki and Fox, 2024). Not all individuals exposed to stress or adversity go on to develop anxiety disorders (Charney, 2003). Vulnerability factors include early life trauma, poor social support, co-existing medical conditions, genetic predisposition and sex-based differences (Lai and Xiong, 2025).

Women are nearly twice as likely to develop anxiety disorders, potentially due to enhanced HPA axis activation under stress and modulatory effects of sex hormones on GABAergic and glucocorticoid signaling (Jaggar et al., 2020). There is a high comorbidity between the anxiety disorders and MDD (Bobo et al., 2022). Heritability estimates range between 30 and 50%, although genome-wide study results have been inconclusive (Meier et al., 2019). From a systems perspective, anxiety disorders is characterized by abnormalities in neurotransmitter functions, neurotrophic signaling, the endocannabinoid system and HPA axis function and these alterations are further compounded by chronic inflammation and maladaptive immune responses (Cai et al., 2025). Interestingly, elevated baseline levels of inflammatory markers such as CRP and IL-6 have been linked to both increased risk and severity of anxiety (Mac Giollabhui et al., 2025), while epidemiological data show that individuals with inflammatory autoimmune diseases like psoriasis have increased risks of experiencing developing anxiety disorders (Lee et al., 2025).

Emerging evidence highlights the MGBA as a critical contributor to anxiety pathophysiology (Abautret-Daly et al., 2018). Genetic studies further showed that several loci associated with GI disorder such as IBS, namely NCAM1, CADM2, and PHF2/FAM120A also correlate with anxiety and mood disorders (Eijsbouts et al., 2021). Moreover, Mendelian randomization analyses support a causal role for specific gut microbes: Actinobacteria and Bifidobacterium taxa appear protective, while Lactobacillaceae increase anxiety risk (Lai and Xiong, 2025). Animal research and scarce human studies confirm these findings, showing that disruptions in microbiota composition or metabolite profiles can induce anxiety-like behaviors via MGBA (Cai et al., 2025).

Gut microbiota alterations are constantly found in individuals with anxiety disorders (Chen et al., 2019). For instance, whilst beta diversity (reflecting differences in microbial community composition) is consistently altered across anxiety disorders, alpha diversity patterns show disorder type and sex-specific patterns (Jiang et al., 2018; Butler et al., 2023; Kim et al., 2023). Sex-dependent effects emerged specifically in a large Korean study with anxious population, where men exhibited reduced alpha diversity while women showed no changes (Kim et al., 2023). However, self-reported anxiety symptoms may limit the generalizability of the findings. Furthermore, a small study with GAD diagnosed patients showed reduced microbial richness among males and females (Jiang et al., 2018) while SAD patients maintained normal diversity (Butler et al., 2023). One hypothesis for these observed differences is that biological sex influences gut microbial composition through hormone-regulated immune and metabolic pathways, with sex steroid hormones and sex-linked genetic factors shaping the immune environment and selectively supporting the growth of certain microbial taxa (Jaggar et al., 2020).

SCFA producing taxa is depleted in anxiety disorders (Burton et al., 2023), mirroring patterns observed in other psychiatric conditions (Bruun et al., 2024). Anxious men showed reduced abundance of butyrate-producing Lachnospiraceae_NK4A136 (Kim et al., 2023), which is essential for epithelial barrier integrity and microglial regulation (Erny et al., 2015). GAD patients demonstrated broader SCFA depletion, with decreased levels of Faecalibacterium, Eubacterium rectale, Butyricicoccus, and Lachnospira, bacteria integral to maintaining mucosal homeostasis and modulating host-microbiota immune interactions. Interestingly, in the remission state, increased levels of Faecalibacterium and Eubacterium rectale were observed (Jiang et al., 2018). Similarly, SAD control group showed an abundance of Parasutterella—a symbiont that supports intestinal mucosal stability with a potential protective role in anxiety (Butler et al., 2023; Yao et al., 2023).

Pro-inflammatory and pathobiont taxa showed disorder-specific enrichment patterns. GAD patients exhibited increased Bacteroides, Ruminococcus gnavus, and Fusobacterium (Jiang et al., 2018), with the latter linked to epithelial disruption, gut inflammation and IBS pathogenesis (Zhou, 2016). Interestingly, about one third of people with IBS have anxiety symptoms, suggesting a potential shared gut–brain inflammatory axis between GAD and IBS (Grover et al., 2021). SAD patients showed enrichment of novel genera Anaeromassilibacillus and Gordonibacter, whereas Anaeromassilibacillus was linked to autism spectrum disorder—a condition with high SAD comorbidity (Butler et al., 2023). Interestingly, the gut metabolic module aspartate degradation I, which converts L-aspartate to oxaloacetate by aspartate aminotransferase, was elevated in SAD patients and the authors hypothesized that bacterial aspartate aminotransferase enzyme activity may represent a link between gut microbiome function and the tryptophan-kynurenine pathway, a key physiological system in psychiatric disorders (Butler et al., 2023). The tryptophan-kynurenine pathway functions as a stress-activated metabolic system that diverts tryptophan from serotonin synthesis toward kynurenic acid production, which acts as a glutamate receptor antagonist and may contribute to anxiety pathophysiology through altered glutamatergic neurotransmission (Butler et al., 2022). Despite consistent patterns of SCFA depletion, the heterogeneity in microbial signatures across anxiety subtypes suggests disorder-specific pathophysiological mechanisms. Small sample sizes and different anxiety types limit clinical translation. Future studies should standardize methodological approaches across populations and increase sample sizes.

Rodent models of anxiety disorders provide causal evidence that stress exposure disrupts the MGBA, leading to microbiota alterations, compromised gut barrier integrity, immune activation and neurotransmitter imbalance (Bear et al., 2021). Alterations in the Firmicutes and Bacteroidetes (F/B) ratio—a key marker of gut dysbiosis—have been reported in male mice exposed to chronic mild stress (CMS; Tyagi et al., 2025) and humid heat environment stress models (Weng et al., 2024) Enrichment of the phylum Proteobacteria was observed across multiple stress paradigms (Jia et al., 2024; Tyagi et al., 2025). Proteobacteria enrichment in the gut serves as a dysbiosis marker (Shin et al., 2015). Moreover, 6 weeks of chronic stress also revealed decreased relative abundance of Bacteroidetes and Deferribacteres (Jia et al., 2024).

Across preclinical anxiety models, there was a consistent enrichment of pathogenic or dysbiosis-associated bacteria. Male mice exposed to CMS for 2 weeks showed increased pathogenic bacteria including Acinetobacter, Proteus, and Enterococcus (Tyagi et al., 2025). Similarly, chronic stress elevated Kineothrix alysoides and Helicobacter bilis compared to controls (Jia et al., 2024). Similarly, a systematic depletion of beneficial and anti-inflammatory taxa, many of which are involved in SCFA production, was observed in stress-exposed animals. Lactobacillus murinus, L. intestinalis, L. reuteri, and Akkermansia muciniphila (Weng et al., 2024). Oscillibacter, Muribaculum, Roseburia, and Alistipes (Tyagi et al., 2025) as well as Muribaculum intestinale, Ligilactobacillus murinus, Duncaniella, and Prevotella (Jia et al., 2024). These losses occurred irrespective of stress model or duration. These microbial alterations were accompanied by functional impairments, with CMS significantly reducing SCFA production, particularly acetic and propionic acid concentrations (Tyagi et al., 2025).

Anxiety involves MGBA alterations that create cascading pathophysiological changes (Rogers et al., 2016). Chronic stress activates the HPA axis, resulting in increased cortisol production (Faravelli, 2012). Mice exposed to chronic unpredictable mild stress (CUMS) for 6 weeks showed increased hypothalamic corticotropin-releasing hormone concentrations, elevated corticosterone levels and increased blood ammonia, which corresponded with anxiety-like behaviors, demonstrating HPA axis involvement in anxiety pathogenesis (Jia et al., 2024). Interestingly, Ammonia (a neurotoxic by-product) can impair the nervous system even at low levels and it has been associated with anxiety disorders—potentially serving as a biomarker (Duan et al., 2015). Furthermore, chronic stress impairs inhibitory neurotransmitter systems. Both GABA and serotonin availability declined with reduced receptor expression for GABA_Aα2 and GABAB1β in prefrontal cortex in the 2 week CMS (Tyagi et al., 2025). Dysregulation in these receptors is linked to anxiety behaviors and it may be considered as a potential therapeutic pathway in anxiety treatment (Solati et al., 2013). Moreover, 6 week exposure to CUMS showed further GABA level reductions in tissues such as hippocampus, blood and feces, suggesting that more widespread neurotransmitter depletion may be stress type and duration dependant (Jia et al., 2024). Furthemore, an increased serotonin metabolism was demonstrated by diminished hypothalamic serotonin levels, lowered 5-hydroxytryptamine (5-HT)/tryptophan ratios and elevated 5-hydroxyindoleacetic acid/5-HT ratios, indicating dysregulated serotonergic system (Jia et al., 2024). Altered serotonergic signaling is considered a hallmark neurochemical feature of anxiety disorders (Yohn et al., 2017).

Moreover, chronic stress exposure triggers systemic inflammatory activation through upregulation of pro-inflammatory cytokine cascades (Ravi et al., 2021). Elevated IL-6 and TNF-α concentrations in CMS exposed mice demonstrate stress-induced inflammatory signaling contribution toward anxiety-like behaviors (Tyagi et al., 2025). Similarly, mice exposed to CUMS for 6 weeks showed an increased interferon-gamma (IFN-γ) and decreased anti-inflammatory IL-10 levels, demonstrating anti-inflammatory suppression with further pro-inflammatory activation (Jia et al., 2024). Intriguingly, correlation analyses linked microbiota changes to alterations in stress hormones, neurotransmitters, inflammatory markers and anxiety-like behaviors, suggesting a gut–brain contribution to the observed behavioral manifestations in anxiety pathology (Jia et al., 2024; Tyagi et al., 2025; Figure 7).

PTSD is a chronic neuropsychiatric condition affecting 1.3–12.2% of the global population (Hu et al., 2024). PTSD is triggered by exposure to a traumatic event involving actual or threatened death, injury or sexual violence (Al Jowf et al., 2023). Remission is achieved by less than 30% of patients and pharmacological interventions remain slow-acting and lack effectiveness (Kelmendi et al., 2016). Core symptoms span intrusive memories, hyperarousal, avoidance and negative shifts in mood and cognition (Petakh et al., 2024), yet clinical presentation is highly heterogeneous—shaped by trauma type and individual neurobiology (Huckins et al., 2020). Structural and functional abnormalities in the amygdala, hippocampus and medial prefrontal cortex underlie persistent, overgeneralized fear responses (Harnett et al., 2020). Not everyone exposed to trauma would develop PTSD. Risk of developing PTSD is influenced by adverse childhood experiences, younger age and socioeconomic disadvantage (Xue et al., 2015) with prevalence rates twice as high in females than in males (Perrin et al., 2014). Furthermore, heritability estimates range from 30 to 40% (Girgenti et al., 2021) with genome-wide studies implicating immune-linked loci such as ANKRD55 among others (Stein et al., 2016; Ugidos et al., 2019). At the systems level, PTSD is characterized by heightened peripheral inflammation, impaired regulatory T cell function (Jergović et al., 2014), dysregulation of the HPA axis, neurotransmitter systems and neuroinflammation (Michopoulos et al., 2015; Aliev et al., 2020). Elevated pre-existing inflammation has emerged as a predictive factor for PTSD onset. Individuals with high baseline CRP are more likely to develop PTSD symptoms following trauma exposure (Eraly et al., 2014).

A growing body of evidence implicates the MGBA as a key modulator of PTSD vulnerability. Given that gut microbiota regulate immune function and inflammation, both key features of PTSD pathophysiology, this axis represents a promising therapeutic target. Early-life gut microbiota imbalances may predispose individuals to PTSD susceptibility after trauma exposure (Leclercq et al., 2016). Supporting this hypothesis, PTSD is more prevalent in individuals with GI inflammatory disorders including, IBD and Crohn's disease (Katrinli et al., 2022; Kent, 2024). Recent Mendelian randomization findings further validate this framework: Dorea and Sellimonas appear protective, whereas Phascolarctobacterium and Ruminococcaceae UCG-004 are associated with increased PTSD risk (He et al., 2024). Multiple clinical studies have characterized the gut microbiome in PTSD patients, revealing patterns of microbial dysbiosis (Hemmings et al., 2017; Bajaj et al., 2019; O'Hare et al., 2024; Yirmiya et al., 2024; Li Y. I. et al., 2025). An early study found decreased abundance of Actinobacteria, Lentisphaerae and Verrucomicrobia in PTSD patients vs. trauma-exposed controls (Hemmings et al., 2017). Decreased Verrucomicrobia (which includes the beneficial bacterium Akkermansia muciniphila, important for gut barrier function) correlated with greater PTSD symptom severity in 26 Iraq/Afghanistan War Veterans from different ethnic backgrounds, though findings were based on self-reported behavioral symptoms (Li Y. I. et al., 2025).

SCFA-producing bacteria are consistently depleted among PTSD patients along with increased pathobionts indicate a shift toward inflammatory environment. SCFA producing Lachnospiraceae and Ruminococcaceae were reduced in US combat veterans with cirrhosis and PTSD compared to those without PTSD, together with increased pathobionts Enterococcus and Escherichia/Shigella (Bajaj et al., 2019), suggesting these microbial changes may reflect or even exacerbate inflammation-driven psychiatric vulnerability. Moreover, a longitudinal study following war-exposed Israeli children for over 15 years found that clinically diagnosed PTSD youth exhibited significantly lower α-diversity, decreased SCFA-producing bacteria (Dialister, Eubacterium) and increased pro-inflammatory pathobionts (Collinsella, Veillonella) compared to controls, along with increased nitrate reductase-associated metabolites linked to nitrogen metabolism pathways. Fecal microbiome transplantation from PTSD adolescents into germ-free mice induced significant anxiety behaviors, confirming functional contribution of gut microbiota to psychiatric symptomatology (Yirmiya et al., 2024). However, the study used only one behavioral test (Elevated Plus Maze). Future studies should employ multiple paradigms to capture the broader spectrum of PTSD-related phenotypes. These findings collectively highlight that PTSD is associated with reproducible patterns of gut dysbiosis, characterized by reduced SCFA-producing taxa and increased inflammatory pathobionts, supporting a functional link between microbial imbalance and psychiatric vulnerability.

Bacteria changes may be linked to geographic location where the study was carried. PTSD-diagnosed South African individuals showed higher levels of Mitsuokella, Odoribacter, Olsenella, and Catenibacterium compared to controls, positively correlating with childhood trauma severity. Intriguingly, these four genera are found in oral microbiota of patients with periodontitis. The authors hypothesized that early life adversity may alter oral microbiome composition, which can shift to gut via saliva, potentially creating a pro-inflammatory state that increases vulnerability to PTSD following subsequent trauma exposure (Malan-Muller et al., 2022). Catenibacterium was also identified in another South African study with self-assessed PTSD symptoms (O'Hare et al., 2024), indicating potential geographic location-specific associations (Parizadeh and Arrieta, 2023). Higher levels of Catenibacterium, Collinsella, and Holdemanella also correlated with higher symptom severity (O'Hare et al., 2024). These bacteria produce lactic acid. Lactate (the ionized active form of lactic acid) has been linked to PTSD through unclear mechanisms. One proposed mechanism is that lactate enhances hippocampal neuronal firing, potentially contributing to panic symptoms (Bergold et al., 2009). Moreover, elevated Holdemanella has been associated with reduced right amygdala and hippocampal volumes (Wanapaisan et al., 2022) brain regions consistently reduced in PTSD individuals (Ben-Zion et al., 2023). Future functional studies should assess whether associations between these bacteria concentrations and brain volumes reflect causal relationships. Together, these findings suggest that microbiome shifts associated with trauma exposure and geography may influence PTSD risk by modulating brain structure and neuroinflammatory signaling.

Additional population studies have expanded these findings. Whole-genome sequencing of 191 American nurses identified specific bacterial alterations in self-reported PTSD: increased ParaBacteroides goldsteinii, Barnesiella intestinihominis, and Paraprevotella unclassified, decreased Eubacterium eligens and Akkermansia muciniphila (Ke et al., 2023).

Differences in findings could be attributed to the fact that participants were from different geographic locations, which are known to influence gut microbiota composition through factors such as diet, environment, and lifestyle-potentially contributing to the observed variation. Furthermore, small sample sizes, different trauma types and symptom assessment methods limit clinical translation. Future studies should standardize methodological approaches across populations and increase sample sizes in order to distinguish between geographic and pathological microbiome variations.

Rodent models of PTSD provide causal evidence that psychological trauma disrupts the MGBA, leading to microbiota alterations, compromised gut barrier integrity, immune activation and neurotransmitter imbalance. Alterations in the Firmicutes and Bacteroidetes (F/B) ratio—a key marker of gut dysbiosis, have been reported in PTSD model rodents, exposed to psychological trauma using Repeated Social Defeat Stress and Single Prolonged Stress (SPS; Zhou et al., 2020; Yadav et al., 2023).

Across preclinical PTSD models, there is consistent enrichment of pathogenic or dysbiosis-associated bacteria. For instance, Zhou et al. (2020) reported elevated levels of Cyanobacteria and Proteobacteria in SPS exposed male rats. Similarly, female rats exposed to trauma exhibited increased abundance of Anaerovorax and Flavonifractor, latter being associated with GABA disruption (Tanelian et al., 2023). In male mice, Laudani et al. (2023) observed elevated Ruminococcaceae and Lachnospiraceae families—taxa known to influence dopaminergic signaling and myelination via production of the neurotoxic metabolite p-cresol, a compound implicated in PTSD related neuropathology (Torrisi et al., 2019; Jak et al., 2020). Similarly, a systematic depletion of beneficial and anti-inflammatory taxa was observed in trauma exposed animals. In female rats, trauma led to reduced abundance of Bifidobacterium, Clostridium sensu stricto, Turicibacter, and Barnesiella—genera some of which are involved in short-chain fatty acid (SCFA) production and serotonergic (Turicibacter) regulation (Laudani et al., 2023; Tanelian et al., 2023) reported reduced levels of Actinobacteria, Proteobacteria, Verrucomicrobia and Bacteroides in male mice with PTSD-like behaviors, consistent with findings from human studies linking similar depletions to PTSD symptomatology (Hemmings et al., 2017). Interestingly, protective baseline microbiome signatures were identified in stress-resilient rodents. Females resilient to trauma exhibited higher pre-trauma levels of Roseburia, Oscillibacter, and Lachnospiraceae, suggesting that baseline enrichment of SCFA-producing bacteria may confer resistance to PTSD onset (Tanelian et al., 2023).

PTSD involves gut–brain axis alterations that create cascading pathophysiological effects. Altered regulation of the HPA axis has been observed in PTSD pathology. Female rats exposed to predator-based psychosocial stress exhibited significantly reduced baseline corticosterone levels and enhanced dexamethasone suppression compared to controls, demonstrating that PTSD is characterized by altered HPA axis function (Zoladz et al., 2021). Furthermore, gut microbiota regulates HPA axis responsiveness. Germ-free mice exhibited exaggerated plasma corticosterone responses compared to specific pathogen-free controls, demonstrating that microbiota regulates HPA axis function (Vagnerová et al., 2019). Moreover, psychological trauma compromises gut barrier function and increases inflammation through stress hormone signaling (Sherin and Nemeroff, 2011). In PTSD mice models, trauma exposure increased tyrosine hydroxylase expression (the rate-limiting enzyme in catecholamine biosynthesis), elevating stress hormones epinephrine and norepinephrine in serum and colon, which upregulated claudin-2 expression, confirming gut barrier dysfunction (Yadav et al., 2023). Trauma exposure also induces intestinal inflammation (increased CD45⁺ leukocytes, CD68⁺ macrophages, and CD3⁺ T cells and upregulated phosphorylated Stat3 and NF-κB) signaling. This shows the causal pathway whereby psychological trauma compromises gut barrier function and intestinal inflammation through stress hormone signaling. The study hypothesized that pro-inflammatory gut environment further promotes changes in microbiota (Yadav et al., 2023). Furthermore, significantly elevated branch-chain fatty acids (BCFA), which are metabolic products of protein breakdown have been hypothesized to induce epithelium inflammation (Aguirre et al., 2016).

These microbial alterations coincided with PTSD symptomatology, BBB dysfunction and hippocampal neuroinflammation, which was confirmed by increased proinflammatory cytokine levels IL-1β and IL-6 (Tanelian et al., 2023). Collectively, these studies confirm that PTSD involves gut–brain axis disruption.

Alterations in gut microbiota can disrupt neurotransmitter homeostasis, particularly affecting serotonin (5-HT), norepinephrine (NE), and dopamine (DA) systems that are dysregulated in PTSD (Zhou et al., 2020). Microbial shifts in a PTSD male rat study coincided with a significant decrease in brain 5-HT and increases in DA and NE, indicating a potential hyperaroused state. Spearman correlation analysis linked the microbiota changes to fear- and anxiety-like behaviors, suggesting a gut–brain contribution to the observed neurotransmitter imbalance in PTSD rat models (Zhou et al., 2020). Intriguingly, serotonin regulation may be particular sensitive to the decreased levels of Turicibacter (particularly T. sanguinis) as this genus influences gut-derived serotonin (Tanelian et al., 2023), which is partly controlled by the microbiota (Fung et al., 2017) and is known contributor to PTSD symptoms (Tanelian et al., 2023). Similarly, trauma induced increased Flavonifractor may potentially compromise GABA availability, since these bacteria primarily utilize GABA for metabolism (Tanelian et al., 2023) potentially affecting this key inhibitory neurotransmitter and contributing to anxiety symptoms observed in PTSD (Strandwitz et al., 2018). Similarly, dopaminergic dysfunction was observed. Male rats with PTSD-like behaviors showed elevated p-cresol (a neurotoxic metabolite linked to overgrowth of Ruminococcaceae and Lachnospiraceae) in prefrontal cortex, leading to dopaminergic dysfunction with increased DA, increased dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), and significantly elevated DA D3 receptor expression compared to controls (Laudani et al., 2023). The prefrontal cortex is highly sensitive to DA and even minor fluctuations can impair prefrontal cortex-dependent functions, making it particularly relevant in PTSD, as it plays a central role in suppressing fear responses, regulating stress reactivity, and enabling emotional control (Cools and D'Esposito, 2011). Collectively, these findings demonstrate that psychological trauma initiates a cascade of interconnected MGBA disruptions in PTSD, encompassing HPA axis dysregulation, microbial dysbiosis, compromised gut barrier integrity, chronic inflammation and neurotransmitter imbalances across serotonergic, dopaminergic, and GABAergic systems. Collectively, these findings demonstrate that PTSD arises through a complex interplay of gut dysbiosis, neuroendocrine disruption, immune activation, and altered neurotransmission, firmly implicating the microbiota–MGBA in the pathophysiology of trauma-related disorders.

CFS, also known as Myalgic Encephalomyelitis (CFS/ME), is a complex disorder marked by persistent fatigue, cognitive impairment, and a range of physical symptoms that are not alleviated by rest (König et al., 2021; Wang J.-H. et al., 2024). The underlying mechanisms are multifactorial and not fully understood, but increasing evidence highlights the gut–brain axis and the intestinal microbiome as critical contributors to disease onset and progression (He et al., 2023; El-Sehrawy et al., 2025). Recent advances in microbiome research have opened new avenues for prevention and intervention, focusing on how gut microbial communities influence immune, metabolic, and neural pathways relevant to CFS/ME. Taken together, these studies underscore the potential of gut-targeted therapies in managing the multi-systemic symptoms of CFS/ME.

Multiple studies have established that individuals with CFS/ME exhibit significant alterations in their gut microbiome composition compared to healthy controls. Dysbiosis in CFS/ME is characterized by reduced microbial diversity and a shift in the abundance of specific bacterial taxa. For example, patients often have lower levels of anti-inflammatory bacteria such as Faecalibacterium and higher proportions of pro-inflammatory species, which may contribute to systemic inflammation and symptom severity (König et al., 2021; Xiong R. et al., 2023). A recent meta-analysis confirmed that CFS/ME is associated with distinct gut microbial signatures, including reduced levels of butyrate-producing bacteria and increased abundance of Enterobacteriaceae (Jurek and Castro-Marrero, 2024). These alterations are thought to impact gut barrier integrity and immune function, both of which are implicated in CFS/ME pathophysiology. In CFS/ME, disruptions in this axis are believed to play a central role in the manifestation of fatigue, cognitive dysfunction, and mood disturbances (König et al., 2021). Microbial metabolites such as SCFAs and tryptophan catabolites can influence brain function directly or via modulation of systemic inflammation. For instance, butyrate, an SCFA produced by certain gut bacteria, supports the integrity of the intestinal barrier and exerts anti-inflammatory effects (Guo et al., 2023; Jurek and Castro-Marrero, 2024). Reduced butyrate levels in CFS/ME patients may contribute to increased gut permeability (“leaky gut”), allowing microbial products like LPS to enter the circulation and trigger systemic immune activation (Wang J.-H. et al., 2024). This immune activation may, in turn, affect the CNS, exacerbating fatigue and cognitive symptoms. This highlights the complexity of host–microbe interactions in CFS/ME and underscores the importance of personalized medicine approaches.

Altered microbial metabolism in CFS/ME extends beyond SCFAs. Dysbiosis can affect the kynurenine pathway of tryptophan metabolism, leading to an imbalance in neuroactive metabolites that influence mood, cognition, and pain perception (He et al., 2023). The gut microbiome modulates the balance of pro- and anti-inflammatory immune responses, which is crucial in light of the chronic low-grade inflammation observed in many CFS/ME patients (Seton et al., 2023). Recent multi-omics studies have revealed that patients with CFS/ME, especially in early disease stages, display pronounced disruptions in both gut microbial composition and metabolic profiles (Wang J.-H. et al., 2024). These disruptions include a reduction in SCFA producers and an increase in bacteria associated with inflammation and metabolic endotoxemia, which may serve as potential biomarkers for disease progression and severity. As the disease progresses, some patients may experience a partial restoration of microbial balance (eubiosis); however, this restoration does not consistently correlate with clinical improvement, highlighting the importance of early intervention (Seton et al., 2023). Moreover, GI comorbidities such as IBS are frequently observed in CFS/ME, further supporting the hypothesis that gut microbiota imbalances are not merely a consequence of illness but may actively contribute to its pathogenesis (He et al., 2023). In addition, emerging data suggest that specific microbial taxa may be causally linked to CFS/ME risk. For example, reductions in Ruminococcaceae and increases in Paraprevotella have been associated with greater disease severity (Guo et al., 2023). Notably, animal models have demonstrated that transferring dysbiotic microbiota from CFS/ME patients to germ-free mice can induce fatigue-like behaviors, supporting a causal role for the microbiome in disease pathogenesis (Bansal et al., 2025). Taken together, these studies demonstrate that alterations in the gut microbiome and its metabolic products are consistently associated with immune dysregulation and symptom severity in CFS/ME, suggesting that targeting the microbiome may offer promising new avenues for diagnosis and treatment.

Stroke is a leading cause of adult-onset neuropsychiatric and neurodegenerative disability, with substantial global prevalence and profound long-term consequences (Elendu et al., 2023). PSCI affects a significant proportion of survivors, manifesting as deficits in memory, executive function, and attention that markedly diminish quality of life and functional independence. In addition to well-established cerebrovascular and inflammatory mechanisms, emerging research highlights the gut microbiota's role in shaping stroke outcomes through the MGBA, influencing neuroinflammation, BBB integrity, and neuronal recovery (Wang et al., 2023a). This chapter will examine how stroke and PSCI are increasingly understood within the context of gut–brain interactions, and explore potential opportunities for intervention by targeting gut dysbiosis to improve neurological recovery and cognitive health.

Growing evidence reveals that stroke not only disrupts CNS homeostasis but also profoundly alters the MGBA, leading to bidirectional interactions that can exacerbate neuroinflammation and hinder recovery. A systematic review of 18 studies highlighted the critical role of aging, inflammation, and shifts in gut microbiota, particularly involving Firmicutes, Bacteroidetes, SCFAs, and TMAO, in the pathogenesis and outcomes of ischemic stroke. This underscores how microbiome alterations may both predispose individuals to stroke and influence recovery (Lee Y. T. et al., 2021). These findings collectively suggest that restoring gut microbial balance could become an integral component of stroke prevention and recovery strategies. In a mouse model of ischemic stroke, Benakis et al. (2016) demonstrated that antibiotic-induced alterations of the gut microbiota significantly reduced brain infarct size. This neuroprotection was associated with increased intestinal regulatory T cells and reduced IL-17–producing γδ T cells, ultimately suppressing the trafficking of pro-inflammatory T cells from the gut to the leptomeninges after stroke. Their findings highlight a crucial MGBA in which intestinal immune modulation directly influences the severity of ischemic brain injury (Benakis et al., 2016). Singh et al. (2016) demonstrated in mouse models of middle cerebral artery occlusion that large ischemic strokes induce gut dysbiosis characterized by reduced diversity and Bacteroidetes overgrowth, leading to intestinal barrier dysfunction. Transplanting this dysbiotic microbiota into germ-free mice worsened stroke outcomes by driving proinflammatory T-cell responses and promoting lymphocyte migration to the injured brain. These findings underscore a bidirectional brain–gut–immune axis in stroke pathology (Singh et al., 2016). These mechanistic studies emphasize that targeting gut-driven immune responses could modulate neuroinflammation and improve stroke outcomes. Dysbiosis-driven disruptions of the MGBA have been implicated in both the development of common stroke risk factors, such as obesity, diabetes, and atherosclerosis, and in poorer recovery post-stroke, with age-related changes further compounding MGBA dysfunction (Honarpisheh et al., 2022). Recent research underscores that stroke-induced gut dysbiosis not only increases intestinal permeability and triggers systemic inflammation, but also facilitates translocation of microbes and immune cells across a compromised BBB, exacerbating neural injury; paradoxically, certain gut-derived metabolites may help limit post-stroke inflammation and support neurorepair (Hu et al., 2022). This highlights the complex bidirectional relationship between the gut microbiota and stroke pathology. Gut microbiota-derived metabolites, particularly SCFAs like butyrate and acetate, play critical roles in maintaining metabolic and immune homeostasis, with dysbiosis-linked alterations implicated in the pathophysiology of numerous neurological disorders including stroke, AD, and PD (Mirzaei et al., 2021). Emerging evidence suggests that modulation of SCFA production may offer therapeutic avenues for neuroinflammatory and neurodegenerative conditions. Together, these insights point toward microbiota-centered interventions—including strategies to enhance SCFA production—as promising approaches to mitigate neuroinflammation and promote brain recovery. In summary, growing evidence underscores that gut microbiota dysbiosis plays a pivotal role in both the development and outcome of ischemic stroke through immune, barrier, and metabolic pathways, suggesting that restoring gut microbial balance could become an essential strategy for stroke prevention and recovery.

Radiation therapy (RT) has redefined the management principles of several types of cancer at various stages, whether a primary neoplasm or metastatic lesion. Although it is effective in targeting cancer cells, it can alter many other tissues like CNS and GI tissue (Bai et al., 2021). The MGBA represents the mutual communication system between the GI tract and the CNS, using various mediators like neural and endocrine signals (Yang Q. et al., 2023). Recent evidence shows that gut microbiota plays a significant role in maintaining homeostasis and regulating the MGBA, which influences the neural and GI responses to RT (Bai et al., 2021). This review focuses on the relationship between gut microbiota, MGBA, and RT, highlighting the microbiota's potential to influence RT-induced neural and intestinal side effects.

Using RT in the abdomino-pelvic region can cause gut dysbiosis, due to the reduction of Firmicutes and Bacteroidetes species accompanied by the surge in Proteobacteria species. This imbalance is strongly linked to the breakdown of the mucosal barrier and high systemic LPS levels (Wang L. et al., 2021). The microbial translocation through the disrupted tight junctions of GI cells promotes systemic inflammation and can alter the BBB or cause other direct CNS effects via the Vagus nerve. Clinically, RT patients often report neuropsychological symptoms such as depression and fatigue, which may be mediated by microbiota-induced BBB dysfunction (Liu X. et al., 2024).

Venkidesh et al. (2023) did a pivotal experiment on rats using a 6 Gy pelvic irradiation causing a significant decrease in the microbiota's diversity, impaired GI morphology, neuroinflammation, and neuronal cell death. Moreover, they documented reduced hippocampal plasticity genes—alongside a change in the rodents behavior (Venkidesh et al., 2023). This study showed that pelvic irradiation can substantially promote pyknosis in the neurons of DG and CA2 regions of the hippocampus, which strongly supports that pelvic irradiation can cause memory and cognitive effects indirectly. Similarly, another study conducted by suggest that the use of antibiotics before cranial irradiation can be a contraindication. The study shows that applying cranial RT to mice after the administration of antibiotics reduced cytokine expression, especially IL-1β and TNF-α in the hippocampus and preserved cognitive functions (Luo et al., 2022). The authors believe that the transmigration of some of the SCFA bacteria, like the Firmicutes and Bacteroidetes species across the damaged tight junctions may exacerbate radiation-induced neurotoxicity (Luo et al., 2022).

The gut microbiota produces key metabolites, such as SCFAs, neurotransmitter precursors, and tryptophan catabolites, which all influence the CNS. Butyrate and propionate, subtypes of SCFAs, are produced by anabolic commensals, such as Faecelibacterium and Roseburia, when they ferment dietary fiber (Wang L. et al., 2021). Butyrate has anti-inflammatory properties and serves as an epigenetic regulator by activating G-protein coupled receptors (GPR41 and GPR43) and inhibiting histone deacetylase activity (Du et al., 2024). Moreover, an experiment on rodents found that providing Butyrate supplementation effectively reduced hippocampus inflammation and preserved hippocampal neurogenesis following RT exposure (Lee et al., 2019a). Furthermore, species like Bifidobacterium longum have been shown to produce tryptophan metabolites that influence serotonergic signaling (Tian et al., 2019a), whereas Lactobacillus Spp. synthesize Gamma-aminobutyric acid (GABA), a crucial inhibitory neurotransmitter (Zheng et al., 2023). This suggests that any disruption of the microbial functions following RT may contribute to some neuropsychological symptoms like fatigue, depression, and cognitive dysfunction (Zhang Y. et al., 2023).

The MGBA can be influenced by many other microbial-derived metabolites, not only SCFAs (Deng et al., 2024). One example is indole-3-propionic acid (IPA), which is one of the iodole derivatives produced by the gut bacteria during tryptophan catabolism. IPA exhibits neuroprotective effects via activation of the aryl hydrocarbon receptor (AhR; Xiao et al., 2020). In preclinical models, IPA has been shown to enhance the expression of tight junction proteins in the BBB, reduce the severity of neuroinflammation, and preserve cognitive performance after CNS injury (Deng et al., 2024). In the radiation setting, any depletion in the IPA-producing species (e.g., Clostridium Spp. and Peptostreptococcus) strongly links to behavioral defects and the rise in pro-inflammatory cytokines in the CNS (Wlodarska et al., 2017; Xiao et al., 2020). Other microbial metabolites, like lactate and secondary bile, have the ability to modulate the neuroinflammatory response and influence synaptic plasticity, even though their roles in the post-radiation pathologies are still unspecified. Overall, microbially produced metabolites act as potent CNS regulators, either by modulating the vagus signaling and systemic immunity or by directly crossing the BBB (Deng et al., 2024). Understanding these complex interactions will open the gates to more promising therapeutic venues to enhance the overall quality of life of patients undergoing RT.

Radiation-induced injuries initiate local and systemic responses, which are closely related to the gut microbiome's integrity. Wang Q. et al. (2025) found that the relation between gut microbiota and radiation-induced injuries could be direct and indirect. Direct interactions are related primarily to gut radiation and microbiota homeostasis, while indirect interactions are more related to other axes, like the MGBA. Pre-clinical studies done on C57BL/6J mice using total body irradiation (9 Gy) found that radiation reduced α-diversity of gut microbiota, while urolithin A (UroA), a gut microbial metabolite, helps in alleviating radiation-induced apoptosis in intestinal cells by suppressing P53 signaling pathway (Zhang et al., 2021c; Wang Q. et al., 2025). This explains that the direct relationship between the gut microbiota and radiation-induced injuries is based on microbial homeostasis (Figure 9). Also, clinical studies done on patients with cervical cancer using pelvic radiation explained that Firmicutes-Proteobacteria ratio (F/P) reflects the severity of radiation toxicity, where it showed that patients with chronic radiation enteritis exhibited a reduction in Firmicutes and an increase in Proteobacteria. Moreover, the same study found that patients with severe enteritis showed high abundance of Shigella and Lachnospiraceae Clostridium. This supports a direct interaction, although their underlying mechanisms are still in the early stages of investigation and further studies with larger sample sizes or validation are required (Wang Q. et al., 2025).

Several pre-clinical studies illustrated the indirect interactions between gut microbiota and radiation injuries, especially brain injuries via the MGBA. A preclinical study used C57BL/6 J mice exposed to head radiation found that the predominet components of the subjects' gut microbiota following radiation were Bacteroidales, Muribaculaceae, Erysipelotrichales, and Ruminococcus. Gut microbiota-derived metabolites, like SCFAs, were shown to play a pivotal role in the MGBA by elevating pro-inflammatory cytokines in the subjects' blood, worsening radiation-induced brain injury (Luo et al., 2022; Hu et al., 2023; Wang Q. et al., 2025). Another pre-clinical study done on C57BL/6J mice using abdominal irradiation (10 Gy) found that the expression level of miR-34a-5p in the small intestine tissue and peripheral blood significantly increased, which mediated distant cognition impairment. Cognitive functions can be maintained by intravenous administration of miR-34a-5p antagomic immediately post-radiation, which blocks miR-34a-5p upregulation in peripheral blood, resulting in restoring the hippocampal expression of BDNF (Cui et al., 2017a; Wang Q. et al., 2025).

The communication between microbial dynamics and the host's immune system play a major role in determining the strength of the systemic inflammation during RT. Ionizing radiation has been proven to increase the expression of TLR on intestinal epithelial and immune cells, making them more sensitive to microbial ligands like LPS ad flagellins. In radiation settings, upregulated expression of TLR4 enhances the sensitivity and response to Proteobacteria-derived ligands, amplifying downstream NF-κB signaling and cytokine secretion (Lu et al., 2020). Recent experiments showed a surge in IL-6, IL-1β, and TNF-α levels within irradiated mice serum, which is revoked in MyD88-deficient animals. This highlights the importance of the innate immune system responses in driving systemic inflammation following RT. Simultaneously, the upregulation of co-stimulatory molecules (CD80/86) of dendritic cells conditioned in the irradiated gut mucosa suggests a pro-inflammatory antigen-presenting phenotype. The previous interactions contribute to the activation of the peripheral immune system and primes CNS microglia, creating a neuroinflammatory environment that aggravate behavioral deficits (Manda et al., 2012; Wolff et al., 2021). Notably, certain commensals, like Clostridium cluster XIVa and segmented filamentous bacteria, have the ability to push the host immune system toward regulatory responses via regulatory Treg expansion and IL-10 production (Atarashi et al., 2011). Deficiency in these taxa following RT is significantly connected with prolong tissue injury and impaired mucosal tolerance (Touchefeu et al., 2014). These findings show that microbial-immune interactions have dual role, mediators and potential modulators of radiation toxicity, along the MGBA.

Given the importance of gut microbiota and its mitigate radiation-induced toxicity., implementing preventative strategies focusing on preserving the microbial diversity and barrier quality is crucial. In murine models, FMT has shown therapeutic benefits by restoring Firmicutes species and attenuating systemic inflammation post-RT. Timing is pivotal; administering FMT pre-RT has been shown to provide more benefits compared to post-RT (Cui et al., 2017b). FMT is beginning to move toward clinical application. Pilot clinical trials found that FMT might be a safe and effective approach for patients that suffer from post-RT enteritis, although it can alter the patients' gut microbiota composition (Ding et al., 2020). Dietary interventions enrich with microbial substrates, such as polyphenols and dietary fiber, may enhance endogenous synthesis of beneficial metabolites like SCFAs and IPA. Recent studies done on animals found that high fiber diets helped in mitigating hippocampal inflammation following abdominal radiation, while preserving goblet cell integrity and tight junction protein expression (Church et al., 2023; Lu et al., 2024). Stress management techniques and exercising regularly have been shown to promote microbial diversity and cognitive resilience, potentially leading to improved neurocognitive outcomes following RT (Matei et al., 2023). Limiting non-indicated use of antibiotics during RT is crucial to prevent excessive loss of microbiota (Poonacha et al., 2022). Personalized multimodal strategies—integrating lifestyle, nutrition, and targeted therapies—require further development and validation in clinical trials.

Although pre-clinical studies are promising, several gaps remain in understanding the exact microbial species and metabolites responsible for reducing RT side effects on the gut and brain. Many clinical studies fail to incorporate longitudinal assessments of both microbiome and neurocognitive data. The limited incorporation of advanced ‘omics platforms, like metabolomics and metatranscriptomics has yet to reliably identify biomarkers of RT response and toxicity (Liu et al., 2021). Fourth industrial revolution tools, such as artificial intelligence and machine learning, are crucial in linking all the variables and further understand their mechanism of action. This is accomplished by developing generalized robust models, that minimize bias, along with explained machine learning techniques for multifactorial longitudinal data to analyze in more accurate manner and ensure future research success. Using these tools will aid the precision of radiation therapy, minimizing the risks of radiation-induced toxicities and injuries, and making medical care more personalized (Herrera-Quintana et al., 2024). Moreover, most of the existing preclinical studies have relied on male rodents, neglecting sex-specific variants in gut microbiota compositions and neuroinflammatory responses (Chakraborty et al., 2025). The field currently lacks the application of standardized approaches for microbiota modulation, like FMT and precision nutrition, which further hinder reproducibility and clinical application (Lu et al., 2024). Subsequent research must further clarify the role of the MGBA axis across varying malignancies, radiation site, and dose parameters (Li et al., 2022). Cross-disciplinary collaboration will be the key in achieving applicable realistic progress in personalized radiation oncology intervention (Yi et al., 2023).

The MGBA represents a dynamic modulator, where microbiota can influence the host's pathophysiological responses to RT. Preclinical evidence shows the significance of microbial metabolites and immune signaling in driving these effects, and recent clinical studies further supports these findings (Touchefeu et al., 2014; Wang et al., 2015). Implementing strategies that targets the MGBA axis can significantly reduce RT-associated morbidities. A clear Interdisciplinary approach containing microbiology, neuroimmunology, and behavioral sciences is needed to turn these theoretical data into realistic therapies. As we refine our knowledge about microbiota-RT interactions, microbiome modulation strategies are poised to play a key role in personalized oncology radiation treatments.

Xenobiotics are chemical substances foreign to the human body, commonly found in pharmaceuticals, food additives, pesticides and environmental pollutants—making exposure unavoidable (Jin et al., 2023). These compounds enter via ingestion, inhalation or dermal absorption and primarily accumulate in the GI tract (Hawkins et al., 2020). The gut microbiota, comprising diverse bacterial species, plays a central role in metabolizing xenobiotics through detoxification, bio activation or conversion into excretable forms (Catron et al., 2019). Given the vast number and variety of xenobiotics encountered by the gut microbiota—over 25,000 compounds, understanding these interactions is critical (Lindell et al., 2022). Xenobiotics can reshape microbial communities, alter spatial organization, and disrupt host–microbiota signaling (Sutherland et al., 2020; Figure 10). These disruptions have been found to impair communication in the MGBA, a pathway increasingly linked to psychiatric symptoms (De Filippis et al., 2024).

Although emerging evidence links xenobiotics, such as antibiotics (most commonly prescribed pharmaceuticals), glyphosate (most widely used herbicide), and microplastics (MPs)—(ubiquitous emerging environmental contaminant) with anxiety and depression, studies remain limited and mechanisms of action are poorly understood (Zhang et al., 2021a; Hsiao et al., 2023; Luo and Lin, 2025). Given that these mental health conditions are projected to become the leading contributor to the global disease burden by 2030 (Liu J. et al., 2024), understanding how xenobiotics disrupt gut–brain communication is urgently needed. This review examines how these three major xenobiotic classes disrupt gut–brain axis communication, potentially contributing to anxiety and depression-like symptoms.

Plastic manufacturing has undergone a rapid expansion since 1950. In 2022, global production reached 400 million tons, and it is expected to double by 2050 (Houssini et al., 2025). These materials degrade slowly, fragmenting into MPs (<5 mm) and nanoplastics (NPs; 1–100 nm), which have emerged as widespread environmental pollutants and a potential threat to human health (Zheng et al., 2024). MPs/NPs are either directly used in cosmetics, detergents, lotions, shampoos, synthetic textiles, and industrial processes, or formed secondarily through the degradation of larger plastic items such as packaging or tire (Zheng et al., 2024). Common polymers include polyethylene (PE), polypropylene (PP), polystyrene (PS), and polyvinyl chloride, often combined with additives such as plasticisers or flame retardants (Zheng et al., 2024). MPs/NPs have been detected across aquatic species including molluscs, fish, and crustaceans, raising concern about bioaccumulation in humans, with estimated intake ranging from 0.1 to 5 g/week via contaminated food, water and air (Li G. et al., 2024; Zheng et al., 2024). This exposure concern has been validated by direct tissue analysis. Postmortem human study demonstrated MPs/NPs were 7–30 times higher in frontal cortex than kidney or liver, with 75% of particles identified as PE (Nihart et al., 2025). Frontal cortex concentrations increased by 50% from 2016 to 2024, with dementia cases exhibiting higher accumulation than controls (Nihart et al., 2025).

Furthermore, a preclinical study demonstrated that circulating MPs may impair brain function via immune-mediated vascular occlusion (Huang et al., 2025). Following MP phagocytosis, immune cells obstructed cortical capillaries, producing neurological deficits that persisted for 4 weeks (Huang et al., 2025). The authors demonstrated that larger particles (5 μm) caused more severe obstruction than smaller ones (2 μm, 80 nm), suggesting size-dependent neurovascular toxicity. Interestingly, while maternal PE MPs/NPs exposure increased umbilical flow by 43% in mice, it did not affect fetal growth or brain circulation—suggesting effective compensatory mechanisms (Hanrahan et al., 2024). Collectively, these studies suggest MPs/NPs potentially exhibiting neurotoxic effects on cerebral tissue and vascular integrity, while negative effects during fetal exposure may be mitigated by placental adaptation.

Human exposure to microplastics can occur via respiratory inhalation, transdermal absorption and oral ingestion via food and plastic packaging (Wu P. et al., 2022) with the gut being a primary site of accumulation (Sun et al., 2025). MPs were found in every stomach examined at autopsy, averaging 9.4 particles per person, with an estimated daily intake of 32.2 particles (Özsoy et al., 2024). Recent preclinical studies found that gut microbiota participates in MPs and NPs induced anxiety and depression-like behaviors by modulating the gut–brain axis. MPs disrupt the Firmicutes/Bacteroidetes (F/B) ratio—a key marker of microbial balance in mice (Chen et al., 2023; Yang J.-Z. et al., 2023; Wang J. et al., 2024) and zebrafish (Qian et al., 2025) suggesting a conserved disruption of dominant phyla across species in response to MPs exposure. This was often accompanied by enrichment of pro-inflammatory Proteobacteria and depletion of protective phyla such as Verrucomicrobia, indicating a shift toward inflammation and barrier dysfunction (Stolfi et al., 2022). Furthermore, MPs induce gut dysbiosis by decreasing probiotic bacteria and increasing pro-inflammatory. In male mice even low-dose exposure to PS-MPs and PS-NPs (0.5 mg/day for 60 days) reduced Lactobacillus, a genus important for epithelial maintenance (Chen et al., 2023). Similar reductions followed in male mice study exposed to low-density polyethylene MPs (LDPE-MPs) and oxidized low-density polyethylene MPs (Ox-LDPE-MPs) for 28 days (Wang et al., 2023b; Wang J. et al., 2024) suggesting microbial vulnerability across polymer types. Similarly, SCFA-producing genera were consistently depleted in male rodent models exposed to PS-MPs and PS-NPs including Faecalibaculum and Akkermansia (Yang J.-Z. et al., 2023), Oscillibacter and Ruminococcus (Jiang et al., 2023), and Lachno Clostridium (Chen et al., 2023). These losses occurred irrespective of dose, duration, or particle size. Moreover, an overgrowth of pro-inflammatory gut bacteria was shown across rodent models and doses. This included Desulfovibrio (Chen et al., 2023), Mucispirillum, Helicobacter, Paraprevotella, and Tuzzerella (Yang J.-Z. et al., 2023). Moreover, gut barrier dysfunction was consistently observed in rodent models following microplastics exposure, marked by reduced expression of tight junction proteins—ZO-1, Occludin, Claudin-1, and Claudin-5 (Jiang et al., 2023; Yang J.-Z. et al., 2023; Wang J. et al., 2024). This epithelial disruption was linked to elevated serum LPS, confirming increased intestinal permeability and microbial translocation. Increased levels of IL-1β, IL-6, and TNF-α further demonstrated systemic immune activation (Yang J.-Z. et al., 2023; Wang J. et al., 2024). Interestingly, Ox-LDPE-MPs showed greater inflammatory responses and intestinal damage compared to LDPE-MPs which was hypothesized to result from their easier cellular accumulation (Wang et al., 2023b).

Furthermore, peripheral immune changes were associated with neuroinflammatory responses in mood-related brain regions. Hippocampal TLR4/MyD88/NF-κB signaling was activated (Yang J.-Z. et al., 2023) the cAMP/PKA/p-CREB pathway was altered in the amygdala alongside neuronal apoptosis (Jiang et al., 2023), and cortical cytokines—including IL-1β, IL-6, and TNF-α were elevated (Wang J. et al., 2024), each coinciding with anxiety- and depression-like behaviors. Exposure to MPs consistently disrupted monoaminergic and cholinergic signaling. In rats, long-term low-dose PS-NPs exposure reduced amygdalar metabolites-N-acetylserotonin, N-acetyl-L-tyrosine, and 4-aminobutyric acid, suggesting impaired neurotransmitter metabolism (Jiang et al., 2023). In mice, 28-day exposure to LDPE and Ox-LDPE MPs reduced acetylcholine levels in the cortex and hippocampus (Wang J. et al., 2024). In zebrafish, 90-day exposure to Polyactic Acid (PLA) and Aged Polyactic Acid (APLA) MPs (1–20 mg/L) suppressed 5-HT and DA, decreased acetylcholinesterase activity in the brain and gut and downregulated BDNF/TrkB signaling, coinciding with neuronal apoptosis. Interestingly, these effects were more pronounced in the high-dose APLA group compared to PLA, suggesting dose- and type-dependent neurotoxicity (Qian et al., 2025). Behavioral alterations from MPs exposure demonstrated clear dose-response and particle-specific patterns (Jiang et al., 2023) reported no alteration in neuropsychiatric symptoms at 12 weeks but observed clear effects after 24 weeks of exposure, supporting cumulative neurotoxicity. There were greater impairments with higher-dose APLA vs. PLA, suggesting dose- and polymer-specific toxic effects on neuropsychiatric symptoms (Qian et al., 2025). Furthermore, Ox-LDPE caused more pronounced anxiety-like behaviors compared to LDPE, with oxidized particles producing more severe behavioral impairments (Wang J. et al., 2024). MPs caused more pronounced anxiety-like behaviors compared to NPs after 30 days of exposure, hypothesizing that NPs are more easily absorbed and removed due to their smaller size, resulting in less neurotoxicity than MPs (Chen et al., 2023). The behavioral toxicity threshold of MPs remains to be defined. Future studies should investigate the effects across polymer types, doses and exposure durations. Several interventions have reversed MPs-induced neurotoxicity by targeting the gut microbiota, supporting a causal role of the MGBA (Yang J.-Z. et al., 2023). A treatment with epigallocatechin gallate (EGCG), a polyphenol from green tea, restored microbial composition, preserved tight junction expression, and reduced systemic inflammation (Yang J.-Z. et al., 2023). Moreover, rats treated with 1% neohesperidin dihydrochalcone for 1 month showed reduced amygdala neuroinflammation via suppression of cAMP/PKA pathway activity, restoration of cortical 5-HT, DA, and NE levels, and reversal of anxiety- and depression-like behaviors (Jiang et al., 2023). Similarly, bile acid treatment rescued microbial diversity and restored 5-HT, DA, acetylcholine, BDNF, and tropomyosin receptor kinase B levels in both brain and gut of zebrafish, alleviating behavioral symptoms (Qian et al., 2025). Moreover, supplementation with Lactobacillus plantarum (DP189) and GOS restored gut microbial composition, improved gut and BBB integrity, reduced cortical inflammation and elevated acetylcholinesterase activity, reversing anxiety and depression-like behaviors in mice (Wang J. et al., 2024).

While human studies remain scarce, emerging in vitro models simulating human gut conditions reveal variable microbiota responses to MPs, ranging from dysbiosis and inflammatory metabolite production to probiotic enrichment and metabolic adaptation (Fournier et al., 2023; Jiménez-Arroyo et al., 2023). In the M-ARCOL model (Mucosal Artificial Colon, an advanced in vitro system using microbiota from healthy donors), daily exposure to PE—MPs for 14 days increased pathobiont Desulfovibrionaceae (Fournier et al., 2023). Elevated levels may contribute to the development of depression by promoting hydrogen sulfide–mediated inflammation (Yang et al., 2017). Furthermore, donor-dependent rises in Enterobacteriaceae, alongside reductions in protective taxa Christensenellaceae and Akkermansiaceae were found (Fournier et al., 2023). Christensenellaceae exhibits a capacity to influence the HPA axis, a central regulator of the body's stress response (Agusti et al., 2024) and depleted levels have been found in individuals with MDD, supporting their proposed role as protective taxa within the MGBA (Liu R. T. et al., 2020).

Moreover, skatole, a tryptophan-derived metabolite typically low in healthy individuals, was also elevated, suggesting disruption of gut homeostasis (Fournier et al., 2023). However, biodegradable plastics show contrasting effects. Interestingly, certain MPs may be metabolically processed by the human gut microbiota without causing detrimental alterations. In the SIMGI^® model (an in vitro simulator of human digestion), a single dose of 0.166 g of PLA—a widely used biodegradable plastic was followed by 72-h colonic fermentation. An increase in probiotic Bifidobacterium was detected in all donors (Jiménez-Arroyo et al., 2023). During this process, PLA particles were colonized by gut microbes, forming surface biofilms and increasing pullulanase activity—an enzyme that degrades branched polysaccharides—the authors suggested this may have broken down PLA into smaller carbon-rich molecules, potentially supporting Bifidobacterium growth, without triggering pathogenic overgrowth or inflammatory responses (Jiménez-Arroyo et al., 2023). These findings were challenged by a more recent in vitro study, using fecal microbiota from healthy donors (Peng et al., 2024). Biodegradable MPs such as PLA and Poly(ε-caprolactone) underwent degradation and oligomerization while significantly depleting beneficial bacteria including Bifidobacterium, Lactobacillus, Faecalibacterium, Blautia, and Ruminococcus (Peng et al., 2024). These play a significant role in neurotransmitter production, inflammation control and barrier regulation and their depletion is frequently observed in individuals with depression and anxiety further suggesting their relevance to mental health (Borkent et al., 2022; Xiong R.-G. et al., 2023). Moreover, biodegradable MPs increased potentially harmful Megamonas and Prevotella with SCFA production impairment, authors hypothesizing that biodegradable plastics may cause greater harm than conventional plastics because their degradation creates oligomers—smaller breakdown products that can more easily penetrate biological barriers and further exhibit detrimental effects on gut microbiota (Peng et al., 2024). However, small donor sample sizes limit generalizability, as they may not capture donor-dependent shifts or reflect broader diversity in age, diet, or health. Moreover, these models used adult microbiota, despite evidence that infants are found to contain higher levels of MPs in fecal samples (Zhang et al., 2021b). Future studies should include larger, diverse cohorts and age-relevant microbiota.

Glyphosate is a widely used herbicide acting via inhibition of the enzyme 5-enolpyruvylshikimate-3-phosphate synthase, which blocks the shikimate pathway responsible for synthesizing aromatic amino acids including phenylalanine, tyrosine and tryptophan (Chiantia et al., 2025). These are known precursors to neurotransmitters that modulate mood, behavior and cognition. The shikimate pathway is absent in mammals; therefore, glyphosate has been considered safe for human health, however, this pathway is present in plants and many microorganisms, including members of the gut microbiota (Mesnage et al., 2021). As some gut bacteria rely on the shikimate pathway for nutrient synthesis or metabolic cross-feeding, glyphosate exposure may alter microbial composition, as 12–26% of human gut bacterial species may be sensitive to glyphosate (Leino et al., 2021; Puigbò et al., 2022). Therefore, GBA may be proposed as a potential mediator of glyphosate-associated neuropsychiatric effects in humans (Lehman et al., 2023). Although glyphosate has been classified as a potentially carcinogenic substance (Guyton et al., 2015) and has been linked to psychiatric symptoms and neurotoxicity (Costas-Ferreira et al., 2022) the debate on glyphosate's detrimental effects on human health continuously persists in the scientific community with scarce number of studies and inconsistent findings.

Preclinical studies found that glyphosate exposure can induce anxiety and depression-like behaviors by disrupting gut microbiome composition, impairing neurotransmitter levels and increasing neuroinflammation (Aitbali et al., 2018). Adult mice exposed to low-dose glyphosate exposure at environmentally relevant levels (10 μg/ml) for 90 days showed reduced levels of beneficial bacteria Lactobacillus and Bifidobacterium (Lehman et al., 2023). These bacteria are found to exhibit a greater sensitivity to glyphosate exposure (Shehata et al., 2013) and are often found at reduced levels in individuals with MDD and may play a role in the development of mood disorders (Aizawa et al., 2019). Moreover, detrimental effects of glyphosate on gut–brain axis exhibit transgenerational effects. Reduced beneficial bacteria Akkermansia and ParaBacteroides and overgrowth of Alistipes and Blautia were found in offspring of mice exposed to glyphosate during pregnancy and lactation (Buchenauer et al., 2023). This microbial shift disrupts multiple gut–brain pathways simultaneously: these shifts coincided with gut barrier disruption (elevated serum endotoxin), triggering elevated hippocampal cytokines (IL-6, TNF-α), which in turn suppress Tph2 expression and induce Tph2 hypermethylation (suggesting neuroinflammation and serotonergic suppression), ultimately manifesting as anxiety and depression-like behaviors (Buchenauer et al., 2023). These effects were dose-dependent, emerging only at 50 mg/kg/day—a level still classified as safe in animals by regulatory standards. Furthermore, the effects were sex-dependant—recorded in female offspring only. The selective vulnerability in females led the authors to hypothesize a role for estrogen-linked mechanisms, although this was not tested. Future studies should determine whether hormonal factors mediate this sex-specific sensitivity (Buchenauer et al., 2023). Moreover, exposing mice to a low dose which reflects a typical American diet (0.01 mg/kg/day), caused gut microbiota alterations across two generations-consistent with earlier findings, Akkermansia muciniphila was depleted, while ParaBacteroides distasonis and Christensenellaceae were elevated in the second generation (Barnett et al., 2024). Interestingly, ParaBacteroides responses appear to vary between studies, as Buchenauer et al. (2023) observed ParaBacteroides depletion rather than enrichment, suggesting exposure timing or generation-dependent effects. Whilst these microbial shifts coincided with gut barrier disruption (loss of ZO-2 tight junction protein and goblet cell depletion), colonic immune activation (elevated pro-inflammatory cytokines), and altered levels of gut-derived metabolites relevant to neuropsychiatric function (reduced GLP-1 and serum kynurenine), affective symptoms were not detected at the time of testing (Barnett et al., 2024), possibly due to delayed onset of behavioral abnormalities (Del Castilo et al., 2022). Future studies should employ longitudinal study designs to clarify the delayed effects of glyphosate on gut–brain interactions.

Antibiotics are commonly prescribed medications in clinical settings and may represent one of the most powerful disruptors of the MGBA (Hao et al., 2021). Antibiotic-induced depression followed by an attempt to suicide was first reported in 2010 (Ahmed et al., 2011). Since then, large human cohort studies have linked antibiotic exposure to increased risk of depression and anxiety, with disruption of the MGBA proposed as a key mechanism (Gudnadottir et al., 2024; Lee et al., 2024). This proposed mechanism has been directly validated in animal models where the surgically severed vagus nerve attenuated anxiety- and depression-like behaviors in mice after oral antibiotic administration, providing direct evidence for neuropsychiatric effects induced by antibiotics through the gut–brain axis (Joo et al., 2023). Preclinical studies have demonstrated that antibiotic treatment induces gut dysbiosis-marked by reduced alpha diversity, a decreased Firmicutes/Bacteroidetes ratio, depletion of beneficial genera, and enrichment of pro-inflammatory taxa (Tejkalová et al., 2023; Thabet et al., 2024). These microbial shifts trigger cascading gut–brain disruption by impairing neurotransmitter signaling, suppressing SCFA production, weakening epithelial barrier integrity, and activating neuroimmune pathways, ultimately resulting in anxiety- and depression-like behaviors in rodent models (Tejkalová et al., 2023; Li N. et al., 2024; Bibi et al., 2025). In mice treated with amoxicillin or ciprofloxacin, depletion of Lactobacillus reuteri (Firmicutes) led to reduced brain and serum GABA, downregulation of GABA-A receptors, and diminished 5-HT and DA, neurochemical changes that coincided with anxiety- and depression-like behaviors (Bibi et al., 2025). Intergenerational exposure to vancomycin and streptomycin resulted in progressive microbial loss, with the most pronounced shifts observed in third-generation offspring (Li N. et al., 2024). Depletion of beneficial taxa such as Odoribacter (Bacteroidetes) and Lachno Clostridium (Firmicutes), along with increased abundance of pro-inflammatory taxa including Ileibacterium and Olsenella, was associated with reduced SCFA gene expression, downregulation of tight junction proteins (occludin and claudin-1), and microglial activation in the amygdala and arcuate nucleus, indicating gut barrier disruption and neuroinflammation that coincided with anxiety-like behavior. Soil microbiota restoration reversed anxiety-like behavior, attenuated microgliosis, and restored gut microbial composition in affected mice (Li N. et al., 2024). However, findings remain inconsistent across studies. A recent two-hit rat model study found that antibiotic-induced dysbiosis, including increased Proteobacteria and reduced Bacteroidetes, failed to amplify anxiety-like behaviors in immune-primed rodents, contradicting prior evidence and highlighting the complexity of gut–brain interactions (Tejkalová et al., 2023). Future studies should clarify the role of immune priming in modulating behavioral responses to antibiotic-induced gut–brain effects.