Parkinson’s disease (PD) is a highly prevalent progressive neurodegenerative disorder whose global burden is rising rapidly alongside population aging; it is projected to affect over 17 million people by 2040^[1,2]. Clinically, PD is characterized by motor dysfunction, including tremor, rigidity, bradykinesia, and gait impairment^[3-5]. However, non-motor symptoms (NMS), particularly neuropsychiatric complications, are increasingly recognized as major contributors to disease burden and reduced quality of life^[6]. Among these, depressive symptoms are particularly prevalent and debilitating, affecting approximately 35%-50% of patients^[7], depending on diagnostic criteria and disease stage, substantially worsening motor function, cognition, and quality of life^[8,9]. Importantly, depressive symptoms may precede motor dysfunction by several years, suggesting that they reflect early pathogenic processes rather than solely a psychological response to disability^[10]. Depression in PD is further associated with accelerated motor progression^[11], cognitive decline and poorer clinical outcomes^[12,13].

Accumulating evidence implicates the microbiota-gut-brain axis in PD pathogenesis. Braak’s staging hypothesis^[14,15] proposes that pathological α-synuclein aggregation may originate within the enteric nervous system (ENS) before propagating centrally through the vagus nerve^[16,17]. Consistent with this concept, experimental studies demonstrate that germ-free or microbiota-depleted α-synuclein-overexpressing mice exhibit attenuated motor deficits, whereas transplantation of microbiota derived from patients with PD exacerbates motor dysfunction relative to microbiota from healthy donors^[18]. Clinical studies similarly report reproducible alterations in gut microbial composition and function in patients with PD^[19]. These alterations have been linked to impaired intestinal barrier integrity, systemic inflammation, altered microbial metabolite production, and disrupted gut-brain signaling^[20,21]. Neuroinflammation mediated by activated microglia and astrocytes is increasingly recognized as a central driver of PD progression and may also contribute to depressive symptomatology through disruption of monoaminergic pathways involved in mood regulation^[22].

Although depression is highly prevalent in PD, depressive Parkinson’s disease (DPD) and non-depressive Parkinson’s disease (NDPD) are increasingly recognized as clinically relevant phenotypes with potentially distinct biological characteristics. Neuroimaging studies have demonstrated reduced serotonin transporter binding, diminished mesolimbic dopamine transporter availability, and greater prefrontal metabolic disruption in DPD relative to NDPD^[23,24]. Cerebrospinal fluid (CSF) studies similarly report selective serotonergic abnormalities in DPD without equivalent alterations in dopaminergic or noradrenergic metabolites^[25,26]. Nevertheless, depression in PD is biologically heterogeneous^[9,27], and current studies are limited by inconsistent diagnostic criteria and inadequate phenotypic stratification. Furthermore, DPD should be distinguished from primary major depressive disorder (MDD), as depressive symptoms in PD occur within the context of ongoing nigrostriatal degeneration, α-synuclein pathology, and progressive monoaminergic dysfunction^[28,29]. Unlike MDD, in which serotonergic dysfunction predominates^[30]. DPD involves concurrent (dopaminergic, serotonergic, and noradrenergic deficits alongside neuroinflammatory processes driven by Lewy body pathology^[9].These distinct metabolic patterns may help in the early differentiation of DPD from MDD in patients with depression, suggesting a distinct neurobiological substrate that may respond differently to both conventional antidepressant therapies and microbiota-targeted interventions.

Emerging evidence suggests that microbiota-derived metabolites may represent a mechanistic interface linking neurodegenerative and neuropsychiatric processes in PD. Alterations in short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), bile acids (BAs), and tryptophan-kynurenine pathway metabolites have been associated with neuroinflammation, intestinal permeability, immune activation, and altered serotonergic signaling^[31]. Rather than acting as isolated disease drivers, these microbial and metabolic alterations may converge on shared molecular pathways, including Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling, microglial activation, and stress-associated neuroendocrine dysregulation, thereby influencing both α-synuclein pathology and depressive symptomatology. However, whether distinct microbiota-metabolite signatures consistently differentiate DPD from NDPD remains unclear because of limited and heterogeneous evidence.

This review examines current evidence linking microbiota-metabolite dysregulation with depressive and non-depressive phenotypes in PD. We synthesize findings from microbiome, metabolomic, and experimental studies to evaluate how gut microbial metabolites may influence neuroinflammation, monoaminergic dysfunction, α-synuclein pathology, and gut-brain communication. We further discuss the mechanistic and therapeutic implications of microbiota-targeted interventions, including probiotics, prebiotics, dietary modulation, and metabolite-based strategies, while highlighting current limitations and key directions for future translational research.

The gut microbiota is a complex and dynamic microbial community shaped by host genetics, diet, aging, and environmental exposures^[32]. In recent years, its role as a key modulator of the gut-brain axis (GBA), a bidirectional network of neural, immune, and endocrine pathways, has become a focal point in understanding neurological disorders, including PD^[33]. A balanced gut microbiome supports intestinal barrier integrity, regulates immune function, and produces bioactive metabolites essential for systemic homeostasis^[34]. Conversely, gut dysbiosis characterized by overgrowth of harmful species and reduction of beneficial ones disrupts this equilibrium. These disruptions can compromise the gut barrier, resulting in a “leaky gut”, which allows microbial products such as lipopolysaccharides (LPS) to translocate into systemic circulation^[35,36]. Once in the bloodstream, LPS can trigger systemic inflammation and, crucially, promote neuroinflammation by activating microglia and astrocytes. This effect is amplified when the blood-brain barrier is compromised^[37]. This cascade of events positions gut dysbiosis as a critical upstream factor in the neuroinflammatory processes central to PD pathogenesis.

Studies specifically stratifying DPD and NDPD remain limited, and further heterogeneity arises from the fact that most available studies do not stratify patients according to disease stage or motor subtype. Early-stage PD is characterized predominantly by nigrostriatal dopaminergic dysfunction with relatively preserved gut microbiome diversity, whereas advanced disease is associated with more pronounced dysbiosis, greater intestinal barrier disruption, and broader monoaminergic involvement including serotonergic and noradrenergic systems, which may differentially influence vulnerability to depressive symptoms^[38]. The tremor-dominant subtype has generally been associated with a more benign disease course and slower progression compared with the PIGD subtype, which exhibits greater cognitive impairment, autonomic dysfunction, and potentially greater neuroimmune dysregulation^[39]. These differences suggest that microbial signatures and their functional consequences may vary substantially across disease stages and subtypes, further complicating efforts to define reproducible DPD-specific microbiota alterations. Consequently, much of the current understanding of microbial signatures in NDPD is derived from broader PD cohorts in which depressive status was either not assessed or not reported. Although this represents an important limitation of the existing literature, these studies provide an essential reference framework for evaluating microbiota alterations potentially associated with depressive phenotypes in PD.

Clinical studies have identified relatively reproducible alterations in the gut microbiota of patients with PD without comorbid depression, although considerable variability remains across cohorts and analytical approaches^[40,41]. At the family level, a meta-analysis by Shen et al. reported decreased abundance of Prevotellaceae, Lachnospiraceae, and Ruminococcaceae, alongside increased Bifidobacteriaceae, Lactobacillaceae, Verrucomicrobiaceae, and Christensenellaceae in PD cohorts^[42]. Genus-level alterations in Prevotella, Bacteroides, and Faecalibacterium have been described in individual case-control studies but did not reach significance in this meta-analytic synthesis^[42,43]. In parallel, several cohort studies have observed enrichment of Akkermansia, Lactobacillus, and Bifidobacterium in PD^[44]. The relative abundance of Enterobacteriaceae was positively associated with the severity of postural instability and gait difficulty (PIGD)^[45]. In contrast, Barichella et al. reported that decreased Lachnospiraceae and increased Lactobacillaceae and Christensenellaceae were linked to worse clinical profiles including cognitive impairment and gait disturbances^[46].

Constipated PD patients additionally exhibit increased relative abundances of Bifidobacteriales and Lactobacillales^[47,48]. The reduction in SCFA-producing taxa, including Roseburia and Faecalibacterium, is of particular mechanistic relevance, as it may reduce butyrate production, a metabolite that supports intestinal barrier integrity and exerts anti-inflammatory effects^[49,50]. Animal models of PD display analogous microbial alterations, and microbiota-targeted interventions can partially ameliorate motor dysfunctions^[51]. Notably, Bifidobacteriaceae abundance at the family level is reported as elevated in PD relative to healthy controls.

Depression, affecting a substantial subset of patients with PD, is associated with gut microbial alterations that partially overlap with, yet remain distinct from, those observed in non-depressive PD^[13,52]. Although both phenotypes share core features of dysbiosis, DPD appears to exhibit more pronounced alterations in microbial communities implicated in gut-brain and neuroimmune signaling pathways. Several studies have reported reductions in commensal and short-chain fatty acid-producing genera, including Prevotella, Romboutsia, and Roseburia, together with enrichment of pro-inflammatory taxa such as Deltaproteobacteria in DPD^[53]. Importantly, these microbial alterations correlate more strongly with depressive symptom severity than with overall motor or non-motor disease burden, indicating that these microbial alterations are associated with depressive symptoms rather than general PD progression [Figure 1].

Experimental evidence further supports the association between depressive phenotypes and gut dysbiosis in PD. In a rotenone-induced PD model with depression-like behavior, dysbiosis was characterized by increased Firmicutes and Proteobacteria together with decreased Bacteroidetes, Actinobacteria, Bacteroides, Alistipes, and Lactobacillus reuteri. Notably, these microbial alterations were partially reversed following prebiotic intervention^[54]. Direct comparative studies involving PD, DPD, and MDD further suggest that DPD may possess partially distinct microbial characteristics. One recent study reported higher relative abundance of Megamonas in MDD compared with PD and DPD, whereas Prevotella abundance was lower in MDD. In contrast, Escherichia-Shigella was more abundant in PD than in DPD and MDD. Within the DPD cohort, resilience scores positively correlated with Vibrio and Shewanella, whereas rumination scores positively correlated with Hydrogenophaga and Rhodococcus. These findings indicate that specific microbial taxa may be associated with distinct psychological dimensions of DPD. Collectively, the microbial signatures reported in DPD only partially overlap with those described in MDD, suggesting that while shared dysbiotic features exist, DPD possesses a partially distinct microbiota profile shaped by the concurrent neurodegenerative context of PD^[55].

Gut microbiota significantly influence the synthesis, metabolism, and signaling of several neurotransmitters involved in gut-brain communication, including dopamine (DA), serotonin (5-HT), γ-aminobutyric acid (GABA), noradrenaline (NA), acetylcholine, and histamine^[56]. Increasing evidence suggests that microbial dysbiosis can alter neurotransmitter homeostasis and contribute to neurological and neuropsychiatric disorders, including PD and depression^[57,58]. Certain microbial taxa can directly produce neuroactive compounds or regulate host neurotransmitter precursor availability^[56]. For instance, species of Lactobacilli and Bifidobacteria can produce GABA, while Escherichia coli influences 5-HT and DA, and Lactobacilli can additionally synthesize acetylcholine^[56,59]. Disruption of this microbial neurochemical balance may therefore influence central nervous system (CNS) function through the microbiota-gut-brain axis.

Neurotransmitter dysregulation appears particularly relevant in DPD. According to Braak staging, serotonergic nuclei may become affected during relatively early stages of PD progression. CSF studies have reported reduced concentrations of 5-hydroxyindoleacetic acid (5-HIAA), a major serotonin metabolite, in patients with DPD compared with NDPD^[26]. A more recent metabolomic study further demonstrated that dopaminergic and noradrenergic metabolites, including DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline, and 3-methoxy-4-hydroxyphenylglycol (MHPG), did not differ significantly between DPD and NDPD, whereas serotonin-related pathway alterations were more prominent^[25,60]. These findings support the hypothesis that depression in PD involves neurochemical disturbances extending beyond classical dopaminergic degeneration.

However, not all studies report consistent serotonergic alterations in DPD. Lian et al. (2020) measured CSF dopamine, serotonin, and norepinephrine concentrations in patients with DPD and NDPD and observed significantly lower dopamine levels in DPD, whereas serotonin and norepinephrine did not differ between groups^[61,62]. Moreover, depressive symptom severity negatively correlated only with dopamine levels, suggesting that dopaminergic dysfunction may also substantially contribute to depressive manifestations in PD.

Preclinical studies further support a role for the gut microbiota in modulating neurotransmitter pathways relevant to PD. Administration of specific probiotic strains has been shown to increase dopamine concentrations in frontal brain regions in rodent models, while in vitro studies demonstrated that Enterococcus faecium can convert levodopa into dopamine under gastrointestinal-like conditions^[63]. These findings suggest that microbiota-targeted interventions may influence neurotransmitter balance and potentially modulate both motor and depressive symptoms in PD.

Gut microbial metabolites are increasingly recognized as functional mediators linking intestinal dysbiosis with neuroinflammation, neurotransmitter imbalance, and neurodegeneration in PD^[64]. Beyond microbial taxonomic composition, microbiota-derived metabolites represent a critical functional layer through which the gut microbiome influences CNS physiology^[65]. A substantial proportion of circulating metabolites are either directly produced or extensively modified by the gut microbiota, including SCFAs, TMAO, BAs, and amino acid-derived metabolites, many of which exert important metabolic, immunological, and neuroactive effects^[66,67].

These microbiota-derived metabolites function as key mediators linking gut dysbiosis with neuroinflammation and gut-brain signaling in PD, as summarized in Figure 2.

Most currently available metabolomic evidence is derived from general PD cohorts without stratification according to depression status, whereas DPD-specific studies remain limited and methodologically heterogeneous. Nevertheless, emerging evidence suggests that although several metabolic disturbances are shared across PD phenotypes, DPD may involve additional alterations associated with serotonergic dysfunction, inflammatory signaling, and stress-related neuroendocrine pathways^[25]. The following sections summarize the principal metabolite-associated mechanisms implicated in PD and highlight pathways that may preferentially contribute to depressive symptomatology.

The gut microbiota is a major regulator of the microbiota-gut-brain axis and contributes to both motor and non-motor manifestations of PD. Through interconnected neural, immune, endocrine, and metabolic pathways, gut microbial dysbiosis influences intestinal permeability, neuroinflammation, neurotransmitter signaling, and α-synuclein pathology, thereby modulating disease progression and vulnerability to depressive symptoms. Increasing evidence suggests that microbiota-derived metabolites and microbiota-associated neurotransmitter pathways contribute differentially to DPD and NDPD, although direct comparative evidence remains limited. Most available studies are cross-sectional, involve relatively small cohorts, or investigate PD and depression independently rather than stratifying patients according to depressive status. Consequently, many proposed microbiota-metabolite mechanisms underlying depressive symptomatology in PD remain associative rather than causally established. The principal microbiota-gut-brain pathways implicated in DPD and NDPD are summarized in Figure 3.

Neurological dysfunction in DPD and NDPD reflects complex interactions between neurotransmitter disturbances, neuroinflammation, and gut microbiota dysbiosis operating through the microbiota-gut-brain axis. Although dopaminergic degeneration remains a core pathological feature of PD, accumulating evidence suggests that depressive symptoms in PD are more strongly associated with serotonergic and stress-related neurocircuitry alterations than with nigrostriatal dopamine loss alone. Neuroimaging studies demonstrate that patients with DPD exhibit greater reductions in striatal dopamine transporter availability compared with NDPD^[23,24]. Importantly, the extent of serotonergic and dopaminergic denervation in DPD appears to worsen with advancing disease stage^[108], suggesting that depressive vulnerability may increase as neurochemical deficits broaden beyond the nigrostriatal system^[109]. Structural neuroimaging studies further identified reduced grey matter density within the orbitofrontal cortex, anterior cingulate cortex, medial temporal regions, and parahippocampal gyrus in DPD independent of disease duration^[110]. Consistent with these observations, positron emission tomography using serotonin transporter ligands in drug-naïve PD patients demonstrated that depressive and anxiety symptoms correlate with serotonergic denervation within the anterior cingulate cortex, whereas apathy is associated with orbitofrontal serotonergic loss. Importantly, these alterations were not significantly associated with dopaminergic degeneration, supporting the concept that depressive symptoms in PD involve partially distinct serotonergic mechanisms.

The vagus nerve represents a major communication pathway linking the gut microbiota with central neurophysiological processes^[111]. Several gut microbial taxa, particularly Lactobacillus and Bifidobacterium species, possess glutamate decarboxylase activity and can produce GABA within the intestinal environment^[112,113]. Experimental administration of Lactobacillus rhamnosus JB-1 altered central GABA receptor expression and reduced corticosterone levels in mice^[114], effects abolished following vagotomy, thereby highlighting vagal signaling as a critical mediator of microbiota-gut-brain communication^[115].

Although GABA does not efficiently cross the blood-brain barrier, microbiota-derived GABA may indirectly modulate CNS function through vagal afferent signaling, immune pathways, HPA regulation, and microbiota-derived metabolites influencing hypothalamic GABAergic metabolism^[116].

Microbial dysbiosis associated with reduced diversity and depletion of beneficial taxa has also been linked to depressive vulnerability in PD^[117]. Reduced abundances of Faecalibacterium prausnitzii and Bifidobacterium infantis have been reported in both PD and depressive disorders, although studies directly comparing DPD and NDPD remain limited^[74,118]. Preclinical studies further demonstrated that B. infantis supplementation restores brainstem norepinephrine levels, normalizes immune responses, and attenuates depressive-like behaviors, supporting its potential psychobiotic relevance, although these findings have not yet been validated specifically in DPD cohorts^[119,120].

In NDPD, pathological progression is primarily characterized by nigrostriatal dopaminergic degeneration and α-synuclein aggregation^[121]. Gut dysbiosis-associated depletion of SCFA-producing bacteria may impair intestinal barrier integrity, promoting a “leaky gut” state and facilitating local α-synuclein accumulation within the ENS^[122]. The presence of Lewy body pathology in enteric neurons further supports the hypothesis that α-synuclein pathology may originate in the gut and subsequently propagate to the CNS through vagal pathways^[120,123]. Altered GABAergic neurotransmission may additionally contribute to axial motor dysfunction in PD, potentially exacerbated by reduced microbial GABA production^[124,125].

Gut microbial metabolites also influence neurotrophic signaling pathways relevant to both DPD and NDPD. Butyrate functions as a histone deacetylase inhibitor capable of regulating brain-derived neurotrophic factor (BDNF) transcription through epigenetic mechanisms^[126]. Reduced butyrate availability in PD may therefore impair histone acetylation at the BDNF promoter, resulting in decreased neuroplasticity. Consistent with this mechanism, serum BDNF concentrations are significantly reduced in PD and further decreased in DPD, where lower BDNF levels correlate with greater depressive symptom severity^[127]. These findings support the concept that depressive symptoms in PD reflect biologically distinct neurochemical and microbiota-associated mechanisms rather than solely psychological responses to motor disability. However, longitudinal and depression-stratified studies integrating microbiome, metabolomic, and neuroimaging analyses remain necessary to clarify the causal interactions linking gut dysbiosis with neurological dysfunction in DPD and NDPD.

The neuroendocrine system, particularly the HPA, is a central component of the microbiota-gut-brain axis regulating stress responses, mood, intestinal permeability, and immune homeostasis^[128]. In PD, chronic stress and HPA axis dysregulation are associated with elevated cortisol levels, impaired negative feedback regulation, altered gut motility, and disruption of intestinal barrier integrity^[129,130]. Increased intestinal permeability facilitates systemic translocation of microbial products such as LPS^[131,132], thereby promoting peripheral and central inflammatory responses^[133].

Evidence suggests that HPA axis dysfunction is more pronounced in DPD than in NDPD. Although Lewy body pathology has been identified within the adrenal glands and peripheral autonomic nervous system, its direct contribution to adrenal dysfunction remains unclear^[134,135]. Nevertheless, progressive neuroendocrine dysregulation is thought to contribute substantially to the high prevalence of depressive symptoms in PD.

Gut dysbiosis further amplifies HPA axis activation through immune-mediated mechanisms^[129,136]. As discussed in Section 3.3, translocated LPS activates TLR4, inducing NF-κB-dependent production of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α. These cytokines influence hypothalamic corticotropin-releasing hormone (CRH) secretion, stimulating adrenocorticotropic hormone (ACTH) release and adrenal cortisol production, thereby sustaining HPA axis hyperactivation and stress responsiveness^[129,137]. Microbiota-derived metabolites also participate directly in neuroendocrine regulation. Reduced SCFA concentrations, particularly butyrate, have been associated with depressive symptoms in PD^[53,138]. Altered BA profiles linked to specific microbial shifts, including increased Verrucomicrobia abundance, have likewise been reported in depression-associated phenotypes^[139]. In addition, microbiota-mediated modulation of GABA signaling contributes to HPA axis feedback regulation and stress resilience, with Bifidobacterium species implicated in these effects^[129]. Emerging evidence further suggests that gut microbial alterations may influence ghrelin and related neuropeptides involved in appetite regulation, stress adaptation, and neuroprotection^[140].

In NDPD, neuroendocrine disturbances are also evident but appear less pronounced. Reduced abundance of SCFA-producing bacteria, including Prevotella and Faecalibacterium, may impair signaling pathways linked to neuroprotective peptides such as growth hormone-releasing peptide (GHRP)^[42,141], potentially compromising dopaminergic neuron survival and contributing to disease progression^[141,142]. These findings indicate that although neuroendocrine dysregulation occurs across PD phenotypes, DPD is characterized by greater HPA axis activation, amplified inflammatory signaling, and impaired inhibitory feedback mechanisms, which together may contribute to increased stress vulnerability and depressive symptomatology.

Immune-mediated neuroinflammation is a major mechanism linking gut dysbiosis with both neurodegenerative and depressive manifestations of PD^[143]. However, direct comparative evidence between DPD and NDPD remains limited, as most available studies are cross-sectional or preclinical in nature. Consequently, the extent to which inflammatory alterations specifically distinguish DPD from NDPD is not yet fully established.

Clinical studies nevertheless indicate that DPD is associated with greater inflammatory activation than NDPD^[144]. CSF TNF-α concentrations are significantly elevated in DPD and correlate positively with depression severity while correlating negatively with dopamine levels, suggesting a link between inflammatory activation and dopaminergic dysfunction in depressive symptomatology^[62]. Similarly, increased CSF IL-6, IL-8, and IL-17 levels have been associated with depression and anxiety in newly diagnosed PD cohorts^[145]. A systematic review further identified IL-17A as the inflammatory marker most consistently associated with depressive symptoms in PD, whereas associations involving C-reactive protein (CRP), IL-10, TNF-α, and IL-6 were more heterogeneous and context-dependent^[146].

These findings align with the cytokine hypothesis of depression, whereby pro-inflammatory cytokines alter monoaminergic neurotransmission by diverting tryptophan metabolism from serotonin synthesis toward the KP, thereby increasing neurotoxic metabolites such as QA while reducing neuroprotective kynurenines^[62,147]. This mechanism provides a plausible link between immune activation and depressive symptomatology in PD.

Gut dysbiosis may further amplify these inflammatory pathways through disruption of intestinal barrier integrity. Increased gut permeability facilitates systemic translocation of LPS derived from Gram-negative bacteria. LPS activates TLR4, triggering myeloid differentiation primary response 88 (MyD88)- and TIR-domain-containing adapter-inducing interferon-β (TRIF)-dependent signaling cascades that converge on NF-κB activation and the subsequent transcription of pro-inflammatory cytokines including TNF-α and IL-1β^[148,149]. These inflammatory pathways contribute to systemic immune activation, blood-brain barrier disruption, and microglial activation within the CNS^[143,150]. Activated microglia release reactive oxygen species and pro-inflammatory mediators that promote dopaminergic neuronal injury within the substantia nigra, thereby exacerbating both motor dysfunction and depressive manifestations in PD^[151,152].

In contrast, beneficial gut microbes and their metabolites exert anti-inflammatory effects. SCFA-producing taxa, including Faecalibacterium, reduce systemic inflammation, whereas Bifidobacterium and lactic acid bacteria produce neuroprotective indole derivatives capable of attenuating microglial activation and inflammatory signaling^[143]. Inflammatory dysbiosis may additionally facilitate α-synuclein pathology. A pro-inflammatory intestinal environment promotes α-synuclein misfolding and aggregation within the ENS, potentially enabling prion-like propagation to the brain via the vagus nerve^[117,153]. Furthermore, microbiota-associated alterations in GABA signaling may influence microglial activation states within PD-relevant brain regions, including the substantia nigra and striatum, thereby accelerating neurodegeneration and worsening depressive symptomatology^[154].

Overall, current evidence supports immune-mediated neuroinflammation as a central mechanistic interface linking gut dysbiosis with PD progression and depressive symptoms, as illustrated in Figure 3. However, longitudinal and depression-stratified studies integrating microbiome, metabolomic, and immune profiling remain necessary to determine whether these inflammatory pathways represent causal drivers or secondary consequences of DPD.

Increasing evidence suggests that gut dysbiosis contributes to both motor and depressive manifestations in PD through disruption of the microbiota-gut-brain axis. Altered microbial composition and metabolite production influence neuroinflammation, neurotransmitter homeostasis, intestinal barrier integrity, and neuroendocrine signaling, thereby contributing to depressive symptoms in DPD. Consequently, microbiota-targeted interventions including probiotics, prebiotics, dietary modulation, and faecal microbiota transplantation (FMT) have emerged as potential adjunctive therapeutic strategies [Figure 4]. Unlike conventional antidepressants, which primarily target monoaminergic neurotransmission and often demonstrate variable efficacy in PD patients, microbiota-directed therapies may exert broader effects by simultaneously modulating inflammatory, metabolic, and neuroendocrine pathways.

Probiotics are live microorganisms that confer health benefits when administered in adequate amounts and are increasingly investigated for their ability to restore microbial homeostasis and regulate microbiota-gut-brain axis signaling^[155,156]. Among the most extensively studied probiotic genera in depression-related disorders are Lactobacillus and Bifidobacterium, both of which influence neurotransmitter synthesis, immune regulation, and intestinal barrier integrity^[157].

Several probiotic strains have demonstrated antidepressant-like effects in experimental and clinical studies. Bifidobacterium breve CCFM1025, Bifidobacterium longum, Lactobacillus rhamnosus^[158,159], and Lactobacillus helveticus have been associated with reduced depressive symptoms, improved stress resilience, and modulation of serotonergic signaling pathways^[160,161]. Experimental evidence indicates that Bifidobacterium species may enhance tryptophan metabolism and increase production of serotonin-related metabolites, whereas Lactobacillus species strengthen epithelial barrier integrity, reduce inflammatory cytokine production, and modulate BDNF signaling^[162]. In particular, Lactobacillus rhamnosus has been shown to influence GABA receptor expression through vagus nerve-dependent mechanisms, supporting its relevance to mood regulation within the microbiota-gut-brain axis^[163]. Similarly, Bifidobacterium strains have been shown to enhance serotonin biosynthesis through tryptophan metabolism and normalise HPA axis hyperactivity in patients with MDD^[164,165], suggesting potentially relevant mechanisms that have not yet been directly validated in PD populations. Whether these findings translate to DPD warrants investigation in PD-specific clinical trials.

Recent interest has also focused on next-generation probiotics, including Akkermansia muciniphila and Faecalibacterium prausnitzii, owing to their anti-inflammatory and SCFA-producing properties^[119,166]. Preclinical studies suggest that these taxa may attenuate neuroinflammation, improve intestinal barrier integrity, and reduce depressive-like behaviors. Similarly, butyrate-producing organisms such as Butyricicoccus pullicaecorum may exert neuroprotective effects through epigenetic and immunomodulatory mechanisms^[167,168].

A 3-month randomized controlled trial in 82 PD patients receiving conventional medication. Adjuvant Bifidobacterium animalis subsp. Lactis ProbioM8 (3 × 10¹⁰ CFU/day) significantly improved sleep quality, alleviated anxiety, and improved gastrointestinal symptoms, along with increased serum acetic acid and dopamine levels^[169].

Despite these promising findings, several limitations remain. Probiotic efficacy appears highly strain-specific, and therapeutic outcomes vary substantially according to dosage, treatment duration, disease stage, and host microbial composition. Most available studies involve relatively small cohorts and short follow-up periods, limiting conclusions regarding long-term efficacy and safety. As shown in Table 1, Dosage ranges studied in clinical trials have varied considerably, typically between 10⁸ and 10¹¹ colony-forming units (CFU) per day, with treatment durations ranging from four to twelve weeks in most published studies^[170]. Regarding safety, short-term probiotic use appears generally well tolerated in most PD patients, with mild gastrointestinal side effects such as bloating and flatulence being the most commonly reported adverse events. However, potential risks in immunocompromised individuals and theoretical concerns regarding bacteremia with certain strains, particularly in patients with compromised intestinal barrier integrity as is common in PD, warrant careful safety monitoring in future trials.

Prebiotics are non-digestible dietary substrates, including fructooligosaccharides (FOS), galactooligosaccharides (GOS), and inulin, that selectively promote the growth of beneficial gut microbiota and enhance microbial metabolite production^[171,172]. Through fermentation by gut bacteria, prebiotics increase SCFA production, improve intestinal barrier integrity, and reduce systemic inflammation, mechanisms that may be particularly relevant to depressive symptoms in PD.

Experimental studies demonstrate that prebiotic supplementation can partially reverse gut dysbiosis and improve neurobehavioral outcomes in PD models. In a rotenone-induced PD model with depressive-like behaviors, administration of FOS and GOS reduced the abundance of Proteobacteria and Helicobacter hepaticus while increasing beneficial taxa including Bacteroides, Alistipes, and Lactobacillus reuteri. These microbial changes were associated with increased butyrate production, restoration of serotonin levels, attenuation of neuroinflammation, and improvement in depressive-like behaviors^[54].

Beyond classical fibres, several dietary phytochemicals exhibit prebiotic-like effects. Polyphenols such as quercetin, chlorogenic acid, and resveratrol selectively promote the growth of Bifidobacterium and Lactobacillus species while suppressing pathogenic taxa^[173,174]. Medicinal plant-derived compounds, including ginsenosides and polysaccharides, have also demonstrated antidepressant-like and neuroprotective effects through modulation of gut microbial composition and neurotransmitter regulation^[175]. Dietary patterns rich in fibre, polyphenols, and omega-3 fatty acids, particularly Mediterranean-style diets, may further enhance microbial diversity, increase SCFA production, and reduce oxidative stress associated with α-synuclein pathology^[176,177].

Similarly, ketogenic diets have shown beneficial effects in experimental PD models through modulation of inflammatory pathways and microbial metabolism^[178]. Prebiotic doses used in experimental studies have generally ranged from 5 to 20 grams per day for fibres such as FOS and inulin, summarized in Table 1^{[179, 180]}, although optimal dosing for PD populations has not been systematically investigated. Nevertheless, the translational relevance of prebiotics in DPD remains incompletely established. Human interventional studies remain limited, and substantial variability exists regarding fibre composition, dosage, and treatment duration. Moreover, gut microbial metabolism may alter the bioavailability and efficacy of PD medications, including levodopa, complicating interpretation of therapeutic outcomes. Additional longitudinal and mechanistic studies are therefore required to define optimal dietary strategies and identify microbial biomarkers predictive of treatment responsiveness.

FMT involves the transfer of faecal microbiota from healthy donors to recipients with the aim of restoring intestinal microbial homeostasis^[181,182]. Because gut dysbiosis is increasingly implicated in PD pathogenesis and depression-related neuroinflammation, FMT has emerged as a potential experimental therapeutic strategy for DPD.

Preclinical studies support a causal relationship between gut microbiota composition and depressive phenotypes. Transfer of microbiota from depressed individuals into germ-free or antibiotic-treated rodents induces depressive-like behaviors, altered tryptophan metabolism, and neurochemical abnormalities in recipient animals^[183,184]. In PD models, FMT has been shown to improve intestinal dysbiosis, suppress TLR4/TANK-binding kinase 1 (TBK1)/NF-κB/TNF-α inflammatory signaling, reduce neuroinflammation, and enhance striatal dopamine and serotonin levels^[185,186]. The most rigorous clinical evidence to date comes from a double-blind, placebo-controlled randomized controlled trial (RCT) by Scheperjans et al. (2024), which enrolled 47 patients with PD^[181]. The primary outcome did not differ significantly between FMT and placebo groups, and secondary outcomes showed stronger improvement in the placebo arm. Gastrointestinal adverse events were significantly more frequent in the FMT group (53% vs. 7%). The authors concluded that FMT was safe but did not offer clinically meaningful improvements in PD. Earlier preliminary observations, including the first documented FMT case in PD, which reported improvement in constipation and partial reduction in tremor severity, and small-scale pilot studies reporting improvements in NMS at two months post-FMT^[187], should therefore be interpreted as hypothesis-generating observations only. Post-FMT microbial alterations in these earlier studies frequently included enrichment of SCFA-producing taxa such as Blautia and members of Lachnospiraceae^[188,189], but whether these microbial changes translate to sustained clinical benefit remains unestablished in light of the negative RCT findings.

However, despite promising preliminary findings, FMT remains an experimental intervention with significant unresolved challenges. Therapeutic outcomes may vary substantially according to donor microbial composition, transplantation protocols, route of administration, and frequency of treatment. Concerns also remain regarding long-term microbial engraftment, safety, and the potential transmission of opportunistic pathogens. Reported adverse events in PD-related FMT studies have included transient gastrointestinal discomfort, fever, and, in rare cases, serious infections, underscoring the necessity of rigorous donor screening protocols. Furthermore, the optimal route of administration, whether via colonoscopic infusion, nasojejunal tube, or oral capsule delivery, the required frequency of transplantation, and the minimum effective donor microbial diversity threshold remain undefined for PD populations. Long-term follow-up data beyond twelve months are currently absent from the literature, making it impossible to assess whether initial clinical improvements are sustained or whether repeated transplantation is necessary to maintain therapeutic effects. Moreover, current clinical studies are limited by small sample sizes, short follow-up durations, and lack of standardized depression-specific outcome measures. Large, rigorously controlled, longitudinal clinical trials are therefore necessary before FMT can be considered a clinically applicable therapy for DPD.

Although an increasing body of evidence has established a link between gut dysbiosis and both the motor and depression-related manifestations of PD, numerous challenges still impede the precision and translational significance of current research findings. Substantial clinical and microbial heterogeneity, arising from disparities in genetics, disease stage, motor subtypes, medication exposures, and baseline microbiome composition, complicates efforts to define reproducible microbial signatures across cohorts. This variability is further magnified by methodological inconsistencies, such as differences in sample handling, sequencing platforms, analytic pipelines, and the clinical criteria used to diagnose depression. A particularly significant shortcoming is that few studies directly compare gut microbial profiles between depressed and non-depressed PD patients, limiting the field’s ability to identify depression-specific alterations. Furthermore, existing studies rarely stratify patients by disease stage or motor subtype, such as tremor-dominant versus PIGD subtypes, limiting understanding of how microbial alterations evolve across the disease continuum and whether distinct dysbiosis signatures characterize early versus advanced PD with or without depression.

Moreover, it remains arduous to disentangle the influence of confounding factors, including diet, lifestyle, geography, aging, and the use of antidepressants or dopaminergic therapies, from disease-driven microbial changes. The current exclusive focus on bacterial taxa also leaves the contributions of other microbial kingdoms, such as fungi and viruses, unexamined. These kingdoms may play significant roles in gut-brain signaling. Addressing these limitations necessitates a coordinated transition toward more rigorous and integrative research strategies. Longitudinal human studies tracking microbial trajectories from the prodromal phase through advanced disease are essential for establishing temporality and determining whether dysbiosis is a driver or a consequence of depressive symptoms in PD.

Mechanistic understanding will be enhanced by multi-omics frameworks that combine metagenomics, metabolomics, and transcriptomics with neuroimaging and immunophenotyping to delineate how specific gut-derived metabolites and neuroactive compounds shape neural circuits, mood regulation, and neuroendocrine-immune interactions. Parallel efforts to identify robust microbial or metabolic biomarkers capable of stratifying patients by depression risk or predicting therapeutic response will be crucial for advancing precision medicine. Progress in personalized therapy will rely on customizing probiotics, prebiotics, and FMT protocols to individual genetic backgrounds, disease stages, medication profiles, and microbial baselines. Ultimately, large-scale, randomized controlled trials with long-term follow-up are needed to determine the safety, durability, and clinical value of microbiota-targeted interventions for depression in PD and to transform the potential of gut-brain research into effective, individualized care.

Gut microbiota dysbiosis and the consequent alterations in metabolites are central modulators in the pathophysiology of DPD and NDPD. These changes influence disease progression through intricate, overlapping mechanisms involving neurotransmitter metabolism, neuroinflammation, and neuroendocrine signaling. Distinct microbial signatures and metabolite profiles, including SCFAs, tryptophan derivatives, and TMAO, interact with key signaling pathways such as the TLR4/NF-κB pathway, GABAergic circuits, and the HPA axis, to shape divergent motor and mood-related phenotypes. Elucidating these gut-brain interactions is crucial for understanding the shared and distinct pathophysiological underpinnings of DPD and PD-ND and for identifying novel targets for microbiota-directed interventions. Future longitudinal, mechanistic, and interventional studies are essential to translating these insights into effective precision therapies that address both motor dysfunction and depressive comorbidities in PD.