The Enteric Nervous System as a Mediator of Microbiota‐Gut‐Brain Interactions in Parkinson's Disease

Parkinson's disease (PD) is a neurodegenerative disorder traditionally defined by its motor symptoms. However, it has become increasingly evident that PD is not confined to the central nervous system (CNS). Patients frequently experience a broad spectrum of non‐motor manifestations, including sleep disturbances, olfactory deficits, cardiovascular abnormalities, and, most prominently, gastrointestinal dysfunction (Schapira et al. 2017). Gastrointestinal symptoms such as constipation, delayed gastric emptying, and dysphagia affect more than 80% of individuals with PD and often precede motor signs by years or even decades (Warnecke et al. 2022). These symptoms not only diminish quality of life but also provide valuable insight into early disease processes that extend beyond the brain. Furthermore, pathological findings, such as the presence of α‐synuclein protein aggregates, highlight the gastrointestinal tract as a potential contributor to disease initiation and progression, suggesting that the gut plays a central role in PD (Warnecke et al. 2022).

Over the past decade, the gut microbiota has been the focus of intense investigation, with numerous studies reporting compositional and functional alterations in patients with PD. These observations have generated considerable interest in the possibility of a PD‐specific microbial "signature" and have driven efforts to elucidate how microbial metabolites and immune modulation might influence neurodegeneration. Despite these advances, however, the microbiota‐centered perspective faces significant challenges. Findings across studies have been inconsistent, and no robust or reproducible microbial signature has yet emerged (Santos et al. 2025). Moreover, attempts to manipulate the microbiota therapeutically have yielded limited and variable outcomes, underscoring the complexity of host–microbe interactions and suggesting that a narrow focus on the microbiota alone may not capture the full spectrum of PD pathophysiology.

Within this broader framework, the enteric nervous system (ENS) has received comparatively little attention, despite being the intrinsic neural network that regulates gut function and communicates bidirectionally with both the microbiota and the CNS. Anatomically, the ENS is organized into two major plexuses—the myenteric plexus, located between the longitudinal and circular muscle layers, and the submucosal plexus, situated within the submucosa—and comprises diverse neuronal subtypes and enteric glial cells. Together, these interconnected neuroglial networks autonomously coordinate motility, secretion, epithelial barrier regulation, and local blood flow, while engaging in close neuroimmune interactions within the intestinal wall. Evidence indicates that the ENS is profoundly altered in PD: enteric neurons and glial cells exhibit pathological changes, including α‐synuclein protein accumulation, disrupted neurochemical signaling, impaired barrier regulation, and neuroinflammation (Montanari et al. 2023). These alterations not only contribute to gastrointestinal dysfunction but may also facilitate disease propagation along the gut–brain axis (Warnecke et al. 2022). Importantly, the ENS serves as a physiological interface through which the gut microbiota exerts many of its effects on host physiology, positioning it as a critical mediator rather than a passive target.

We argue that advancing the understanding of PD requires a shift in focus from the microbiota in isolation to the interactions among the microbiota, the ENS, and the host. The ENS integrates microbial, immune, and neural signals, shaping both local gut physiology and systemic brain–gut communication. Neglecting this dimension risks oversimplifying the pathogenesis of PD and overlooking therapeutic opportunities. In this review, we examine current knowledge of ENS alterations in PD and critically evaluate their intersection with changes in the gut microbiota. We propose that a comprehensive exploration of this interplay is essential to unraveling the role of the gut–brain axis in PD and to identifying strategies capable of addressing both motor and non‐motor aspects of the disease.

Over the past four decades, it has become increasingly evident that PD is not confined to the CNS but also affects the peripheral nervous system, including the gastrointestinal tract. As previously noted, gastrointestinal dysfunction in PD not only compromises patients' quality of life but may also participate in the earliest stages of the disorder (Warnecke et al. 2022). At present, three major lines of inquiry guide gastrointestinal‐related PD research: (1) elucidating gastrointestinal pathology to improve symptom management; (2) identifying metabolite biomarkers, given the accessibility of the gut; and (3) investigating the contribution of the gut to early pathogenic mechanisms of PD (Shannon and vanden Berghe 2018).

In this context, the ENS, the division of the autonomic nervous system located in the gut, has become a key focus in PD research. Numerous alterations have been reported in the ENS of both PD patients and animal models, including changes that precede the onset of motor symptoms. Biochemical and functional abnormalities in enteric neurons and enteric glial cells have been directly linked to gastrointestinal dysmotility, increased intestinal epithelial barrier permeability, neuroinflammation, and disease progression in PD (Montalbán‐Rodríguez et al. 2024; Montanari et al. 2023; Shannon and vanden Berghe 2018). In this section, we provide an overview of the main ENS alterations reported in PD.

The first studies connecting the ENS to PD were published in the 1980s, when Lewy neurites were identified in enteric neurons of PD patients (Wakabayashi 1989; Wakabayashi et al. 1990). Since these early reports, numerous studies have described Lewy neurites in enteric neurons from PD gastrointestinal biopsies and animal models; however, their exact role in PD pathophysiology remains unclear. The Braak hypothesis, proposed in 2003, suggests that the ENS and the olfactory bulb serve as initial sites of α‐synuclein protein aggregation, the main component of Lewy bodies and neurites, with subsequent propagation of pathology to the CNS via the vagus nerve (Braak et al. 2003). Although α‐synuclein transport between neurons has been demonstrated and gut‐to‐brain spread of α‐synuclein pathology has been documented in preclinical models, the underlying mechanisms and their relevance in human PD remain elusive (Bieri et al. 2018; Chen and Mor 2023; Uemura et al. 2021).

While Lewy bodies in the CNS are associated with neurodegeneration, evidence for enteric neuronal loss in PD is inconclusive, and no consensus exists on whether the ENS undergoes a true neurodegenerative process (O'Day et al. 2022). Age‐related enteric neuronal loss further complicates the distinction between PD‐specific changes and normal aging (Cirillo et al. 2013; Saffrey 2013). Moreover, most patient biopsy samples examine only the submucosal plexus, leaving the myenteric plexus, where most enteric neurons reside, largely unexplored. Lebouvier et al. reported a modest reduction in neurofilament M‐positive submucosal neurons in the colon, whereas other studies found no differences in duodenal and colonic neuron counts in PD subjects (Corbillé et al. 2014; Desmet et al. 2017; Lebouvier et al. 2008). Although full‐thickness gut analysis is feasible in rodent models, variability among PD models hinders definitive conclusions regarding enteric neurodegeneration (Han et al. 2025; Jiang et al. 2023; Palanisamy et al. 2022).

Conversely, multiple studies have documented changes in the chemical profile of the ENS that correlate with PD‐related gastrointestinal symptoms. Schaffernicht et al. showed that in a rotenone‐based PD animal model, excitatory cholinergic input in the ENS is reduced, leading to diminished gastrointestinal contractility and constipation before motor symptoms emerge (Schaffernicht et al. 2021). In patients with PD and chronic constipation, submucosal colonic neurons downregulate vasoactive intestinal peptide (VIP) without neuronal loss, suggesting that constipation may arise from dysfunction rather than depletion of VIP‐ergic secretomotor neurons (Chalazonitis and Rao 2018; Giancola et al. 2017). Altered dopaminergic and nitrergic signaling has also been reported and linked to PD symptoms (Anderson et al. 2007; Blandini et al. 2009; Coletto et al. 2021). A comprehensive characterization of the specific enteric neuronal subpopulations involved, and whether they undergo cell death or functional and phenotypic shifts, remains to be achieved.

Enteric glial cells, which are essential for epithelial integrity, neurotransmission, and immune regulation, have increasingly been recognized as key contributors to PD‐related gut dysfunction (Thomasi et al. 2023). In the gut, glial cells represent the main ENS component mediating immune–nervous system crosstalk, thereby contributing to neuroinflammation—a hallmark of many neurodegenerative diseases (Seguella and Gulbransen 2021). This process, characterized by persistent immune activation and subsequent neuronal damage, is considered a crucial pathological mechanism where the ENS plays a central role. Multiple studies have documented a reactive glial state in PD, marked by increased glial fibrillary acidic protein (GFAP) expression and changes in glial morphology and localization, which are linked to dysmotility, tissue damage, heightened epithelial barrier permeability, and dysbiosis (Emmi et al. 2023; Thomasi et al. 2023; Thomasi et al. 2024; Thomasi et al. 2022). These features collectively contribute to gut dysfunction in PD, though the specific relationships between them, such as the connection between glial activation and dysbiosis, need further research. The pathophysiological ENS changes discussed here, particularly those occurring in the early stages of PD, have significant clinical implications because gut tissue is accessible through endoscopy and colonoscopy. Indeed, intensive research on the ENS aims to establish an early diagnostic biomarker for PD. Among potential ENS biomarkers, Lewy pathology in enteric neurons is notable, as it can be detected in colonic biopsies up to 20 years before the onset of motor symptoms. α‐Synuclein accumulation appears to follow a rostrocaudal gradient, with temporal progression but a static spatial distribution over time (Shin et al. 2024). Glial markers such as GFAP have also been proposed as potential biomarkers, given that neuroinflammation is a hallmark of early gastrointestinal dysfunction in PD (Clairembault et al. 2014; Devos et al. 2013). However, the feasibility of using colonic biopsies for early PD diagnosis still faces many challenges. Current studies present several limitations, including the lack of a standardized comprehensive protocol, uncertainty regarding the most suitable gut region for sampling, sensitivity issues, and heterogeneity across populations (Pouclet et al. 2012; Schröder et al. 2025).

ENS involvement in PD has been extensively explored, yet the exact mechanisms underlying gastrointestinal symptoms and the spread of α‐synuclein pathology to the CNS remain unresolved. Methodological heterogeneity across studies complicates the interpretation of the ENS's role in PD. A review by Shannon and Van der Berghe highlights several outstanding questions, including how the ENS interacts with the gut microbiota, another critical player in PD pathophysiology, as discussed above (Shannon and vanden Berghe 2018). Despite extensive research on both the ENS and the microbiota, the ways in which their interaction contributes to PD development are still poorly understood.

Beyond the ENS, the gut microbiota has also emerged as a critical factor in PD pathophysiology. The intestinal microbial composition is now a central focus in studies investigating the disease. Over the past decade, a consistent association has been established between PD symptomatology and dysbiotic gut microbiota (del Rey et al. 2018; Qian et al. 2018). Clinical investigations across diverse populations worldwide (Nuzum et al. 2020; Mehanna et al. 2023; Proano et al. 2023; Zhang, Tang, and Guo 2023) have linked alterations in bacterial phyla, families, and genera to the multiple phenotypes of the disease, as well as onset time, duration, and disease state (Cilia et al. 2021; Hill‐Burns et al. 2017; Barichella et al. 2019). Compared with healthy individuals, patients with PD show an increased relative abundance of bacteria associated with inflammatory processes, along with a decrease in bacteria that support intestinal and systemic homeostasis (Ran et al. 2025). However, defining a specific gut microbial signature for PD remains challenging. A recent study reported elevated levels of Streptococcus mutans and its metabolite imidazole propionate in patients, identifying them as drivers of PD‐related features in mice, such as nigrostriatal dopaminergic degeneration and motor impairment. Nonetheless, further investigation is required to clarify how elevated levels of imidazole propionate contribute to PD pathophysiology (Park et al. 2025). The difficulty in defining a PD‐associated microbial signature stems from numerous individual and methodological limitations, including ethnic differences, sex‐based variation, dietary diversity, comorbidities, small sample sizes, varying analytical methods, a lack of longitudinal data, and insufficient exploration of bacterial interactions (Heravi et al. 2023).

More than the fluctuating presence of specific microbial taxa, the shift in metabolic products and bioactive molecules derived from intestinal bacteria provides the most meaningful insight into PD (Ran et al. 2025) (Figure 1). In line with this perspective, several studies have consistently reported increased levels of Enterobacteriaceae and Akkermansia, taxa strongly linked to pro‐inflammatory and bioactive molecular changes, in fecal samples from patients with severe postural instability, gait difficulties, and exacerbated non‐motor symptoms (Scheperjans et al. 2015; Heintz‐Buschart et al. 2018; Zhang, Tang, and Guo 2023). Notably, repeated oral exposure to curli‐producing bacteria led to increased neuronal α‐syn deposition in both the gut and brain of aged rats (Cheng et al. 2023; Kustrimovic et al. 2024). In addition to this, the elevated abundance of these Gram‐negative, lipopolysaccharide (LPS)‐producing bacteria contributes to both intestinal and systemic inflammation and oxidative stress (Engler et al. 2009; Scheperjans et al. 2015) (Figure 1). For instance, Akkermansia muciniphila has been shown to enhance mitochondrial Ca²⁺ uptake in enterocyte cultures, resulting in mitochondrial dysfunction, increased reactive oxygen species (ROS) production, and pathological α‐synuclein aggregation in vitro (Amorim Neto et al. 2022). This epithelial injury aligns with the increased intestinal epithelial permeability observed in colonic tissue samples from PD patients (Clairembault et al. 2015). Compelling evidence suggest that under such conditions, LPS may translocate into intestinal tissue and interact with the complex enteric neuroglial network via Toll‐like receptor 4 (TLR4), which is abundantly expressed in the ENS of the distal colon in murine models and in the human ileum (Barajon et al. 2009; Boller and Felix 2009). Beyond local effects, LPS can enter the bloodstream, cross the compromised blood–brain barrier, and activate TLR4 on microglial cells (Clairembault et al. 2015; Perez‐Pardo et al. 2019; Blasco et al. 2020). It is widely recognized this activation induces the production of pro‐inflammatory cytokines and oxidative stress both locally and systemically, thereby promoting neuroinflammation, neuronal death, cognitive decline, and reduced intestinal motility, as demonstrated in PD mouse models (Houser and Tansey 2017; Perez‐Pardo et al. 2019; Zhao et al. 2021).

In parallel with these inflammatory processes, several studies have reported a reduction in the abundance of the family Prevotellaceae in both fecal and colonic mucosal samples from PD patients, which is associated with decreased levels of mucin, short‐chain fatty acids (SCFAs), and neuroprotective factors (Keshavarzian et al. 2015; Scheperjans et al. 2015; Unger et al. 2016; Bedarf et al. 2017; Petrov et al. 2017; Lin et al. 2019; Zhang, Xu, et al. 2023). A marked decline in this bacterial family has also been correlated with reduced circulating levels of the hormone ghrelin during PD progression. Ghrelin influences mitochondrial respiration, modulates ROS levels, inhibits α‐synuclein accumulation, and regulates dopaminergic neuron function in the substantia nigra and striatum in PD animal models (Andrews et al. 2005; Conti et al. 2005; Andrews et al. 2009; Bayliss and Andrews 2013; Lin et al. 2019; Zhang, Ye, et al. 2023).

Among the most relevant microbial metabolites are the SCFAs, central mediators of gut–brain communication and immune regulation. In fecal samples from PD patients, their reduced availability has been consistently linked to the pronounced loss of SCFA‐producing bacteria, particularly members of the Lachnospiraceae family (Unger et al. 2016; Tan et al. 2021; Chen et al. 2022; Voigt et al. 2022; Yang, Ai, et al. 2022). Low levels of acetate, propionate, and butyrate can drive metabolic alterations, as the oxidation of these metabolites is estimated to account for approximately 8% of total daily energy expenditure in humans (Astbury and Corfe 2012; Blaak et al. 2020; Elford et al. 2024). Moreover, butyrate exerts a dual influence: it modulates the peripheral immune system, thereby indirectly affecting the CNS, and it can also act directly on the CNS, despite being largely metabolized in the periphery (Filiano et al. 2015; Pierre and Pellerin 2005; Kekuda et al. 2013). In the gut, butyrate additionally stimulates the secretion of serotonin, glucagon‐like peptide‐1 (GLP‐1), peptide YY (PYY), insulin, and amylin in the gastrointestinal tract. The release of these molecules can activate the vagus nerve and initiate neuroendocrine signaling pathways (Fukumoto et al. 2003; Cryan et al. 2019). There is strong evidence that reduced fecal butyrate levels have been associated with worsened symptoms, including postural instability, gait disturbances, cognitive impairment, motor dysfunction, and depressive symptoms (Tan et al. 2021; Chen et al. 2022; Wu et al. 2022). In vitro studies have demonstrated that sodium butyrate (NaB), for example, exerts neuroprotective effects against α‐synuclein aggregation (Chen et al. 2025; Getachew et al. 2020; Paiva et al. 2017; Sadeghloo et al. 2025; Zhang et al. 2022). However, Zhang and colleagues reported that acetate and propionate did not protect cells from rotenone‐induced toxicity. They attributed NaB's protective effects to its capacity to modulate autophagic responses to toxic α‐synuclein species via histone deacetylase (HDAC) inhibition, thereby reducing dopaminergic neurodegeneration (Zhang et al. 2022).

These findings underscore the potential therapeutic relevance of restoring gut microbiota homeostasis in PD treatment. Nevertheless, the current literature remains far from fully elucidating the mechanisms underlying this complex connection. Thus, rather than focusing solely on microbial community composition, the spectrum of their metabolic products represents the most promising avenue to understand and therapeutically target PD progression—a process in which the ENS emerges as a pivotal mediator of gut–brain communication.

Given that both the ENS and gut microbiota are altered in PD, understanding how these two systems interact is critical for unraveling PD‐related gastrointestinal dysfunction. It has been extensively reported that the ENS responds to changes in the composition of the microbiota, as well as to its metabolites, including those altered in patients with PD. The crosstalk between the gut microbiota and the ENS occurs through both direct and indirect mechanisms; however, it remains unclear which specific ENS–microbiota signaling pathways are disrupted in PD and whether these alterations precede, accompany, or result from early α‐synuclein pathology in the gut. This section provides an overview of the main findings on ENS–microbiota interactions, discussing potential targets that may be relevant for PD pathology (Figure 2).

Given the evidence linking the ENS and gut microbiota in PD, as highlighted in this review, this section addresses nutritional strategies and microbiota‐targeted therapies as potential approaches to modulate this interaction. By focusing on the gut–brain axis, these interventions aim not only to alleviate gastrointestinal and neurological symptoms but also to influence underlying disease mechanisms, offering promising avenues for managing PD pathology.

Both the ENS and the gut microbiota are key players in gut–brain axis homeostasis and PD pathology. Extensive research shows that both contribute to disease initiation and progression through processes such as neuroinflammation and gut‐to‐brain α‐synuclein transfer, thereby contributing to gastrointestinal and neurological dysfunction. Although research on microbiota alterations in PD is abundant, it is increasingly evident that attempting to define a PD‐specific microbiota signature and develop microbiota‐based therapies presents substantial challenges.

First, microbiota composition is highly variable across populations, ages, sexes, lifestyles, and environments, making it extremely difficult to develop standardized treatments (Fenn et al. 2023; Shanahan et al. 2023; Sun et al. 2024). One potential solution is to focus on personalized therapies; however, the high costs associated with such approaches would likely limit their accessibility to PD patients worldwide. Second, our understanding of the gut microbiota as a whole remains incomplete. The optimal method for sampling microbiota for profiling is still debated, as stool samples often fail to detect individual‐level differences in the intestinal mucosal microbiota (Tang et al. 2020; Szóstak et al. 2022). Moreover, there is no consensus on what constitutes a "healthy" microbiota. Recently, Hul et al. argued that the concepts of a healthy or imbalanced microbiota should be linked to gut health. They emphasized the need for continued research and a nuanced approach to understanding this complex and evolving concept, highlighting the importance of more precise and inclusive definitions and methodologies in microbiota research (van Hul et al. 2024).

Given the challenges in profiling the microbiota and the incomplete understanding of its interactions with the host, microbiota modulation can lead to severe and unpredictable adverse effects. Indeed, mild to severe side effects have been reported in up to 39.3% of FMT procedures (Sahle et al. 2024). While most adverse effects are minor and transient, severe complications include transmission of multidrug‐resistant Escherichia coli, transmission of other infectious agents, and hospitalization (Sahle et al. 2024). Overall, researchers face substantial technical and logistical barriers to implementing safe, effective, and well‐regulated microbiota‐based treatments in clinical practice.

The magnitude of these challenges raises the question of whether microbiota modulation is a feasible approach for developing effective, precise, and safe PD therapies. While it is clear that the microbiota is essential for maintaining systemic homeostasis and that dysbiosis plays an important role in PD pathophysiology, concentrating research efforts exclusively on microbiota modulation may be an unproductive path.

Alternatively, targeting the signaling pathways between the microbiota and the host may offer an opportunity to harness the therapeutic potential of the microbiota while enabling the development of more precise and effective treatments. Although microbiota–host crosstalk is highly complex, a deeper understanding of these interactions is essential for this strategy. In this context, the ENS is a central player in gut–brain communication and PD pathology that has been largely overlooked in microbiota research. In this review, we have outlined crosstalk pathways between the ENS and the microbiota, based on current evidence, that are relevant for understanding and treating gut–brain dysfunction in PD. Investigating how the ENS and gut microbiota interact, both directly and indirectly, and how this interaction impacts PD‐related gastrointestinal and gut–brain dysfunction represents an urgent and promising research avenue that could yield critical insights and inform the development of novel therapeutic targets.

Taken together, these considerations point to the need for a conceptual shift in how gut involvement in PD is approached. Rather than seeking a definitive microbial profile, future work should focus on functional outputs, such as microbial metabolites, that more directly impact host physiology and can serve as clinically relevant biomarkers. Yet, identifying these molecules is only the first step. The critical challenge ahead lies in deciphering how the enteric nervous system perceives, integrates, and responds to such signals. By focusing on this neuro–metabolic interface, future research may move beyond descriptive correlations to mechanistic understanding, clarifying the role of the microbiota within the gut–brain axis. Importantly, strategies that directly modulate enteric neuronal and glial populations, or that experimentally probe how these cell types respond to specific microbial metabolites in PD models, may provide a means to determine how ENS–microbiota communication can influence early gut dysfunction and downstream brain pathology. Ultimately, this perspective positions the ENS not as a passive target, but as an active mediator whose interactions with microbial metabolites may reveal novel therapeutic avenues and refine strategies for managing both gastrointestinal and neurological manifestations of PD. Although evidence from other gut–brain axis disorders remains limited, this largely reflects the early stage of ENS‐focused research rather than a lack of biological relevance. A clearer understanding of the ENS is therefore needed to determine its potential role as an early interface through which gut‐derived signals influence brain function.

Luisa Valdetaro: writing – original draft, data curation. Maria Carolina Ricciardi: writing – original draft, visualization, data curation. Patricia Pereira Almeida: writing – original draft, data curation. Milena Barcza Stockler‐Pinto: writing – review and editing. Ana Lucia Tavares‐Gomes: conceptualization, writing – review and editing, supervision.

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico, Process number 313320/2025‐0. Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Process number E‐26/210.126/2025. Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Finance Code 001.

The authors declare no conflicts of interest.