A number of studies^[13-17] [Table 1] have collectively demonstrated that patients with IBD face a heightened risk of developing PD compared to control groups. Notably, a retrospective cohort study from Taiwan^[13] revealed a 35% increase in PD risk among IBD patients compared to those without IBD. Similarly, a U.S.-based retrospective cohort study^[17] found a 28% greater incidence of PD among IBD patients relative to the control group. In the nationwide Danish cohort study^[14], a significant association was observed between IBD and late-onset PD. In addition, stratified analysis of this cohort study further demonstrated that the risk of PD was significantly higher in patients with UC, whereas no significant difference was observed in patients with CD. Nevertheless, earlier studies reporting a positive IBD-PD association, however, failed to consider surveillance bias. For instance, a Swedish study initially identified a strong link between IBD and elevated PD risk. However, after adjusting for the frequency of medical visits, this association was no longer evident^[15], implying that surveillance or detection bias may have influenced the results. In contrast, the South Korean study found an elevated likelihood of PD among individuals with IBD, even following adjustment for healthcare utilization^[16].

These epidemiological findings support a higher risk of PD in IBD patients, though some studies disagree. A re-analysis of the Truven Health Marketscan database showed that no statistically significant correlation between IBD and PD was observed after adjusting for a range of potential external confounders, with an adjusted HR of 1.01 (95%CI: 0.72-1.42)^[18]. Prior observed associations between these disorders may have been influenced by environmental and socioeconomic confounding factors. A prospective analysis^[19] of 468,556 individuals within the UK Biobank similarly revealed no material link of IBD with PD (HR: 1.356, 95%CI: 0.941-1.955, P = 0.103), though increased PD risk was observed in certain subgroups (e.g., females, those with high polygenic risk scores, and UC patients without hypertension). The variation in results may be due to baseline characteristics that might change during follow-up. An analysis^[20] of German primary care records (N = 35,988) also revealed no markedly raised PD frequency in the overall IBD cohort. However, a rising but non-significant tendency was noted among men with CD (HR: 1.55, 95%CI: 0.98-2.45, P = 0.064).

The epidemiological link between IBD and PD is complex and appears to be influenced by population-specific factors^[21]. While a cohort study have demonstrated a positive association^[16], the other one has reported null findings or effect modification by sex and age^[19]. These discrepancies may partly be attributed to detection bias, as patients with IBD might undergo more frequent medical examinations^[15]. Moreover, the residual confounding effect by lifestyle factors - particularly smoking, which is known to be protective in PD, has been highlighted as a potential source of overestimation in studies that did not adequately adjust for these variables^[22]. In the future, it is necessary to further validate the true association between the two and their underlying mechanisms through prospective designs, refined phenotypic stratification (such as age, disease subtypes, and treatment history), and integration of multi-omics data.

The role of IBD incidence among patients with PD remains a contentious topic, with a current lack of sufficient epidemiological studies. Research from a Taiwan-based cohort found that the observed variations in IBD incidence among subjects with PD was statistically insignificant^[23]. An analysis of U.S. insurance records indicated a 15% reduction in IBD incidence among individuals with PD relative to the comparison group^[24]. This inconsistency may arise from the distinct ages at which each condition typically emerges, with IBD presenting most frequently in early adult life and PD rarely developing before 50. Additionally, the presence of delayed gastric emptying and constipation symptoms in PD may mask the diarrhea symptoms associated with IBD, potentially leading to underdiagnosis of IBD in PD patients. These factors could contribute to a lower prevalence of IBD in PD patients compared to non-PD controls. A Swedish case-control study further reported an association between IBD and PD at the time of diagnosis (OR = 1.4, 95%CI: 1.2-1.8). This increased risk was consistent in subgroup analyses for both CD (OR = 1.6, 95%CI: 1.1-2.3) and UC (OR = 1.4, 95%CI: 1.1-1.9), suggesting a higher probability of pre-existing PD in these patients compared to non-PD controls^[15]. This suggests that the probability of PD existing before the diagnosis of IBD is higher, indicating that PD may be a risk factor for the future development of IBD.

All the aforementioned studies are observational in nature, with the majority of them initially collecting administrative data for non-statistical purposes. This data may be influenced by confounding factors (such as history of poor lifestyle habits and medication use), making it challenging to distinguish true causal relationships. Mendelian Randomization (MR) is a causal inference method that leverages genetic variations (particularly single nucleotide polymorphisms, SNPs) highly correlated with the target exposure, while ensuring these variations being independent of confounding factors^[25,26].

However, the validity of MR depends on three core assumptions: (1) the genetic variants are robustly associated with the exposure (IBD); (2) they are independent of confounders; and (3) they influence the outcome (PD) only through the exposure, with no horizontal pleiotropy (i.e., no alternative pathways bypassing the exposure). Several recent MR studies have applied this framework to investigate the IBD-PD relationship. For instance, Freuer et al. conducted an MR study analyzing data related to IBD (7,045 cases and 456,327 controls) and PD (56,306 cases and 1,417,791 controls) with a total of 463,372 IBD-related data points. The results indicated no association between IBD and PD risk [Odds Ratio-Inverse Variance Weighted (OR_IVW) = 0.98; 95%CI: (0.93; 1.04); P = 0.48]^[27]. Another MR analysis yielded similar results [IVW (95%CI): 1.01 (0.98-1.05), P = 0.50]^[28] although their analysis was one-directional and could not determine whether PD increases the risk of IBD.

The null findings from these MR studies warrant careful interpretation. First, while sensitivity analyses (e.g., MR-Egger, weighted median) can detect pleiotropy, the possibility of weak instrument bias or residual horizontal pleiotropy cannot be fully excluded, especially if the genetic variants explain only a modest proportion of IBD variance. Second, these studies predominantly involved populations of European ancestry, limiting generalizability to other ethnic groups. One study using multiple MR methods reported that while the IVW and Robust Adjusted Profile Score (RAPS) methods suggested an increased risk of IBD in patients with PD (OR_IVW = 1.062, P < 0.05), other methods did not, highlighting the sensitivity of findings to methodological choices^[29]. A bidirectional MR analysis conducted in 2024 revealed that the IVW analysis showed no significant correlation between genetically predicted PD risk and IBD risk (OR = 1.04, 95%CI: 0.98-1.11; P = 0.182), similar results were obtained in the reverse analysis (OR = 0.98, 95%CI: 0.94-1.03; P = 0.530)^[30].

Taken together, the current body of MR evidence does not support a strong causal relationship between IBD and PD. While observational studies have reported positive associations, these may be attributed to confounding factors, detection bias, or reverse causation rather than a direct biological link. Future MR studies with larger sample sizes, more diverse populations, and more refined genetic instruments for specific IBD subtypes may help clarify whether any subtle or subgroup-specific causal effects exist.

Genetic susceptibility offers another perspective on the heightened risk of PD, and related studies further substantiate this notion. A 2017 analysis employing GWAS and pathway analyses identified 17 novel pleiotropic loci from cohorts of patients with PD and seven autoimmune diseases, such as CD and UC^[31]. The most significant genome-wide pleiotropic enrichment was identified between PD and CD. Based on the National Genome Research Institute GWAS Catalog^[32] and the evaluation by Lee et al.^[33], six loci exhibit strong associations with both PD and IBD. This section summarizes several of these typical genes whose encoded proteins may functionally connect the two diseases.

Growing evidence of gut-CNS interaction has inspired the “GBA” theory, involving two-way communication between the central and ENS. It influences diverse physiological functions within both the central nervous and gastrointestinal systems, and is involved in the pathogenesis of PD^[55] [Figure 1]. A rodent study demonstrated that mouse fetuses exposed to small amounts of penicillin in the uterus or shortly after birth exhibited enduring consequences later in life. These effects included an altered gut microbiome, elevated frontal cortex cytokine expression, impaired blood brain barrier (BBB) integrity, and manifestations of anxiety-like behavioral abnormalities^[56]. Utilizing metagenomic approaches, Yang and colleagues uncovered disrupted gut viral and bacterial ecology in patients with major depression, where notably decreased levels of Blautia and Eubacterium were clinically associated with symptom severity^[57]. Collectively, these findings highlight a bidirectional interplay: the gut microenvironment influences behavior via microbial metabolites and inflammatory signals (gut-to-brain axis), while psychological stress reciprocally disrupts microbiota composition (brain-to-gut axis).

More evidence indicates that PD extends beyond a movement disorder to include significant gastrointestinal involvement. PD may be associated with gut dysbiosis or intestinal barrier dysfunction, or both. According to research conducted by Cersosimo and Benarroch, the gastrointestinal profile of PD is characterized by sialopenia, dysphagia, gastroparesis, constipation, and dysfunctional defecation. Notably, these problems often precede motor symptoms by decades and affect a significant majority of patients, over 80%. Their research further indicates that a strong link between these gastrointestinal manifestations and neurodegenerative changes involving α-synuclein within the ENS^[58]. Evidence indicates that α-synuclein accumulation occurs not only in the gastrointestinal tract of PD patients exhibiting gastrointestinal symptoms^[59], but also in individuals prior to the manifestation of PD motor symptoms^[60]. These findings support the idea that PD may originate from the ENS, where α-synuclein misfolding first occurs. However, it is important to note that this “bottom-up” model is not universally accepted, as some studies have failed to observe a consistent caudal-to-rostral spread of pathology in all PD patients, suggesting that alternative or parallel initiation sites (e.g., the olfactory bulb or CNS itself) may also exist^[61].

Serving as a major conduit between the gut and the brain, the vagus nerve enables bidirectional signaling. Kim et al. demonstrated that duodenal and pyloric administration of α-synuclein in a murine model led to its translocation via the vagus nerve to multiple areas of the brain, such as the cerebellum, olfactory bulb, brainstem, and substantia nigra^[62]. This process was linked to the emergence of PD symptoms, encompassing motor and non-motor dysfunctions. Additionally, the research highlighted vagotomy can decrease the risk of PD^[63]. Several reports have demonstrated a preferential influence of the right vagus nerve on the SNpc, which displays a characteristic pattern of asymmetric degeneration. For example, a study^[64] on 28-day and 63-day DSS (dextran sulfate sodium) treatment models found that in the 28-day DSS model, a 40% loss of dopaminergic neurons was observed in the right SNpc, while the left SN showed no significant loss, reflecting asymmetry. However, in the 63-day DSS model, both sides of the SN showed significant dopaminergic neuronal loss, suggesting that neurodegeneration starts unilaterally and later spreads bilaterally.

The previous discussion explored the connection between PD and IBD, with IBD increasing the incidence of PD. Therefore, could medications used to treat IBD reduce the risk of PD? Common medications used to treat IBD include aminosalicylates, corticosteroids, immunosuppressants, and biologic agents. According to a retrospective cohort study, early treatment with anti-TNF (tumor necrosis factor) was associated with a significantly lower risk of developing PD among IBD subjects. The treated cohort showed a 78% reduction in incidence compared to that without a history of anti-TNF exposure^[17]. More investigations are needed to ascertain whether TNF inhibition therapy ought to be implemented in individuals with IBD to reduce PD risk. A recent MR study assessed how long-term inhibition of TNF affects the risk of PD onset and the age at which it develops, and the findings failed to verify the idea that inhibiting the TNF-TNFR1 signaling pathway can prevent or delay PD^[87]. Unlike the study by Peter et al.^[17], this research primarily focused on selective inhibition of TNF-TNFR1 signaling, a pathway believed to be central to TNF-related neurotoxicity in PD. Additionally, a cross-sectional study in Spain revealed that individuals under 65 using 5-aminosalicylic acid (5-ASA) had a significantly lower likelihood of receiving PD medication (OR = 0.28, P = 0.01)^[88]. Moreover, administration of these medications (azathioprine and corticosteroids) demonstrated a significant correlation with decreased PD incidence^[89]. The above studies suggest that some common medications used to treat IBD may have a protective effect on the onset of PD, providing a reference for future PD treatments and the potential for “repurposing” existing drugs. MR analyses of PD and IBD indicate that the Cxcr4 gene represents a promising drug target. Encoding the chemokine receptor CXCR4, this gene represents a target whereby flavonoids might offer therapeutic benefits in both PD and IBD via CXCR4 protein inhibition^[90]. Consequently, the identification of drug-related genetic targets may advance the development of novel therapeutic strategies targeting PD and IBD.

Fecal microbiota transplantation (FMT) is an intervention to modulate the host microbiome by restoring gut microbial balance, aiming to treat dysbiosis-related diseases. The first recorded medical application of FMT dates back to 1958, for treating pseudomembranous colitis^[91]. The involvement of gut dysbiosis in the progression of PD indicates that the restoration of gut microbiota may serve as a new therapeutic option for PD, thereby attracting considerable interest in FMT as a potential treatment strategy. A case report indicates that FMT may alleviate gastrointestinal and motor dysfunctions in PD patients^[92]. Additionally, animal studies have proposed several mechanisms by which FMT could influence PD, including altering gut microbiota composition, enhancing gut barrier function, inhibiting pathogens, and modulating immune responses. Research by Sun et al. indicated that FMT was shown to mitigate manifestations in a murine PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), through the amelioration of both microbial imbalance and central inflammation^[93]. Zhao et al also showed that FMT improved rotenone-induced PD mouse models by correcting dysbiosis and inhibiting the lipopolysaccharide-TLR4 signaling pathway^[94].

Therefore, FMT holds significant potential as a future treatment for PD. Nevertheless, it is essential to consider the potential risks linked to FMT, including infections, sepsis, the spread of harmful intestinal organisms, bleeding, reactivation of dormant viruses like cytomegalovirus, and respiratory complications, such as pneumonia^[95].

Despite promising preclinical evidence, several critical limitations must be acknowledged when translating these findings to human PD. First, current animal models of PD, whether neurotoxin-induced (e.g., MPTP, rotenone) or transgenic, fail to fully recapitulate the chronic, progressive nature of human sporadic PD, particularly the age-dependent accumulation of α-synuclein pathology and the complex gut-brain interactions over decades^[96]. Second, most FMT studies on PD models have been short-term, whereas PD is a lifelong condition, making it difficult to assess long-term efficacy and safety. Third, the optimal donor selection, route of administration, dosing frequency, and timing of intervention (prodromal vs. established disease) remain undefined.

To advance the broader clinical application of FMT in PD, larger-scale, high-quality, randomized, double-blind, placebo-controlled clinical trials with long-term follow-up are urgently needed to gather sufficient clinical evidence and to determine whether the benefits observed in animals can be replicated in PD patients.

Most existing studies report that the administration of probiotics yields neuroprotective effects and alleviates cognitive impairment^[97]. Probiotics are esteemed for possessing antioxidant, anti-inflammatory, and neuroprotective efficacies. Their impact on neurological processes is mediated by multifaceted biological interactions, encompassing the mitigation of oxidative stress, immunomodulation, and the governance of apoptotic pathways^[98]. According to Liu et al., combined probiotic-prebiotic treatment yielded significantly greater efficacy than either monotherapy in murine models of PD^[99]. A study led by Sun et al. revealed that supplementing standard PD treatments with Probio-M8, a probiotic formulation, significantly enhanced therapeutic effectiveness. This intervention further modified the intestinal microbiota, shifted microbial metabolic capabilities, and altered serum biochemical markers in the host^[100]. An in vitro study revealed that probiotics (lactobacilli and bifidobacteria) inhibit the production of inflammatory cytokines and reactive oxygen species (ROS) in PD patients^[101].

Psychobiotics refer to a specific class of probiotics known to confer benefits to psychological health^[102]. They are under investigation as stand-alone or adjunctive treatments for psychiatric, neurodevelopmental, and neurodegenerative disorders, showing promise as future clinical interventions for brain-related conditions. Recent studies have identified Lactobacillus plantarum DP189 as an effective psychobiotic capable of mitigating α-synuclein degradation in MPTP-induced PD mice through modulation of oxidative stress, inflammatory response, and gut microbiota dysfunction^[103]. The above studies suggest that gut microbiota modulation holds potential in the treatment of both PD and IBD. However, it is crucial to interpret these findings with caution due to substantial translational barriers. The majority of evidence for probiotics in PD is derived from in vitro assays or animal models, which do not account for the complexity of the human gut ecosystem, including host-microbe interactions, inter-individual variability in microbiota composition, and the confounding effects of diet and co-medications. Furthermore, the viability, colonization capacity, and metabolic activity of probiotic strains in the human gastrointestinal tract are highly variable and often poorly characterized.

In conclusion, although PD and IBD appear to be distinctly different diseases at first glance, existing research suggests a connection between them in terms of epidemiology and pathophysiological mechanisms. The dual issues of chronic gut inflammation and dysbiosis are pivotal drivers in the pathogenesis of these conditions. The abnormal aggregation of α-synuclein is hypothesized to connect the pathological processes of IBD and PD. Additionally, treatment for IBD has shown some protective effects against PD, and current IBD therapies might be cautiously repurposed for PD treatment. Despite recent progress, our understanding of the complex interactions between these two diseases remains limited. Future research needs to further explore the molecular basis of these connections and assess the efficacy of existing IBD treatments in the management of PD. Furthermore, these results carry substantial clinical relevance, indicating that neurological symptom surveillance warrants greater emphasis during extended care for individuals with IBD. Collectively, these insights could lay the foundation for advanced management strategies, ultimately improving quality of life of individuals with IBD and PD.