Helicobacter pylori infection might be a protective factor against Parkinson’s disease

Helicobacter pylori infection might be a protective factor against Parkinson’s disease | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Helicobacter pylori infection might be a protective factor against Parkinson’s disease Xiao Xiao, Zuo Wang, Huiwang Zhang, Binghong Li, Qinchuan Hou, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5973815/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 May, 2025 Read the published version in Scientific Reports → Version 1 posted 6 You are reading this latest preprint version Abstract Background : The gastrointestinal tract is not only an important component of the digestive system but also a crucial part of the body's immune system. Numerous studies have reported that gastrointestinal immunity plays a critical role in many extraintestinal diseases, including neurodegenerative disorders. However, the relationship between gastric mucosal immunity and neurodegenerative diseases, such as Parkinson’s disease(PD), remains underexplored. Methods : The rate of H. pylori infection was assessed using the 13C-Urea Breath Test (13C-UBT) in a case-control study involving 315 PD patients and a control group of 22,383 outpatients. Multivariate regression and propensity score matching (PSM) analyses were employed to adjust for confounding factors. Results : A lower H. pylori infection rate was found in PD cases compared to outpatient controls (DOB ≥ 8, 22.5% versus 27.5%, p = 0.049; DOB ≥ 4, 28.6% versus 33.9%, p = 0.046). After adjusting for confounding factors, the H. pylori infection rate remained lower in PD cases compared to controls. Conclusions : The study revealed an inverse correlation between H. pylori infection and PD, suggesting that H. pylori infection could potentially act as a protective factor against the development of PD. Health sciences/Neurology/Neurological disorders/Parkinsons disease Health sciences/Gastroenterology/Gastrointestinal system/Stomach Health sciences/Health care/Public health/Epidemiology H. pylori infection parkinson’s disease gastrointestinal mucosal immune Figures Figure 1 Figure 2 Introduction The gastrointestinal tract serves not merely as a principal organ of digestion but also constitutes a critical immunological interface, orchestrating both local and systemic immune responses [ 1 , 2 ]. A substantial body of evidence has established that gut-associated lymphoid tissue (GALT)-mediated immunity exerts profound pathophysiological effects on the development and progression of diverse extraintestinal disorders [ 3 , 4 ]. Nevertheless, the potential mechanistic links between gastric mucosal immune regulation and the pathogenesis of extragastric diseases remain underexplored, with extant literature offering only fragmentary insights into this association. Helicobacter pylori( H. pylori ) is a microaerophilic Gram-negative bacterium and the most prevalent pathogen in the gastrointestinal tract worldwide, infecting approximately half of the global population [ 5 – 8 ]. Furthermore, H. pylori can persist long-term in the gastric antrum, triggering corresponding mucosal immune responses and exerting significant effects on human gastric mucosal immunity[ 9 – 12 ]. Research indicates its potential influence on various extragastric conditions, acting as a risk factor for some diseases while potentially offering protection against others[ 13 – 15 ], such as Multiple sclerosis(MS) and inflammatory bowel disease (IBD), where the presence of H. pylori has shown protective effects[ 15 , 42 ]. However, research on the impact of H. pylori on extraintestinal diseases, particularly central nervous system disorders, is limited, with inconsistent conclusions and unclear mechanisms. Given H. pylori 's protective role against intestinal mucosal inflammation in IBD, there is speculation about its potential inverse correlation with neurodegenerative diseases like Parkinson’s disease(PD). PD is currently the second most prevalent neurodegenerative disorder worldwide, primarily affecting the elderly, with incidence increasing with age[ 16 – 19 ]. In addition to motor symptoms, over 80% of patients may experience a range of gastrointestinal symptoms, including swallowing difficulties, delayed gastric emptying, severe constipation, and anorectal dysfunction, which can occur years before the onset of motor symptoms [ 20 , 21 ]. The pathological features of PD include progressive apoptosis of dopaminergic neurons in the substantia nigra pars compacta of the midbrain and the formation of Lewy bodies composed of abnormal α-synuclein aggregates within neurons. Post-mortem anatomical and animal experimental studies have shown that Lewy bodies can also be found in the enteric nervous system and vagal nerve axis in PD patients[ 22 ]. Current evidence regarding the association between gastrointestinal immunity and PD remains limited, characterized by insufficient mechanistic investigations in basic research and clinically heterogeneous studies with inadequate sample sizes and inconsistent findings. To address this critical knowledge gap, particularly concerning the potential link between H. pylori infection and PD pathogenesis, large-scale population-based studies with robust methodological designs are imperative. In this context, we implemented a nationwide population-based cohort study to systematically evaluate the epidemiological and pathophysiological relationship between H. pylori infection and PD risk. Method Ethical statement and study design This was a case-control study with the subjects derived from the outpatients and inpatients in the Sichuan Provincial People's Hospital, a provincial comprehensive hospital in Chengdu, China. All individuals provided their written, informed permission for the use of their clinical data in this study. Adhering strictly to the Declaration of Helsinki guidelines, this study received full approval from the Institutional Review Board for Clinical Research at the Sichuan Provincial People's Hospital. The PD cases were those definitively diagnosed by the Neurology Clinic and who agreed to participate in this study at this hospital from March 2022 to July 2024. During this period, the outpatients who undergopasting the 13C Urea Breath Test (13C-UBT) were included in the control group. Additionally, since the PD patients were sourced from outpatient clinics, we collected data on all patients at this hospital who had undergone 13C-UBT for H. pylori infection detection from 2022 to 2024. Written informed consent was obtained from all participants. Definition of participants Parkinson’s disease cases: Inclusion Criteria: Patients diagnosed with PD were established by neurologists through Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD) [23] , which was combined with comprehensive neurologic examinations, patient age, family history, and Parkinson’s diseasetous clinical manifestations. Only the initial test result will be recorded if multiple results are available and we did not exclude participants with eradication treatment. Exclusion Criteria: Participants with other severe neurodegenerative diseases besides Parkinson's disease, such as Alzheimer's disease, multiple system atrophy, progressive supranuclear palsy, etc., were excluded from the study. Outpatient controls: Inclusion Criteria: Participants from different outpatient departments in Sichuan provincial people’s hospital after 2022, who underwent 13C-UBT. Only the initial test result will be recorded if multiple results are available and we did not exclude participants with eradication treatment. Exclusion Criteria: Participants with severe neurodegenerative diseases were excluded from the study. Definition of H. pylori infection H. pylori infection was determined using the 13C-UBT with the UREA-13C breath test Heliforce kits (Beijing Richen-Force Science & Technology, Beijing, China). Breath samples were collected before and 30 minutes after ingestion of 75 mg of 13C-urea by fasting patients (or those who had fasted for at least two hours). The breath samples were analyzed using an infrared heterodyne radiometer (Guangzhou Huayou Mingkang Optoelectronics Technology Co., Ltd, Guangzhou, China). Subjects who had taken histamine-2 receptor antagonists, proton pump inhibitors, antibiotics, bismuth compounds, or nonsteroidal anti-inflammatory drugs (excluding low doses of aspirin) in the preceding four weeks were excluded to avoid false-negative chances. This test provided a delta over baseline (DOB) value. The determination of H. pylori infection positivity was conducted the following two criteria: (i) DOB≥4.0: A DOB value of ≥4.0 was considered positive for H. pylori infection. Values below this threshold were considered negative by most of based health check-up population study. (ii)DOB≥8.0: A DOB value of ≥8.0 was considered positive for H. pylori infection. Values below this threshold were considered negative. The magnitude of the DOB value is related to the severity of H. pylori infection, with higher DOB values correlating with greater H. pylori density, as well as histopathological chronicity and activity indices. In selecting two distinct cutoff values for the 13C-UBT, we adopted DOB≥4 as the threshold, a standard widely utilized in the majority of epidemiological surveys to facilitate comparisons across studies. However, acknowledging the potential for false positives at the DOB≥4 level, we also employed a DOB≥8 cutoff to enhance the reliability of H. pylori infection detection. The DOB≥8 threshold maintains detection sensitivity while improving specificity for H. pylori infection. This dual-threshold approach offers a more comprehensive assessment of infection status and contributes to the increased reliability of our research findings. Covariate Definitions Self-designed questionnaire and the electronic medical records are used to collect the sociodemographic and medical characteristics of PD patients and outpatient controls. Participants who PD and non-Parkinson’s diseasetous population are interviewed face to face by the research assistants being trained standard. The covariates include sex, age, area, disease history (e.g. hypertension, diabetes mellitus, coronary artery disease, Peptic ulcer(Gastric and/or duodenal ulcers), Digestive tract cancer(Gastric cancer, colorectal cancer and/or esophageal cancer)), et al. Statistical analysis Means ± standard deviations (SD) were calculated for continuous variables, while percentages were used for categorical variables in both the PD and comparison populations. Continuous variables were compared using the independent samples t-test. Categorical variables were compared using the χ² test, where applicable. Multivariate logistic regression and propensity score matching (PSM) analysis were utilized to exclude the selection bias and confounding factors. All variables with P < 0.05 in the univariate analysis were included in the multivariate logistic regression to investigate the associations between risk factors and H. pylori infection. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Data were analyzed using SPSS, version 24.0 (IBM Corp), GraphPad Prism version 9.5.0, and RStudio software, version R-4.2.3 (R Core Team, 2024). P value of less than 0.05 was considered statistically significant (two-tailed tests). Result 1. The general situation of PD patients and outpatients population. From 2022 to 2024, 315 PD patients diagnosed by neurologist in the department of neurology of this hospital were included. The average age of PD patients was 64.67 ± 10.21 years, and 50% of them were male. During the same period, 22383 outpatients population outpatients (older than 18 years) in the same hospital who had undergone the 13C-UBT for H. pylori infection were included, comprising the hospital-based controls. The average age was 45.14 ± 10.31 years with 42% of them were male. The age and gender distribution were still different between the PD cases with outpatients’ population (Table 1). Table 1. Comparison of the PD group and the outpatients population Characteristic PD(315) outpatients(22383) P value Sex, n (%) Male 157(49.8) 9384(41.9) 0.003 Female 158(50.2) 12999(58.1) Age, M(SD) 64.67(10.2) 45.14(14.3) ＜0.001 Area, n (%) Urban 143(45.4) 18754(83.8) ＜0.001 Rural 172(54.6) 3629(16.2) Hypertension, n (%) 83(26.3) 2080(9.3) ＜0.001 Diabetes Mellitus, n (%) 36(11.4) 1049(4.7) ＜0.001 Coronary Artery Disease, n (%) 12(3.8) 316(1.4) ＜0.001 Peptic ulcer, n (%) 11(3.5) 731(3.3) 0.823 Digestive tract cancer, n (%) 3(1.0%) 452(2.0%) 0.180 n (%) indicates the number of constituents (n) and the composition ratio (%). 2. Comparison of H. pylori infection rate between PD patients and outpatients population by univariate and multivariate logistic regression analysis Due to significant differences in H. pylori infection rates across regions, study periods, and detection methods, we compared whether the baseline infection rate in this study exhibited substantial selection bias. Based on recent studies on H. pylori infection rates across various regions of China, we have compiled data from January 2020 to the present. The subjects in these studies were all aged 18 years or older, and the detection of H. pylori infection was conducted using the 13C-UBT. These data are consistent with the H. pylori infection prevalence observed in our hospital’s outpatient control group [24-30]. In our statistical results, the univariate analysis showed that the H. pylori infection rate in PD patients was significantly lower than that of the overall outpatient controls (DOB≥8, 22.5% vs 27.5%, OR 0.77, 95% CI: 0.59-1.00, p =0.049; DOB≥4, 28.6% vs 33.9%, OR 0.78, 95% CI: 0.61-1.00, p =0.046)(Fig 1A). Considering the potential influence of other factors, including gender, age, area, hypertension, diabetes, coronary artery disease, Peptic ulcer(Gastric and/or duodenal ulcers) and Digestive tract cancer(Gastric cancer, colorectal cancer and/or esophageal cancer), we conducted a multivariate analysis of H. pylori infection rates between PD patients and the outpatient controls. The results showed that the infection rate in PD patients was still significantly lower than that in the control group (DOB ≥ 8: OR 0.74, 95% CI: 0.56–0.97, p = 0.030; DOB ≥ 4: OR 0.73, 95% CI: 0.56–0.94, p = 0.015) (Fig 1B). Additionally, regardless of whether the population was urban or rural, the H. pylori infection rate in PD patients was lower with a more pronounced and statistically significant difference observed in the rural population (Supplement table 1, Supplement Fig 1). 3. Comparison of H. pylori infection rate between PD patients and outpatient controls after PSM To further validate the accuracy of these findings, we performed a PSM analysis. After balancing covariates, PSM confirmed lower H. pylori infection rates in PD cases than in outpatient controls(DOB ≥ 8: OR 0.69, 95% CI: 0.52–0.91, p = 0.009; DOB ≥ 4: OR 0.71, 95% CI: 0.55–0.92, p = 0.009) (Table 2 and Fig2A). Logistic regression post-PSM revealed the same results with the above (DOB ≥ 8: OR 0.68, 95% CI: 0.52–0.90, p = 0.008; DOB ≥ 4: OR 0.70, 95% CI: 0.54–0.91, p = 0.007) (Fig 2B). In conclusion, the infection rate in PD patients remained significantly lower than that in the control group, with a statistically significant difference. Table 2. Comparison of the PD group and the outpatient controls after PSM Characteristics PD(315) Outpatients(2205) P value Age, M(SD) 64.7±10.2 63.7±10.2 0.106 Sex (Male), n (%) 158(50.2) 1088(49.3) 0.786 Hypertension, n (%) 83(26.3%) 547(24.8%) 0.554 Diabetes Mellitus, n (%) 36(11.4%) 217(9.8%) 0.381 Coronary Artery Disease, n (%) 12(3.8%) 65(2.9%) 0.407 Peptic ulcer, n (%) 51(2.3%) 11(3.5%) 0.210 Digestive tract cancer, n (%) 12(0.5%) 3(1.0%) 0.385 Area(Rural) , n (%) 172(54.6%) 1105(50.1%) 0.136 H. pylori Infection (DOB≥4) 90(28.6%) 795(36.1%) 0.009 H. pylori Infection (DOB≥8) 71(22.5%) 655(29.7%) 0.009 n (%) indicates the number of constituents (n) and the composition ratio (%). Discussion As we know, Parkinson's disease (PD) is an age-related neurodegenerative disorder. Its onset is associated with multiple factors, including genetics and environmental influences, though the exact pathogenesis remains unclear. In this study, we found that the rate of H. pylori infection in PD patients was consistently lower than that in the outpatient control group across various analytical methods, including univariate analysis, multivariate analysis, and propensity score matching (PSM) analysis. Additionally, we observed that, regardless of whether the population was urban or rural, the H. pylori infection rate in PD patients was lower than that in the control group, with a more pronounced and statistically significant difference observed in the rural population. This may be related to the simpler lifestyle and fewer confounding factors in rural areas(supplement Table 1 ). Considering that PD is associated with aging, we divided the PD and outpatients population groups using 65 years of age as a cutoff for comparison. In the univariate analysis and multivariate analysis, the infection rate in PD patients under 65 was significantly lower than in outpatients population patients, with statistical significance(supplement Table 2 ). Previous studies have reported limited discussion on the relationship between H. pylori and PD, with most findings contrary to our results. Dobbs et al. [ 31 ] reported a higher infection rate of H. pylori in PD patients (50 out of 105, or 47.6%) compared to non-PD patients (39.5%), with a more pronounced difference in those under 72 years old. The statistical analyses by Nafisah et al., Nielsen et al., and Bu et al. [ 32 – 34 ] also indicated a higher infection rate in PD patients. Lee et al. [ 35 ] found that H. pylori infection could reduce levodopa absorption during treatment, exacerbating symptom fluctuations. Mridula et al. [ 36 ] noted that H. pylori infection affected levodopa absorption, leading to increased medication dosage. Liu et al. [ 37 ] concluded from a three-group controlled trial that eradicating H. pylori improved clinical symptoms in PD patients, particularly in terms of bradykinesia. Lolekha et al. [ 38 ] suggested that eliminating H. pylori could reduce symptom fluctuations in PD patients. However, other studies raised doubts. Nafisah et al., Narozanska et al., and Tan et al. [ 33 , 39 , 40 ] argued that there were no significant improvements in clinical manifestations or UPDRS scores after H. pylori eradication in positive PD patients. Nonetheless, these studies have certain limitations: first, current research largely consists of small-sample case-control and cross-sectional studies, with unclear theoretical mechanisms; second, because of the differences of the H. pylori infection rate in rural and urban area, past research has more focused on developed regions while studies in developing countries or rural areas are lacking. This study aims to address these limitations. Based on recent findings in further research on H. pylori and our statistical results, we suspect that the relationship between PD and H. pylori infection differs from earlier research. The clinical research results merit further discussion. The pathogenesis of PD remains unclear. Brakk's theory posits that PD may originate outside the CNS, with pathogens crossing the gastrointestinal barrier and entering the CNS via the vagus nerve, with non-motor symptoms like gastrointestinal dysfunction often preceding motor symptoms[ 22 ]. Also, some evidence suggests it may involve immune-related or autoimmune mechanisms[ 43 – 46 ]. This study found a negative correlation between PD and H. pylori , indicating a potential protective role of H. pylori , possibly through its modulation of immune responses, such as promoting regulatory T cell (Treg) activity in childhood and reducing inflammation[ 41 ].The "hygiene hypothesis"[ 47 , 48 ] ,which suggests that early exposure to enteric infections in less hygienic environments may prevent immune-related diseases later in life, further support the idea that early environmental exposures, including H. pylori , may influence PD development by affecting immune regulation and gut-brain interactions, warranting further investigation into H. pylori 's role in PD. This clinical study does have limitations. First, it consists solely of single-center data, which may not fully represent the situation in different countries and regions. Conducting multicenter studies is necessary to confirm these findings. Second, variations in extra-gastric diseases associated with H. pylori may arise from diverse immune responses in hosts, yet we did not assess immune states in participants. Comparing immune responses between H. pylori -positive and -negative individuals among both PD patients and controls is essential. In conclusion, the prevalence of H. pylori infection in PD patients was significantly lower than that in the outpatient control group, with this difference reaching statistical significance. Given that H. pylori infection is highly prevalent among middle-aged and younger populations, we propose that H. pylori colonization might exert a protective effect against PD development, particularly during the early stages of the disease. However, further experimental and clinical studies are warranted to validate this hypothesis. Declarations Funding This work was granted by the National Natural Science Foundation of China (82450003, 82370560) and the Sichuan Science and Technology Programgrants (2023YFS0022). Competing interests The authors declare no competing interests. Data Availability Statement The datasets generated and/or analysed during the current study are not publicly available. Due to privacy protection and data security concerns, the data cannot be shared. However, upon reasonable request, the data may be made available from the corresponding author. References Furness JB, Rivera LR, Cho HJ, Bravo DM, Callaghan B. The gut as a sensory organ. Nature reviews Gastroenterology & hepatology. 2013;10(12):729-740. Guo N, Li N, Jia L, et al. Immune subset-committed proliferating cells populate the human foetal intestine throughout the second trimester of gestation. Nature Communications. 2023;14(1). doi:10.1038/s41467-023-37052-4 Rogler G, Singh A, Kavanaugh A, Rubin DT. 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Parkinsonism & related disorders , 21 (8), 877–881. https://doi.org/10.1016/j.parkreldis.2015.05.015 Nafisah, Wan Yahya; Mohamed Ibrahim, Norlinah; Najman Achok, Hamdi; Hamizah, Razlan; Azmin, Shahrul; Remli, Rabani; Shah, Shamsul Azhar (2013). High prevalence of Helicobacter pylori infection in Malaysian Parkinson's disease patients. Journal of Parkinsonism and Restless Legs Syndrome, (), 63–. Nielsen, H. H., Qiu, J., Friis, S., Wermuth, L., & Ritz, B. (2012). Treatment for Helicobacter pylori infection and risk of Parkinson's disease in Denmark. European journal of neurology , 19 (6), 864–869 Lee, W. Y., Yoon, W. T., Shin, H. Y., Jeon, S. H., & Rhee, P. L. (2008). Helicobacter pylori infection and motor fluctuations in patients with Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society , 23 (12), 1696–1700 Mridula, K. R., Borgohain, R., Chandrasekhar Reddy, V., Bandaru, V., & Suryaprabha, T. (2017). 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H., Mahadeva, S., Marras, C., Thalha, A. M., Kiew, C. K., Yeat, C. M., Ng, S. W., Ang, S. P., Chow, S. K., Loke, M. F., Vadivelu, J. S., Ibrahim, N., Yong, H. S., Tan, C. T., Fox, S. H., Lang, A. E., & Lim, S. Y. (2015). Helicobacter pylori infection is associated with worse severity of Parkinson's disease. Parkinsonism & related disorders , 21 (3), 221–225. Chen, Z., Chen, S., & Liu, J. (2018). The role of T cells in the pathogenesis of Parkinson's disease. Progress in neurobiology, 169, 1–23. Jaruvongvanich, V., Sanguankeo, A., Jaruvongvanich, S., & Upala, S. (2016). Association between Helicobacter pylori infection and multiple sclerosis: A systematic review and meta-analysis. Multiple sclerosis and related disorders, 7, 92–97. Tan, E. K., Chao, Y. X., West, A., Chan, L. L., Poewe, W., & Jankovic, J. (2020). Parkinson disease and the immune system - associations, mechanisms and therapeutics. Nature reviews. Neurology, 16(6), 303–318. Bonam, S. R., & Muller, S. (2020). 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Supplementary Files supplementaryfile.docx Cite Share Download PDF Status: Published Journal Publication published 14 May, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 28 Apr, 2025 Reviews received at journal 26 Apr, 2025 Reviewers agreed at journal 26 Apr, 2025 Reviewers invited by journal 24 Apr, 2025 Submission checks completed at journal 23 Apr, 2025 First submitted to journal 10 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5973815","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":447370057,"identity":"9aa325e6-4678-4822-8273-c8cedf1faf40","order_by":0,"name":"Xiao Xiao","email":"","orcid":"","institution":"Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 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China","correspondingAuthor":false,"prefix":"","firstName":"An","middleName":"","lastName":"Li","suffix":""},{"id":447370080,"identity":"3ae27a48-0a36-45e0-9daf-092b4322a96e","order_by":15,"name":"Xiong Zhu","email":"","orcid":"","institution":"Chengdu Women’s and Children’s Central Hospital, University of Electronic Science and Technology of China","correspondingAuthor":false,"prefix":"","firstName":"Xiong","middleName":"","lastName":"Zhu","suffix":""},{"id":447370082,"identity":"0f52cc92-2999-4f79-8fc5-7c714d6d02a9","order_by":16,"name":"Caiping Gao","email":"","orcid":"","institution":"Department of Gastroenterology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China","correspondingAuthor":false,"prefix":"","firstName":"Caiping","middleName":"","lastName":"Gao","suffix":""},{"id":447370084,"identity":"0ec37d53-01c1-49ef-9a0d-fcd8df40a060","order_by":17,"name":"Chong He","email":"","orcid":"","institution":"Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China","correspondingAuthor":false,"prefix":"","firstName":"Chong","middleName":"","lastName":"He","suffix":""},{"id":447370085,"identity":"c34239a1-0672-491f-8a6e-94ef20c46f72","order_by":18,"name":"Fang Lu","email":"","orcid":"","institution":"Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China","correspondingAuthor":false,"prefix":"","firstName":"Fang","middleName":"","lastName":"Lu","suffix":""},{"id":447370086,"identity":"5d473a5c-9fe5-47c6-8e9e-aecf2682d766","order_by":19,"name":"Ping Shuai","email":"data:image/png;base64,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","orcid":"","institution":"Health Management Center \u0026 Health Management Research Institute, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China","correspondingAuthor":true,"prefix":"","firstName":"Ping","middleName":"","lastName":"Shuai","suffix":""}],"badges":[],"createdAt":"2025-02-06 13:08:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5973815/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5973815/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-01562-6","type":"published","date":"2025-05-14T15:57:13+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82066901,"identity":"5c5874b4-1fb4-4d97-b9ca-e92a39c84a0c","added_by":"auto","created_at":"2025-05-06 12:39:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":129901,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eH. pylori \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003einfection rates in PD patients with outpatients population for confounding factors by multivariate logistic regression analysis. \u003c/strong\u003eA. Comparison of \u003cem\u003eH. pylori \u003c/em\u003einfection rates in PD patients with outpatients population. B. Association of \u003cem\u003eH. pylori \u003c/em\u003einfection and PD by a multivariate logistic regression analysis. Odds ratio (ORs) was adjusted for the sex (male=1, female =0), age (years), Hypertension (Yes=1, No=0), Diabetes Mellitus (Yes=1, No=0), Coronary Artery Disease (Yes=1, No=0), Peptic ulcer (Yes=1, No=0), Digestive tract cancer(Yes=1, No=0), \u003cem\u003eH. pylori \u003c/em\u003einfection (Positive=1, Negative=0). *p \u0026lt; 0.05.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5973815/v1/ba2db9cb0f0bb2752cef8045.png"},{"id":82066900,"identity":"77a930d5-0732-4d9b-9af9-4a9dfd39fbe2","added_by":"auto","created_at":"2025-05-06 12:39:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":130124,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eH. pylori \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003einfection rates in PD patients with outpatient controls for confounding factors by PSM. \u003c/strong\u003eA. Comparison of \u003cem\u003eH. pylori \u003c/em\u003einfection rates in PD patients with outpatients population after PSM. B. Association of \u003cem\u003eH. pylori \u003c/em\u003einfection and PD by a Logistic regression post-PSM. Odds ratio (ORs) was adjusted for the sex (male=1, female =0), age (years), Hypertension (Yes=1, No=0), Diabetes Mellitus (Yes=1, No=0), Coronary Artery Disease (Yes=1, No=0), Peptic ulcer (Yes=1, No=0), Digestive tract cancer(Yes=1, No=0), \u003cem\u003eH. pylori \u003c/em\u003einfection (Positive=1, Negative=0). **\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5973815/v1/86466484659c951f16af77ce.png"},{"id":83067889,"identity":"96410e0f-0978-4550-bb8e-bb08521610f1","added_by":"auto","created_at":"2025-05-19 16:07:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1137015,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5973815/v1/2c9901ce-da8e-4287-ba5d-9725a36c01da.pdf"},{"id":82067536,"identity":"db219bc4-ec68-4098-ba2d-01e567c1dbe9","added_by":"auto","created_at":"2025-05-06 12:47:06","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":90612,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryfile.docx","url":"https://assets-eu.researchsquare.com/files/rs-5973815/v1/337eb9ce8373bff4c81d64d3.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Helicobacter pylori infection might be a protective factor against Parkinson’s disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe gastrointestinal tract serves not merely as a principal organ of digestion but also constitutes a critical immunological interface, orchestrating both local and systemic immune responses [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. A substantial body of evidence has established that gut-associated lymphoid tissue (GALT)-mediated immunity exerts profound pathophysiological effects on the development and progression of diverse extraintestinal disorders [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Nevertheless, the potential mechanistic links between gastric mucosal immune regulation and the pathogenesis of extragastric diseases remain underexplored, with extant literature offering only fragmentary insights into this association.\u003c/p\u003e \u003cp\u003eHelicobacter pylori(\u003cem\u003eH. pylori\u003c/em\u003e) is a microaerophilic Gram-negative bacterium and the most prevalent pathogen in the gastrointestinal tract worldwide, infecting approximately half of the global population [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Furthermore, \u003cem\u003eH. pylori\u003c/em\u003e can persist long-term in the gastric antrum, triggering corresponding mucosal immune responses and exerting significant effects on human gastric mucosal immunity[\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Research indicates its potential influence on various extragastric conditions, acting as a risk factor for some diseases while potentially offering protection against others[\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], such as Multiple sclerosis(MS) and inflammatory bowel disease (IBD), where the presence of \u003cem\u003eH. pylori\u003c/em\u003e has shown protective effects[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. However, research on the impact of \u003cem\u003eH. pylori\u003c/em\u003e on extraintestinal diseases, particularly central nervous system disorders, is limited, with inconsistent conclusions and unclear mechanisms. Given \u003cem\u003eH. pylori\u003c/em\u003e's protective role against intestinal mucosal inflammation in IBD, there is speculation about its potential inverse correlation with neurodegenerative diseases like Parkinson\u0026rsquo;s disease(PD).\u003c/p\u003e \u003cp\u003ePD is currently the second most prevalent neurodegenerative disorder worldwide, primarily affecting the elderly, with incidence increasing with age[\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In addition to motor symptoms, over 80% of patients may experience a range of gastrointestinal symptoms, including swallowing difficulties, delayed gastric emptying, severe constipation, and anorectal dysfunction, which can occur years before the onset of motor symptoms [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The pathological features of PD include progressive apoptosis of dopaminergic neurons in the substantia nigra pars compacta of the midbrain and the formation of Lewy bodies composed of abnormal α-synuclein aggregates within neurons. Post-mortem anatomical and animal experimental studies have shown that Lewy bodies can also be found in the enteric nervous system and vagal nerve axis in PD patients[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurrent evidence regarding the association between gastrointestinal immunity and PD remains limited, characterized by insufficient mechanistic investigations in basic research and clinically heterogeneous studies with inadequate sample sizes and inconsistent findings. To address this critical knowledge gap, particularly concerning the potential link between \u003cem\u003eH. pylori\u003c/em\u003e infection and PD pathogenesis, large-scale population-based studies with robust methodological designs are imperative. In this context, we implemented a nationwide population-based cohort study to systematically evaluate the epidemiological and pathophysiological relationship between \u003cem\u003eH. pylori\u003c/em\u003e infection and PD risk.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003e\u003cstrong\u003eEthical statement and study design\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a case-control study with the subjects derived from the outpatients and inpatients in the Sichuan Provincial People's Hospital, a provincial comprehensive hospital in Chengdu, China. All individuals provided their written, informed permission for the use of their clinical data in this study. Adhering strictly to the Declaration of Helsinki guidelines, this study received full approval from the Institutional Review Board for Clinical Research at the Sichuan Provincial People's Hospital.\u003c/p\u003e\n\u003cp\u003eThe PD cases were those definitively diagnosed by the Neurology Clinic and who agreed to participate in this study at this hospital from March 2022 to July 2024. During this period, the outpatients who undergopasting the 13C Urea Breath Test (13C-UBT) were included in the control group. Additionally, since the PD patients were sourced from outpatient clinics, we collected data on all patients at this hospital who had undergone 13C-UBT for \u003cem\u003eH. pylori\u003c/em\u003e infection detection from 2022 to 2024. Written informed consent was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinition of participants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParkinson’s disease cases:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInclusion Criteria:\u003c/p\u003e\n\u003cp\u003ePatients diagnosed with PD were established by neurologists through\u0026nbsp;Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD) [23]\u0026nbsp;, which was combined with comprehensive neurologic examinations, patient age, family history, and Parkinson’s diseasetous clinical manifestations. Only the initial test result will be recorded if multiple results are available and\u0026nbsp;we did not exclude participants with eradication treatment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExclusion Criteria:\u003c/p\u003e\n\u003cp\u003eParticipants with other severe neurodegenerative diseases besides Parkinson's disease, such as Alzheimer's disease, multiple system atrophy, progressive supranuclear palsy, etc., were excluded from the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutpatient controls:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInclusion Criteria:\u003c/p\u003e\n\u003cp\u003eParticipants from different outpatient departments in Sichuan provincial people’s hospital after 2022, who underwent 13C-UBT. Only the initial test result will be recorded if multiple results are available and\u0026nbsp;we did not exclude participants with eradication treatment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eExclusion Criteria:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParticipants with severe neurodegenerative diseases were excluded from the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinition of \u003cem\u003eH. pylori\u003c/em\u003e infection \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eH. pylori\u003c/em\u003e infection was determined using the 13C-UBT with the UREA-13C breath test Heliforce kits (Beijing Richen-Force Science \u0026amp; Technology, Beijing, China). Breath samples were collected before and 30 minutes after ingestion of 75 mg of 13C-urea by fasting patients (or those who had fasted for at least two hours). The breath samples were analyzed using an infrared heterodyne radiometer (Guangzhou Huayou Mingkang Optoelectronics Technology Co., Ltd, Guangzhou, China). Subjects who had taken histamine-2 receptor antagonists, proton pump inhibitors, antibiotics, bismuth compounds, or nonsteroidal anti-inflammatory drugs (excluding low doses of aspirin) in the preceding four weeks were excluded to avoid false-negative chances. This test provided a delta over baseline (DOB) value.\u003c/p\u003e\n\u003cp\u003eThe determination of \u003cem\u003eH. pylori\u003c/em\u003e infection positivity was conducted the following two criteria:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(i) DOB≥4.0: A DOB value of ≥4.0 was considered positive for \u003cem\u003eH. pylori\u003c/em\u003e infection. Values below this threshold were considered negative by most of based health check-up population study.\u003c/p\u003e\n\u003cp\u003e(ii)DOB≥8.0: A DOB value of ≥8.0 was considered positive for \u003cem\u003eH. pylori\u0026nbsp;\u003c/em\u003einfection. Values below this threshold were considered negative. The magnitude of the DOB value is related to the severity of H. pylori infection, with higher DOB values correlating with greater H. pylori density, as well as histopathological chronicity and activity indices.\u003c/p\u003e\n\u003cp\u003eIn selecting two distinct cutoff values for the 13C-UBT, we adopted DOB≥4 as the threshold, a standard widely utilized in the majority of epidemiological surveys to facilitate comparisons across studies. However, acknowledging the potential for false positives at the DOB≥4 level, we also employed a DOB≥8 cutoff to enhance the reliability of \u003cem\u003eH. pylori\u003c/em\u003e infection detection. The DOB≥8 threshold maintains detection sensitivity while improving specificity for \u003cem\u003eH. pylori\u003c/em\u003e infection. This dual-threshold approach offers a more comprehensive assessment of infection status and contributes to the increased reliability of our research findings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCovariate Definitions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSelf-designed questionnaire and the electronic medical records are used to collect the sociodemographic and medical characteristics of PD patients and outpatient controls. Participants who PD and non-Parkinson’s diseasetous population are interviewed face to face by the research assistants being trained standard. The covariates include sex, age, area, disease history (e.g. hypertension, diabetes mellitus, coronary artery disease, Peptic ulcer(Gastric and/or duodenal ulcers), Digestive tract cancer(Gastric cancer, colorectal cancer and/or esophageal cancer)), et al.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMeans ± standard deviations (SD) were calculated for continuous variables, while percentages were used for categorical variables in both the PD and comparison populations. Continuous variables were compared using the independent samples t-test. Categorical variables were compared using the χ² test, where applicable. Multivariate logistic regression and propensity score matching (PSM) analysis were utilized to exclude the selection bias and confounding factors. All variables with \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05 in the univariate analysis were included in the multivariate logistic regression to investigate the associations between risk factors and \u003cem\u003eH. pylori\u0026nbsp;\u003c/em\u003einfection. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Data were analyzed using SPSS, version 24.0 (IBM Corp), GraphPad Prism version 9.5.0, and RStudio software, version R-4.2.3 (R Core Team, 2024). \u003cem\u003eP\u003c/em\u003e value of less than 0.05 was considered statistically significant (two-tailed tests).\u003c/p\u003e"},{"header":"Result","content":"\u003cp\u003e\u003cstrong\u003e1.\u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eThe general situation of PD patients and outpatients population.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrom 2022 to 2024, 315 PD patients diagnosed by neurologist in the department of neurology of this hospital were included. The average age of PD patients was 64.67\u003cins cite=\"mailto:admin\" datetime=\"2025-01-05T10:40\"\u003e\u0026nbsp;\u003c/ins\u003e\u0026plusmn; 10.21 years, and 50% of them were male.\u003c/p\u003e\n\u003cp\u003eDuring the same period, 22383 outpatients population outpatients (older than 18 years) in the same hospital who had undergone the 13C-UBT for \u003cem\u003eH. pylori\u003c/em\u003e infection were included, comprising the hospital-based controls. The average age was 45.14 \u0026plusmn; 10.31 years with 42% of them were male. The age and gender distribution were still different between the PD cases with outpatients\u0026rsquo; population (Table 1).\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 549px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1. Comparison of the PD\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;group and the outpatients population\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003ePD(315)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003eoutpatients(22383)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eSex, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e157(49.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e9384(41.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e158(50.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e12999(58.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eAge, M(SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e64.67(10.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e45.14(14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e＜0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eArea, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eUrban\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e143(45.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e18754(83.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e＜0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eRural\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e172(54.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e3629(16.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eHypertension, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e83(26.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e2080(9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e＜0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 189px;\"\u003e\n \u003cp\u003eDiabetes Mellitus, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e36(11.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e1049(4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e＜0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eCoronary Artery Disease, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e12(3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e316(1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e＜0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003ePeptic ulcer, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e11(3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e731(3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.823\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eDigestive tract cancer, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e3(1.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e452(2.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.180\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003en (%) indicates the number of constituents (n) and the composition ratio (%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eComparison of \u003cem\u003eH. pylori\u003c/em\u003e infection rate between PD patients and outpatients population by univariate and multivariate logistic regression analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDue to significant differences in \u003cem\u003eH. pylori\u003c/em\u003e infection rates across regions, study periods, and detection methods, we compared whether the baseline infection rate in this study exhibited substantial selection bias. Based on recent studies on \u003cem\u003eH. pylori\u003c/em\u003e infection rates across various regions of China, we have compiled data from January 2020 to the present. The subjects in these studies were all aged 18 years or older, and the detection of \u003cem\u003eH. pylori\u003c/em\u003e infection was conducted using the 13C-UBT. These data are consistent with the \u003cem\u003eH. pylori\u003c/em\u003e infection prevalence observed in our hospital\u0026rsquo;s outpatient control group [24-30].\u003c/p\u003e\n\u003cp\u003eIn our statistical results, the univariate analysis showed that the \u003cem\u003eH. pylori\u003c/em\u003e infection rate in PD patients was significantly lower than that of the overall outpatient controls (DOB\u0026ge;8, 22.5% vs 27.5%, OR 0.77, 95% CI: 0.59-1.00, \u003cem\u003ep\u003c/em\u003e=0.049; DOB\u0026ge;4, 28.6% vs 33.9%, OR 0.78, 95% CI: 0.61-1.00, \u003cem\u003ep\u003c/em\u003e=0.046)(Fig 1A).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsidering the potential influence of other factors, including gender, age, area, hypertension, diabetes, coronary artery disease, Peptic ulcer(Gastric and/or duodenal ulcers) and Digestive tract cancer(Gastric cancer, colorectal cancer and/or esophageal cancer), we conducted a multivariate analysis of \u003cem\u003eH. pylori\u003c/em\u003e infection rates between PD patients and the outpatient controls. The results showed that the infection rate in PD patients was still significantly lower than that in the control group (DOB \u0026ge; 8: OR 0.74, 95% CI: 0.56\u0026ndash;0.97, \u003cem\u003ep\u003c/em\u003e = 0.030; DOB \u0026ge; 4: OR 0.73, 95% CI: 0.56\u0026ndash;0.94, \u003cem\u003ep\u003c/em\u003e = 0.015) (Fig 1B). Additionally, regardless of whether the population was urban or rural, the \u003cem\u003eH. pylori\u003c/em\u003e infection rate in PD patients was lower with a more pronounced and statistically significant difference observed in the rural population (Supplement table 1, Supplement Fig 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eComparison of \u003cem\u003eH. pylori\u003c/em\u003e infection rate between PD patients and outpatient controls after PSM\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo further validate the accuracy of these findings, we performed a PSM analysis. After balancing covariates, PSM confirmed lower \u003cem\u003eH. pylori\u003c/em\u003e infection rates in PD cases than in outpatient controls(DOB \u0026ge; 8: OR 0.69, 95% CI: 0.52\u0026ndash;0.91, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.009; DOB \u0026ge; 4: OR 0.71, 95% CI: 0.55\u0026ndash;0.92,\u003cem\u003e\u0026nbsp;p\u003c/em\u003e = 0.009) (Table 2 and Fig2A). Logistic regression post-PSM revealed the same results with the above (DOB \u0026ge; 8: OR 0.68, 95% CI: 0.52\u0026ndash;0.90, p = 0.008; DOB \u0026ge; 4: OR 0.70, 95% CI: 0.54\u0026ndash;0.91, p = 0.007) (Fig 2B). In conclusion, the infection rate in PD patients remained significantly lower than that in the control group, with a statistically significant difference.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Comparison of the PD group and the outpatient controls after PSM\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ePD(315)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eOutpatients(2205)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003eAge, M(SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e64.7\u0026plusmn;10.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e63.7\u0026plusmn;10.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.106\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003eSex (Male), n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e158(50.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1088(49.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.786\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003eHypertension, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e83(26.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e547(24.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.554\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 212px;\"\u003e\n \u003cp\u003eDiabetes Mellitus, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e36(11.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e217(9.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.381\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003eCoronary Artery Disease, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e12(3.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e65(2.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.407\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003ePeptic ulcer, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e51(2.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e11(3.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.210\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 212px;\"\u003e\n \u003cp\u003eDigestive tract cancer, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e12(0.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3(1.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.385\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003eArea(Rural)\u0026nbsp;, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e172(54.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1105(50.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.136\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003eH. pylori Infection (DOB\u0026ge;4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e90(28.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e795(36.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003eH. pylori Infection (DOB\u0026ge;8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e71(22.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e655(29.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003en (%) indicates the number of constituents (n) and the composition ratio (%).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAs we know, Parkinson's disease (PD) is an age-related neurodegenerative disorder. Its onset is associated with multiple factors, including genetics and environmental influences, though the exact pathogenesis remains unclear. In this study, we found that the rate of \u003cem\u003eH. pylori\u003c/em\u003e infection in PD patients was consistently lower than that in the outpatient control group across various analytical methods, including univariate analysis, multivariate analysis, and propensity score matching (PSM) analysis. Additionally, we observed that, regardless of whether the population was urban or rural, the \u003cem\u003eH. pylori\u003c/em\u003e infection rate in PD patients was lower than that in the control group, with a more pronounced and statistically significant difference observed in the rural population. This may be related to the simpler lifestyle and fewer confounding factors in rural areas(supplement Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Considering that PD is associated with aging, we divided the PD and outpatients population groups using 65 years of age as a cutoff for comparison. In the univariate analysis and multivariate analysis, the infection rate in PD patients under 65 was significantly lower than in outpatients population patients, with statistical significance(supplement Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePrevious studies have reported limited discussion on the relationship between \u003cem\u003eH. pylori\u003c/em\u003e and PD, with most findings contrary to our results. Dobbs et al. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] reported a higher infection rate of \u003cem\u003eH. pylori\u003c/em\u003e in PD patients (50 out of 105, or 47.6%) compared to non-PD patients (39.5%), with a more pronounced difference in those under 72 years old. The statistical analyses by Nafisah et al., Nielsen et al., and Bu et al. [\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] also indicated a higher infection rate in PD patients. Lee et al. [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] found that \u003cem\u003eH. pylori\u003c/em\u003e infection could reduce levodopa absorption during treatment, exacerbating symptom fluctuations. Mridula et al. [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] noted that \u003cem\u003eH. pylori\u003c/em\u003e infection affected levodopa absorption, leading to increased medication dosage. Liu et al. [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] concluded from a three-group controlled trial that eradicating \u003cem\u003eH. pylori\u003c/em\u003e improved clinical symptoms in PD patients, particularly in terms of bradykinesia. Lolekha et al. [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] suggested that eliminating \u003cem\u003eH. pylori\u003c/em\u003e could reduce symptom fluctuations in PD patients. However, other studies raised doubts. Nafisah et al., Narozanska et al., and Tan et al. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] argued that there were no significant improvements in clinical manifestations or UPDRS scores after \u003cem\u003eH. pylori\u003c/em\u003e eradication in positive PD patients. Nonetheless, these studies have certain limitations: first, current research largely consists of small-sample case-control and cross-sectional studies, with unclear theoretical mechanisms; second, because of the differences of the \u003cem\u003eH. pylori\u003c/em\u003e infection rate in rural and urban area, past research has more focused on developed regions while studies in developing countries or rural areas are lacking. This study aims to address these limitations. Based on recent findings in further research on \u003cem\u003eH. pylori\u003c/em\u003e and our statistical results, we suspect that the relationship between PD and \u003cem\u003eH. pylori\u003c/em\u003e infection differs from earlier research. The clinical research results merit further discussion.\u003c/p\u003e \u003cp\u003eThe pathogenesis of PD remains unclear. Brakk's theory posits that PD may originate outside the CNS, with pathogens crossing the gastrointestinal barrier and entering the CNS via the vagus nerve, with non-motor symptoms like gastrointestinal dysfunction often preceding motor symptoms[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Also, some evidence suggests it may involve immune-related or autoimmune mechanisms[\u003cspan additionalcitationids=\"CR44 CR45\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. This study found a negative correlation between PD and \u003cem\u003eH. pylori\u003c/em\u003e, indicating a potential protective role of \u003cem\u003eH. pylori\u003c/em\u003e, possibly through its modulation of immune responses, such as promoting regulatory T cell (Treg) activity in childhood and reducing inflammation[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].The \"hygiene hypothesis\"[\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e] ,which suggests that early exposure to enteric infections in less hygienic environments may prevent immune-related diseases later in life, further support the idea that early environmental exposures, including \u003cem\u003eH. pylori\u003c/em\u003e, may influence PD development by affecting immune regulation and gut-brain interactions, warranting further investigation into \u003cem\u003eH. pylori\u003c/em\u003e 's role in PD.\u003c/p\u003e \u003cp\u003eThis clinical study does have limitations. First, it consists solely of single-center data, which may not fully represent the situation in different countries and regions. Conducting multicenter studies is necessary to confirm these findings. Second, variations in extra-gastric diseases associated with \u003cem\u003eH. pylori\u003c/em\u003e may arise from diverse immune responses in hosts, yet we did not assess immune states in participants. Comparing immune responses between \u003cem\u003eH. pylori\u003c/em\u003e-positive and -negative individuals among both PD patients and controls is essential.\u003c/p\u003e \u003cp\u003eIn conclusion, the prevalence of \u003cem\u003eH. pylori\u003c/em\u003e infection in PD patients was significantly lower than that in the outpatient control group, with this difference reaching statistical significance. Given that \u003cem\u003eH. pylori\u003c/em\u003e infection is highly prevalent among middle-aged and younger populations, we propose that \u003cem\u003eH. pylori\u003c/em\u003e colonization might exert a protective effect against PD development, particularly during the early stages of the disease. However, further experimental and clinical studies are warranted to validate this hypothesis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was granted by the National Natural Science Foundation of China (82450003, 82370560) and the Sichuan Science and Technology Programgrants (2023YFS0022).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eThe datasets generated and/or analysed during the current study are not publicly available. Due to privacy protection and data security concerns, the data cannot be shared. However, upon reasonable request, the data may be made available from the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eFurness JB, Rivera LR, Cho HJ, Bravo DM, Callaghan B. The gut as a sensory organ. Nature reviews Gastroenterology \u0026amp; hepatology. 2013;10(12):729-740.\u003c/li\u003e\n \u003cli\u003eGuo N, Li N, Jia L, et al. Immune subset-committed proliferating cells populate the human foetal intestine throughout the second trimester of gestation. Nature Communications. 2023;14(1). doi:10.1038/s41467-023-37052-4\u003c/li\u003e\n \u003cli\u003eRogler G, Singh A, Kavanaugh A, Rubin DT. Extraintestinal Manifestations of Inflammatory Bowel Disease: Current Concepts, Treatment, and Implications for Disease Management. Gastroenterology. 2021;161(4):1118-1132.\u003c/li\u003e\n \u003cli\u003ePeng K, Xiao J, Wang J, et al. 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Q., Xu, Z. Q., Zhou, H. D., \u0026amp; Wang, Y. J. (2015). The association between infectious burden and Parkinson\u0026apos;s disease: A case-control study. \u003cem\u003eParkinsonism \u0026amp; related disorders\u003c/em\u003e, \u003cem\u003e21\u003c/em\u003e(8), 877\u0026ndash;881. https://doi.org/10.1016/j.parkreldis.2015.05.015\u003c/li\u003e\n \u003cli\u003eNafisah, Wan Yahya; Mohamed Ibrahim, Norlinah; Najman Achok, Hamdi; Hamizah, Razlan; Azmin, Shahrul; Remli, Rabani; Shah, Shamsul Azhar (2013). \u003cem\u003eHigh prevalence of Helicobacter pylori infection in Malaysian Parkinson\u0026amp;#39;s disease patients. Journal of Parkinsonism and Restless Legs Syndrome, (), 63\u0026ndash;.\u0026nbsp;\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003eNielsen, H. H., Qiu, J., Friis, S., Wermuth, L., \u0026amp; Ritz, B. (2012). 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Neurology, 16(6), 303\u0026ndash;318.\u003c/li\u003e\n \u003cli\u003eBonam, S. R., \u0026amp; Muller, S. (2020). Parkinson\u0026apos;s disease is an autoimmune disease: A reappraisal. Autoimmunity reviews, 19(12), 102684.\u003c/li\u003e\n \u003cli\u003eCampos-Acu\u0026ntilde;a, J., Elgueta, D., \u0026amp; Pacheco, R. (2019). T-Cell-Driven Inflammation as a Mediator of the Gut-Brain Axis Involved in Parkinson\u0026apos;s Disease. Frontiers in immunology, 10, 239.\u003c/li\u003e\n \u003cli\u003eChen, Z., Chen, S., \u0026amp; Liu, J. (2018). The role of T cells in the pathogenesis of Parkinson\u0026apos;s disease. Progress in neurobiology, 169, 1\u0026ndash;23.\u003c/li\u003e\n \u003cli\u003eKira J ichi. Helicobacter pylori infection might prove the hygiene hypothesis in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015;86(6):603-607.\u003c/li\u003e\n \u003cli\u003eBach JF. The hygiene hypothesis in autoimmunity: The role of pathogens and commensals. Nature Reviews Immunology. 2018;18(2):105-120.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"H. pylori infection, parkinson’s disease, gastrointestinal mucosal immune","lastPublishedDoi":"10.21203/rs.3.rs-5973815/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5973815/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: The gastrointestinal tract is not only an important component of the digestive system but also a crucial part of the body's immune system. Numerous studies have reported that gastrointestinal immunity plays a critical role in many extraintestinal diseases, including neurodegenerative disorders. However, the relationship between gastric mucosal immunity and neurodegenerative diseases, such as Parkinson’s disease(PD), remains underexplored.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: The rate of \u003cem\u003eH. pylori\u003c/em\u003e infection was assessed using the 13C-Urea Breath Test (13C-UBT) in a case-control study involving 315 PD patients and a control group of 22,383 outpatients. Multivariate regression and propensity score matching (PSM) analyses were employed to adjust for confounding factors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: A lower\u003cem\u003e H. pylori\u003c/em\u003e infection rate was found in PD cases compared to outpatient controls (DOB ≥ 8, 22.5% versus 27.5%,\u003cem\u003e p \u003c/em\u003e= 0.049; DOB ≥ 4, 28.6% versus 33.9%, \u003cem\u003ep \u003c/em\u003e= 0.046). After adjusting for confounding factors, the \u003cem\u003eH. pylori\u003c/em\u003e infection rate remained lower in PD cases compared to controls.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: The study revealed an inverse correlation between \u003cem\u003eH. pylori\u003c/em\u003e infection and PD, suggesting that \u003cem\u003eH. pylori\u003c/em\u003e infection could potentially act as a protective factor against the development of PD.\u003c/p\u003e","manuscriptTitle":"Helicobacter pylori infection might be a protective factor against Parkinson’s disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-06 12:39:02","doi":"10.21203/rs.3.rs-5973815/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-28T05:13:10+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-27T02:04:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"70778210525896365014113658083111597376","date":"2025-04-26T09:19:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-24T09:10:26+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-23T12:56:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-04-10T04:21:25+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1e5034cc-8dea-497c-a8b6-ecba8f978db8","owner":[],"postedDate":"May 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":47617686,"name":"Health sciences/Neurology/Neurological disorders/Parkinsons disease"},{"id":47617687,"name":"Health sciences/Gastroenterology/Gastrointestinal system/Stomach"},{"id":47617688,"name":"Health sciences/Health care/Public health/Epidemiology"}],"tags":[],"updatedAt":"2025-05-19T16:02:42+00:00","versionOfRecord":{"articleIdentity":"rs-5973815","link":"https://doi.org/10.1038/s41598-025-01562-6","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-05-14 15:57:13","publishedOnDateReadable":"May 14th, 2025"},"versionCreatedAt":"2025-05-06 12:39:02","video":"","vorDoi":"10.1038/s41598-025-01562-6","vorDoiUrl":"https://doi.org/10.1038/s41598-025-01562-6","workflowStages":[]},"version":"v1","identity":"rs-5973815","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5973815","identity":"rs-5973815","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}