Impaired Gut Barrier Integrity and Reduced Colonic Expression of Free Fatty Acid Receptors in Patients with Parkinson's Disease

Overview

Journal Neurol Sci

Specialty Neurology

Date 2024 Jun 11

PMID 38862654

Authors

Peng-Hsiang Liao

Hsiao-Yen Tung

Wee Shin Lim

Jyh-Shing Roger Jang

Hsun Li

Chia-Tung Shun

Han-Mo Chiu

Ming-Shiang Wu

Chin-Hsien Lin

Affiliations

Soon will be listed here.

Abstract

Background: Altered gut metabolites, especially short-chain fatty acids (SCFAs), in feces and plasma are observed in patients with Parkinson's disease (PD).

Objective: We aimed to investigate the colonic expression of two SCFA receptors, free fatty acid receptor (FFAR)2 and FFAR3, and gut barrier integrity in patients with PD and correlations with clinical severity.

Methods: In this retrospective study, colonic biopsy specimens were collected from 37 PD patients and 34 unaffected controls. Of this cohort, 31 participants (14 PD, 17 controls) underwent a series of colon biopsies. Colonic expression of FFAR2, FFAR3, and the tight junction marker ZO-1 were assayed by immunofluorescence staining. The You Only Look Once (version 8, YOLOv8) algorithm was used for automated detection and segmentation of immunostaining signal. PD motor function was assessed with the Movement Disorder Society (MDS)-Unified Parkinson's Disease Rating Scale (UPDRS), and constipation was assessed using Rome-IV criteria.

Results: Compared with controls, PD patients had significantly lower colonic expression of ZO-1 (p < 0.01) and FFAR2 (p = 0.01). On serial biopsy, colonic expression of FFAR2 and FFAR3 was reduced in the pre-motor stage before PD diagnosis (both p < 0.01). MDS-UPDRS motor scores did not correlate with colonic marker levels. Constipation severity negatively correlated with colonic ZO-1 levels (r = -0.49, p = 0.02).

Conclusions: Colonic expression of ZO-1 and FFAR2 is lower in PD patients compared with unaffected controls, and FFAR2 and FFAR3 levels decline in the pre-motor stage of PD. Our findings implicate a leaky gut phenomenon in PD and reinforce that gut metabolites may contribute to the process of PD.

References

Braak H, Del Tredici K, Rub U, de Vos R, Jansen Steur E, Braak E . Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2002; 24(2):197-211. DOI: 10.1016/s0197-4580(02)00065-9. View

Savica R, Carlin J, Grossardt B, Bower J, Ahlskog J, Maraganore D . Medical records documentation of constipation preceding Parkinson disease: A case-control study. Neurology. 2009; 73(21):1752-8. PMC: 2788809. DOI: 10.1212/WNL.0b013e3181c34af5. View

Romano S, Savva G, Bedarf J, Charles I, Hildebrand F, Narbad A . Meta-analysis of the Parkinson's disease gut microbiome suggests alterations linked to intestinal inflammation. NPJ Parkinsons Dis. 2021; 7(1):27. PMC: 7946946. DOI: 10.1038/s41531-021-00156-z. View

Lin C, Chen C, Chiang H, Liou J, Chang C, Lu T . Altered gut microbiota and inflammatory cytokine responses in patients with Parkinson's disease. J Neuroinflammation. 2019; 16(1):129. PMC: 6598278. DOI: 10.1186/s12974-019-1528-y. View

Tan A, Lim S, Lang A . The microbiome-gut-brain axis in Parkinson disease - from basic research to the clinic. Nat Rev Neurol. 2022; 18(8):476-495. DOI: 10.1038/s41582-022-00681-2. View

Chen S, Lin C . Gut microenvironmental changes as a potential trigger in Parkinson's disease through the gut-brain axis. J Biomed Sci. 2022; 29(1):54. PMC: 9327249. DOI: 10.1186/s12929-022-00839-6. View

Blacher E, Levy M, Tatirovsky E, Elinav E . Microbiome-Modulated Metabolites at the Interface of Host Immunity. J Immunol. 2017; 198(2):572-580. DOI: 10.4049/jimmunol.1601247. View

Unger M, Spiegel J, Dillmann K, Grundmann D, Philippeit H, Burmann J . Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls. Parkinsonism Relat Disord. 2016; 32:66-72. DOI: 10.1016/j.parkreldis.2016.08.019. View

Aho V, Houser M, Pereira P, Chang J, Rudi K, Paulin L . Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson's disease. Mol Neurodegener. 2021; 16(1):6. PMC: 7869249. DOI: 10.1186/s13024-021-00427-6. View

10.

Yang X, Ai P, He X, Mo C, Zhang Y, Xu S . Parkinson's Disease Is Associated with Impaired Gut-Blood Barrier for Short-Chain Fatty Acids. Mov Disord. 2022; 37(8):1634-1643. DOI: 10.1002/mds.29063. View

11.

Chen S, Chen C, Liao H, Lin Y, Wu Y, Liou J . Association of Fecal and Plasma Levels of Short-Chain Fatty Acids With Gut Microbiota and Clinical Severity in Patients With Parkinson Disease. Neurology. 2022; 98(8):e848-e858. PMC: 8883514. DOI: 10.1212/WNL.0000000000013225. View

12.

Kumari S, Goyal V, Kumaran S, Dwivedi S, Srivastava A, Jagannathan N . Quantitative metabolomics of saliva using proton NMR spectroscopy in patients with Parkinson's disease and healthy controls. Neurol Sci. 2020; 41(5):1201-1210. DOI: 10.1007/s10072-019-04143-4. View

13.

Wu G, Jiang Z, Pu Y, Chen S, Wang T, Wang Y . Serum short-chain fatty acids and its correlation with motor and non-motor symptoms in Parkinson's disease patients. BMC Neurol. 2022; 22(1):13. PMC: 8740341. DOI: 10.1186/s12883-021-02544-7. View

14.

Sampson T, Debelius J, Thron T, Janssen S, Shastri G, Ilhan Z . Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell. 2016; 167(6):1469-1480.e12. PMC: 5718049. DOI: 10.1016/j.cell.2016.11.018. View

15.

Ghosh S, Whitley C, Haribabu B, Jala V . Regulation of Intestinal Barrier Function by Microbial Metabolites. Cell Mol Gastroenterol Hepatol. 2021; 11(5):1463-1482. PMC: 8025057. DOI: 10.1016/j.jcmgh.2021.02.007. View

16.

Dalile B, Van Oudenhove L, Vervliet B, Verbeke K . The role of short-chain fatty acids in microbiota-gut-brain communication. Nat Rev Gastroenterol Hepatol. 2019; 16(8):461-478. DOI: 10.1038/s41575-019-0157-3. View

17.

Mishra S, Karunakar P, Taraphder S, Yadav H . Free Fatty Acid Receptors 2 and 3 as Microbial Metabolite Sensors to Shape Host Health: Pharmacophysiological View. Biomedicines. 2020; 8(6). PMC: 7344995. DOI: 10.3390/biomedicines8060154. View

18.

Smith P, Howitt M, Panikov N, Michaud M, Gallini C, Bohlooly-Y M . The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013; 341(6145):569-73. PMC: 3807819. DOI: 10.1126/science.1241165. View

19.

Sivaprakasam S, Gurav A, Paschall A, Coe G, Chaudhary K, Cai Y . An essential role of Ffar2 (Gpr43) in dietary fibre-mediated promotion of healthy composition of gut microbiota and suppression of intestinal carcinogenesis. Oncogenesis. 2016; 5(6):e238. PMC: 4945739. DOI: 10.1038/oncsis.2016.38. View

20.

Lin C, Lin H, Ho E, Ke Y, Cheng M, Shiue C . Mild Chronic Colitis Triggers Parkinsonism in LRRK2 Mutant Mice Through Activating TNF-α Pathway. Mov Disord. 2021; 37(4):745-757. DOI: 10.1002/mds.28890. View