Lewy body diseases and the gut
Abstract Gastrointestinal (GI) involvement in Lewy body diseases (LBDs) has been observed since the initial descriptions of patients by James Parkinson. Recent experimental and human observational studies raise the possibility that pathogenic alpha-synuclein (⍺-syn) might develop in the GI tract and...
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| Format: | Article |
| Language: | English |
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BMC
2025-01-01
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| Series: | Molecular Neurodegeneration |
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| Online Access: | https://doi.org/10.1186/s13024-025-00804-5 |
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| author | Timothy R. Sampson Malú Gámez Tansey Andrew B. West Rodger A. Liddle |
| author_facet | Timothy R. Sampson Malú Gámez Tansey Andrew B. West Rodger A. Liddle |
| author_sort | Timothy R. Sampson |
| collection | DOAJ |
| description | Abstract Gastrointestinal (GI) involvement in Lewy body diseases (LBDs) has been observed since the initial descriptions of patients by James Parkinson. Recent experimental and human observational studies raise the possibility that pathogenic alpha-synuclein (⍺-syn) might develop in the GI tract and subsequently spread to susceptible brain regions. The cellular and mechanistic origins of ⍺-syn propagation in disease are under intense investigation. Experimental LBD models have implicated important contributions from the intrinsic gut microbiome, the intestinal immune system, and environmental toxicants, acting as triggers and modifiers to GI pathologies. Here, we review the primary clinical observations that link GI dysfunctions to LBDs. We first provide an overview of GI anatomy and the cellular repertoire relevant for disease, with a focus on luminal-sensing cells of the intestinal epithelium including enteroendocrine cells that express ⍺-syn and make direct contact with nerves. We describe interactions within the GI tract with resident microbes and exogenous toxicants, and how these may directly contribute to ⍺-syn pathology along with related metabolic and immunological responses. Finally, critical knowledge gaps in the field are highlighted, focusing on pivotal questions that remain some 200 years after the first descriptions of GI tract dysfunction in LBDs. We predict that a better understanding of how pathophysiologies in the gut influence disease risk and progression will accelerate discoveries that will lead to a deeper overall mechanistic understanding of disease and potential therapeutic strategies targeting the gut-brain axis to delay, arrest, or prevent disease progression. |
| format | Article |
| id | doaj-art-7871d539902b4dd4b3bb328ff055aea7 |
| institution | Kabale University |
| issn | 1750-1326 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj-art-7871d539902b4dd4b3bb328ff055aea72025-02-02T12:42:29ZengBMCMolecular Neurodegeneration1750-13262025-01-0120111810.1186/s13024-025-00804-5Lewy body diseases and the gutTimothy R. Sampson0Malú Gámez Tansey1Andrew B. West2Rodger A. Liddle3Department of Cell Biology, Emory University School of MedicineAligning Science Across Parkinson’s (ASAP) Collaborative Research NetworkAligning Science Across Parkinson’s (ASAP) Collaborative Research NetworkAligning Science Across Parkinson’s (ASAP) Collaborative Research NetworkAbstract Gastrointestinal (GI) involvement in Lewy body diseases (LBDs) has been observed since the initial descriptions of patients by James Parkinson. Recent experimental and human observational studies raise the possibility that pathogenic alpha-synuclein (⍺-syn) might develop in the GI tract and subsequently spread to susceptible brain regions. The cellular and mechanistic origins of ⍺-syn propagation in disease are under intense investigation. Experimental LBD models have implicated important contributions from the intrinsic gut microbiome, the intestinal immune system, and environmental toxicants, acting as triggers and modifiers to GI pathologies. Here, we review the primary clinical observations that link GI dysfunctions to LBDs. We first provide an overview of GI anatomy and the cellular repertoire relevant for disease, with a focus on luminal-sensing cells of the intestinal epithelium including enteroendocrine cells that express ⍺-syn and make direct contact with nerves. We describe interactions within the GI tract with resident microbes and exogenous toxicants, and how these may directly contribute to ⍺-syn pathology along with related metabolic and immunological responses. Finally, critical knowledge gaps in the field are highlighted, focusing on pivotal questions that remain some 200 years after the first descriptions of GI tract dysfunction in LBDs. We predict that a better understanding of how pathophysiologies in the gut influence disease risk and progression will accelerate discoveries that will lead to a deeper overall mechanistic understanding of disease and potential therapeutic strategies targeting the gut-brain axis to delay, arrest, or prevent disease progression.https://doi.org/10.1186/s13024-025-00804-5Parkinson’s diseaseDementia with Lewy bodiesParkinson’s disease dementiaGastrointestinal tractImmunityInflammation |
| spellingShingle | Timothy R. Sampson Malú Gámez Tansey Andrew B. West Rodger A. Liddle Lewy body diseases and the gut Molecular Neurodegeneration Parkinson’s disease Dementia with Lewy bodies Parkinson’s disease dementia Gastrointestinal tract Immunity Inflammation |
| title | Lewy body diseases and the gut |
| title_full | Lewy body diseases and the gut |
| title_fullStr | Lewy body diseases and the gut |
| title_full_unstemmed | Lewy body diseases and the gut |
| title_short | Lewy body diseases and the gut |
| title_sort | lewy body diseases and the gut |
| topic | Parkinson’s disease Dementia with Lewy bodies Parkinson’s disease dementia Gastrointestinal tract Immunity Inflammation |
| url | https://doi.org/10.1186/s13024-025-00804-5 |
| work_keys_str_mv | AT timothyrsampson lewybodydiseasesandthegut AT malugameztansey lewybodydiseasesandthegut AT andrewbwest lewybodydiseasesandthegut AT rodgeraliddle lewybodydiseasesandthegut |