Age-associated temporal decline in butyrate-producing bacteria plays a key pathogenic role in the onset and progression of neuropathology and memory deficits in 3×Tg-AD mice
Alterations in the gut-microbiome-brain axis are increasingly being recognized to be involved in Alzheimer’s disease (AD) pathogenesis. However, the functional consequences of enteric dysbiosis linking gut microbiota and brain pathology in AD progression remain largely undetermined. The present work...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Gut Microbes |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19490976.2024.2389319 |
| _version_ | 1827138635571396608 |
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| author | Paula M. Chilton Smita S. Ghare Benjamin T. Charpentier Scott A. Myers Aakarsha V. Rao Joseph F. Petrosino Kristi L. Hoffman John C. Greenwell Neetu Tyagi Jyotirmaya Behera Yali Wang Lucy J. Sloan JingWen Zhang Christopher B. Shields Gregory E. Cooper Leila Gobejishvili Scott R. Whittemore Craig J. McClain Shirish S. Barve |
| author_facet | Paula M. Chilton Smita S. Ghare Benjamin T. Charpentier Scott A. Myers Aakarsha V. Rao Joseph F. Petrosino Kristi L. Hoffman John C. Greenwell Neetu Tyagi Jyotirmaya Behera Yali Wang Lucy J. Sloan JingWen Zhang Christopher B. Shields Gregory E. Cooper Leila Gobejishvili Scott R. Whittemore Craig J. McClain Shirish S. Barve |
| author_sort | Paula M. Chilton |
| collection | DOAJ |
| description | Alterations in the gut-microbiome-brain axis are increasingly being recognized to be involved in Alzheimer’s disease (AD) pathogenesis. However, the functional consequences of enteric dysbiosis linking gut microbiota and brain pathology in AD progression remain largely undetermined. The present work investigated the causal role of age-associated temporal decline in butyrate-producing bacteria and butyrate in the etiopathogenesis of AD. Longitudinal metagenomics, neuropathological, and memory analyses were performed in the 3×Tg-AD mouse model. Metataxonomic analyses showed a significant temporal decline in the alpha diversity marked by a decrease in butyrate-producing bacterial communities and a concurrent reduction in cecal butyrate production. Inferred metagenomics analysis identified the bacterial acetyl-CoA pathway as the main butyrate synthesis pathway impacted. Concomitantly, there was an age-associated decline in the transcriptionally permissive acetylation of histone 3 at lysines 9 and 14 (H3K9/K14-Ac) in hippocampal neurons. Importantly, these microbiome-gut-brain changes preceded AD-related neuropathology, including oxidative stress, tau hyperphosphorylation, memory deficits, and neuromuscular dysfunction, which manifest by 17–18 months. Initiation of oral administration of tributyrin, a butyrate prodrug, at 6 months of age mitigated the age-related decline in butyrate-producing bacteria, protected the H3K9/K14-Ac status, and attenuated the development of neuropathological and cognitive changes associated with AD pathogenesis. These data causally implicate age-associated decline in butyrate-producing bacteria as a key pathogenic feature of the microbiome-gut-brain axis affecting the onset and progression of AD. Importantly, the regulation of butyrate-producing bacteria and consequent butyrate synthesis could be a significant therapeutic strategy in the prevention and treatment of AD. |
| first_indexed | 2025-03-20T18:26:29Z |
| format | Article |
| id | doaj.art-68fececdccb84cc983088b9ee897f11c |
| institution | Directory Open Access Journal |
| issn | 1949-0976 1949-0984 |
| language | English |
| last_indexed | 2025-03-20T18:26:29Z |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Gut Microbes |
| spelling | doaj.art-68fececdccb84cc983088b9ee897f11c2024-08-25T17:38:42ZengTaylor & Francis GroupGut Microbes1949-09761949-09842024-12-0116110.1080/19490976.2024.2389319Age-associated temporal decline in butyrate-producing bacteria plays a key pathogenic role in the onset and progression of neuropathology and memory deficits in 3×Tg-AD micePaula M. Chilton0Smita S. Ghare1Benjamin T. Charpentier2Scott A. Myers3Aakarsha V. Rao4Joseph F. Petrosino5Kristi L. Hoffman6John C. Greenwell7Neetu Tyagi8Jyotirmaya Behera9Yali Wang10Lucy J. Sloan11JingWen Zhang12Christopher B. Shields13Gregory E. Cooper14Leila Gobejishvili15Scott R. Whittemore16Craig J. McClain17Shirish S. Barve18Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USADepartment of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USADepartment of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USADepartment of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USADepartment of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USAAlkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX, USAAlkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX, USADepartment of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USADepartment of Physiology, University of Louisville School of Medicine, Louisville, KY, USADepartment of Physiology, University of Louisville School of Medicine, Louisville, KY, USADepartment of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USADepartment of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USADepartment of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USANorton Neuroscience Institute, 4915 Norton Healthcare Blvd, Louisville, KY, USANorton Neuroscience Institute, 4915 Norton Healthcare Blvd, Louisville, KY, USADepartment of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USADepartment of Anatomical Sciences & Neurobiology, University of Louisville School of Medicine, Louisville, KY, USADepartment of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USADepartment of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USAAlterations in the gut-microbiome-brain axis are increasingly being recognized to be involved in Alzheimer’s disease (AD) pathogenesis. However, the functional consequences of enteric dysbiosis linking gut microbiota and brain pathology in AD progression remain largely undetermined. The present work investigated the causal role of age-associated temporal decline in butyrate-producing bacteria and butyrate in the etiopathogenesis of AD. Longitudinal metagenomics, neuropathological, and memory analyses were performed in the 3×Tg-AD mouse model. Metataxonomic analyses showed a significant temporal decline in the alpha diversity marked by a decrease in butyrate-producing bacterial communities and a concurrent reduction in cecal butyrate production. Inferred metagenomics analysis identified the bacterial acetyl-CoA pathway as the main butyrate synthesis pathway impacted. Concomitantly, there was an age-associated decline in the transcriptionally permissive acetylation of histone 3 at lysines 9 and 14 (H3K9/K14-Ac) in hippocampal neurons. Importantly, these microbiome-gut-brain changes preceded AD-related neuropathology, including oxidative stress, tau hyperphosphorylation, memory deficits, and neuromuscular dysfunction, which manifest by 17–18 months. Initiation of oral administration of tributyrin, a butyrate prodrug, at 6 months of age mitigated the age-related decline in butyrate-producing bacteria, protected the H3K9/K14-Ac status, and attenuated the development of neuropathological and cognitive changes associated with AD pathogenesis. These data causally implicate age-associated decline in butyrate-producing bacteria as a key pathogenic feature of the microbiome-gut-brain axis affecting the onset and progression of AD. Importantly, the regulation of butyrate-producing bacteria and consequent butyrate synthesis could be a significant therapeutic strategy in the prevention and treatment of AD.https://www.tandfonline.com/doi/10.1080/19490976.2024.2389319Alzheimer’s diseasegut microbiomegut dysbiosismetagenomicsbutyrate-producing bacteriahistone acetylation |
| spellingShingle | Paula M. Chilton Smita S. Ghare Benjamin T. Charpentier Scott A. Myers Aakarsha V. Rao Joseph F. Petrosino Kristi L. Hoffman John C. Greenwell Neetu Tyagi Jyotirmaya Behera Yali Wang Lucy J. Sloan JingWen Zhang Christopher B. Shields Gregory E. Cooper Leila Gobejishvili Scott R. Whittemore Craig J. McClain Shirish S. Barve Age-associated temporal decline in butyrate-producing bacteria plays a key pathogenic role in the onset and progression of neuropathology and memory deficits in 3×Tg-AD mice Gut Microbes Alzheimer’s disease gut microbiome gut dysbiosis metagenomics butyrate-producing bacteria histone acetylation |
| title | Age-associated temporal decline in butyrate-producing bacteria plays a key pathogenic role in the onset and progression of neuropathology and memory deficits in 3×Tg-AD mice |
| title_full | Age-associated temporal decline in butyrate-producing bacteria plays a key pathogenic role in the onset and progression of neuropathology and memory deficits in 3×Tg-AD mice |
| title_fullStr | Age-associated temporal decline in butyrate-producing bacteria plays a key pathogenic role in the onset and progression of neuropathology and memory deficits in 3×Tg-AD mice |
| title_full_unstemmed | Age-associated temporal decline in butyrate-producing bacteria plays a key pathogenic role in the onset and progression of neuropathology and memory deficits in 3×Tg-AD mice |
| title_short | Age-associated temporal decline in butyrate-producing bacteria plays a key pathogenic role in the onset and progression of neuropathology and memory deficits in 3×Tg-AD mice |
| title_sort | age associated temporal decline in butyrate producing bacteria plays a key pathogenic role in the onset and progression of neuropathology and memory deficits in 3 tg ad mice |
| topic | Alzheimer’s disease gut microbiome gut dysbiosis metagenomics butyrate-producing bacteria histone acetylation |
| url | https://www.tandfonline.com/doi/10.1080/19490976.2024.2389319 |
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