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
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
Affiliations
Paula M. Chilton
Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
Smita S. Ghare
Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
Benjamin T. Charpentier
Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
Scott A. Myers
Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
Aakarsha V. Rao
Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
Joseph F. Petrosino
Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX, USA
Kristi L. Hoffman
Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX, USA
John C. Greenwell
Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
Neetu Tyagi
Department of Physiology, University of Louisville School of Medicine, Louisville, KY, USA
Jyotirmaya Behera
Department of Physiology, University of Louisville School of Medicine, Louisville, KY, USA
Yali Wang
Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
Lucy J. Sloan
Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
JingWen Zhang
Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
Christopher B. Shields
Norton Neuroscience Institute, 4915 Norton Healthcare Blvd, Louisville, KY, USA
Gregory E. Cooper
Norton Neuroscience Institute, 4915 Norton Healthcare Blvd, Louisville, KY, USA
Leila Gobejishvili
Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
Scott R. Whittemore
Department of Anatomical Sciences & Neurobiology, University of Louisville School of Medicine, Louisville, KY, USA
Craig J. McClain
Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
Shirish S. Barve
Department of Medicine, Division of Gastroenterology, Hepatology & Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
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.
