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. 2024 Jan-Dec;16(1):2389319.
doi: 10.1080/19490976.2024.2389319. Epub 2024 Aug 25.

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  1   2   3 , Smita S Ghare  1   2   3   4 , Benjamin T Charpentier  1   2   5 , Scott A Myers  1   2   5 , Aakarsha V Rao  1   2 , Joseph F Petrosino  6 , Kristi L Hoffman  6 , John C Greenwell  1   2 , Neetu Tyagi  7 , Jyotirmaya Behera  7 , Yali Wang  1   2   7 , Lucy J Sloan  1   2   8 , JingWen Zhang  1   2 , Christopher B Shields  3   9 , Gregory E Cooper  3 , Leila Gobejishvili  1   2   4   7 , Scott R Whittemore  5   9 , Craig J McClain  1   2   4   10 , Shirish S Barve  1   2   3   4
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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 et al. Gut Microbes. 2024 Jan-Dec.

Abstract

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.

Keywords: Alzheimer’s disease; butyrate-producing bacteria; gut dysbiosis; gut microbiome; histone acetylation; metagenomics; tau hyperphosphorylation; tributyrin.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Age-associated decrease in microbial diversity and alterations in microbial composition in 3×Tg mice.
Figure 2.
Figure 2.
Oral administration of TB prevents the decrease in microbial diversity and composition in 18 month old 3×Tg mice.
Figure 3.
Figure 3.
Alterations in the abundance of butyrate-synthesizing genes observed in 3×Tg mice.
Figure 4.
Figure 4.
TB prevents hyper-phosphorylation of tau, a critical component of ad-like pathology in 3×Tg mice.
Figure 5.
Figure 5.
Age-associated oxidative stress is abrogated in 3×Tg mice through oral TB administration.
Figure 6.
Figure 6.
TB supplementation prevents the age-related decrease of H3K9/K14-ac in 3×Tg mice.
Figure 7.
Figure 7.
TB protects 3×Tg mice from developing memory and neuromuscular deficits at 17 months.
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