Garrett Fissel

Background: Alzheimer’s disease (AD) presents a pressing challenge in public health, with increasing prevalence rates worldwide. Research into its etiology and potential therapeutic avenues has intensified, particularly focusing on the intricate interplay between the gut microbiome, metabolic alterations, and neurodegeneration^1,2,3. Recent studies have highlighted significant shifts in the gut microbiota composition in AD, with distinct microbial profiles observed in transgenic AD mouse models compared to wild-type controls^1,4,6. Moreover, alterations in bile acid metabolism, driven by dysbiosis of gut microbiota, have emerged as potential contributors to cognitive impairment in AD². The gut-brain axis, a bidirectional communication pathway between the gastrointestinal tract and the central nervous system, is implicated in AD pathogenesis, with gut microbiota-derived metabolites potentially influencing neuroinflammation and neurodegeneration³. Furthermore, modulation of gut microbiota composition through interventions like capsaicin treatment has shown promise in ameliorating AD pathology, highlighting the therapeutic potential of targeting the gut-brain axis⁵. However, despite advancements in understanding the role of gut microbiota and metabolic dysregulation in AD, significant gaps remain in elucidating the underlying mechanisms and translating preclinical findings into clinical interventions^2,7. Addressing these knowledge gaps is crucial for developing effective preventive and therapeutic strategies to mitigate the burden of AD on individuals and society. This review aims to synthesize existing literature on the gut microbiome, metabolic alterations, and their implications for AD pathogenesis, with a focus on identifying avenues for future research and therapeutic development.

Objective: This narrative review delves into the intricate relationship between AD and the gut microbiome, aiming to elucidate potential diagnostic and therapeutic avenues. Drawing from existing literature, we explore the multifaceted etiology of AD, encompassing genetic, environmental, and microbial factors. Notably, alterations in gut microbiota composition have been implicated in AD development, with specific bacterial strains linked to the emergence of AD-related biomarkers.

Search Methods: A search was conducted in the PubMed database from 2018 to 2024 using relevant keywords including “Alzheimer’s disease,” “gut microbiome,” “bile acids,” and “neuroinflammation.”.

Results: The results of several studies shed light on the intricate relationship between gut microbiome alterations and Alzheimer’s disease (AD), offering valuable insights into disease pathogenesis and potential therapeutic avenues ^1,2,3,4,5. Analysis of fecal samples from APP/PS1 transgenic mice, employed as an AD model, revealed distinct shifts in gut microbiota diversity and abundance compared to normal controls, with notable increases in Proteobacteria and Erysipelotrichaceae, suggesting inflammation’s involvement in AD pathology¹. Additionally, research suggests a link between cholesterol metabolism in the liver, bile acid production, and AD, highlighting the potential role of gut microbiota in modulating metabolic pathways relevant to disease pathogenesis ². Specific bacterial genera, such as Dubosiella and Erysipelatoclostridium, were associated with altered metabolite production, including palmitoleic acid and deoxycholic acid, respectively, suggesting their involvement in AD-related metabolic dysregulation ⁴. Moreover, metabolomic analysis of human fecal samples revealed correlations between altered bacterial genera and fecal metabolites in AD patients, indicating potential links between gut microbiome alterations, estrogen biosynthesis, and immune markers relevant to disease progression⁵. Capsaicin treatment in APP/PS1 mice led to favorable alterations in gut microbiota composition, favoring beneficial bacteria while reducing harmful ones, highlighting its potential as a therapeutic intervention for AD⁵.

Conclusions: In summary, our review underscores the significant link between Alzheimer’s disease (AD) and the gut microbiome, highlighting alterations in microbial composition and metabolite production associated with AD pathogenesis. These findings suggest therapeutic potential in targeting the gut microbiota for AD management. However, further research is needed to elucidate mechanistic insights and optimize interventions. Questions about the causal relationship, microbial pathways, and efficacy of microbiome-targeted therapies remain. By bridging microbiology, neuroscience, and clinical medicine, our review emphasizes the importance of leveraging the gut microbiome in advancing AD research and therapy development.

Works Cited:

1. Bäuerl, C., Collado, M. C., Cuevas, A. D., Viña, J., & Martínez, G. P. (2018). Shifts in gut microbiota composition in an APP/PS1 transgenic mouse model of Alzheimer’s disease during lifespan. Letters in Applied Microbiology, 66(6), 464–471. https://doi.org/10.1111/lam.12882
2. MahmoudianDehkordi, S., Arnold, M., Nho, K., et al. (2019). Altered bile acid profile associates with cognitive impairment in Alzheimer’s disease-An emerging role for gut microbiome. Alzheimer’s & Dementia, 15(1), 76–92. https://doi.org/10.1016/j.jalz.2018.07.217
3. Chen, Y., Li, Y., Fan, Y., et al. (2024). Gut microbiota-driven metabolic alterations reveal gut-brain communication in Alzheimer’s disease model mice. Gut Microbes, 16(1), 2302310. https://doi.org/10.1080/19490976.2024.2302310
4. Xi, J., Ding, D., Zhu, H., et al. (2021). Disturbed microbial ecology in Alzheimer’s disease: evidence from the gut microbiota and fecal metabolome. BMC Microbiology. https://doi.org/10.1186/s12866-021-02286-z
5. Li, J., Liao, X., Yin, X., et al. (2022). Gut Microbiome and Serum Metabolome Profiles of Capsaicin with Cognitive Benefits in APP/PS1 Mice. Nutrients, 15(1), 118. https://doi.org/10.3390/nu15010118
6. Czarnik W, Fularski P, Gajewska A, et al. The Role of Intestinal Microbiota and Diet as Modulating Factors in the Course of Alzheimer’s and Parkinson’s Diseases. Nutrients. 2024;16(2):308. Published 2024 Jan 19. doi:10.3390/nu16020308
7. Aljumaah MR, Bhatia U, Roach J, Gunstad J, Azcarate Peril MA. The gut microbiome, mild cognitive impairment, and probiotics: A randomized clinical trial in middle-aged and older adults. Clin Nutr. 2022;41(11):2565-2576. doi:10.1016/j.clnu.2022.09.012