Identification of Enterotype for Patients with Alzheimer's Disease

Overview

Journal J Transl Med

Publisher Biomed Central

Specialties Biomedical Engineering
General Medicine

Date 2025 Mar 11

PMID 40065353

Authors

Guang-Sheng Liu

Yang Song

Jin-Sheng Yan

Yi-Jie Chai

Yun-Fei Zhao

Huan Ma

Affiliations

Soon will be listed here.

Abstract

Background: Alzheimer's disease (AD) is a progressive and chronic neurodegenerative disorder of the central nervous system, characterized by behavioral and dysexecutive deficits. Its pathogenesis is closely associated with the intestinal flora. This study aimed to explore the enterotypes in AD by identifying key bacteria through machine learning and species co-occurrence network analysis.

Methods: The collection of fecal samples from AD patients was followed by 16 S rRNA analysis using QIIME2. Enterotype clustering was conducted at the genus level, and deep neural network (DNN) classification models were developed for AD and healthy controls within each enterotype.

Results: Analysis of three 16 S rRNA gut microbiome datasets identified three distinct enterotypes: Escherichia_Shigella (ET-E), Faecalibacterium (ET-F), and Bacteroides (ET-B). The ET-E is mainly characterized by the absence of Akkermansia in AD group. The Akkermansia was significantly positively correlated with Eubacterium_coprostanoligenes_group and negatively correlated with biosynthesis and amino acid metabolism. The ET-F highly expressed Agathobacter, un_f__Lachnospiraceae, Lachnoclostridium, and low expressed Dorea in AD group. Among them, Agathobacter was significantly positively correlated with un_f__Lachnospiraceae, and un_f__Lachnospiraceae was significantly positively correlated with Lachnoclostridium. The Dorea was significantly negatively correlated with Lachnoclostridium. The AD from ET-B group had high expression of two beneficial bacteria, Butyricicoccus and Parabacteroides. The findings suggest that the ET-E enterotype may predispose individuals to AD, with Akkermansia identified as a potential risk factor. Conversely, the ET-B enterotype appears to be associated with milder symptoms, with Butyricicoccus and Parabacteroides potentially serving as protective factors. Therefore, a comprehensive understanding of the species characteristics and interactions within different enterotypes is essential for modulating the gut-brain axis and mitigating AD symptoms.

References

Greer R, Dong X, Moraes A, Zielke R, Fernandes G, Peremyslova E . Akkermansia muciniphila mediates negative effects of IFNγ on glucose metabolism. Nat Commun. 2016; 7:13329. PMC: 5114536. DOI: 10.1038/ncomms13329. View

Dao M, Everard A, Aron-Wisnewsky J, Sokolovska N, Prifti E, Verger E . Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2015; 65(3):426-36. DOI: 10.1136/gutjnl-2014-308778. View

Forbes J, Van Domselaar G, Bernstein C . The Gut Microbiota in Immune-Mediated Inflammatory Diseases. Front Microbiol. 2016; 7:1081. PMC: 4939298. DOI: 10.3389/fmicb.2016.01081. View

Erny D, Hrabe de Angelis A, Jaitin D, Wieghofer P, Staszewski O, David E . Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015; 18(7):965-77. PMC: 5528863. DOI: 10.1038/nn.4030. View

Ou Z, Deng L, Lu Z, Wu F, Liu W, Huang D . Protective effects of Akkermansia muciniphila on cognitive deficits and amyloid pathology in a mouse model of Alzheimer's disease. Nutr Diabetes. 2020; 10(1):12. PMC: 7176648. DOI: 10.1038/s41387-020-0115-8. View

Furusawa Y, Obata Y, Fukuda S, Endo T, Nakato G, Takahashi D . Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013; 504(7480):446-50. DOI: 10.1038/nature12721. View

Vogt N, Kerby R, Dill-McFarland K, Harding S, Merluzzi A, Johnson S . Gut microbiome alterations in Alzheimer's disease. Sci Rep. 2017; 7(1):13537. PMC: 5648830. DOI: 10.1038/s41598-017-13601-y. View

Plovier H, Everard A, Druart C, Depommier C, Van Hul M, Geurts L . A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med. 2016; 23(1):107-113. DOI: 10.1038/nm.4236. View

Cani P, de Vos W . Next-Generation Beneficial Microbes: The Case of . Front Microbiol. 2017; 8:1765. PMC: 5614963. DOI: 10.3389/fmicb.2017.01765. View

10.

Chandra S, Sisodia S, Vassar R . The gut microbiome in Alzheimer's disease: what we know and what remains to be explored. Mol Neurodegener. 2023; 18(1):9. PMC: 9889249. DOI: 10.1186/s13024-023-00595-7. View

11.

Bajaj J, Ahluwalia V, Steinberg J, Hobgood S, Boling P, Godschalk M . Elderly patients have an altered gut-brain axis regardless of the presence of cirrhosis. Sci Rep. 2016; 6:38481. PMC: 5138827. DOI: 10.1038/srep38481. View

12.

Eeckhaut V, Machiels K, Perrier C, Romero C, Maes S, Flahou B . Butyricicoccus pullicaecorum in inflammatory bowel disease. Gut. 2012; 62(12):1745-52. DOI: 10.1136/gutjnl-2012-303611. View

13.

Cani P, Depommier C, Derrien M, Everard A, de Vos W . Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms. Nat Rev Gastroenterol Hepatol. 2022; 19(10):625-637. DOI: 10.1038/s41575-022-00631-9. View

14.

Knopman D, Amieva H, Petersen R, Chetelat G, Holtzman D, Hyman B . Alzheimer disease. Nat Rev Dis Primers. 2021; 7(1):33. PMC: 8574196. DOI: 10.1038/s41572-021-00269-y. View

15.

Vital M, Howe A, Tiedje J . Revealing the bacterial butyrate synthesis pathways by analyzing (meta)genomic data. mBio. 2014; 5(2):e00889. PMC: 3994512. DOI: 10.1128/mBio.00889-14. View

16.

Dalile B, Van Oudenhove L, Vervliet B, Verbeke K . The role of short-chain fatty acids in microbiota-gut-brain communication. Nat Rev Gastroenterol Hepatol. 2019; 16(8):461-478. DOI: 10.1038/s41575-019-0157-3. View

17.

Monda V, Villano I, Messina A, Valenzano A, Esposito T, Moscatelli F . Exercise Modifies the Gut Microbiota with Positive Health Effects. Oxid Med Cell Longev. 2017; 2017:3831972. PMC: 5357536. DOI: 10.1155/2017/3831972. View

18.

Chang S, Shen M, Liu C, Pu C, Hu J, Huang C . A gut butyrate-producing bacterium regulates short-chain fatty acid transporter and receptor to reduce the progression of 1,2-dimethylhydrazine-associated colorectal cancer. Oncol Lett. 2020; 20(6):327. PMC: 7577080. DOI: 10.3892/ol.2020.12190. View

19.

Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P . Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013; 504(7480):451-5. PMC: 3869884. DOI: 10.1038/nature12726. View

20.

Douglas G, Maffei V, Zaneveld J, Yurgel S, Brown J, Taylor C . PICRUSt2 for prediction of metagenome functions. Nat Biotechnol. 2020; 38(6):685-688. PMC: 7365738. DOI: 10.1038/s41587-020-0548-6. View