Gut Microbiota Regulate Alzheimer's Disease Pathologies and Cognitive Disorders Via PUFA-associated Neuroinflammation

Overview

Journal Gut

Specialty Gastroenterology

Date 2022 Jan 12

PMID 35017199

Authors

Chun Chen

Jianming Liao

Yiyuan Xia

Xia Liu

Rheinallt Jones

John Haran

Beth McCormick

Timothy Robert Sampson

Ashfaqul Alam

Keqiang Ye

Affiliations

Soon will be listed here.

Abstract

Objective: This study is to investigate the role of gut dysbiosis in triggering inflammation in the brain and its contribution to Alzheimer's disease (AD) pathogenesis.

Design: We analysed the gut microbiota composition of 3×Tg mice in an age-dependent manner. We generated germ-free 3×Tg mice and recolonisation of germ-free 3×Tg mice with fecal samples from both patients with AD and age-matched healthy donors.

Results: Microbial 16S rRNA sequencing revealed Bacteroides enrichment. We found a prominent reduction of cerebral amyloid-β plaques and neurofibrillary tangles pathology in germ-free 3×Tg mice as compared with specific-pathogen-free mice. And hippocampal RNAseq showed that inflammatory pathway and insulin/IGF-1 signalling in 3×Tg mice brain are aberrantly altered in the absence of gut microbiota. Poly-unsaturated fatty acid metabolites identified by metabolomic analysis, and their oxidative enzymes were selectively elevated, corresponding with microglia activation and inflammation. AD patients' gut microbiome exacerbated AD pathologies in 3×Tg mice, associated with C/EBPβ/asparagine endopeptidase pathway activation and cognitive dysfunctions compared with healthy donors' microbiota transplants.

Conclusions: These findings support that a complex gut microbiome is required for behavioural defects, microglia activation and AD pathologies, the gut microbiome contributes to pathologies in an AD mouse model and that dysbiosis of the human microbiome might be a risk factor for AD.

Citing Articles

Akkermansia muciniphila Modulates Central Nervous System Autoimmune Response and Cognitive Impairment by Inhibiting Hippocampal NLRP3-Mediated Neuroinflammation.

Li X, Lin D, Hu X, Shi X, Huang W, Ouyang Y CNS Neurosci Ther. 2025; 31(3):e70320.

PMID: 40050112 PMC: 11884925. DOI: 10.1111/cns.70320.

How the gut microbiota impacts neurodegenerative diseases by modulating CNS immune cells.

Schaible P, Henschel J, Erny D J Neuroinflammation. 2025; 22(1):60.

PMID: 40033338 PMC: 11877772. DOI: 10.1186/s12974-025-03371-0.

Impact of fracture fixation surgery on cognitive function and the gut microbiota in mice with a history of stroke.

Lu Y, Li Z, Xu R, Xu Y, Zhang W, Zhang Y Open Life Sci. 2025; 20(1):20221061.

PMID: 40026365 PMC: 11868713. DOI: 10.1515/biol-2022-1061.

Exploring the microbiota-gut-brain axis: impact on brain structure and function.

Yassin L, Nakhal M, Alderei A, Almehairbi A, Mydeen A, Akour A Front Neuroanat. 2025; 19:1504065.

PMID: 40012737 PMC: 11860919. DOI: 10.3389/fnana.2025.1504065.

Immune Modulation in Alzheimer's Disease: From Pathogenesis to Immunotherapy.

Balkhi S, Di Spirito A, Poggi A, Mortara L Cells. 2025; 14(4).

PMID: 39996737 PMC: 11853524. DOI: 10.3390/cells14040264.

References

Kang Y, Mbonye U, DeLong C, Wada M, Smith W . Regulation of intracellular cyclooxygenase levels by gene transcription and protein degradation. Prog Lipid Res. 2007; 46(2):108-25. PMC: 3253738. DOI: 10.1016/j.plipres.2007.01.001. View

Chu J, Giannopoulos P, Ceballos-Diaz C, Golde T, Pratico D . 5-Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of Alzheimer disease. Ann Neurol. 2012; 72(3):442-54. PMC: 3464917. DOI: 10.1002/ana.23642. View

Kalsotra A, Anakk S, Brommer C, Kikuta Y, Morgan E, Strobel H . Catalytic characterization and cytokine mediated regulation of cytochrome P450 4Fs in rat hepatocytes. Arch Biochem Biophys. 2007; 461(1):104-12. PMC: 2574503. DOI: 10.1016/j.abb.2007.02.027. View

Straccia M, Dentesano G, Valente T, Pulido-Salgado M, Sola C, Saura J . CCAAT/enhancer binding protein β regulates prostaglandin E synthase expression and prostaglandin E2 production in activated microglial cells. Glia. 2013; 61(10):1607-19. DOI: 10.1002/glia.22542. View

Medzhitov R . Recognition of microorganisms and activation of the immune response. Nature. 2007; 449(7164):819-26. DOI: 10.1038/nature06246. View

Farooqui A, Horrocks L, Farooqui T . Modulation of inflammation in brain: a matter of fat. J Neurochem. 2007; 101(3):577-99. DOI: 10.1111/j.1471-4159.2006.04371.x. View

Sanchez-Mejia R, Mucke L . Phospholipase A2 and arachidonic acid in Alzheimer's disease. Biochim Biophys Acta. 2010; 1801(8):784-90. PMC: 3024142. DOI: 10.1016/j.bbalip.2010.05.013. View

Brandscheid C, Schuck F, Reinhardt S, Schafer K, Pietrzik C, Grimm M . Altered Gut Microbiome Composition and Tryptic Activity of the 5xFAD Alzheimer's Mouse Model. J Alzheimers Dis. 2016; 56(2):775-788. DOI: 10.3233/JAD-160926. View

Rinne J, Laakso K, Lonnberg P, Molsa P, Paljarvi L, Rinne J . Brain muscarinic receptors in senile dementia. Brain Res. 1985; 336(1):19-25. DOI: 10.1016/0006-8993(85)90411-1. View

10.

Diaz Heijtz R, Wang S, Anuar F, Qian Y, Bjorkholm B, Samuelsson A . Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A. 2011; 108(7):3047-52. PMC: 3041077. DOI: 10.1073/pnas.1010529108. View

11.

Mapstone M, Cheema A, Fiandaca M, Zhong X, Mhyre T, MacArthur L . Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med. 2014; 20(4):415-8. PMC: 5360460. DOI: 10.1038/nm.3466. View

12.

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

13.

Griciuc A, Serrano-Pozo A, Parrado A, Lesinski A, Asselin C, Mullin K . Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron. 2013; 78(4):631-43. PMC: 3706457. DOI: 10.1016/j.neuron.2013.04.014. View

14.

Firuzi O, Zhuo J, Chinnici C, Wisniewski T, Pratico D . 5-Lipoxygenase gene disruption reduces amyloid-beta pathology in a mouse model of Alzheimer's disease. FASEB J. 2007; 22(4):1169-78. PMC: 2698428. DOI: 10.1096/fj.07-9131.com. View

15.

Choi S, Bosetti F . Cyclooxygenase-1 null mice show reduced neuroinflammation in response to beta-amyloid. Aging (Albany NY). 2010; 1(2):234-44. PMC: 2806008. DOI: 10.18632/aging.100021. View

16.

Cortes-Canteli M, Luna-Medina R, Sanz-SanCristobal M, Alvarez-Barrientos A, Santos A, Perez-Castillo A . CCAAT/enhancer binding protein beta deficiency provides cerebral protection following excitotoxic injury. J Cell Sci. 2008; 121(Pt 8):1224-34. DOI: 10.1242/jcs.025031. View

17.

Riviere A, Selak M, Lantin D, Leroy F, De Vuyst L . Bifidobacteria and Butyrate-Producing Colon Bacteria: Importance and Strategies for Their Stimulation in the Human Gut. Front Microbiol. 2016; 7:979. PMC: 4923077. DOI: 10.3389/fmicb.2016.00979. View

18.

Yang H, Chen C . Cyclooxygenase-2 in synaptic signaling. Curr Pharm Des. 2008; 14(14):1443-51. PMC: 2561288. DOI: 10.2174/138161208784480144. View

19.

Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Toth M . The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med. 2014; 6(263):263ra158. PMC: 4396848. DOI: 10.1126/scitranslmed.3009759. View

20.

Chen C, Ahn E, Kang S, Liu X, Alam A, Ye K . Gut dysbiosis contributes to amyloid pathology, associated with C/EBPβ/AEP signaling activation in Alzheimer's disease mouse model. Sci Adv. 2020; 6(31):eaba0466. PMC: 7439296. DOI: 10.1126/sciadv.aba0466. View