The role of the gut microbiota in Alzheimer’s disease

By Michelle Lam

Alzheimer’s disease (AD) is the leading cause of dementia, affecting over 50 million people worldwide.1 With improvements in global health, dementia cases are projected to triple by 2050.2 Despite advancements in understanding disease progression, there are still no disease-modifying therapies available. Therefore, it is crucial that new biomarkers are identified to overcome this.1 Currently, the accepted model for AD pathogenesis is the amyloid cascade hypothesis, which states that neurodegeneration is the result of the accumulation of extracellular amyloid beta (Aβ) plaques within various regions of the brain. This triggers a cascade of events, such as the formation of intracellular neurofibrillary tangles (NFTs), and neuroinflammation through increased microglia and astrocyte activation, which eventually leads to neuronal death.3

More recently, the gut-brain axis and microbiota have been identified as potential modulators of AD progression. The gut-brain axis is the bidirectional communication between the CNS and the gut microbiota through microbiota-associated metabolites (MAMs); the enteric and autonomic nervous systems; the immune system; and the hypothalamic-pituitary-adrenal (HPA) axis.4-5 The gut-brain axis is involved in processes such as regulating blood-brain barrier (BBB) integrity, food intake and brain behaviour, and is also implicated in disorders such as irritable bowel syndrome and obesity.4 Gut dysbiosis refers to alterations in the gut microbiota, often caused by ageing, antibiotics, and high-fat diet (HFD).6 Gut dysbiosis has been observed in faecal samples of AD patients, with reports showing an increase in Bacteroides and decreased Bifidobacterium compared to controls.7Moreover, Saiyasit et al. demonstrated that HFD-induced gut dysbiosis in rodents resulted in systemic inflammation, and thus, microgliosis (microglial activation) and hippocampal dysplasia, giving further evidence of the role of the gut microbiota in AD.8

The exact mechanism by which gut dysbiosis may influence AD is unknown, although evidence suggests that it could be through modulation of BBB permeability. The BBB lines the blood vessels of the CNS and has a cardinal role in maintaining homeostasis in the brain. It is a barrier that must be tightly regulated, as it must allow sufficient blood flow to meet the high metabolic demand of the brain and allow the passage of important ions and nutrients. On the contrary, it must also protect it from dangerous threats such as blood-borne pathogens and anaphylatoxins. The BBB is enriched with tight junctions at the endothelium, which are protein complexes of predominately claudins and occludins which bind to tight junctions on adjacent cells. This creates a seal that prevents the flow of ions and solutes between endothelial cells, which is known as the paracellular pathway.9 Germ-free mice, which lack a microbiota, and antibiotic-treated mice, have been reported to have decreased levels of claudin-5 and occluding.10-11Thus, an altered gut microbiota could increase BBB permeability through modulation of tight junctions. This allows toxic molecules to bypass the BBB, such as CCL11, a risk factor of late onset AD. CCL11 can modulate glial cells and promote the formation of amyloid-beta plaques.12 Furthermore, lipopolysaccharides (LPS), a major component of Gram-negative bacterial cell membranes, can be secreted by the intestinal microbiota and bind to toll-like receptor (TLR) 4.13 Activated TLR4 downregulates tight junction proteins, which allows neurotoxins, including LPS itself, to cross the BBB.14 LPS can bind then bind to TLR4 on microglial cells and promote the production of inflammatory cytokines through NF-κB signalling, which may accelerate amyloidosis and AD pathogenesis.13,15

In addition, another way in which the gut microbiota may contribute to AD pathogenesis is through the production of bacterial amyloids. Bacteria produce amyloids to facilitate binding to other bacterial cells in order to create a biofilm, and also to evade the immune system. Bacterial amyloids have a different primary structure to the CNS-produced Aβ, however, share similarities in their tertiary structures. Because of this, it is possible that the presence of gut bacterial amyloids primes the immune system for amyloid attack, which results in a greater immune response to endogenously produced amyloids.16 Curli is an example of a bacterial amyloid, produced by Escherichia coli. A study by Chen et al. found that when rats were exposed to Curli-producing E. coli, increased amounts of Aβ in the gut and brain, along with elevated astrogliosis and microgliosis, were observed compared to control rats which were exposed to non-Curli-producing bacteria. The study also determined that there was expression of the immune markers TLR2, interleukin-6 and TNF were upregulated in the E. coli exposed rats, providing more evidence that these rats had enhanced neuroinflammation.17 Bacterial amyloids may promote amyloidosis through molecular mimicry, in which the bacterial amyloids act as prion proteins that cause another amyloid protein to misfold into the pathogenic β-sheet structure.16,18

The novel role of the gut microbiota in AD has revealed the potential for new therapeutic interventions, one being the administration of probiotics. A study found that Enterococcus faecium and Lactobacillus rhamnosus supplementation lowered TNF-alpha production, reduced reactive oxygen species production and upregulated antioxidant enzyme activity in the brain, suggesting that these probiotics could alleviate neuroinflammation in the brain.19 Perhaps the best characterised probiotics are those belonging to the Lactobacillus and Bifidobacteria genera. Several studies have provided evidence of the potential of these probiotics to treat AD. In a clinical study, Lactobacilli and Bifidobacteria probiotics were administered to AD patients and the results found that the Mini-Mental State Examination scores, a test that assesses the severity of dementia, significantly improved in the patients.20 One study suggested that these probiotics could work by acetylcholinesterase (AchE) inhibition. LPS-treated mice who were supplemented with Lactobacilli probiotics had improved memory, compared to LPS-treated controls who were not administered with probiotics, and this was accompanied with AchE inhibition.21 The study also hypothesised that the observed decrease of neuroinflammation in the Lactobacillus supplemented mice could be partly due to AchE inhibition, formed on the basis that previous studies have reported that administration of AchE inhibitors has reduced neuroinflammation and neurodegeneration in the hippocampus and cortex of rodents.21-22

Currently, AD is diagnosed on cognitive dysfunctions, however it can be up to 20 years after onset before these are observed. Thus, there is a pressing need for the design of disease-modifying therapies for AD that can delay the irreversible neurodegeneration.23 It is clear that the amyloid cascade hypothesis cannot fully explain the pathogenesis of AD due to the lack of success of anti-Aβ therapies.24 One of the main problems in discovering a successful disease-modifying therapy is the lack of biomarkers for early detection. Therefore, the growing body of knowledge regarding the role of the gut microbiota in the disease will aid in understanding disease progression and designing suitable biomarkers for AD.23 New therapeutics will also ameliorate the socioeconomic burden that AD imposes. For instance, Alzheimer’s association reported a total cost of $236 billion associated with AD, which will only increase, with the expected exponential increase in cases, if a cure is not found.25 Since the role of the gut microbiota in AD is a relatively new concept, more research can be conducted in investigating the ways in which the gut microbiota can be manipulated to treat AD.


1. Hodson R. Alzheimer’s disease. Nature 2018 25 Jul,;559(7715):S1-S1.

2. Lane CA, Hardy J, Schott JM. Alzheimer’s disease. European Journal of Neurology 2017 4 Sept,;25(1):59-70.

3. Barage SH, Sonawane KD. Amyloid cascade hypothesis: Pathogenesis and therapeutic strategies in Alzheimer’s disease. Neuropeptides 2015 Aug,;52:1-18.

4. Osadchiy V, Martin CR, Mayer EA. The Gut-Brain Axis and the Microbiome: Mechanisms and Clinical Implications. Clin Gastroenterol Hepatol 2019 Jan,;17(2):322-332.

5. Wang H, Wang Y. Gut Microbiota-brain Axis. Chin Med J (Engl) 2016 Oct 5,;129(19):2373-2380.

6. Goyal D, Ali SA, Singh RK. Emerging role of gut microbiota in modulation of neuroinflammation and neurodegeneration with emphasis on Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 2021 -03-02;106:110112.

7. Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, et al. Gut microbiome alterations in Alzheimer’s disease. Sci Rep 2017 Oct 19,;7(1):13537.

8. Saiyasit N, Chunchai T, Prus D, Suparan K, Pittayapong P, Apaijai N, et al. Gut dysbiosis develops before metabolic disturbance and cognitive decline in high-fat diet-induced obese condition. Nutrition 2020 Jan,;69:110576.

9. Kealy J, Greene C, Campbell M. Blood-brain barrier regulation in psychiatric disorders. Neurosci Lett 2020 May 1,;726:133664.

10. Zhu S, Jiang Y, Xu K, Cui M, Ye W, Zhao G, et al. The progress of gut microbiome research related to brain disorders. J Neuroinflammation 2020 Jan 17,;17(1):25.

11. `Shi Y, Kellingray L, Zhai Q, Gall GL, Narbad A, Zhao J, et al. Structural and Functional Alterations in the Microbial Community and Immunological Consequences in a Mouse Model of Antibiotic-Induced Dysbiosis. Front Microbiol 2018 Aug 21,;9:1948.

12. Minter MR, Hinterleitner R, Meisel M, Zhang C, Leone V, Zhang X, et al. Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPSWE/PS1ΔE9 murine model of Alzheimer’s disease. Sci Rep 2017 Sep 5,;7(1):10411.

13. Jaeger LB, Dohgu S, Sultana R, Lynch JL, Owen JB, Erickson MA, et al. Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer’s disease. Brain Behav Immun 2009 May,;23(4):507-517.

14. Lin C, Zhao S, Zhu Y, Fan Z, Wang J, Zhang B, et al. Microbiota-gut-brain axis and toll-like receptors in Alzheimer’s disease. Comput Struct Biotechnol J 2019 Oct 24,;17:1309-1317.

15. Bayer TA, Wirths O. Intracellular accumulation of amyloid-Beta – a predictor for synaptic dysfunction and neuron loss in Alzheimer’s disease. Front Aging Neurosci 2010 Mar 10,;2:8.

16. Kowalski K, Mulak A. Brain-Gut-Microbiota Axis in Alzheimer’s Disease. J Neurogastroenterol Motil 2019 Jan 31,;25(1):48-60.

17. Chen SG, Stribinskis V, Rane MJ, Demuth DR, Gozal E, Roberts AM, et al. Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans. Sci Rep 2016 Oct 6,;6:34477.

18. Zhou Y, Smith D, Leong BJ, Brännström K, Almqvist F, Chapman MR. Promiscuous cross-seeding between bacterial amyloids promotes interspecies biofilms. J Biol Chem 2012 Oct 12,;287(42):35092-35103.

19. Divyashri G, Krishna G, Muralidhara n, Prapulla SG. Probiotic attributes, antioxidant, anti-inflammatory and neuromodulatory effects of Enterococcus faecium CFR 3003: in vitro and in vivo evidence. J Med Microbiol 2015 Dec 1,;64(12):1527-1540.

20. Akbari E, Asemi Z, Daneshvar Kakhaki R, Bahmani F, Kouchaki E, Tamtaji OR, et al. Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Alzheimer’s Disease: A Randomized, Double-Blind and Controlled Trial. Front Aging Neurosci 2016 Nov 10,;8:256.

21. Musa NH, Mani V, Lim SM, Vidyadaran S, Abdul Majeed AB, Ramasamy K. Lactobacilli-fermented cow’s milk attenuated lipopolysaccharide-induced neuroinflammation and memory impairment in vitro and in vivo. J Dairy Res 2017 Nov 20,;84(4):488-495.

22. Kalb A, von Haefen C, Sifringer M, Tegethoff A, Paeschke N, Kostova M, et al. Acetylcholinesterase inhibitors reduce neuroinflammation and -degeneration in the cortex and hippocampus of a surgery stress rat model. PLoS One 2013 May 3,;8(5):e62679.

23. Frozza RL, Lourenco MV, De Felice FG. Challenges for Alzheimer’s Disease Therapy: Insights from Novel Mechanisms Beyond Memory Defects. Front Neurosci 2018 Feb 6,;12:37.

24. Uddin MS, Kabir MT, Rahman MS, Behl T, Jeandet P, Ashraf GM, et al. Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease. Int J Mol Sci 2020 Aug 14,;21(16).

25. Deb A, Thornton JD, Sambamoorthi U, Innes K. Direct and indirect cost of managing alzheimer’s disease and related dementias in the United States. Expert Rev Pharmacoecon Outcomes Res 2017 Apr 12,;17(2):189-202.

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