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BY 4.0 license Open Access Published by De Gruyter Open Access December 27, 2021

Effects of gut microbiota and probiotics on Alzheimer’s disease

  • Libing Guo , Jiaxin Xu , Yunhua Du , Weibo Wu , Wenjing Nie , Dongliang Zhang , Yuling Luo , Huixian Lu , Ming Lei , Songhua Xiao and Jun Liu EMAIL logo

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with high morbidity, disability, and fatality rate, significantly increasing the global burden of public health. The failure in drug discovery over the past decades has stressed the urgency and importance of seeking new perspectives. Recently, gut microbiome (GM), with the ability to communicate with the brain bidirectionally through the microbiome–gut–brain axis, has attracted much attention in AD-related studies, owing to their strong associations with amyloids, systematic and focal inflammation, impairment of vascular homeostasis and gut barrier, mitochondrial dysfunction, etc., making the regulation of GM, specifically supplementation of probiotics a promising candidate for AD treatment. This article aims to review the leading-edge knowledge concerning potential roles of GM in AD pathogenesis and of probiotics in its treatment and prevention.

1 Introduction

The characteristic symptom of Alzheimer’s disease (AD) is cognitive deficiency in at least one cognitive areas, including memory recall, learning, concentration, etc., often accompanied by behavioral and psychological disorders [1]. It can be classified into different levels according to the severity, ranging from mild cognitive impairment (MCI) to dementia [2]. With high morbidity, disability, and fatality rate, AD is now a critical health problem that significantly increases global financial burden [3]. The prevalence of AD increases with age, reaching 23% in people over 86 years old, affecting millions of elderly people [4]. The fact that there is still no treatment that can effectively improve the crucial clinical outcomes of AD reveals that there is still a considerable gap in our knowledge of its complex pathogenesis, making a broader perspective urgent.

Gut microbiome (GM) is composed of the totality of microorganisms and their collective genetic materials in the gastrointestinal tract (GIT) [5]. GM has been found to play crucial roles in keeping homoeostasis and modulating functions of almost all major body systems, including the central nervous system (CNS) [6]. Research into the impacts of GM on the pathogenesis of AD has rapidly increased over the last decades. The discovery of the microbiota–gut–brain axis, a communication pathway between GM and the brain, has enhanced researchers’ confidence to regard the modification of GM as a potential approach to prevent or treat AD [7]. Thus, probiotics, live microbes which can positively alter the GM when taken in suitable amounts [8], are now regarded as potential candidates in the treatment of AD. In this article, we make a summary of the present knowledge on possible influences of gut microbiota on AD onset and progression and possible protective roles of probiotics against AD.

2 Gut microbiota and microbiota–gut–brain axis

There are over 1,000 species of microorganisms, including bacteria, archaea, yeasts, single-celled eukaryotes, helminth parasites, and viruses, with millions of genes totally in the human GIT [9]. There are various factors that can influence the GM population, such as modes of birth, age, diet, antibiotic exposure, and stress [10], some of which can also influence the pathogenesis of AD. A growing body of research has investigated the role of GM in human growth and health maintenance. In addition to interacting with human immune system via toll-like receptors (TLRs), GM can also act as a biological barrier to prevent abnormal microbiota from invading [11] and even participate in the maturation process of our immune system [12]. GM have been found to affect maturation and function of microglia [13,14]. As for metabolism, GM could play different roles, ranging from regulating the glucose and lipid homeostasis [15] to immunomodulatory effects [16]. Notably, there are some important metabolites produced by the microbiota, which include neurotransmitters such as γ-aminobutyric acid (GABA), serotonin (5-HT) and dopamine, and short-chain fatty acids (SCFAs), which have been found to be associated with changes of host brain functions [17,18].

GM communicates with brain bidirectionally via the microbiome–gut–brain axis involving various routes, including the immune system, vascular system, enteric nervous system, and the vagus nerve [19]. The lack of GM in germ-free (GF) mice could lead to multiple alterations in the nervous system, such as altered concentration of various neurotransmitters (5-HT, dopamine, GABA, etc.) and modulation of synaptic plasticity and transmission, leading to behavioral and emotional abnormalities [20]. Thus, the axis has received considerable attention in studies on neurological disorders, including AD.

3 Gut microbiota and AD

AD is a progressive neurodegenerative disorder, with extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) made of hyperphosphorylated tau as its pathological hallmarks [21]. In addition, chronic neuroinflammation led by excessive microglial activation, astrocyte reactivity, and increased load of proinflammatory cytokines and chemokines has also been found to play a vital role in AD pathology [22,23,24]. Neuroinflammation can not only precede Aβ and tau aggregation but also influence Aβ production, aggregation, and clearance [13], whereas Aβ complexes can bind to pattern recognition receptors expressed in microglia and astrocytes and contribute to neuroinflammation dysregulation and generation of reactive oxygen species (ROS), leading to death of neurons and glial cells [22]. Vascular risk factors such as hypertension, atherosclerosis, and diabetes can also increase the risk of AD. Vascular lesions and dysfunction are also now regarded as important early events in AD pathophysiology [25,26]. The etiology and pathogenesis of AD are still not fully understood, leading to the failure in clinical trials of drugs targeting toward generally acknowledged molecules, especially Aβ. AD is now regarded as a multifaceted disorder influenced by various risk factors such as age, cerebrovascular risk factors, psychogenic diseases [27], and GM.

Increasing evidence indicates a strong association between GM and AD. GM changes have been noticed in fecal samples from patients with AD [6] and transgenic AD mice [28,29]. Studies on the mechanisms behind this illuminating association may provide new viewpoints on the pathogenesis and intervention of AD.

3.1 Gut microbiota and amyloid-related pathogenesis

Amyloids can be secreted by various members of human GM, such as E. coli, S. typhimurium, Bacillus subtilis, Staphylococcus aureus, Pseudomonas fluorescens, etc. [30]. GM-derived and human amyloids are involved in complex interactions with the immune system. Although microbial amyloids like CsgA do not have the same amino acid sequences as human Aβ1-42, they still contain similar pathogen-associated molecular patterns (PAMPs) and thus could interact with the same TLR2, inducing proinflammatory interleukin IL-17A and potent inflammatory mediators such as IL-22, followed by the activation of NF-κB signaling pathway and cyclooxygenase-2 (COX-2) [31,32,33]. Bacterial amyloid proteins are also found to promote misfolding and aggregation of neuronal Aβ peptides through cross-seeding [30,34,35]. Recent evidence indicates that Aβ can also act as an antimicrobial peptide that participates in host immune response to microbes through fibrillation, entrapping pathogens, and disrupting cell membranes [36].

3.2 Gut microbiota dysbiosis and inflammation-driven pathogenesis

Increasing evidence suggests that the association between dysregulation of GM and altered inflammatory states might explain the influences of GM in the initiation or exacerbation of AD. Cattaneo et al. investigated the GM taxa changes in patients with CI and brain amyloidosis, showing an increased abundance of Escherichia/Shigella, a proinflammatory taxon and a decreased abundance of E. rectale, an anti-inflammatory taxon, which was found associated with changes of peripheral inflammation [37]. The GF condition or chronic antibiotic treatment in AD mice could result in reduced insoluble amyloid plaques and suppressed neuroinflammation, attenuated microglia, and astrocyte aggregation around the plaques in the hippocampus [28,38,39].

Lipopolysaccharide (LPS), which is located in the outer membrane of Gram-negative bacteria, is considered as an important mediator between GM dysbiosis and AD pathology (Figure 1). It can initiate potent immune responses by interacting with CD14 and the TLR4-MD-2 complex of immune cells. TLR4 can interact with TIRAP and MyD88 and then induce the activation of NF-κB, a pro-inflammatory transcription factor which is known for triggering pathogenic pathways in AD by promoting the secretion of proinflammatory cytokines [4043]. Zhang et al. reported that the level of plasma LPS was elevated in AD patients, which was correlated positively with the level of blood monocyte/macrophage activation [44]. LPS was also detected in the hippocampus and superior temporal lobe neocortex in patients with AD [45]. LPS was found to colocalize with Aβ1-40/42 in amyloid plaques and around vessels [46]. Interestingly, Marizzoni et al. reported that amyloid standardized uptake value ratio uptake was positively associated with the levels of blood LPS, proinflammatory cytokines, and endothelial dysfunction [47].

Figure 1 
                  Proposed mechanism of LPS affecting the pathogenensis of AD. AD-related GM dysbiosis contributes to an increased level of plasma LPS, which promotes blood monocyte/macrophage activation and the secretion of pro-inflammatory cytokines mainly through NF-κB pathway. LPS can also cross the BBB, promote neuroinflammation and colocalize with Aβ1-40/42 in amyloid plaques and around vessels in the brain, possibly affecting Aβ pathology and endothelial function.
Figure 1

Proposed mechanism of LPS affecting the pathogenensis of AD. AD-related GM dysbiosis contributes to an increased level of plasma LPS, which promotes blood monocyte/macrophage activation and the secretion of pro-inflammatory cytokines mainly through NF-κB pathway. LPS can also cross the BBB, promote neuroinflammation and colocalize with Aβ1-40/42 in amyloid plaques and around vessels in the brain, possibly affecting Aβ pathology and endothelial function.

3.3 Gut microbiota dysbiosis impairs vascular homeostasis and gut barrier

It is well established that the impairment of vascular homeostasis plays an essential role in the development of AD [25]. Furthermore, the invasion of GM and their metabolites into the brain depends heavily on the permeability of the blood–brain barrier (BBB) and the gut epithelial barrier, which can also be affected by GM dysbiosis [48]. Transplant of the fecal microbiota from pathogen-free adult mice was found to upregulate the expression of tight junction proteins and decrease BBB permeability in GF adult mice [49]. Engen et al. reported a link between increased proinflammatory GM with impaired gut barrier function [50]. Bacterial products such as LPS and amyloids have been found to impair BBB through triggering chronic neuroinflammatory responses [51]. GM dysbiosis can also affect trimethylamine oxide levels that regulate vascular microRNA, leading to atherosclerosis, a common risk factor for AD [52].

3.4 Gut microbiota dysbiosis causes mitochondrial dysfunction

Mitochondrial dysfunction, existing as an early event of AD, can lead to decreased energy metabolism and oxidative phosphorylation of key enzymes. It is also found to contribute to neuronal apoptosis and calcium homeostasis disorders [53]. The imbalance of mitochondrial/cellular antioxidant system may lead to the decrease of PTEN-induced putative kinase 1 (PINK1) expression, resulting in reduced ATP production and abnormal brain metabolism and eventually leading to cognitive dysfunction [54,55]. Due to the symbiotic relationship between mitochondrial metabolic diversity and primitive aerobic and anaerobic bacteria, it can provide energy for the host under both aerobic and anaerobic conditions. The differences in bacterial composition and the changes of metabolite production caused by GM dysbiosis may lead to mitochondrial dysfunction, thus increasing oxidative stress and inflammatory response of the host [56]. Therefore, the prevention of mitochondrial dysfunction and reduction of oxidative stress may be promising methods for the prevention or alleviation of cognitive dysfunction.

3.5 Other pathways

Glutamate acts as a major excitatory neurotransmitter involved in the process of memory and learning [57]. Recent studies have shown that GM including Bacteroides vulgatus and Campylobacter jejuni could influence the metabolism of glutamate. Moreover, d-glutamate metabolized by GM may interact with the glutamate N-methyl-D-aspartate-receptor and influence cognitive function in AD patients [58]. Brain-derived neurotrophic factor (BDNF) is a major protective factor fighting neurodegeneration, particularly in AD [59]. It is proposed that GM are able to affect the level of brain BDNF as decreased BDNF level and abnormal behavior in GF mice could be normalized after colonized with probiotic administration [60]. SCFAs, including acetate, butyrate, and propionate, can act as modulators of both peripheral NS and CNS based on their ability to cross and even influence gut barrier and BBB. [61] SCFAs can also regulate microglia homeostasis as there was a microglia defect in the mice that lack the free fatty acid receptor 2 (FFAR2), one of the SCFA receptors. A similar change occurred under a GF condition [14]. Administration of sodium butyrate at an advanced stage of progression was reported to improve memory in AD mice, possibly through increasing expression of learning-associated genes and restoring histone acetylation [62]. Butyrate also acts as a major energy source of intestinal cells and is able to make mitochondrial respiration rate and ATP production higher [63,64].

4 Probiotics as potential therapeutics for AD

Accumulated clinical evidence has implied therapeutic potential for probiotics in AD through various mechanisms. A meta-analysis conducted in 2019 indicated that probiotics could improve cognitive performance in MCI and AD patients, possibly due to their anti-inflammatory and antioxidative effects [65]. In a randomized, double-blind and controlled trial, probiotic milk containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum for 12 weeks was reported to significantly improve cognitive performance in AD patients. Further assessment showed positive influence of probiotics on markers of insulin resistance, plasma level of malondialdehyde, and serum levels of high-sensitivity C-reactive protein, triglyceride, and very low density lipoprotein, whereas it shows no improvement in fasting plasma glucose, other lipid profiles, and biomarkers of inflammation and oxidative stress [66] Large-scale, long-period, randomized controlled trials are needed for more reliable evidence.

Attempts have been made to unravel the effects of probiotics on AD pathology and pathophysiology. Previous studies have implied significant anti-inflammatory effects and cognitive benefits of various probiotics [6770]. Bonfili et al. reported that the administration of SLAB51 mixture (a formulation including Streptococcus thermophilus, bifidobacteria, and lactobacilli) could positively influence levels of plasma inflammatory cytokines, restore the impaired ubiquitin proteasome system and autophagy, reduce Aβ load, and ameliorate cortical atrophy in AD mice [69]. Previous studies have also demonstrated respective anti-inflammatory effects of Lactobacillus johnsonii and Bifidobacterium infantis through modulating the kynurenine pathway of tryptophan degradation [71,72]. Kobayashi et al. found that Bifidobacterium breve A1 could restore the Aβ-induced changes in the expression of inflammation and immune-reactive genes in the hippocampus. They also noticed an increase in the plasma level of acetate, which could partially alleviate behavioral deficits in AD model mice [68]. Lactobacillus plantarum C29 was reported to regulate microglia activation, suppress NF-κB activation, and reduce Aβ deposition in the brain of 5xFAD transgenic mice [70].

Despite current supportive evidence on therapeutic potential of probiotics, more studies are warranted to develop an effective and safe probiotic formulation for AD prevention or treatment. In fact, no probiotic formulation has been approved as a therapeutic modality by major medical regulatory authorities due to the lack of better evidence-based proof of their health-promoting ability and adverse effects [73]. It is important to note that probiotic intake may cause serious adverse events such as sepsis, especially among vulnerable population including the elderly, critically ill, and immunocompromised patients [61,73]. Interestingly, several studies implied that probiotics use after antibiotic treatment could increase the risk of communicable diseases by inducing a persistent long-term dysbiosis [7377]. Another noteworthy adverse event of probiotics is serotonin syndrome, which is often caused by selective serotonin reuptake inhibitor (SSRI) use in patients with depression. Tryptophan-metabolizing probiotics alone can rarely trigger the syndrome while its combination with potent SSRI can significantly increase the risk [61,78]. As people with or at risk of AD are always elderly and sometimes with depression, probiotics should be administered much more carefully among these people.

5 Conclusion

The bottleneck in current AD therapy is the poor understanding of AD pathogenesis, for which the studies on the association between GM and AD may open new horizons. GM dysbiosis has been found correlated with various AD biomarkers, thus correcting it through supplementation of probiotics may be a potential method to treat AD. Several well-designed clinical and mechanistic studies are warranted to further elucidate the underlying mechanisms and develop an effective and safe probiotic formulation for AD prevention and treatment. Emerging novel probiotic drugs are being studied and designed to reduce related risks and enhance their therapeutic ability. While there are many challenges that remain, researchers around the world should still be optimistic about this flourishing field linking AD to gut microbiota.


These authors contributed equally to this work.

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  1. Funding information: This work was funded by the National Natural Science Foundation of China (grant numbers 81801083, 81872261) and the Natural Science Foundation of Guangdong Province (grant number 2017A030313459). The funding body did not participate in the writing of the manuscript.

  2. Author contributions: LBG and JXX: summarizing and writing – original draft preparation. YHD, WBW, WJN, DLZ, YLL, and HXL: literature search. ML and SHX: review and editing. JL: supervision. All the authors have read and agreed to the published version of the manuscript.

  3. Conflict of interest: The authors state no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

[1] Apostolova LG. Alzheimer disease. Contin (Minneap Minn). 2016;22(2 Dementia):419–34.10.1212/CON.0000000000000307Search in Google Scholar

[2] Ljubenkov PA, Geschwind MD. Dementia. Semin Neurol. 2016;36(4):397–404.10.1055/s-0036-1585096Search in Google Scholar

[3] Sacuiu SF. Dementias. Handb Clin Neurol. 2016;138:123–51.10.1016/B978-0-12-802973-2.00008-2Search in Google Scholar

[4] Niu H, Álvarez-Álvarez I, Guillén-Grima F, Aguinaga-Ontoso I. Prevalence and incidence of Alzheimer’s disease in Europe: a meta-analysis. Neurologia. 2017;32(8):523–32.10.1016/j.nrleng.2016.02.009Search in Google Scholar

[5] Cresci GAM, Izzo K. Chapter 4 – Gut microbiome. In Corrigan ML, Roberts K, Steiger E, editors. Adult Short Bowel Syndrome. United States: Academic Press; 2019. p. 45–54.10.1016/B978-0-12-814330-8.00004-4Search in Google Scholar

[6] Cryan JF, O’Riordan KJ, Sandhu K, Peterson V, Dinan TG. The gut microbiome in neurological disorders. Lancet Neurol. 2020;19(2):179–94.10.1016/S1474-4422(19)30356-4Search in Google Scholar

[7] Collins SM, Bercik P. Gut microbiota: Intestinal bacteria influence brain activity in healthy humans. Nat Rev Gastroenterol Hepatol. 2013;10(6):326–7.10.1038/nrgastro.2013.76Search in Google Scholar PubMed

[8] Ambalam P, Raman M, Purama RK, Doble M. Probiotics, prebiotics and colorectal cancer prevention. Best Pract Res Clin Gastroenterol. 2016;30(1):119–31.10.1016/j.bpg.2016.02.009Search in Google Scholar PubMed

[9] Cani PD. Human gut microbiome: hopes, threats and promises. Gut. 2018;67(9):1716–25.10.1136/gutjnl-2018-316723Search in Google Scholar PubMed PubMed Central

[10] Khan MS, Ikram M, Park JS, Park TJ, Kim MO. Gut microbiota, its role in induction of Alzheimer’s disease pathology, and possible therapeutic interventions: special focus on anthocyanins. Cells. 2020;9(4):853.10.3390/cells9040853Search in Google Scholar PubMed PubMed Central

[11] Okumura R, Takeda K. Maintenance of intestinal homeostasis by mucosal barriers. Inflamm Regen. 2018;38:5.10.1186/s41232-018-0063-zSearch in Google Scholar PubMed PubMed Central

[12] Bäckhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Sci (N York, NY). 2005;307(5717):1915–20.10.1126/science.1104816Search in Google Scholar PubMed

[13] Cerovic M, Forloni G, Balducci C. Neuroinflammation and the gut microbiota: possible alternative therapeutic targets to counteract Alzheimer’s disease? Front Aging Neurosci. 2019;11:284.10.3389/fnagi.2019.00284Search in Google Scholar PubMed PubMed Central

[14] Erny D, Hrabě de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18(7):965–77.10.1038/nn.4030Search in Google Scholar PubMed PubMed Central

[15] Duparc T, Plovier H, Marrachelli VG, Van Hul M, Essaghir A, Ståhlman M, et al. Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism. Gut. 2017;66(4):620–32.10.1136/gutjnl-2015-310904Search in Google Scholar PubMed PubMed Central

[16] Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature. 2009;461(7268):1282–6.10.1038/nature08530Search in Google Scholar PubMed PubMed Central

[17] Dinan TG, Cryan JF. Gut-brain axis in 2016: brain-gut-microbiota axis – mood, metabolism and behaviour. Nat Rev Gastroenterol Hepatol. 2017;14(2):69–70.10.1038/nrgastro.2016.200Search in Google Scholar PubMed

[18] González-Arancibia C, Urrutia-Piñones J, Illanes-González J, Martinez-Pinto J, Sotomayor-Zárate R, Julio-Pieper M, et al. Do your gut microbes affect your brain dopamine? Psychopharmacology. 2019;236(5):1611–22.10.1007/s00213-019-05265-5Search in Google Scholar PubMed

[19] Cryan JF, O’Riordan KJ, Cowan CSM, Sandhu KV, Bastiaanssen TFS, Boehme M, et al. The microbiota-gut-brain axis. Physiol Rev. 2019;99(4):1877–2013.10.1152/physrev.00018.2018Search in Google Scholar PubMed

[20] Sampson TR, Mazmanian SK. Control of brain development, function, and behavior by the microbiome. Cell Host Microbe. 2015;17(5):565–76.10.1016/j.chom.2015.04.011Search in Google Scholar PubMed PubMed Central

[21] Tiwari S, Atluri V, Kaushik A, Yndart A, Nair M. Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics. Int J Nanomed. 2019;14:5541–54.10.2147/IJN.S200490Search in Google Scholar PubMed PubMed Central

[22] Minter MR, Taylor JM, Crack PJ. The contribution of neuroinflammation to amyloid toxicity in Alzheimer’s disease. J Neurochem. 2016;136(3):457–74.10.1111/jnc.13411Search in Google Scholar PubMed

[23] Price BR, Johnson LA, Norris CM. Reactive astrocytes: the nexus of pathological and clinical hallmarks of Alzheimer’s disease. Ageing Res Rev. 2021;68:101335.10.1016/j.arr.2021.101335Search in Google Scholar PubMed PubMed Central

[24] Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci. 2015;16(6):358–72.10.1038/nrn3880Search in Google Scholar PubMed

[25] Sweeney MD, Montagne A, Sagare AP, Nation DA, Schneider LS, Chui HC, et al. Vascular dysfunction-the disregarded partner of Alzheimer’s disease. Alzheimers Dement. 2019;15(1):158–67.10.1016/j.jalz.2018.07.222Search in Google Scholar PubMed PubMed Central

[26] Vipin A, Loke YM, Liu S, Hilal S, Shim HY, Xu X, et al. Cerebrovascular disease influences functional and structural network connectivity in patients with amnestic mild cognitive impairment and Alzheimer’s disease. Alzheimers Res Ther. 2018;10(1):82.10.1186/s13195-018-0413-8Search in Google Scholar PubMed PubMed Central

[27] Baumgart M, Snyder HM, Carrillo MC, Fazio S, Kim H, Johns H. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: A population-based perspective. Alzheimer’s Dementia: J Alzheimer’s Assoc. 2015;11(6):718–26.10.1016/j.jalz.2015.05.016Search in Google Scholar PubMed

[28] Harach T, Marungruang N, Duthilleul N, Cheatham V, Mc Coy KD, Frisoni G, et al. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep. 2017;7:41802.10.1038/srep41802Search in Google Scholar PubMed PubMed Central

[29] Zhang L, Wang Y, Xiayu X, Shi C, Chen W, Song N, et al. Altered Gut microbiota in a mouse model of Alzheimer’s disease. J Alzheimer’s Disease: JAD. 2017;60(4):1241–57.10.3233/JAD-170020Search in Google Scholar PubMed

[30] Friedland RP, Chapman MR. The role of microbial amyloid in neurodegeneration. PLoS Pathog. 2017;13(12):e1006654.10.1371/journal.ppat.1006654Search in Google Scholar PubMed PubMed Central

[31] Zhou Y, Blanco LP, Smith DR, Chapman MR. Bacterial amyloids. In: Sigurdsson EM, Calero M, Gasset M, editors. Amyloid proteins: methods and protocols. Totowa, NJ: Humana Press; 2012. p. 303–20.10.1007/978-1-61779-551-0_21Search in Google Scholar PubMed PubMed Central

[32] Nishimori JH, Newman TN, Oppong GO, Rapsinski GJ, Yen J-H, Biesecker SG, et al. Microbial amyloids induce interleukin 17 A (IL-17A) and IL-22 responses via toll-like receptor 2 activation in the intestinal mucos. Infect Immunit. 2012;80(12):4398.10.1128/IAI.00911-12Search in Google Scholar PubMed PubMed Central

[33] Hill JM, Lukiw WJ. Microbial-generated amyloids and Alzheimer’s disease (AD). Front Aging Neurosci. 2015;7(9). 10.3389/fnagi.2015.00009.Search in Google Scholar PubMed PubMed Central

[34] 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;6(1):34477.10.1038/srep34477Search in Google Scholar PubMed PubMed Central

[35] Friedland RP. Mechanisms of molecular mimicry involving the microbiota in neurodegeneration. J Alzheimers Dis. 2015;45(2):349–62.10.3233/JAD-142841Search in Google Scholar PubMed

[36] Gosztyla ML, Brothers HM, Robinson SR. Alzheimer’s amyloid-β is an antimicrobial peptide: a review of the evidence. J Alzheimer’s Disease: JAD. 2018;62(4):1495–506.10.3233/JAD-171133Search in Google Scholar PubMed

[37] Cattaneo A, Cattane N, Galluzzi S, Provasi S, Lopizzo N, Festari C, et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging. 2017;49:60–8.10.1016/j.neurobiolaging.2016.08.019Search in Google Scholar PubMed

[38] Dodiya HB, Kuntz T, Shaik SM, Baufeld C, Leibowitz J, Zhang X, et al. Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes. J Exp Med. 2019;216(7):1542–60.10.1084/jem.20182386Search in Google Scholar PubMed PubMed Central

[39] 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 APP/PS1 murine model of Alzheimer’s disease. Sci Rep. 2017;7(1):10411.10.1038/s41598-017-11047-wSearch in Google Scholar PubMed PubMed Central

[40] Beutler B. TLR4 as the mammalian endotoxin sensor. In: Beutler B, Wagner H, editors. Toll-like receptor family members and their ligands. Berlin, Heidelberg: Springer Berlin Heidelberg; 2002. p. 109–20.10.1007/978-3-642-59430-4_7Search in Google Scholar PubMed

[41] Park BS, Lee JO. Recognition of lipopolysaccharide pattern by TLR4 complexes. Exp Mol Med. 2013;45(12):e66.10.1038/emm.2013.97Search in Google Scholar PubMed PubMed Central

[42] Ciesielska A, Matyjek M, Kwiatkowska K. TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling. Cell Mol Life Sci. 2021;78(4):1233–61.10.1007/s00018-020-03656-ySearch in Google Scholar PubMed PubMed Central

[43] LukiwWJ. Lipopolysaccharide and inflammatory signaling in Alzheimer’s disease. Front Microbiol. 2016;7:1544.Search in Google Scholar

[44] Zhang R, Miller RG, Gascon R, Champion S, Katz J, Lancero M, et al. Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol. 2009;206(1-2):121–4.10.1016/j.jneuroim.2008.09.017Search in Google Scholar PubMed PubMed Central

[45] Zhao Y, Jaber V, Lukiw WJ. Secretory products of the human GI tract microbiome and their potential impact on Alzheimer’s disease (AD): detection of lipopolysaccharide (LPS) in AD hippocampus. Front Cell Infect Microbiol. 2017;7:318.10.3389/fcimb.2017.00318Search in Google Scholar PubMed PubMed Central

[46] Zhan X, Stamova B, Jin L-W, DeCarli C, Phinney B, Sharp FR. Gram-negative bacterial molecules associate with Alzheimer disease pathology. Neurology. 2016;87(22):2324–32.10.1212/WNL.0000000000003391Search in Google Scholar PubMed PubMed Central

[47] Marizzoni M, Cattaneo A, Mirabelli P, Festari C, Lopizzo N, Nicolosi V, et al. Short-chain fatty acids and lipopolysaccharide as mediators between gut dysbiosis and amyloid pathology in Alzheimer’s disease. J Alzheimers Dis. 2020;78(2):683–97.10.3233/AIAD220007Search in Google Scholar

[48] Thevaranjan N, Puchta A, Schulz C, Naidoo A, Szamosi JC, Verschoor CP, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. 2018;23(4):570.10.1016/j.chom.2018.03.006Search in Google Scholar PubMed PubMed Central

[49] Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Tóth M, et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med. 2014;6(263):263ra158.10.1126/scitranslmed.3009759Search in Google Scholar PubMed PubMed Central

[50] Engen PA, Dodiya HB, Naqib A, Forsyth CB, Green SJ, Voigt RM, et al. The Potential role of gut-derived inflammation in multiple system atrophy. J Parkinsons Dis. 2017;7(2):331–46.10.3233/JPD-160991Search in Google Scholar PubMed

[51] Lin L, Zheng LJ, Zhang LJ. Neuroinflammation, gut microbiome, and Alzheimer’s disease. Mol Neurobiol. 2018;55(11):8243–50.10.1007/s12035-018-0983-2Search in Google Scholar PubMed

[52] Komaroff AL. The microbiome and risk for atherosclerosis. JAMA. 2018;319(23):2381–2.10.1001/jama.2018.5240Search in Google Scholar

[53] Desler C, Lillenes MS, Tønjum T, Rasmussen LJ. The role of mitochondrial dysfunction in the progression of Alzheimer’s disease. Curr Medicinal Chem. 2018;25(40):5578–87.10.2174/0929867324666170616110111Search in Google Scholar

[54] Du F, Yu Q, Yan S, Hu G, Lue LF, Walker DG, et al. PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer’s disease. Brain. 2017;140(12):3233–51.10.1093/brain/awx258Search in Google Scholar

[55] Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta. 2014;1842(8):1240–7.10.1016/j.bbadis.2013.10.015Search in Google Scholar

[56] Franco-Obregón A, Gilbert JA. The microbiome-mitochondrion connection: common ancestries, common mechanisms, common goals. mSystems. 2017;2(3):e00018–17.10.1128/mSystems.00018-17Search in Google Scholar

[57] Riedel G, Platt B, Micheau J. Glutamate receptor function in learning and memory. Behav Brain Res. 2003;140(1–2):1–47.10.1016/S0166-4328(02)00272-3Search in Google Scholar

[58] Chang CH, Lin CH, Lane HY. d-glutamate and gut microbiota in Alzheimer’s disease. Int J Mol Sci. 2020;21(8):2676.10.3390/ijms21082676Search in Google Scholar PubMed PubMed Central

[59] Colucci-D’Amato L, Speranza L, Volpicelli F. Neurotrophic factor BDNF, physiological functions and therapeutic potential in depression, neurodegeneration and brain cancer. Int J Mol Sci. 2020;21(20):7777.10.3390/ijms21207777Search in Google Scholar PubMed PubMed Central

[60] Maqsood R, Stone TW. The gut-brain axis, BDNF, NMDA and CNS disorders. Neurochem Res. 2016;41(11):2819–35.10.1007/s11064-016-2039-1Search in Google Scholar PubMed

[61] Arora K, Green M, Prakash S. The microbiome and Alzheimer’s disease: potential and limitations of prebiotic, synbiotic, and probiotic formulations. Front Bioeng Biotechnol. 2020;8:537847.10.3389/fbioe.2020.537847Search in Google Scholar PubMed PubMed Central

[62] Govindarajan N, Agis-Balboa RC, Walter J, Sananbenesi F, Fischer A. Sodium butyrate improves memory function in an Alzheimer’s disease mouse model when administered at an advanced stage of disease progression. J Alzheimer’s Dis. 2011;26:187–97.10.3233/JAD-2011-110080Search in Google Scholar PubMed

[63] Sochocka M, Donskow-Lysoniewska K, Diniz BS, Kurpas D, Brzozowska E, Leszek J. The gut microbiome alterations and inflammation-driven pathogenesis of Alzheimer’s disease-a critical review. Mol Neurobiol. 2019;56(3):1841–51.10.1007/s12035-018-1188-4Search in Google Scholar PubMed PubMed Central

[64] Nagpal R, Neth BJ, Wang S, Craft S, Yadav H. Modified mediterranean-ketogenic diet modulates gut microbiome and short-chain fatty acids in association with Alzheimer’s disease markers in subjects with mild cognitive impairment. EBioMedicine. 2019;47:529–42.10.1016/j.ebiom.2019.08.032Search in Google Scholar PubMed PubMed Central

[65] Den H, Dong X, Chen M, Zou Z. Efficacy of probiotics on cognition, and biomarkers of inflammation and oxidative stress in adults with Alzheimer’s disease or mild cognitive impairment – a meta-analysis of randomized controlled trials. Aging. 2020;12(4):4010–39.10.18632/aging.102810Search in Google Scholar PubMed PubMed Central

[66] Leblhuber F, Egger M, Schuetz B, Fuchs D. Commentary: effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer’s disease: a randomized, double-blind and controlled trial. Front Aging Neurosci. 2018;10:54.10.3389/fnagi.2018.00054Search in Google Scholar PubMed PubMed Central

[67] Abraham D, Feher J, Scuderi GL, Szabo D, Dobolyi A, Cservenak M, et al. Exercise and probiotics attenuate the development of Alzheimer’s disease in transgenic mice: role of microbiome. Exp Gerontol. 2019;115:122–31.10.1016/j.exger.2018.12.005Search in Google Scholar PubMed

[68] Kobayashi Y, Sugahara H, Shimada K, Mitsuyama E, Kuhara T, Yasuoka A, et al. Therapeutic potential of Bifidobacterium breve strain A1 for preventing cognitive impairment in Alzheimer’s disease. Sci Rep. 2017;7(1):13510.10.1038/s41598-017-13368-2Search in Google Scholar PubMed PubMed Central

[69] Bonfili L, Cecarini V, Berardi S, Scarpona S, Suchodolski JS, Nasuti C, et al. Microbiota modulation counteracts Alzheimer’s disease progression influencing neuronal proteolysis and gut hormones plasma levels. Sci Rep. 2017;7(1):2426.10.1038/s41598-017-02587-2Search in Google Scholar PubMed PubMed Central

[70] Lee HJ, Hwang YH, Kim DH. Lactobacillus plantarum C29-fermented soybean (DW2009) alleviates memory impairment in 5XFAD transgenic mice by regulating microglia activation and gut microbiota composition. Mol Nutr Food Res. 2018;62(20):e1800359.10.1002/mnfr.201800359Search in Google Scholar PubMed

[71] Desbonnet L, Garrett L, Clarke G, Bienenstock J, Dinan TG. The probiotic bifidobacteria infantis: an assessment of potential antidepressant properties in the rat. J Psychiatr Res. 2008;43(2):164–74.10.1016/j.jpsychires.2008.03.009Search in Google Scholar PubMed

[72] Valladares R, Bojilova L, Potts AH, Cameron E, Gardner C, Lorca G, et al. Lactobacillus johnsonii inhibits indoleamine 2,3-dioxygenase and alters tryptophan metabolite levels in BioBreeding rats. FASEB J. 2013;27(4):1711–20.10.1096/fj.12-223339Search in Google Scholar PubMed

[73] Suez J, Zmora N, Segal E, Elinav E. The pros, cons, and many unknowns of probiotics. Nat Med. 2019;25(5):716–29.10.1038/s41591-019-0439-xSearch in Google Scholar PubMed

[74] Suez J, Zmora N, Zilberman-Schapira G, Mor U, Dori-Bachash M, Bashiardes S, et al. Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell. 2018;174(6):1406–23.e16.10.1016/j.cell.2018.08.047Search in Google Scholar PubMed

[75] Grazul H, Kanda LL, Gondek D. Impact of probiotic supplements on microbiome diversity following antibiotic treatment of mice. Gut Microbes. 2016;7(2):101–14.10.1080/19490976.2016.1138197Search in Google Scholar PubMed PubMed Central

[76] Kabbani TA, Pallav K, Dowd SE, Villafuerte-Galvez J, Vanga RR, Castillo NE, et al. Prospective randomized controlled study on the effects of Saccharomyces boulardii CNCM I-745 and amoxicillin-clavulanate or the combination on the gut microbiota of healthy volunteers. Gut Microbes. 2017;8(1):17–32.10.1080/19490976.2016.1267890Search in Google Scholar PubMed PubMed Central

[77] Spinler JK, Brown A, Ross CL, Boonma P, Conner ME, Savidge TC. Administration of probiotic kefir to mice with Clostridium difficile infection exacerbates disease. Anaerobe. 2016;40:54–7.10.1016/j.anaerobe.2016.05.008Search in Google Scholar PubMed PubMed Central

[78] Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112–20.10.1056/NEJMra041867Search in Google Scholar PubMed

Received: 2021-09-26
Revised: 2021-11-21
Accepted: 2021-11-23
Published Online: 2021-12-27

© 2021 Libing Guo et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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