Gut Microbiota and Alzheimer’s Disease: Pathophysiology and Therapeutic Perspectives

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and is characterized by a progressive decline in cognitive function. Amyloid-β protein accumulation is believed to be the key pathological hallmark of AD. Increasing evidence has shown that the gut microbiota has a role in brain function and host behaviors. The gut microbiota regulates the bidirectional interactions between the gut and brain through neural, endocrine, and immune pathways. With increasing age, the gut microbiota diversity decreases, and the dominant bacteria change, which is closely related to systemic inflammation and health status. Dysbiosis of the gut microbiota is related to cognitive impairment and neurodegenerative diseases. The purpose of this review is to discuss the impacts of the gut microbiota on brain function and the development of AD. It is a feasible target for therapeutic invention. Modulating the composition of the gut microbiota through diet, physical activity or probiotic/prebiotic supplements can provide new prevention and treatment options for AD.

Keywords

Keywords: Alzheimer’s disease dysbiosis gut microbiota microbiota-gut-brain axis pathophysiology therapeutics

INTRODUCTION

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, accounting for up to 60%of all dementia cases [1], and its incidence increases with increasing age. AD typically manifests through a progressive loss of learning and recall of recently learned information, and in the later stages, a deficiency of language, visuospatial abilities, and cognitive function. Such changes are often accompanied by behavioral disorders such as apathy, aggressiveness, and depression [2]. The occurrence of this disease has a huge impact on the life of patients’ families, in addition to imposing a high financial cost on society.

Amyloid-β protein accumulation is believed to be the key pathological hallmark of AD, which can trigger tau protein hyperphosphorylation, neuroinflammation, oxidative stress, and neurite degeneration and ultimately lead to dementia [3]. However, increasing evidence has shown that the amyloid hypothesis alone cannot explain the pathogenesis of AD, which indicates that the pathogenesis of AD involves many different mechanisms [4]. Therefore, the exploration of the mechanism of AD and finding effective prevention and treatment approaches for AD is urgent.

A growing body of experimental and clinical data has confirmed a key role of gut dysbiosis and gut microbiota-host interactions in neurodegeneration [5 –9]. Alterations in the gut microbiota composition induce increased permeability of the gut barrier and immune activation, leading to systemic inflammation, which in turn may impair the blood-brain barrier and promote neuroinflammation, neural injury, and ultimately neurodegeneration [10, 11]. More importantly, the pathological permeability of the intestinal mucosa and blood-brain barrier begin to increase over time and form a vicious cycle, leading to an irreversible destruction of neurons. The combination of gut inflammation, aging, and an unhealthy diet in the elderly may be one of the pathogenesis of AD. Adjusting the composition of the gut microbiota through diet, physical exercise, or probiotic/prebiotic supplements can provide new prevention and treatment options for AD. In this review, we discuss the role of gut microbiota in the pathogenesis of AD and then discuss the possibility of its prevention based on modulation of the gut microbiota.

GUT MICROBIOTA AND BRAIN HEALTH

Gut microbiota

The human intestine harbors up to 100 trillion microorganisms, ten times greater than the total number of human cells in the body. It is a complex ecosystem comprised of bacteria, fungi, and viruses, which is called the gut microbiota and is known as the “second genome” of humans [12]. Microbial densities in the proximal and middle small intestine are relatively low but increase dramatically in the distal small intestine (approximately 10⁸ bacteria/ml of luminal contents) and colon (10¹¹∼10¹²/g) [13]. The gut microbiota of healthy adults has two dominant bacterial phyla: Firmicutes and Bacteroidetes. The two bacterial phyla commonly dominate this ecosystem [14]. The remnants belong to Actinobacteria, Fusobacteria, Proteobacteria, and Verrucomicrobia [15]. Proteobacteria are common but usually not dominant [16].

The microbiota is established shortly after birth and stabilizes during the first 2 to 3 years of life [17]. For decades, the microbiota has coevolved with the host to live together and establish a symbiotic relationship. The human gut microbiota plays a significant role on nutrient metabolism, maintenance of structural integrity of the gut mucosal barrier and immunomodulation [18]. For example, Bacteroides thetaiotaomicron is a prominent mutualist in the distal intestinal habitat of adult humans [19]. It allows us to extract calories from otherwise indigestible dietary polysaccharides, including plant-derived pectin, cellulose, hemicellulose, and resistant starches [20]. It occurs because the microbiota may adaptively deploy a large array of glycoside hydrolases and polysaccharide lyases that we humans do not encode in our genome [19, 21]. There is also evidence that gut microbiota maintain the structure and function of gut mucosal barrier. It is reported that Bacteroides thetaiotaomicron induce expression of the small proline-rich protein 2A (sprr2A), which is required for maintenance of desmosomes at the epithelial villus [22]. And the tight junction is maintained by Toll-like receptor 2 (TLR2) mediated signaling that is stimulated by the microbial cell wall peptidoglycan [23, 24]. In addition, Bacteroides are shown to activate intestinal dendritic cells (DCs), which induces plasma cells in the intestinal mucosa to express secretory IgA (sIgA). It can restrict the translocation of the microbiota from the intestinal lumen to the circulation, thereby preventing a systemic immune response [25]. The gut microbiota plays a crucial role in the development of innate and adaptive immune responses, modulation of gut motility and intestinal barrier homeostasis, absorption of nutrients, and distribution of fat [26, 27].

Microbiota-gut-brain axis

The gut-brain axis describes the complex and bidirectional communication system between the brain and gut [28, 29]. Increasing evidence also suggests that the gut microbiota greatly impacts gut-brain communication and plays a very important role in communication between the brain and gut [30]. The gut microbiota regulates the bidirectional interactions between the gut and brain through neural, endocrine, and immune pathways, which has been called the microbiota-gut-brain axis (Fig. 1) [31 –35].

Fig. 1

Microbiota-gut-brain axis. The gut microbiota regulates the bidirectional interactions between the gut and brain through neural, endocrine and immune pathways.

The vagus nerve has been shown to have a crucial role in modulating gut-brain axis function [36, 37]. As a primary nerve, the vagus nerve connects the enteric nervous system (ENS) with the central nervous system (CNS), which can transmit the peripheral state to the CNS [38]. The gut microbiome generates nerve signaling molecules such as catecholamine, γ-GABA, 5-HT, melatonin, and acetylcholine and influences the central nervous system through the vagus nerve. The vagus nerve has the ability to regulate the expression of γ-GABA, c-fos protein, 5-HT, and other neurotransmitters and can transmit the signaling molecules released by the gut microbiota into the brain to regulate brain function and host behavior. L. rhamnosus (JB-1) has been proven to regulate central GABA receptor expression and reduce stress-induced corticosterone and anxiety- and depression-related behavior. However, these neurochemical and behavioral effects will disappear in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the gut and the brain [36]. Infection with the noninvasive parasite Trichuris muris can cause mild to moderate colonic inflammation and anxiety-like behavior in mice. Anxiety-like behavior was still present in infected mice after vagotomy. It has been suggested that there are other avenues of communication besides the vagal pathway [39].

The gut microbiota can also modulate mucosal immune responses, and the effect of the microbiota on the central nervous system may be transmitted through the immune system [40]. The immune system plays an important role in maintaining gastrointestinal homeostasis and health. The immune function of elderly individuals declines, so communication between the microbiota and brain may be reduced. Behavioral changes observed in patients with systemic or intestinal infections also support this immune pathway. Some molecular structures present on microbiota, such as lipopolysaccharide (LPS), bacterial lipoproteins, and flagellin, can activate various immune cells, such as macrophages, neutrophils, and dendritic cells. Once activated, immune cells produce a large number of proinflammatory cytokines, such as IL-1α, IL-1β, TNF-α, and IL-6. Locally produced cytokines can either activate neurons that project to specific brain areas or diffuse by volume transmission into the brain parenchyma to reach their targets [41].

The gut microbiota can regulate hormone secretion by endocrine cells and produce hormones such as brain-gut peptide, leptin, corticotropin-releasing hormone, and adrenocorticotropic hormone, which act directly on the brain [42]. The microbiota itself is capable of producing neuroendocrine hormones, which are known as microbial endocrinology-based mechanisms and are involved in gut-to-brain interactions [43]. Tryptophan, a precursor of 5-HT, is synthesized by the gut microbiota and can pass through the blood-brain barrier to generate 5-HT in the central nervous system [44]. Approximately 90%of the human body’s total 5-HT is located in enterochromaffin cells in the gut. Enterochromaffin cells are hormone-secreting enteroendocrine cells scattered in the intestinal epithelium, accounting for only 1%of the intestinal epithelium. They express specific chemosensory receptors and can sense various stimuli in the intestine. Recent studies have found that bacterial metabolites may act on enterochromaffin cells and transmit information directly from the gut to the nervous system through the secretion of 5-HT [45]. Serum 5-HT is decreased in germ-free (GF) mice, and the levels of 5-HT precursors and metabolites are decreased accordingly in the intestine and urine [46]. The neurotransmitters regulated by the gut microbiota also include γ-GABA and dopamine [47].

Impacts of gut microbiota dysbiosis on brain health

The gut microbiota shows host specificity and may change in response to environmental variations inside and outside of their hosts, such as life stresses, current health status, diet, and age. An imbalance in gut microbiota is called dysbiosis and is characterized by decreased diversity of the gut microbiota, a reduced number of beneficial bacteria and an increased number of pathobionts or bacterial species associated with disease [48].

The gut microbiota is essential for the neurodevelopment and maturation of the nervous system. Microbiota dysbiosis may affect neurodevelopment. GF mice show significant abnormalities in the myenteric plexi of the jejunum and ileum, characterized by a decrease in nerve density, a decrease in the number of neurons per ganglion, and an increase in the proportion of myenteric nitrergic neurons [49]. The expression of postsynaptic density protein 95 (PSD-95) and synaptophysin in the striatum is increased, so GF mice display increased motor activity and reduced anxiety compared with specific pathogen-free (SPF) mice with a normal gut microbiota [50]. Administration of oral antimicrobials to SPF mice transiently alters the composition of the microbiota and increases exploratory behavior and hippocampal expression of brain-derived neurotrophic factor (BDNF). BDNF can stimulate neurogenesis and synapse formation and regulate synaptic plasticity. The gut microbiota influences host behavior through the hypothalamus pituitary adrenal axis (HPA axis), which may suggest that the hippocampal expression of BDNF is related to the host behavior [51].

Accumulating evidence has supported that the gut microbiota plays an important role in regulating cognitive functions, such as learning and memory, anxiety, development of schizophrenia, and autism-like behaviors. GF mice exhibit deficits in nonspatial memory in the novel object test and deficits in working memory in the T-maze test compared with SPF mice colonized with intact gut microbiota [52]. SPF mice infected with C. rodentium exhibit stress-induced memory dysfunction at 10 and 30 days after infection. Probiotics administered before and during infection prevent memory dysfunction [52]. Savignac et al. suggested that an improvement in learning and memory was found on the mice fed Bifidobacterium longum 1714, which was demonstrated by increased performance in an object recognition test and a Barnes maze test [53]. Gut microbiota dysbiosis induced by a combination of antibiotics (ampicillin, bacitracin, meropenem, neomycin, and vancomycin) impaired novel object recognition memory in mice but not spatial memory [54]. Lactobacillus fermentum strain NS9 alleviated the ampicillin-induced impairment in memory retention [55]. In addition, Yuan et al. reported that a mechanistic link between cognition and gut microbiota might be in a nematode model of AD, the gut microbiota-derived metabolite ‘urolithins’ can prevent beta-amyloid fibrillation [56]. Also, Duerkop et al. suggested that gut microbiota can cause cognition deficits through inflammation [57]. These results highlight the role of the gut microbiota in mediating cognition.

Dysbiosis of the gut microbiota and aging

Aging is one of the greatest risk factors for many chronic diseases, including AD. Increasing evidence has shown that the gut microbiota changes continuously with age. With increasing age, gut microbiota diversity decreases, the dominant bacteria change, and probiotics and short-chain fatty acids decrease [58]. 16S rRNA gene sequencing of stool samples, which were collected from 161 elderly people and 9 non-elderly adults who lived in the same area, showed that the gut microbiota of the elderly individuals was significantly different from that of non-elderly adults. Compared with that of the non-elderly adults, the proportion of Firmicutes in the elderly decreased, and the ratio of Bacteroidetes/Firmicutes increased [59]. However, the findings from different studies were quite variable. For example, some studies found an increase in Bacteroides with age, while others found a decrease [60, 61]. These differences may be due to the different populations or different research methods [62].

A recent study analyzed 3,663 gut microbiota samples from 1,165 healthy people around the world and developed a method to predict the physiological age of the host based on the gut microbiota using a deep learning method. This prediction model is called the human microbiome aging clock. Further study found that 39 bacteria were significantly correlated with age prediction. As people get older, some bacteria increase, such as Eubacterium hallii, while others decrease, such as Bacteroides vulgatus. This microbiome clock can be used as a baseline to predict an individual’s age and aging rate [63]. The composition of the gut microbiota in the elderly is closely related to systemic inflammation and health status [64]. Transplanting the microbiota from aged rats into young rats led to increased systemic inflammation and neuroinflammation in the young recipient rats, which caused cognitive decline [65]. Ragonnaud et al. have shown that gut dysbiosis is increased in aging, and the dysbiosis triggers a chain of pathological and inflammatory events, and result in consequent aging-associated pathology [66]. Coman et al. indicated that aging-related gut dysbiosis may contribute to the initiation and/or progress of other metabolic diseases, and consequently, to a decrease in healthy longevity [67]. In addition, a previous study discussed the possible mechanisms between gut microbiota and aging, and the results shown that prebiotics, probiotics, and synbiotics might contribute to longevity through gut microbiota modulating [68]. Thus, gut microbiota might emerge as a therapeutic target in the elderly.

DYSBIOSIS OF THE GUT MICROBIOTA AND AD

Evidence has indicated a link between the gut microbiota and cognition. As AD is characterized by memory loss and multiple cognitive impairments, we have reason to speculate that gut microbiota plays a significant role in the occurrence and development of AD. Some clinical studies have shown that the gut microbiota of AD patients differs from that of healthy individuals. Microbial diversity is decreased in AD patients compared with healthy controls [6]. In addition, decreased Firmicutes, increased Bacteroidetes, and decreased Bifidobacterium were observed in AD participants [6]. Our previous study of 43 AD patients from China and 43 healthy people also found microbiological differences between groups in Bacteroidetes and Actinobacteria [69]. In another study, Escherichia was observed to be increased at the genus level in patients with AD and mild cognitive impairment (MCI) [70]. Moreover, compared with the normal controls, the abundance of 7 genera in the fecal microbiota was higher (Lactobacillus, Blautia, Streptococcus, etc.), and the abundance of 11 genera was lower in the patients with AD (Prevotella, Sutterella, Haemophilus, etc.) [70]. A previous study showed that the abundance of the genus Bacteroides was decreased in patients with MCI and AD [71].

Similar results have been observed in AD model animals. It was found that amyloid precursor protein (APP) transgenic mice have a remarkable shift in the gut microbiota compared to nontransgenic wild-type (WT) mice, including reduced Firmicutes, Verrucomicrobia, Proteobacteria, and Actinobacteria and a concurrent increase in Bacteroidetes and Tenericutes. Subsequently, they generated germ-free APP transgenic mice and found a drastic reduction in cerebral Aβ pathology as compared to control mice with gut microbiota. Importantly, colonization of germ-free APP transgenic mice with microbiota from conventionally raised APP transgenic mice increased cerebral Aβ pathology, while colonization with microbiota from wild-type mice was less effective in increasing cerebral Aβ levels [72]. In addition to fecal microbiota transplantation (FMT), other interventions, such as antimicrobial-based strategies, were used to assess the role of the microbiota in cognition or AD-related changes. It was reported that prolonged shifts in gut microbial composition and diversity induced by long-term broad-spectrum antibiotic treatment decreased Aβ plaque deposition in the APPswe/PS1ΔE9 mouse model of AD [73]. These results indicated microbial involvement in the development of Aβ pathology and suggested that the microbiota may contribute to the development of AD.

The precise mechanisms of how the gut microbiota contributes to AD pathogenesis are far from completely understood. However, there is a clear indication that the gut microbiota influences AD pathogenesis through multiple pathways, including metabolites, neurotransmitters, and chronic neuroinflammation (Fig. 2).

Fig. 2

Mechanism underlying the impact of the gut microbiota on AD. The gut microbiota regulates the interactions between the gut and brain through vagus nerve, immune, and neuroendocrine pathways. Dysbiosis of the gut microbiota leads to altered levels of neurotransmitters, such as 5-HT and GABA, which may contribute to abnormal signaling through vagus nerve. Gut bacteria and bacterial endotoxins may disrupt the intestinal barrier and result in the “leaky gut”. Metabolites and bacteria from gut microbiota activate immune cells and cause a chronic inflammatory. These signal pathways influence AD pathogenesis, including Aβ deposition, neurofibrillary tangles (NFL), neuroinflammation and neurodegeneration in the brain. 5-HT, 5-hydroxytryptamine; GABA, gamma-aminobutyric acid; TMAO, Trimethylamine N-oxide; LPS, lipopolysaccharide; BMAA, β-N-methylamino-L-alanine; NFL, neurofibrillary tangles; ECs, endocrine cells.

Metabolites

Some metabolic products of the gut microbiota, such as endotoxin LPS, trimethylamine N-oxide (TMAO), and β-methylamino-l-alanine (BMAA), have been reported to influence the central nervous system. It has previously been demonstrated that bacterial LPS is significantly increased in brain tissue from AD patients. In AD, mean LPS levels had twofold increases in the neocortex and threefold increases in the hippocampus when compared to age-matched non-AD brains [74]. Compared to control brains, Escherichia coli K99 and LPS levels were higher in the brain parenchyma and vessels of AD brains. LPS colocalizes with Aβ_1–40/42 in amyloid plaques [75]. In vitro studies found that Escherichia coli LPS can promote the fibrillogenesis of Aβ peptides [76]. Gut microbiota disturbance augments LPS, which enters the brain by impairing the blood-brain barrier, thereby exacerbating the progression of Aβ pathology. Trimethylamine N-oxide (TMAO) is a small molecule produced via gut microbial metabolism. Elevated levels of biomarkers (NFT and Aβ₄₂) and TMAO have been reported in AD and MCI patients and are accompanied by neuronal degeneration [77]. β-N-methylamino-L-alanine (BMAA) is a neurotoxic nonproteinogenic amino acid from cyanobacteria that possibly causes protein misfolding and aggregation. This may be a possible mechanism of Aβ aggregation and senile plaque formation in AD patients [78]. In addition, studies have shown that some bacterial strains, such as Escherichia coli, Salmonella enterica serovar Typhimurium, Bacillus subtilis, Staphylococcus aureus, and Mycobacterium tuberculosis, produce extracellular amyloid fibers [79]. Bacterial amyloids can aggregate into toxic oligomers, which cause damage to lipid membranes and promote amyloid fibril formation by acting as nucleators for aggregation [80]. The aggregation of proteins into amyloid fibers is a common characteristic of many neurodegenerative disorders, including AD and Parkinson’s disease.

Neurotransmitters

Some neurotransmitters, such as GABA and 5-HT, are involved in the pathology of AD. In severe cases of AD, GABA levels in the brain have been shown to be significantly reduced, which could underlie the cognitive and neuropsychiatric symptoms of AD [81]. Compared with WT mice, the 5-HT content in 18-month-old APPswe/PS1ΔE9 (APP/PS1) transgenic mice was reduced in the neocortex [82]. The gut microbiota is capable of producing most neurotransmitters found in the human brain. Lactobacillus and Bifidobacterium spp. can produce gamma-aminobutyric acid (GABA); Candida, Streptococcus, Escherichia, and Enterococcus spp. can produce 5-HT; Bifidobacterium infantis has been shown to elevate plasma tryptophan levels and thus influence central 5-HT transmission [83]. These neurotransmitters produced by the gut microbiota may be closely related to clinical syndromes of AD. Ingestion of L. rhamnosus regulated GABA (Aα2) mRNA expression in the brain and reduced stress-induced anxiety- and depression-related behavior [36]. Despite this, these microbially synthesized neurotransmitters are incapable of crossing the blood-brain barrier, so their impact on brain function is likely to be indirect.

Chronic neuroinflammation

It has been reported that gut microbe-triggered inflammatory responses are involved in the pathogenesis of AD. Early epidemiological studies have shown that long-term use of nonsteroidal anti-inflammatory drugs was associated with a reduction in the risk of AD [84]. In clinically diagnosed AD patients, the abundance of proinflammatory gut bacterial taxa, including Escherichia and Shigella, increased, while anti-inflammatory E. rectale decreased [71]. In addition, increasing support for the role of the gut microbiota in AD is provided from AD mouse models. In AD mice, alteration of the gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of proinflammatory T helper 1 (Th1) cells. Brain-infiltrated peripheral Th1 immune cells are associated with M1 microglial activation, contributing to AD-associated neuroinflammation [10]. Transplantation of the fecal microbiota from WT mice into amyloid and neurofibrillary tangles (ADLP^APT) transgenic mice ameliorated the formation of Aβ plaques and neurofibrillary tangles, glial reactivity, and cognitive impairment [85]. Long-term broad-spectrum antibiotic treatment decreased glial reactivity and Aβ plaque deposition in the APPswe/PS1ΔE9 mouse model of AD [73]. The results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD.

AD PREVENTION FROM THE MICROBIOTA PERSPECTIVE

Despite all of the research attempting to understand and treat AD, there has been a high rate of failure in AD drug development programs [86]. The World Alzheimer Report of 2014 and the Lancet Commission on Dementia Intervention, Prevention, and Care of 2017 emphasized modifiable risk factors, which have been shown to potentially delay the onset and/or progression of cognitive impairment [87, 88]. Here, we review some interventions, including physical activity, different types of diets, probiotics or prebiotics, and FMT.

Physical activity

Physical inactivity is an important risk factor for cognitive decline in aging and for AD [89]. In a systematic review, most experiments showed that physical activity was negatively correlated with the risk of AD [90]. Maintaining high leisure-time physical activity (LTPA) or increasing LTPA after midlife was associated with a lower dementia risk [91]. Regular physical activity increases the endurance of cells and tissues to oxidative stress, vascularization, energy metabolism, and neurotrophin synthesis, all of which are important in neurogenesis, memory improvement, and brain plasticity [92]. There is some evidence that physical activity levels may modify disease pathology in preclinical AD. NSE/APPsw Tg mice were subjected to exercise on a treadmill for 16 weeks, and their Aβ₄₂ peptides were significantly decreased [93]. In humans, habitual physical activity levels, as measured by self-report questionnaires, are associated with a lower brain amyloid load and lower insulin, triglyceride, and Aβ_{1–42/1 –40} levels [94].

Aside from these direct interactions, physical activity also has the potential to influence other modifiable risk factors for AD, such as insulin resistance [95]. Insulin resistance in middle-aged to older adults is associated with reduced glucose metabolism in the medial temporal lobe, and this association is even stronger than that with APOE4 status [96], which is a risk factor for AD and is associated with reduced brain glucose metabolism [97]. Exercise can improve insulin sensitivity [98] and could thereby potentially contribute indirectly to improving memory function.

In recent years, several studies have demonstrated that physical activity increases the microbiota diversity and modulates its distribution [99, 100]. Bacterial diversity is decreased in sedentary elderly individuals compared with elderly individuals who take physical exercise. The gut microbiota of professional rugby players was more diverse than that of nonathlete healthy subjects [99]. Santacruz et al. compared changes in the gut microbial distribution of obese adults who underwent moderate to strenuous aerobic exercise for 10 weeks and found increased Bacteroidetes and decreased Firmicutes [101]. Evans et al. showed that the ratio of Bacteroidetes to Firmicutes correlated inversely with the amount of exercise performed [102]. A previous study showed that during diet induced obesity, the ratio of Bacteroidetes to Firmicutes of fecal microbiota were increased by high-intensity interval training [103]. Besides, it was suggested that physical exercise could decrease the proportions of Bacteroides/Prevotella spp. and Methanobrevibavter spp. [104]. These studies suggest that exercise can alter the microbiota diversity and distribution. It has been suggested that changes in the human gut microbiota mediated by exercise could influence the development and progression of AD, and a new term, the “muscle-gut-brain axis”, has been introduced [105]. Physical activity in humans seems to correlate with the gut microbiota and can prevent the incidence and development of AD. However, further research is needed.

Diet

It is well known that diet can influence the microbiota composition in the gut. A Mediterranean diet (MeDi) has been recognized as a healthy dietary pattern. The MeDi is characterized by frequent consumption of bread, legumes, vegetables, fruits, and fats rich in unsaturated fatty acids, moderate intake of fish and poultry, low intake of dairy and meat, and regular but moderate consumption of wine with meals [106]. The diet has previously been related to the composition of the gut microbiota and related metabolome. Subjects who consume a MeDi have higher levels of fecal short-chain fatty acids, while low adherence to the MeDi corresponds to an increase in urinary trimethylamine oxide levels, a potential risk factor for cardiovascular disease [107].

Epidemiologic investigations showed that higher adherence to MeDi was associated with a lower risk of incident cognitive impairment [108]. Adherence to MeDi has been associated with a reduced risk of MCI and AD [109]. Numerous studies have explored the potential mechanisms by which MeDi may protect against AD. MeDi may have a protective role due to its high content of antioxidants and anti-inflammatory compounds [110].

Recently, some studies have explored whether MeDi has an effect on the gut microbiota to protect against AD. Eleven subjects with MCI underwent a modified Mediterranean-ketogenic diet (MMKD) for 6 weeks, and their abundances of Enterobacteriaceae, Akkermansia, Slackia, Christensenellaceae, and Erysipelotriaceae increased, while those of Bifidobacterium and Lachnobacterium decreased in the gut. MMKD slightly reduces fecal lactate and acetate while increasing propionate and butyrate. The data suggest that MMKD can modulate the gut microbiome and metabolites in association with improved AD biomarkers in the cerebrospinal fluid [111]. MeDi contains an unusually large quantity of lactobacilli, which reduces blood ammonia levels, is very effective in preventing AD [112]. After intervention with coconut oil-enriched MeDi, improvements in episodic, temporal orientation, and semantic memory in women with mild-moderate states were observed [113]. To date, there is sufficient evidence to recommend the MeDi to delay the onset of AD. Future research should focus on larger, controlled trials in diverse populations [114].

Probiotics and prebiotics

Probiotics are bacteria that have a beneficial effect on the health of the recipient, while prebiotics are mainly fiber substances that serve as food for these bacteria. AD mice with exercise training and probiotic treatments significantly outperformed controls in the Morris maze test, and the number of Aβ plaques decreased in the hippocampus [115]. Treatment with the SLAB51 probiotic formulation in AD mice caused changes in the composition of the gut microbiota and its metabolites, such as short chain fatty acids, that improve cognitive functions [116]. Oral administration of Bifidobacterium breve strain A1 ameliorated the cognitive decline observed in AD mice [117]. Pistollato et al. have found that healthy diet patterns characterized by a large intake of probiotics and prebiotics are related to other nutrients, which can delay the decline of neurocognitive ability and reduce the AD risk [118]. Tillisch et al. suggested that supplementation of probiotic diet has an effect on normal brain activity [119], and Akbari et al. based on 60 AD patients to evaluate the probiotics effects, and the results also shown that compared to controls, the probiotic could significantly improve the cognitive function in AD patients [120]. These data revealed that probiotic treatment can decrease the progression of AD and that the beneficial effects could be partly mediated by alteration of the microbiota.

More importantly, the latest randomized, double-blind, and controlled clinical trial demonstrated that a mixture of probiotics (Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum) consumed for 12 weeks had a positive effect on cognitive function (Mini-Mental State Examination score) and some metabolic statuses in AD patients [120]. To summarize, certain probiotic strains show efficacy in modulating cognitive behavior and AD-related pathogenesis. Consequently, there is a need for future studies focusing on the best combinations of probiotic strains, the timing of administration, and the identification of the mechanism by which each strain exerts its effects.

Fecal microbiota transplantation

FMT is a type of bacteriotherapy that introduces healthy donor stool into the bowel of the recipient to re-establish a protective gut flora. FMT can change the gut microecology more robustly than food or probiotics. FMT has become an important therapeutic option for Clostridium difficile infection [121]. Whether FMT is feasible in treating various nervous system diseases remains to be investigated.

Recent studies have shown that transplantation of the fecal microbiota from WT mice into ADLP^APT transgenic mice ameliorated the formation of Aβ plaques and neurofibrillary tangles, glial reactivity, and cognitive impairment [85]. Jiang et al. indicated that although FMT seems to be a drastic treatment, the change in the composition of the gut microbiota may positively affect the cognition or pathology of AD [122]. Hazan et al. found that in AD patients, FMT may prevent the translocation of neuroactive compounds and metabolites within the CNS that regulate mood and cognition and contribute to inflammation [123]. In addition, Sun et al. found that FMT alleviated AD-like pathogenesis in APP/PS1 transgenic mice [124]. Thus, FMT may have beneficial effects on AD treatment. However, further human clinical research is needed to evaluate its effectiveness in AD patients.

CONCLUSIONS AND FUTURE PERSPECTIVES

It is widely recognized that the human gut microbiota is critical to health and disease. Dysbiosis of the gut microbiota is relevant to a variety of diseases. In AD, at least a proportion of individuals show dysbiosis of the gut microbiota. However, it remains unclear whether dysbiosis of the gut microbiota is caused by disorders of the nervous system modulating gut function or is a major factor affecting brain function. Hence, there is a need for further investigations of the interactions between the gut microbiota and AD. It is expected that in the near future, a better understanding of the pathological contribution of gut microbiota dysbiosis in AD development and the molecular mechanisms of the bacterial species significantly regulated by drug administration to retard AD will provide useful directions for the development of gut microbiota-based therapeutic interventions for this disorder [125].

A large number of studies have confirmed the interaction between the gut microbiota and the CNS and preliminarily described the interaction through neural, endocrine and immune pathways, the so-called microbiota-gut-brain axis [31]. However, the underlying mechanisms of the gut microbiota and its metabolites in AD remain unclear. Metagenomics and metabolomics as the tools to reveal the relationship between disease and gut microbiota, which could help to identify more metabolic pathways and provide a strong rationale for approaches to the treatment of many CNS disorders.

It is a feasible strategy to regulate the gut microbiota through long-term individualized diet adjustment, physical activity, probiotic interventions or FMT, which can be used for innovative treatment of neurodegenerative diseases, including AD. The gut microecology environment contains the largest number and types of microorganisms in the human body. It is of great significance to study gut microecology for the prevention and treatment of various human diseases. Thus, intervention research in microecology will possibly bring hope to understanding AD and finding new methods to prevent and treat AD.

Footnotes

ACKNOWLEDGMENTS

This work was supported by grants from the National Natural Science Fund (Grant Number: 81871125); Fund from Department of Science and Technology of Shanxi Province (No.201704D13111584); Open Fund from Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, China (No. KLMEC/SXMU-202010) and Shanxi “1331 project” Key Subjects Construction (1331KSC) (XK201708).

Authors’ disclosures avaialble online ().

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