Modulating the Gut Microbiota as a Therapeutic Intervention for Alzheimer’s Disease

Abstract

Growing evidence suggested that the change of composition and proportion of intestinal microbiota may be related to many diseases, such as irritable bowel syndrome, bipolar disorder, Parkinson’s disease, as well as Alzheimer’s disease. Current literature supports the fact that unbalanced gut microbial composition (gut dysbiosis) is a risk factor for AD. In our review, we briefly sum up the recent progress regarding the correlations between the gut microbiota and AD. Therapeutic interventions capable of modulating the make-up of the gut microflora may exert beneficial effects on AD, preventing or delaying the beginning of AD or counteracting its development. Additionally, well-documented approaches that can positively influence AD may exert their beneficial effects through modifying the gut microbiota. Therefore, other novel interventions which can target on gut microbiota will also be potential therapies for AD. The chances and challenges that AD is confronted with in the research field of microbiomics are also discussed in this review.

Introduction

Alzheimer’s disease is an irreversible, degenerative disease of the central nervous system which is characterized by specific clinical symptoms including impaired cognition, including memory loss, language problems, mood fluctuation, deprivation of intention, and intellectual coordination skills, eventually affecting a person's ability to carry out routine activities in daily life. Nowadays, AD is one of the common chronic diseases leading to disability, which brings heavy burdens on patients and their families, as well as obviously influences the socio-economic and medical burden. Currently, it still lacks effective approaches capable of reverse the pathological changes happened in the brain of AD patients despite intense studies have been carried out. It is possible to prevent or delay the development and progression of AD if we have a thorough elucidation about the pathophysiology of AD [1]. In recent years, more and more researches seek for therapeutic interventions based on the pathophysiology of AD. Among these researches, intestinal microbiota is gradually becoming a new and appealing focus for latent therapeutic approaches. Our review focuses on the currently available evidence of therapeutic approaches modulating the gut microbiota in AD, and discuss the limitations and challenges in this emerging field. A schematic of possible approaches mentioned in our review that may exert effects on Alzheimer’s disease through microbiota modulation is shown in Fig. 1.

Fig. 1.

Possible approaches that may exert effects on Alzheimer’s disease through microbiota modulation. FMT: Fecal microbiota transplantation

Characteristics of AD

AD is a progressive disease, which becomes more serious over time. At present, it is considered that it begins 20 years or even early before the initial symptoms of cognitive decline appear. Therefore, potential treatments that can retard or prevent the progression of Alzheimer's disease may be most valid when applied in the early stage of the disease continuum rather than in the late clinical stage.

The pathological features of AD include chronic neuroinflammation, deposition of extracellular beta-amyloid (Aβ) plaque and intracellular neurofibrillary tau tangles in the brain. The deposition of Aβ aggregates in the central nervous system is affected by the levels of Aβ in the brain as well as from peripheral tissues. Some convincing evidence demonstrates that Aβ injected into the gastrointestinal tract can induce amyloidosis in the brain and cause Alzheimer’s disease-like cognitive deficits, which suggests Aβ from the periphery may conduce to the development of AD [2]. So the critical role of circulating Aβ peptide in AD pathology cannot be easily ignored. The Aβ polymerizes into fibrils through self-aggregation in the central nervous system and further causes inflammation and neurotoxicity. Recent studies have shown that microbial dysfunction has an impact on the incidence of AD, in particular, it participates in the process of neuroinflammation activation and amyloid formation [3]. There are extensive researches on the pathophysiological mechanisms involved in AD, and it becomes more clear that not only Aβ deposits in the brain but also the infiltration of bacterial amyloids into the brain be a critical causative factor of neuroinflammation in AD [4, 5].

Microbiota in Human Gastrointestinal Tract

The gut microbiota occupies a large quantity and density of microbes found in the human body. Human gut microbiota include bacteria, fungi, viruses, archaea, and protozoa, the most common of which being bacteria. Near ninety percent of the gut bacteria pertain to the Bacteroidetes phyla (~ one fifth of all gut bacteria) which contain around 20 genera (such as Bacteroides) and Firmicutes phyla (~ four fifths of all gut bacteria) which contain over 250 genera (such as Lactobacillus and Clostridium), while the rest belongs to Proteobacteria, Actinobacteria, Verrucomicrobia and Fusobacteria phyla (together, typically about one percent of all gut bacteria) [6, 7].

The genus Bacteroides is capable of producing a variety of intense neurotoxins endogenously, such as lipopolysaccharide (LPS), and bacterial amyloids, which can induce substantia inflammatory processes both in the periphery and in the central nervous system [8, 9]. For instance, the production, and secretion of toxic LPS confined to the gut can contribute to AD-type neurodegenerative changes by participating in multiple aspects of AD-type neuropathology [10]. Bacterial amyloids are different from mammal ones in primary structure, but share similarities in tertiary structure, so they might serve as a scaffold for aggregation of other amyloidogenic proteins, such as amyloid Aβ, provoking amyloidogenesis, Aβ deposition and formation of amyloid plaques in AD [4, 11], what is called cross-seeding effect in technical terms.

Gut Dysbiosis and AD

Gut dysbiosis refers to the changes of microbial quantity and quality that contains less diverse microbiota, fewer beneficial microbiota, and more harmful microbiota, and it is characterized by increasing inflammation and participating in AD pathogenesis. More and more scientific researches clearly state the significant roles of the gut microflora play in AD and studies of several groups have demonstrated that the occurrence and progression of AD is closely linked with gut dysbiosis. For example, studied showed that LPS from gut dysbiosis can act as a mediator in amyloid pathology in Alzheimer’s disease. What’s more, gut dysbiosis can lead to disturbance of the gut epithelial barriers, and then increase inflammation through the microbiota-brain-gut axis mentioned above, thus constituting as an important aspect of AD pathogenesis [12].

The neuroinflammation in AD can be influenced by gut microbiome through the production of a range of proinflammatory cytokines and bacterial metabolites. The gut microbiota can product LPS, as mentioned above, with the latter can lead to neurodegeneration by mediating the production of inflammatory factors from astrocytes. Meanwhile, gut microbiota can product short chain fatty acids (SCFAs), with the latter can suppress the production of LPS as well as proinflammatory cytokines and ameliorate amyloidosis by interfering with the conversion of monomeric Aβ into Aβ fibrils, thereby decreasing neurotoxic Aβ plaque formation.

On the one hand, accumulating data from animal models and humans illustrate the close associations between gut microbiota and immune system [13]. Gut microbiota and their metabolic products regulate both innate and adaptive immune systems. Therefore, the disruption of gut microbiota homeostasis is related to the onset and progression of many immune-related diseases, such as autoimmune diseases, and inflammatory bowel disease. The hotspot mechanisms for the pathological connections above focuses on impaired intestinal barrier, the leakage and translocation of bacteria and metabolic products, activation of different signaling pathways, stimulation of inflammatory immune responses. On the other hand, compelling evidence from studies of animal models of AD-like pathology and AD patients demonstrate that the pathophysiology of AD involves innate immune processes as well as adaptive immune processes in neuroinflammatory conditions [14, 15]. In this case, the unfavorable crosstalk between immune system and AD can be further deteriorated by gut microbiota dysbiosis.

Current data and observations show that dysbiosis of gut microbiota can be induced by a consumption of a high sugar or fat diet, which further participates in promoting hindbrain inflammation, as well as causes an increase of LPS and inflammatory cytokines in the gut [16]. Consequently, remodeling gut microbiota composition to specific phyla supporting the generation of SCFAs and / or inhibiting the production of neurotoxins may help protect against AD, in part, by interfering with the formation of toxic soluble Aß aggregates. A recent longitudinal study showed that, in the mouse model, the change of intestinal microbiota occurred earlier than the formation of amyloid plaque and neuroinflammation of AD. Thus, early interventions targeting on gut microbiota might provide validity for AD prevention at an early stage.

Targeting Microbiota in AD

There are complex and multifactorial factors drawn into the nosogenesis and progression of AD, from genetic as well as environmental ones, including age, gender, sedentary behavior, diet, sleep, and these factors have been found to exert important effects on the composition of gut microbiota. It is possible that altered gut microbiota composition may participate in these factors’ influence on AD. The risk factors for AD can be classified into non-mutable risk factors (such as age, sex and hereditary factors) and mutable risk factors (such as lifestyle, obesity and environment). Herein, gut dysbiosis can be viewed as a mutable risk factor for AD. Based on estimate of population-attributable risk models, a third cases of AD may be supposed to ascribe to mutable risk factors and hence may be stopped from occurring. The current focus on therapeutic manipulation that can remodel gut microbes include probiotic, prebiotic, antibiotics, and fecal microbiota transplantation. Besides, many potential strategies can also modulate gut microbiota composition and probably exert beneficial roles through this modulation effect. Current possible approaches that modulate gut microbiota and their influences on AD is shown in Table 1, while the sections of herbal medicine and their extracts, diets are shown in Tables 2, 3, separately.

Table 1.

Current possible approaches that modulate gut microbiota and their influences on AD

Possible Approaches	Connections with Microbiota	Influences on AD	References
Probiotics/Prebiotics	Harmful bacteria↓; benefcial bacteria in the gut↑	Aβ plaque size↓, memory↑ and learning impairment↓	[17–19]
Broad-spectrum Antibiotics	No specific target on the types of bacteria	Aβ plaque deposition ↓	[20]
FMT	Correct gut dysbiosis of the recipient	Cognitive improvement, Aβ accumulation ↓	[21]; [22]
APOE alleles	A higher abundance of the Lactobacillaceae family in APOE4 mice	A potent mechanism for APOE genotype’s influence on AD risk	[23]
Age	Firmicutes ↑ in the young adults; Bacteroidetes ↑ in the elderly	Firmicutes, Bifidobacterium ↓ and Bacteroidetes ↑ in AD patients	[24, 25]
Gender	Difference in microbiota abundance between females and males	Affect the response to AD treatment approaches	[26]
Traditional Drugs	Only a high consumption of memantine leading to decreased E. coli biofifilm formation	Can not slow or halt the irreversible pathological damage of neurons already happened in the brain	[27]
Physical Exercise	Abundance of butyrate-producing bacteria ↑; pro-inflammatory bacteria ↓; microbial diversity and richness of genera belonging to the Firmcutes phyla ↑	Risk of age-related brain volume loss ↓	[28, 29]
Sleep Problems	Increase of gut microbiome diversity can promote a healthier sleep	Indirectly impacts amyloid burden in brain regions	[30–32]
Ammonia and lactic acid	Independently of dysregulation of gut microbiome	Separate indicators for dementia	[33]

↑: Higher, ↓: Lower, AD: Alzheimer's disease, FMT: fecal microbiota transplantation, APOE: apolipoprotein E

Table 2.

Examples of herbal medicine and their extracts that modulate gut microbiota and their influences on AD

	Examples	Connections with Microbiota	Influences on AD	References
Herbal Medicine and their extracts	TTK	Erysipelotrichales, Clostridiales, Desulfovibrionales, Enterobacteriales ↓; Bacteroidales and Lactobacillales ↑	Amyloid deposit ↓, the memory function ↑	[41]
	Rg1	Population of Lactobacillus salivarius ↑; abundance of Bacteroidetes ↓	Production of Aβ ↓, cognitive impairment ↓	[42]
	DHF	Detrimental bacteria ↓; gut microbial diversity in female ↑, but not male, mice	Synaptic loss ↓, restoring synaptic plasticity ↑, Aβ deposition ↓	[26, 43]
	OMO	Proinflammatory microbiota↓; anti-inflammatory microbiota ↑	Brain tissue swelling ↓, neuronal loss ↓, levels of AD intracellular markers ↓	[44]

↑: Higher, ↓: Lower, TTK: Tetragonia tetragonioides Kuntze, Rg1: Ginsenoside Rg1, DHF: flavonoid 7,8-dihydroxyflavone, OMO: Oligosaccharides extracted from M. officinalis

Table 3.

Examples of diets that modulate gut microbiota and their influences on AD

Examples	Connections with Microbiota	Influences on AD	References
Diets
Nutritional Components
RS	Bacteroidetes and Bifidobacterium, Akkermansia, and Allobaculum species ↑; Firmicutes ↓; Bacteroidetes phylum ↑; Firmicutes/Bacteroidetes ratio ↓	Not systematically investigated	[57]
Whey Protein	Lactobacillus ↑; Stenotrophomonas ↓	Encourage the rebuilding of gut microbiota in aged model mice	[45]
Omega-3 Fatty Acids	Firmicutes phyla ↑	Hard to establish comparative analysis	[46]
Polyphenols	Firmicutes and Bacteroidetes communities ↑; Akkermansia population ↑; Bifidobacterium and lactobacillus ↑; Proteobacteria, Actinobacteria, and Bifidobacterium↑	Not systematically investigated	[48, 49, 51, 52]
Vitamin D	Pseudomonas, Escherichia/Shigella ↓; bacterial richness ↑	Not systematically investigated	[53]
Substances obtained from Seaweeds	Modulating the bacterial richness and diversity of the gut microbiota	Not systematically investigated	[54]
Dietary Patterns
MD	Richness of specific taxa in the microbiome ↑	Cognitive function ↑, inflammation ↓	[55, 56]

↑: Higher, ↓: Lower, RS: Resistant Starch, MD: Mediterranean diet

Probiotics / Prebiotics and AD

Probiotics refer to live microorganisms while prebiotics are substances which can serve as food for these bacteria. The most commonly used probiotics are Lactobacilli and Bifidobacteria species that also exist naturally in the gastrointestinal tract, both of whom belonging to lactic acid bacteria strains [19].These probiotics can inhibit harmful bacteria and increase the proportion of benefcial bacteria in the gut, leading to altered gut microbiota composition, variety, and function. Prebiotics can be obtained from various sources, and the most commonly used prebiotics are nondigestible carbohydrates, which are fermented by the gut bacteria and lead to increase of SCFAs production, playing vital roles in positively modulating the intestinal microbiota. There are several data about the effects of probiotics and/or prebiotics in AD [18, 34]. Treatment of multiple combination of probiotics belonging to Lactobacilli and Bifidobacteria species in an AD rat model reduced Aβ plaque size and ameliorated memory and learning impairment, the mechanism of which may be mediated by modifying microbiota. A clinical study in patients with AD estimated that a supply of probiotics exerted profitable effects on cognitive function of these patients. It was demonstrated that an administration for 12 weeks of multi-strains probiotics including Lactobacilli and Bifidobacteria could improve cognitive behavior with positive effects on MMSE score of the AD patients [35]. A double-blind, placebo-controlled, randomized clinical trial showed that the cognitive dysfunction in middle-aged and older adults could be alleviated by the supplementation of a single-strain probiotic called Lactobacillus rhamnosus GG, with several possible mechanistic pathways involved,for instance, the modulation on the make-up and functionality of the gut microbiota by Lactobacillus rhamnosus GG [17].

Antibiotics and AD

Broad-spectrum antibiotics are usually used to remove or prevent bacterial colonization in the host body with no specific target on the types of bacteria, and can greatly affect the gut microbiota composition and decrease its biodiversity and disturb its colonization after administration. Existing researches demonstrated that a standing transformation in the make-up and variety of gut microbiota could be caused after the application of therapeutic schedule with broad spectrum antibiotics over a long period of time, and this effect was asscioated with decreased Aβ plaque deposition in the animal model of Aβ amyloidosis [20]. However, in the course of medication, antibiotics are widely used, particularly those possessing broad-spectrum properties, which can cause microbial resistance in humans to the available antibiotics, and has become as a principal menace to public health to this day. In this regard, an effective and alternative option to restore healthy gut microbiota is to combine antibiotics with the pre- and probiotics.

FMT and AD

Fecal microbiota transplantation (FMT) is an approach that infuses feces from healthy donors to receptors to restore their healthy microbiota. This approach has already been proved to be highly efficient, secure, and economical for the treatment of recurrent Clostridioides difficile infection (CDI) [36], which has been assessed in real-world clinical settings.

The evidence of improvement in cognitive function after FMT has been documented in animal models as well as human patients. The spatial and recognition memory was enhanced by FMT in a mouse model of Alzheimer’s. Also, the cognitive deficits and Aβ accumulation were obviously alleviated by FMT treatment, which was linked to its effect on modulating gut microbiota [21]. One case study of an 82 year-old man with AD showed that following FMT for recurrent CDI, the AD symptoms were reversed rapidly, which was observed as early as 2 months and lasted until 6 months after FMT, with paralleled improvements in the patient’s MMSE scores[22]. Another case report of a 90-year-old woman with AD also showed cognitive improvement after FMT for recurrent severe CDI, and it was connected with the corrected gut dysbiosis of the recipient by FMT treatment [37]. The conventional used stool products for FMT include fresh stool, frozen stool, which is delivered to the recipients through endoscopic infusion. The next generation FMT include liquid capsule, spore formulation, specific bacterial product, and sterile fecal filtrate, and their clinical efficacy still needs to be further investigated in AD patients [38, 39]. Even though FMT is a promising therapeutic strategy for AD, it cannot be ignored that there are adverse events related to FMT, including short-term risks and long-term side effects.The short-term risks are usually caused by the delivery methods of FMT, while studies revealed that long-term effects of FMT include vulnerability to diseases of the recipients [40]. In order to minimize the risks of FMT, rigorous donor screening and testing needs to be mandated.

Other Factors Related to Gut Microbiota in AD

APOE Alleles

There are three apolipoprotein E (APOE) polymorphic alleles called APOE 2, 3 and 4, respectively, which are associated with AD risk. Specifically, AD risk is increased by APOE4 allele but reduced by APOE2 allele when compared with APOE3 allele. A recent research confirmed that APOE genotype was strongly associated with microbial community composition but not with the abundance and degree of homogeneity of the gut microbiota in a murine mice model. The researchers found that APOE4 mice showed a higher abundance of the Lactobacillaceae family relative to APOE2 mice, which may be related to improved gastrointestinal health [23]. However, it is not yet evaluated in murine models that whether the influence of APOE-realted microbiome has an association with on AD phenotypes, which is necessary for clarifying whether APOE genotype-related gut microbiome alteration represents a potent mechanism for APOE genotype’s influence on AD risk.

Age

Gram-negative Bacteroidetes and Gram-positive Firmicutes coexist symbiotically in the healthy gut. Researchers had found that the composition of the microbiome in the gut changes when humans age, with an obvious change in the relative proportions of the Firmicutes and the Bacteroidetes. That is, higher proportions of Firmicutes are observed in the young adults, whereas higher proportions of Bacteroidetes are observed in the elderly. The reduced F/B ratio is related to gut dysbiosis, so it can be used as an important indicator of gut microbiome homeostasis. Clinical studies show that AD patients have different bacterial abundance from control age- and sex-matched individuals. Specifically, AD patients have a decreased Firmicutes and Bifidobacterium and an increased Bacteroidetes [24]. In healthy adults, changes in the immune system can be caused by aging, resulting in chronic, low-grade inflammation called “inflammaging”. One potential mechanism of inflammaging is the change of gut microbiota associated with aging, as well as age- associated changes in gut permeability. This may explain why age is an isolated risk factor for AD. However, age itself is a non-modifiable factor related to AD. Nevertheless, we can explore novel interventions that can target age-related gut microbial composition alteration.

Gender

Healthy human adults have a high level of Bacteroidetes and Firmicutes in the gut microbial composition while female had obviously different gut microbiome composition from male overall, especially a lower Bacteroidetes abundance. Microbiome have been reported that the modulative effect on disease phenotype is gender-specific. Thus, the response to AD treatment approaches may also be gender-specific. For instance, a decreased Aβ burden following longer-term (antibiotic cocktail) ABX-perturbed gut microbiome treatment is selectively observed in male APPPS1-21 mice compared with female ones, the latter showed a greater richness of Allobaculum and Akkermansia without any change of Aβ amyloidosis. A greater proportion of certain Allobaculum and Akkermansia species can thin the thickness of the mucin layer because they can degrade mucin, thus resulting in greater inflammatory activation and increasing the possibility of translocations of bacteria and / or bacterial metabolites from the gastrointestinal tract into circulating system. Besides, it was documented that supplementation of a commercially available probiotic cocktail, VSL#3, which contains eight strains of lactic acid-producing bacteria, could reduce Aβ plaque deposition in female mice but no effects in males in the mouse model of AD. While antibiotics treatment produced a signifificant reduction in Aβ plaque load in male mice but not in females [26]. These results demonstrated the effects of probiotic and antibiotics treatments are sex-specific, which may be attributed to sex differences in microbiota composition exist in male and female mice. Therefore, these data indicate that we need to consider the basal gut microbiota composition and sex when developing therapeutic gut microbiome manipulation in AD.

Drugs

Traditional Drugs

The drugs available today for the treatment of AD can not slow or halt the irreversible pathological damage of neurons already happened in the brain, and the approved five treatment options are—donepezil, rivastigmine, galantamine, memantine, and combined donepezil with memantine. In a mouse model, researchers observed that all ex vivo administered of the four drugs mentioned above had no direct influence on gut bacteria activity, with only a high consumption of memantine leading to decreased E. coli biofifilm formation, the latter known as having the potential to influence different intestinal functions [27]. This indicates that we should search for other potential drugs capable of modulating gut microbiota for AD.

Herbal Medicine and their Extracts

Tetragonia tetragonioides Kuntze (TTK), a 70% ethanol extract, has been proved to be capable of decreasing amyloid deposit in the hippocampus of an AD rat model and enhance the memory function. The effect is partly mediated by altering gut microbiome composition, specifically TTK can reverse the increased percentage of Erysipelotrichales, Clostridiales, Desulfovibrionales, Enterobacteriales and the decreased amount of Bacteroidales and Lactobacillales in AD rats [41]. Long-term use of ginseng extract can significantly increase the number of profitable bacteria, including Bifidobacterium, Lactobacillus and Clostridium, and decrease the deleterious bacteria, including Butyricimonas, Parabacteroides, Alistipes, Helicobacter, in the gut of rats. Ginsenoside Rg1 (Rg1) is another traditional Chinese medicine. It is demonstrated that Rg1 can reduce the production of Aβ and improve the cognitive impairment in a tree shrew AD model by increasing the population of Lactobacillus salivarius, a type of beneficial bacteria and reducing the abundance of Bacteroidetes [42]. Supplementation of flavonoid 7,8-dihydroxyflavone (DHF), a naturally occurring compound enriched in several plants, was observed to significantly decrease detrimental bacteria and increase gut microbial diversity in female, but not male, mice [26]. Chronic oral administration of 7,8-DHF was proved to be able to prevent memory deficits and cognitive decline in AD mouse models by decreasing synaptic loss, restoring synaptic plasticity, and alleviating Aβ deposition [43]. However, it is still not elucidated that whether the modulation of DHF on the gut microbiota is one possible mechanism by which DHF confers protection against AD. Oligosaccharides extracted from M. officinalis (OMO), represented by fructooligosaccharides, have a prebiotic effect on gut microbiota composition represented by a change of decreased proinflammatory microbiota and increased anti- inflammatory microbiota. This is in accordance with the conventionally prebiotic role fructooligosaccharides exert in increasing abundance of profitable bacteria, i.e., Bifidobacteria and Lactobacilli. OMO administration could significantly improve the learning and memory abilities in AD-like animal models, through attenuating brain tissue swelling, neuronal loss, and downregulating levels of AD intracellular markers, also probably altering the diversity and richness in the gut bacteria community [44]. Examples of herbal medicine and their extracts that modulate gut microbiota and their influences on AD are illustrated in Table 2.

Diet

Diet is an important element that can shape microbiota composition in the gut. Microbiota composition in the gut can be affected by specific nutritional components as well as dietary patterns.

Specific Nutritional Components

1. Resistant Starch (RS)

   Resistant starch (RS) is a microbiome-accessible carbohydrate that can be viewed as a type of fermentable fiber and a type of prebiotic that serves as substrate for bacteria living in the large intestine. RS can beneficially rebuild gut microbiota in elderly mice to a colonization of larger amount of Bacteroidetes and Bifidobacterium, Akkermansia, and Allobaculum species while fewer Firmicutes. As it is convinced that chronic intake of a high fat (HF) diet is related to cognitive dysfunction by inducing alterations in neurotransmitter receptor densities in brain regions associated with cognition, a HF diet with RS supplementation for 4 weeks in rats could prevent these alterations, suggesting beneficial effects of RS supplementation on improving learning and memory. Although an obviously beneficial change in the microbiota can be obtained by resistant starch fermented in rodent animals, it has not been systematically investigated the exact role of the altered gut microbiota configuration has in mediating the effects of RS in AD models.

2. Whey Protein

   It is estimated that whey protein (WP) from cows and goats can substantiallly raise the diversity of gut microbiota, increase the relative richness of profitable bacteria (such as Lactobacillus) and suppress the growth of deleterious bacteria (such as Stenotrophomonas) in aged mice models treated by D-galactose, suggesting that WP diet can encourage the rebuilding of gut microbiota in aged model mice [45].

3. Omega-3 Fatty Acids

   Omega-3 Fatty Acids (FAs) are a class of polyunsaturated fatty acids which are involved in diverse physiological functions in the brain. Various evidence highlighted that an increase in the richness of beneficial bacterial genera, for example, Firmicutes phyla, could be achieved by a supplementation of omega-3 FAs, indicating its significant effect on gut microbiota configuration. Several groups reported a significantly reduction of cerebral omega-3 as well as in plasma in patients with AD, which was related to an increase in the progression of AD. It was evaluated intensely whether omega-3 FAs supplementation had an effect on cognitive outcomes in AD, and it was shown that the higher the omega-3 FA plasma level, the lower the rate of cognitive impairment, but this efficacy was demonstrated only in mild forms of AD. Since the effects of nutritional supplementation are dose-dependent and time-dependent, it is hard to establish comparative analysis about the influence of omega-3 FAs supplementation have on AD’s cognitive impairment, thus it is currently impossible to evaluate the role of omega-3 FAs supplementation-related gut microbiota composition alteration plays in cognition outcomes of AD [46].

4. Polyphenols

   Polyphenols are secondary metabolites of plants and constitute an abundant group of compounds. Polyphenols in our daily diet are ample micronutrients mainly intaken from vegetables, fruits, tea, coffee, red wine and soybeans. Polyphenols can benefit human body health by displaying various activities, including antioxidant, anti-inflammatory and neuroprotective activities. These activities were related to the protective effect of plant polyphenols in AD which were supported by results of many studies [47]. In recent decades, more and more studies have assessed the effect of polyphenol-rich dietary sources on the gut microbiota configuration. Gut microbiota dysbiosis can be alleviated by tea polyphenols through stimulating the growth of the population of Firmicutes and Bacteroidetes communities [48]. Akkermansia population in the gut microbiota of mice can be enlarged by an extract from cranberry which is rich in polyphenol [49, 50]. Polyphenols from daily intake of orange juice positively increased the population of gut Bifidobacterium and lactobacillus [51]. Blueberry polyphenol extracts had a modulation effect on specific bacteria such as Proteobacteria, Actinobacteria, and Bifidobacterium [52]. However, whether the microbiota modulation effect is engaged in the plant polyphenols’ protection against the development of AD remains to be further investigated.

5. Vitamin D

   Studies observed that vitamin D supplementation can modulate the gut microbiota, which can decrease the relative abundance of Gammaproteobacteria including Pseudomonas and Escherichia/Shigella and increase bacterial richness [53]. This might explain its protective influence on gastrointestinal diseases, including inflammatory bowel disease or bacterial infections. However, whether this modulation could also exert beneficial effects in AD patients still lacks relevant researches.

6. Substances obtained from Seaweeds

   Macroalgae, or seaweeds are large plant like structures which are abundant in polysaccharides, polyphenols and peptides. Current evidence from external and internal animal studies showed these substances obtained from seaweeds have the capability to exert positive effects on the mammalian gut microbiota gut by modulating the bacterial richness and diversity of the gut microbiota [54]. This may suggest dietary intervention with seaweed-originated components in humans be a potential therapeutic option on modulating the gut microbiota, while we need more human dietary intervention studies to confirm whether this intervention option have any possible therapeutic benefits on AD patients.

Dietary Patterns

There are specific and healthy dietary patterns which can attribute to improved cognitive function and a lower risk of cognitive impairment. Take Mediterranean diet (MD) as an example, it is characteristic of high intake in plant foods and olive oil, moderate intake in marine products and eggs, low intake in red meat and processed products. The evidence from the current latest systematic review and meta-analysis indicate an opposite connection between Mediterranean diet and the chance of developing cognitive dysfunction. According to estimates of a brain imaging study in young to late middle-aged adults which lasts for three years, higher MeDi adherence may provide provide 1.5 to 3.5 years of protection against brain aging and AD, indicating that dietary intervention can truly affect AD progression in the preclinical phases of AD with no or minimal cognitive dysfunction [55]. The administration of a one-year MedDiet intervention across five European countries in older individuals led to enlarged richness of specific taxa in the microbiome, and this effect was associated with elevated cognitive function and decreased inflammation [56]. The examples of diets that modulate gut microbiota and their influences on AD is demonstrated in Table 3.

Physical Exercise

Nowadays, a sedentary lifestyle is common in large numbers of adult workers. Data shows that the sedentary lifestyle can lead to cognitive decline. Accumulating evidence indicates that physical activity or exercise can alter gut microbiota configuration by increasing abundance of butyrate-producing bacteria as well as decreasing pro-inflammatory bacteria [29]. It is documented that physical exercise combined with probiotics can lessen the development of AD, of which the profitable effects is partly mediated by altered gut microbiome, whereas physical activity alone has a weak influence on dementia. Regular physical aerobic exercise of moderate intensity for 6 months in aging humans could reduce the risk of age-related brain volume loss, suggesting a role of aerobic fifitness in maintaining and enhancing cognitive functioning in older adults. Several human exercise studies confirmed that aerobic exercise were capable of improving the microbial diversity and richness of genera belonging to the Firmcutes phyla [28]. These results may indicate alterations in the gut microbiome correlated with exercise may be a crucial aspect of beneficial effects of physical exercise has on neurodegenerative diseases, such as AD.

Sleep Problems

Sleep problems have become a common problem confusing the population in the current society. A clinical study showed that acute sleep deprivation negatively impacts amyloid burden in brain regions that have been implicated in AD, providing primary evidence for the role of sleep deprivation on Aβ accumulation in the human brain [58]. The relationship between sleep and AD has been demonstrated by mounting evidence, and it is proved that interrupted or insufficient sleep is also an element related to etiology of AD. People with different forms of sleep problems have an obviously higher risk for cognitive dysfunction or AD and near fifteen percent of AD cases in the population may be ascribed to sleep disorders [30]. Therefore, a well sleep seems to have an essential effect in AD prevention. Research articles demonstrated that sleep efficiency was positively correlated with total microbiome diversity and richness within the Bacteroidetes and Firmicutes phyla through microbiome composition analysis [32]. In other words, this indicated that the increase of gut microbiome diversity can promote a healthier sleep. It is possible that increased gut microbiome diversity can positively impact sleep and subsequently exert beneficial effects on cognitive outcomes in AD patients, which still warrants further investigation by prospective and experimental studies.

Other Therapeutic Options

A sub-analysis study meant to elucidtate the association between the gut microbiome and dementia, demonstrated that ammonia was positively and lactic acid concentration inversely from the feces associated with the existence of dementia, which were separate indicators for dementia, independently of dysregulation of the gut microbiome [33].

Conclusions and Future Perspectives

This review concentrates on the current research status of connections between gut microbiota and AD, and gives a brief understanding of possible AD interventions associated with intestinal microbiome composition alterations. Factors that can disturb the gut microbiota, thus causing GM dysbiosis, could be linked with the pathogenesis of AD. From another perspective, microbiota-modulating intervention strategies that can maintain or restore the intestinal microbiota at a reminiscent state of healthy adults will be effective and feasible for AD prevention, which can inhibit the development or slow down the neureodegenerative progression of AD patients [59].

It seems that remodeling of the gut microbiome in AD patients is a potential new door for AD prevention and treatment, however, this area is nascent and some current research results obtained are debatable. Most related studies above between gut microbiota modulation and AD remain at a descriptive level and it still lacks prospectively functional studies about microbiome involving transcriptomics, which means mechanistic researches are required to determine mechanisms of combinatorial interactions and crosstalks between the gut microbiota and AD.What is more, We need to consider personalized characteristics of patient-specific gut microbiota composition when developing potential therapies for AD clinically, as the response to the same intervention between individuals may be variable. At the same time, as numerous confounding factors may have an impact on the gut microbiota, prospective researches about possible mechanisms of the gut microbiota’s effect on AD will be quite difficult to conduct. To sum up, more potential strategies can be explored which can modulate microbiota and exert neuroprotection, especially in the presymptomatic phases of AD.

Declarations

Conflict of interest

The authors declare that they have no competing interests.