“Muscle-Gut-Brain Axis”: Can Physical Activity Help Patients with Alzheimer’s Disease Due to Microbiome Modulation?

Abstract

Alzheimer’s disease (AD) is one of the most common forms of dementia, which cannot be cured at the moment. Therefore, researchers also look for the alternative approaches to its treatment. It is suggested that changes in human gut microbiome mediated by exercise could influence the development and progression of AD and a new term “muscle-gut-brain axis” is introduced. There is much evidence to support this assumption. The gut microbiology is closely related to a wide range of diseases of the nervous system and therefore any negative qualitative and quantitative changes in the composition of the gut microbiota can potentially contribute to the pathophysiology of AD. Research shows that the treatment of intestinal dysbiosis with probiotics/synbiotics/eubiotics can prevent or alleviate the symptoms of these chronic neurological diseases. Studies also point to the positive effects of movement on the health of seniors. A positive correlation can be found between cognitive functions and physical stress, both in the elderly and in AD patients. Even short-term interventions with a relatively low frequency seem to produce positive results, while physical activities can be performed by using relatively simple and cost-effective means. In addition, physical activity can significantly modulate gut microbiome. Thus, it can be concluded that physical activity in humans seems to correlate with gut microbiome, which can prevent the incidence and development of AD.

Keywords

Alzheimer’s disease cognitive disorders dementia exercise microbiome physical activity probiotics

INTRODUCTION

Alzheimer’s disease (AD) is one of the most common forms of dementia, which cannot be cured at the moment. AD accounts for 60–80% of all dementia cases [1]. It damages neurons and their connections in parts of the brain involved in memory. Thus, the one of the earliest symptoms of AD is memory loss— a sign of cognitive decline, which manifests itself especially in forgetting recently learned information [2]. Later on, other symptoms develop, such as language impairments, apathy, depression, delusions, hallucinations, aggression, and eating, walking, and sleeping problems, which eventually results in inability to execute the tasks of daily living [3].

Unfortunately, due to the changing demographic trends, the epidemiology of AD is growing and AD represents a serious social, economic, and health problem. Currently, there are about 50 million people living with AD. However, it is predicted that by 2050 this number should reach 152 million [4]. Although the researchers all over the world attempt to find new drugs for the treatment of AD, so far only four have been approved and used. These include cholinesterase inhibitors, donepezil, rivastigmine, and galantamine, and the NMDA-glutamatergic receptor antagonist, memantine.

The drugs only delay or maintain cognitive decline in patients with AD for some time. In addition, the state of health of most of the patients in a more advanced stage requires professional care, which burdens national budgets. For example, in Europe in 2050, the direct medical costs of care are estimated to be 6,716 mil EUR, with the direct non-medical costs of care at 14,236 mil EUR [5]. Therefore, researchers look for the alternative approaches to the treatment of AD. One of these approaches include physical activities, which are part of a healthy lifestyle, one of the modifying risk factors of AD [3]. Research [6] indicates that physical activities have a positive effect on patients’ mental function and the development of dementia. In fact, a lack of physical activity is associated with 20% of AD cases in the UK, USA, and Europe [7].

Thus, the purpose of this article is to explore the correlation between gut microbiome and physical activity/exercise in the development and progression of AD.

METHODS

The methodology is based on a literature review, which was conducted in three main databases: Web of Science, Scopus, and PubMed. The end of the search period is limited by April 2019. The collocated keywords were as follows: microbiome AND Alzheimer’s disease, physical activity AND microbiome, exercise AND microbiome, microbiome AND cognition, gut-brain axis and Alzheimer’s disease, exercise AND Alzheimer’s disease, physical activity AND Alzheimer’s disease, physical activity AND cognition, exercise AND cognition. The keywords were combined and integrated in database and journal searches. The terms used were searched using AND to combine the keywords listed and using OR to remove search duplication where possible. The backward search was also conducted, i.e., references of retrieved articles were assessed for relevant articles that authors’ searches may have missed.

Altogether 2,721 articles were identified in all these databases. After removing duplicates and titles/abstracts unrelated to the research topic, 435 English-written studies remained. Of these, only 240 articles were relevant for the research topic. These studies were investigated in full and they were considered against the following inclusion and exclusion criteria.

The inclusion criteria were as follows: the period of the publishing of the article was limited by the end search, April 2019; reviewed full-text studies in scientific journals in English were only included; the primary outcomes focused on the correlation of: 1) microbiome and Alzheimer’s disease, 2) Alzheimer’s disease and physical activity/exercise, and 3) physical activity/exercise and microbiome.

The exclusion criteria were as follows: review and summary articles, meta-analyses, conference abstracts; descriptive studies not including patients with AD; animal studies.

Based on these criteria, 72 studies were included in the final analysis. Figure 1 illustrates the selection procedure.

Fig.1

An overview of the selection procedure.

“Muscle-gut-brain axis”: fiction or a new possible term in sport medicine and neurology?

The human gut microbiome consists of billions of cells and its genetic information exceeds host information by about 150 times. This complex biomass may play a role in the emergence and progression of a variety of disorders and diseases, even outside the gastrointestinal system [8]. The microbiome communicates with the brain through the so-called gut-brain axis. This means that on the one hand, the brain can affect the intestines by interfering with their motility, secretion, blood flow, or affect the intestinal immune response. Triggering stimuli can be both psychological (e.g., stress) and physical (e.g., toxins). On the other hand, microbiome through neuronal, immune, metabolic, and endocrine signaling pathways can modulate the brain. Everything is done through the conjunction— the nerve vagus [9, 10]. Factors such as aging, nutrition, and physical exercise have been shown to modify microbes in both a positive and negative sense [11].

AD is one of the most common neurodegenerative diseases of the elderly and leads to irreversible cognitive defect and dementia. A typical feature of AD is the proliferation and deposition of amyloid-β in the brain along with the local inflammatory response at the site of storage [12]. Microbiome seems to be partly associated with this accumulation, since for many microorganisms of human intestinal content, the formation of proper functional amyloid proteins is typical, including those found in the brain of AD patients [9, 12]. Short-chain fatty acids (SCFAs) have also been shown to be involved in animal models [13].

“Muscle-gut-brain axis”? Based on available data, it is considered that physical activity may reduce AD incidence [14, 15]. Microbiome has been reported to be associated with AD, and exercise is believed to positively influence microbiome [16, 17]. However, there has been no research study yet describing that the changes in microbiome generated by exercises would affect AD. In addition, the term “muscle-gut-brain axis” has not been used in the literature yet. This review seeks to bring an overview of current information.

Microbiome and Alzheimer’s disease

Since gut microbiome is closely related to nervous system disease, negative qualitative and quantitative changes in the composition of gut microbiota may potentially contribute to the pathophysiology of AD. For the sake of completeness, it should be noted that the literature refers to the association of human intestinal microorganisms and a variety of neuro(auto)-immune, neurodegenerative, or psychiatric diseases such as multiple sclerosis, neuromyelitis optica spectrum disorders, Parkinson’s disease, amyotrophic lateral sclerosis, depression, anxiety, schizophrenia, and autism [18]. Interestingly, neurodegenerative diseases, including AD, have a high rate of gastrointestinal comorbidities, and therefore there is an assumption that the treatment of intestinal dysbiosis with probiotics/synbiotics/eubiotics could prevent or alleviate the symptoms of these chronic diseases [19]. However, the views on this issue are not very uniform.

Two recent studies by Paley et al. have been of great interest to intestinal microbioma and AD [20, 21]. The studies link neurodegeneration and cell death induced by tryptophan-derived tryptamine with the presence of gut bacterial Na(+)-transporting NADH:ubiquinone reductase sequence associated with AD. Tryptophan-derived tryptamine presents in human diet and gut microbiome. Tryptamine inhibits tryptophanyl-tRNA synthetase with consequent neurodegeneration in cell and animal models. Thus, gut microbial tryptamine overproduction correlates with AD-associated sequence occurrence. Antibiotic and diet additives induce AD-associated sequence and tryptamine.

An overview of the studies focusing on microbiota and AD is presented in Table 1 (postmortem brain samples) and Table 2 (living subjects).

Table 1

An overview of the studies focusing on microbiota and Alzheimer’s disease: Postmortem samples

Study	N	Pathogen	Main outcome
Hammond et al. [22]	5/5	Chlamydia pneumoniae	Chlamydia pneumoniae antigens + amyloid deposits, and neurofibrillary tangles were present in frontal and temporal cortices of the AD brain.
Poole et al. [23]	10/10	Treponema denticola, Tannerella forsythia, Porphyromonas gingivalis	LPS from periodontal bacteria Porphyromonas gingivalis can access the AD brain during life.
Miklossy et al. [24]	10/4	Borrelia burgdorferi	Aβ and spirochete specific DNA are key components of both pure spirochetal biofilms and senile plaques in AD.
Zhan et al. [25]	24/18	Escherichia coli K99	EC K99 levels were greater in AD compared to control brains; EC K99 was localized to neuron-like cells in AD but not control brains; LPS levels were also greater in AD compared to control brain; LPS colocalized with Aβ_1 - 40/42 in amyloid plaques and with Aβ_1 - 40/42 around vessels in AD brains.
Emery et al. [26]	14/12	Mixture of bacterial populations	Data strongly suggest that AD brains tend to have strikingly large bacterial loads compared to controls - species associated with skin, nasopharyngeal and oral areas such as Firmicutes and most consistently Actinobacteria, especially Propionibacterium acnes (up to 94% of Actinobacteria) are responsible for this.
Zhao et al. [27]	10/8	Bacteroides fragilis, Escherichia coli	Presence bacterial LPS in brain lysates from the hippocampus and superior temporal lobe neocortex of AD brains; mean LPS levels varied from two-fold increases in the neocortex to three-fold increases in the hippocampus, AD over age-matched controls.
Zhao et al. [28]	7/7	N/A	Major source of proinflammatory signals in AD brain may originate from internally derived noxious exudates of the GI-tract microbiome; due to aging, vascular deficits or degenerative disease these neurotoxic molecules may “leak” into the systemic circulation, cerebral vasculature, and on into the brain; this internal source of microbiome-derived neurotoxins may play a particularly strong role in shaping the human immune system and contributing to neural degeneration, particularly in the aging CNS.
Zhao et al. [29]	15/12	N/A	LPS was accumulated in neocortical neurons of AD brain and impaired transcription in human neuronal-glial primary co-cultures.

N, number of subjects (AD/control); LPS, lipopolysaccharide; Aβ, amyloid-beta; GI, gastrointestinal.

Table 2

An overview of the studies focusing on microbiota and Alzheimer’s disease: Living subjects.

Study	N	Pathogen	Main outcome
Kountouras et al. [30]	50/30	Helicobacter pylori	Histologic prevalence of HP was 88% in patients with AD and 46.7% in controls.
Kountouras et al. [31]	27/27	Helicobacter pylori	HP-specific IgG antibody levels are significantly increased in cerebrospinal fluid and serum of AD and its titer in cerebrospinal fluid might reflect the AD severity.
Zhang et al. [32]	18/23/18*	endotoxin / LPS	Elevated levels of endotoxin/LPS concentrations in plasma from patients with sporadic amyotrophic lateral sclerosis and AD as compared to healthy controls; levels of plasma LPS showed a significant positive correlation with degree of blood monocyte/macrophage activation in disease groups.
Roubaud-Baudron et al. [33]	53/0	Helicobacter pylori	AD patients infected by HP tended to be more cognitively impaired.
Sparks Stein et al. [34]	35/46/77**	Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Campylobacter rectus, Treponema denticola, Fusobacterium nucleatum, Tannerella forsythia, Prevotella intermedia	Elevated antibodies to periodontal disease bacteria (F. nucleatum and P. intermedia) in subjects years prior cognitive impairment; it suggests that periodontal disease could potentially contribute to the risk of AD onset/progression.
Noble et al. [35]	110/109	Porphyromonas gingivalis, Tannerella forsythia, Actinobacillus actinomycetemcomitans, Treponema denticola, Campylobacter rectus, Eubacterium nodatum, Actinomyces naeslundii	Serum IgG levels to common periodontal microbiota are associated with risk for developing incident AD; high anti-A. naeslundii titer was associated with increased risk of AD; high anti-E. nodatum IgG was associated with lower risk of AD.
Kamer et al. [36]	0/38	N/A	History of periodontal inflammatory/infectious burden, was associated with increased 11C-PIB uptake in Aβ vulnerable brain regions; association between periodontal disease and brain Aβ load; peripheral inflammation/infections are sufficient to produce brain Aβ accumulations.
Akbari et al. [37]	60	Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, Lactobacillus fermentum	After 12 weeks intervention, compared with the control group, the probiotic treated AD patients showed a significant improvement in the MMSE score; positively affects cognitive function and some metabolic statuses in the AD patients.
Cattaneo et al. 60 [38]	40/33/10***	Escherichia/Shigella, Pseudomonas aeruginosa, Eubacterium rectale, Eubacterium hallii, Faecalibacterium prausnitzii, Bacteroides fragilis	Increase in the abundance of a pro-inflammatory Escherichia/Shigella taxon; reduction in the abundance of an anti-inflammatory Eubacterium rectale; this is probably associated with a peripheral inflammatory state in patients with cognitive impairment.
Vogt et al. 95 [39]	25/25	mixture of bacterial populations	Decreased Firmicutes and Bifidobacterium, increased Bacteroidetes in the microbiome of AD participants; correlations between levels of differentially abundant genera and cerebrospinal fluid biomarkers of AD.

N, number of subjects (AD/control); HP, Helicobacter pylori; LPS, lipopolysaccharide; PIB, Pittsburgh compound B (image amyloid-β plaques in neuronal tissue); MMSE, Mini-Mental State Examination Score; *AD patients/sporadic amyotrophic lateral sclerosis patients/healthy control; **AD patients/patients with mild-cognitive impairment/healthy control; ***cognitively impaired patients with brain amyloidosis/ cognitively impaired patients without brain amyloidosis/healthy control.

Alzheimer’s disease and physical activity

The issue of the links between the physical activities of man and his health condition is a very hot topic nowadays. Westernization (inappropriate eating habits, excess energy intake, and lifestyle without enough physical activity) is a huge challenge for medical research. Westernization affects all age categories and does not avoid people with disabilities. Like other specific groups, patients with AD also deserve attention and care in connection with their movement mode.

Table 3 below shows a list of studies using aerobic load within the intervention. It contains basic research information including main outcomes. In almost all cases, the detected studies were randomized control trials.

Table 3

Aerobic load

Study	N	Age	Duration	Frequency	Intervention	Main outcome
Yu et al. [40]	N/A	60+	6M	3x W, 15–45 min	60–75% HR, bicycle; without CG	Improvement of QOL and of overall cognitive functions.
Vidoni et al. [41]	N/A	55+	182D	N/A	1. treadmill, 40–75% VO2max; 2. stretching and toning exercises, exercises with a large ball, yoga	Pilot study, without any specific results.
Venturelli et al. [42]	21	84±5	6M	4x W, 30 min	30 min of walking, medium intensity	↑6 min walking test; index ADL; ↓MMSE (fewer than in CG).
Tappen et al. [43]	65	87	112D	3x W, 30 min	1. walking; 2. conversation; 3. walking, conversation	↑6 min walking test (3. best).
Sobol et al. [44]	162	N/A	112D	3x W, 1 h.	3×10 min 70–80% HR max	0 chair stand test (30 s), 400 m walk test, up-go-test; ↑VO2max, dual task.
Hoffmann et al. [45]	200	N/A	112D	3x W, 1h	3×10 min 70–80% HR max	0 difference in cognitive tests; ↓neuropsychiatric symptoms.
Friedman &Tappen [46]	30	N/A	70D	3x W, 1h	1. 30 min walking, conversation; 2. conversation	↑MMSE, communicative skills.
Frederiksen et al. [47]	8	N/A	98D	3x W, 1h	3×8 min (50–80% HRmax), bicycle, cross trainer, treadmill	↑power outputs (on machines); hand grip strength, aerobic fitness; ↓chair test (30 s).
Cott et al. [48]	74	82±8	112D	5x W, 30 min	1. walking with communication; 2. talks	↑2 min walking, mental and communicative tests, 2. group performed best; 0 almost in all 1. versus CG
Arcoverde et al. [49]	20	N/A	112D	2x W, 30 min	10 min 40%, 20 min 60% VO2max, 5 min stretching	↑Cambridge cognitive examination, Berg balance test, up-and-go test 0 dual task.
Palleschi et al. [50]*	15	74±1.5	3M	3x W, 20 min	bicycle (70% HRmax)
without CG	↑MMSE, verbal tests.
Rolland et al. [51]*	23	N/A	49D	N/A	Aerobic exercises 35 min (walking, bicycle)	↑MMSE, reduction of the risk of falls, behavioral problems 0 ADL.

N, number of patients; M, Month; D, Days; W, weekly; h, hour; HR, heart rate; CG, control group; QOL, quality of life; MMSE, Mini-Mental State Exam; ADL, Activities of Daily Living; ↑, improvement; 0, without any difference when compared with the control group; *nutrition was taken into account.

The interventions using force load as a means of working with AD patients are shown in Table 4. The description of the load method differs in the studies— exercises, loads, or repetitions are described in various ways by the authors. This is not surprising because it is not easy to define the exact form of the exercise for such a specific target group, such as AD patients. The balance exercise was included among the strength exercises.

Table 4

Resistance/force load

Study	N	Age	Duration	Frequency	Intervention	Main outcome
Vital et al. [52]	34	N/A	112D	3x W, 1 h	1. exercises on machines (peck deck, leg press, curls), 20 repetitions; 2. walking, talks, relaxation, music	0 differences in cognitive tests (clock drawing test, Brief cognitive battery, Verbal fluency test).
Vidoni et al. [41]	N/A	55+	182D	N/A	1. treadmill, 40–75% VO2max; 2. Stretching and toning exercises, exercises with a big ball, yoga	Pilot study, without any specific results.
Roach et al. [53]	82	N/A	84D	5x W, 1 h	1. power exercises (7–9 repetitions), stand up, push/ pull against the nurse, balance exercises, dance positions; 2. walking; 3. talks	The best results in group 1, ↑6 min walking test, Acute care index of function, MMSE.
Lindenmuth &Moose [54]	43	65–98	56D	daily	Exercises while sitting –rotation, isotonic, breathing exercise	↑Cognitive tests.
Garuffi et al. [55]	34	N/A	112D	3x W, 1 h	1. exercises on machines, with dumbbells (3×20 repetitions); 2. social activities	↑ Dynamic balance, walking up the stairs, putting on socks, moving around the house.
Francese et al. [56]	12	N/A	49D	3x W, 20 min	1. exercise with the ball, squeezing the balloon, load on legs; 2. watching videos	↑Physical therapy assessment (power tests), ADL.
Ahn &Kim [57]	23	74.2±6.1	5M	3x W, 1 h	bands strengthening (pressure, pull, bicep, kicking)	↑Chair test (30 s), one leg balance test, gait speed test, 0 up-and-go test.
Yáguèz et al. [58]	27	70.5±5	42D	1x W, 2 h	stretching, circular movements, isometric work, balance exercise, drawing	↑ Attention, visual memory.
Holthoff et al. [59]	30	72.4±4.3	84D	3x W, 30 min	1. passive and active movements	↑ ADL score, ↓ MMSE, neuropsychiatric symptoms in CG.

N, number of patients; M, Month; D, Days; W, weekly; h, hour; HR, heart rate; CG, control group; MMSE, Mini-Mental State Exam; ADL, Activities of Daily Living; ↑, improvement; 0, without any difference when compared with the control group.

Table 5 lists research studies that used a mixed load in physical activities. The table provides a description of the exercise or the load intensity. In all investigations, a control group was also used, including patients with AD.

Table 5

Mixed load

Study	N	Age	Duration	Frequency	Intervention	Main outcome
Williams &Tappen [60]	45	N/A	112D	5x W, 1 h	1. bodyweight exercises, balance exercises, 20-min walking; 2. walking for 30 min; 3. talks	↑Mood scale, depression.
Teri et al. [61]	153	N/A	3M	daily, 30 min	aerobic, power and balance exercises	↑Physical health (without any specification), depression
Suttanon et al. [62]	40	81.9±5.7	6M	5x W, 1 h	1. balance exercises in the standing, strengthening exercises, walking; 2. educational visits	↑ Functional range, lower score at risk of falling (balance abilities).
Steinberg et al. [63]	27	N/A	84D	N/A	1. tasks for a week: walking, exercises for big muscle groups, bands, wrist and ankles loads, balance exercises; 2. light activities without equipment	↑8 foot walk test, sit-to-stand, Yale Physical Activity Survey, cognitive tests.
Rolland et al. [51]	242	N/A	12M	2x W, 1 h	stretching, walking (20–30 min), bodyweight exercises (legs, sitting down), standing and sitting balance exercises	↑ADL 0 walk speed, up-go-test, one leg balance test.
Roach et al. [53]	82	N/A	84D	5x W, 1 h	1. strength exercises (7–9 opposite), stand up, push/ pull against the nurse, balance exercises, dance position; 2. walking; 3. talks	The best results in group 1, ↑6 min walking test, Acute care index of function, MMSE.
Pitkälä et al. [64]	210	N/A	12M	2x W, 1 h	1. exercise set by a specialist (not specific); 2. exercise in the center - for endurance, balance, strength	↓1. and 2. Functional independence measure, short physical performance battery, but less than in CG.
Pedroso et al. [65]	21	77.9±7.1	4M	3x W, 1 h	balance exercises, aerobic exercise, exercise with weights, cognitive tasks with verbal response	↑MMSE, Berg balance test, cognitive functions, 0 up-and-go test.
Nascimento et al. [66]^*	20	N/A	6M	3x W, 1 h	mostly aerobic load (60–80% HR max), compound exercises (15–20 repetitions), balance and rhythm exercises	Smaller worsening in neuropsychiatric and functional tests. 0 instrumental activities.
de Andrade et al. [67]	30	77±6.3	112D	3x W, 1 h	20-min aerobic activity, 35-min dual task (balance exercise, exercise with weights, stretching, cognitive tasks	↑Sit-to-stand (30 s), Berg functional scale, ↑cognitive functions (also dual task) ↓timed up-and-go test (improvement in CG).
Arkin [68]	24	78.8±8	70D	2x W, 1 h	20–30-min aerobic activity (bike, walking), 20–30-min strength exercises on machines	↑6 min walking test, the strength of the upper and lower body.
Öhman et al. [69]^**	210	≥65	12M	2x W, 1 h	1. exercise at home, 15-min bicycle, nordic walking, dance, 15-min exercise with dumbbells, 15-min dual tasking, 15 min: walk up the stairs, lifting things from the ground; 2. in a group, 15 min: rower, bike, walking, 15 min: exercise in the gym, 15 min: lifting things from the ground, climbing the ladder, balance exercises 15 min: dual tasking; 3. nothing	↑ clock drawing test in group 1, ↓ verbal fluency and MMSE in both groups.
Vreugdenhil et al. [70]	40	51–89	112D	dennç	Exercises at home - 10 exercises, 30-min walk	↑Balance test, up-go-test, sit-to-stand, cognitive tests.

N, number of patients; M, Month; D, Days; W, weekly; h, hour; CG, control group; MMSE, Mini-Mental State Exam; ADL, Activities of Daily Living; ↑, improvement; ↓, worsening; 0, without any difference when compared with the control group; *only females; **nutrition was taken into account.

A list of studies using alternative approaches is shown in Table 6. These are interventions that differ from commonly used approaches. However, research design was standard, containing control groups. In two research studies, the authors used a case study, which corresponds to the purpose of a given study.

Table 6

Alternative movement approaches

Study	N	Age	Duration	Frequency	Intervention	Main outcome
Abreu &Hartley [71]	1	N/A	84D	2x W, 1 h	Based on salsa dance	↑Up-and-go test, Berg balance test, 6-min walk test, reduction of the number of falls in the six-month follow up period.
Sobel [72]	50	82	N/A	2x W, 45 min	1. Bingo + talks; 2. walking/ exercises while sitting + talks	↑Word naming test, word list recognition (in group 1).
Santana-Sosa et al. [73]	16	76±4	84D	3x W, 1 h	exercise accompanied by music, walking, light stretching, mobility, resistance exercise with expander, 3×15 repetitions	0 activities of daily living, up-go-test, flexibility, ↑arm curl, chair stand test (30 s), 2 min step test.
Myers et al. [74]	1	N/A	N/A	N/A	aquatic therapy	↑Physical tests.
Öhman et al. [69]	210	≥65	12M	2x W, 1 h	1. exercise at home, 15-min bike, nordic walking, dance, 15-min exercise with dumbbells, 15-min dual tasking, 15 min: walking up the stairs, lifting things from the ground; 2. in a group, 15 min: rower, bike, walking, 15 min: gym exercises, 15 min: lifting things from the ground, climbing the ladder, balance exercises, 15 min: dual tasking; 3. nothing	↑ Clock drawing test in group 1, ↓ verbal fluency and MMSE in both groups.

N, number of patients; M, Month; D, Days; W, weekly; h, hour; ↑, improvement; ↓, worsening; 0, without any difference when compared with the control group.

Physical activity and microbiome

In terms of gastroenterological indications, the protective effect of targeted physical activity in humans is associated with a reduction in the risk of gastrointestinal malignancies, gastroesophageal reflux and gastric/duodenal ulcers, liver steatosis, irritable bowel syndrome, and diverticulitis [75].

A number of animal model studies have been reported to indicate that qualitative and quantitative changes in the intestinal flora, under targeted physical activity conditions, can be linked to influencing nutrient absorption, energy distribution, immunity, and gut-brain axis effect [76]. The opposite situation is with experiments on humans. There is an insufficient number of adequately designed controlled trials leading to a difficult assessment of the effect of physical activity on the composition and function of the human intestinal microflora. Interactions such as genetics, nutrition, exercise, individual habits with the environment in which the individual is located also contribute to the possible distortion in data interpretation.

Table 7 provides an overview of individual studies dealing with the effect of physical load/ exercise on gut microbiota.

Table 7

Human studies: Effects of exercise on gut microbiota

Study	N	Age	Main outcome
Clarke et al. [77]	40/23+23*	23–36	Exercise increases gut microbial diversity; protein consumption positively correlates with microbial diversity and creatine kinase.; athletes and low BMI group higher proportions of the genus Akkermansia.
Estaki et al. [78]	39	18–35	Cardiorespiratory fitness is correlated with increased microbial diversity in healthy humans; increased microbiota diversity and butyrate production is associated with overall host health.
Barton et al. [79]	40/46**	N/A	Microbial-derived SCFAs are enhanced within the athletes; differences in fecal microbiota between athletes and controls - more evident at the functional or metabolic level.
Bressa et al. [80]	19/21***	18–40	Higher abundance of health-promoting bacterial species in active group (incl. Faecalibacterium prausnitzii, Roseburia hominis and Akkermansia muciniphila); body fat percentage, muscular mass and physical activity significantly correlated with gut microbiota composition.
Paulsen et al. [81]	12****	18–70	Gut microbiota composition is correlated with positive changes in cardiorespiratory fitness level.
Stewart et al. [82]	10/10*****	N/A	Gut microbiota and bacterial profiles from patients with long-standing T1D in good glycemic control and high physical fitness levels are comparable with those of matched people without diabetes.
Yang et al. [83]	71	19–49	Cardiorespiratory fitness is associated with gut microbiota composition, independent of age and carbohydrate or fat intake.

N, number of subjects; *elite athletes/low+high BMI controls; **professional male athletes/healthy controls; ***active/sedentary group; ****breast cancer survivors; *****T1D patients/controls.

Considering the results from animal studies, one can reasonably believe that exercise could affect the gut microbiome. This means that exercise and physical activity may induce positive qualitative and quantitative changes in the human gut microbiota, which may appropriately interfere with the onset and development of AD.

DISCUSSION

As it has been mentioned in the introduction, changes in the composition of human microbiome may be associated with the development of a number of gastrointestinal or metabolic diseases, but may also affect central nervous system function. Research reveals that gut microorganisms act on the “gut-brain” axis. The development of the nervous system is a continuous complex process that begins before birth and ends in death and is also partly dependent on signals coming from the gut environment, specifically signals from microorganisms. Microbiome and its metabolites are both involved in neuroinflammation but also regulate processes such as blood-brain barrier formation, myelination, neurogenesis, or microglia maturation [84 –89]. Microglia maturation has been shown to be dependent on sufficient SCFA and SCFA is produced by gut microorganisms [90]. Furthermore, if the blood-brain barrier formation is affected during its development in terms of its greater permeability, pathogen penetration into the brain and neuroinflammation can be expected [84, 85].

Metabolites and molecules produced by intestinal microorganisms also play a very important role. It is known that γ-aminobutyric acid (GABA) is a major human inhibitory neurotransmitter and is produced by strains of Lactobacillus and Bifidobacterium. GABA is also involved in progenitor neuronal proliferation, synapse formation, and suppression of inflammatory reactions in the body [91, 92]. Another important molecule affected by the gut microbiota is serotonin (5-HT). Up to 95% of the total serotonin in the body is found in the gastrointestinal tract [93]. 5-HT plays an irreplaceable role in the motility function of GIT, but also affects appetite, mood, sleep and cognitive function. Microorganisms are thought to indirectly stimulate cells in the intestine to store and release 5-HT [94].

Moreover, a very specific group are metabolites, the so-called SCFA, including acetic, propionic, butyric, and lactic acids. In addition to being the major energy source of colonocytes (epithelial cells of the colon mucosa), butyrate also induces sprouting dendrites, increases the amount of neurosynapsis, supports learning processes and long-term memory. Butyrate contributes directly to increased motility in the intestine, while propionate reduces bowel motility and facilitates secretion there [95, 96].

Gut microbiome is also very closely associated with systemic inflammatory changes. Microbes stimulates epithelial cells and lymphatic tissue of the intestinal mucosa, releasing amyloid proteins. Microbial dysbiosis and increased intestinal permeability may induce an inflammatory response in the body by increasing IL-6 levels. This molecule is regularly found in the serum and brain of AD patients [97].

Experiments can be found in the literature where certain gut microorganisms have been associated with the occurrence or development of AD. Some of the studies have been performed on post-mortem samples in AD patients, which in part reduces the plausibility of their causality in the pathophysiology of dementia. The pathogens described include Chlamydia pneumonia [22], Borrelia burgdorferi [24], and Helicobacter pylori (HP) [30, 31]. HP positive patients with AD had lower Mini-Mental State Examination (MMSE) scores, which corresponded to more severe cognitive disorders, and moreover, the degree of disease severity was determined by the titer of significantly elevated levels of HP-specific IgG antibodies found in cerebrospinal fluid and serum [30, 31]. The way bacteria enter the brain of AD patients is still under investigation, but one theory suggests that the permeability of the blood-brain barrier may be increased [98]. Since higher levels of antibodies to periodontitis-causing bacteria have been found in serum in AD patients, another possible theory for entry of microorganisms into the CNS pathway is through the olfactory bulb [34 , 99].

The studies also show the association of quantitative changes in human gut microbiota and AD. An excess of pro-inflammatory strains of Escherichia, Shigella, and Bacteroidetes are described [38]. Conversely, strains with anti-inflammatory properties were reduced in AD patients: Firmicutes, Bifidobacterium, and Eubacterium rectale [38, 39]. In general, increased amounts of bacteria correlated with higher AD markers in cerebrospinal fluid. On the other hand, there are bacterial strains that have purely anti-inflammatory properties such as Akkermansia muciniphila and Faecalibacterium prausnitzii [80]. In clinical practice, patients should not forget that many drugs also affect the composition of the gut micro-environment, especially antibiotics, metformin, and proton pump inhibitors [100].

The inclusion of movement programs in the lifestyles of all ages is an undeniable fact. Research shows a complex effect of movement on the health of seniors, for example, Larson et al. [101]. Physical fitness seems to have an impact on the onset of AD, as well as a correlation with its further course [102]. When comparing healthy seniors to patients with AD, positive correlation of cognitive functions and physical tests in both groups, such as Bruce-Keller et al. [103], likewise Burns et al. [104], who complements tasks with dual tasks, or Buchman et al. [105] and their testing the hand grip strength. The interrelation of physical and cognitive components, including bilateral prediction, is reported by Hebert et al. [106]. However, there is some diversity in AD patients. The authors do not agree whether movement interventions have demonstrable benefits in cognition and functional performance parameters [107, 108].

Table 8 lists studies in AD patients with descriptive character. They also investigate the relationship between physical parameters, physical activities and the course of resp. AD status. In some cases, it is indicated if a group of healthy seniors was used for comparison.

Table 8

Descriptive studies (without the intervention)

Study	N	Age	Duration	Note	Main outcome
Winchester et al. [109]	104	65+	12M	Monitoring of movement activities	The most common activity is walking,
					2 h weekly ↑ better MMSE, mood state.
Scarmeas et al. [102]	357	65+	N/A	N/A	The importance of physical activity before AD, the relationship of physical activity with the later course of AD.
Hebert [106]	367	65+	48M	N/A	Decrease in cognitive function predicts impairment of upper and lower limb functions.
Coelho et al. [110]	21/18	N/A	N/A	1. patients with AD; 2. healthy people	In patients with AD, there is an increase in the brain derived neurotrophic factor in aerobic load.
Burns et al. [104]	31/31	65+	N/A	1. patients with AD; 2. healthy people	AD - lower aerobic fitness, lower values in physical performance test (picking up a pencil, filing a book, walking 50 feet, writing a sentence).
Buchman et al. [105]	877	N/A	N/A	N/A	Hand grip strength force associated with slower AD development.
Bruce-Keller et al. [103]	50/50	N/A	N/A	1. patients in the initial stage of dementia; 2. healthy people	Positive correlation between cognitive functions and physical tests in both groups.
Perry &Hodges [111]	24	N/A	N/A	N/A	There is no connection between memory and physical activity in patients with AD.

N, number of subjects; M, Month.

The interventions where aerobic load is used are quite frequent. It is usually a means of walking (with an accompaniment), walking on a treadmill or a stationary bicycle. In some studies, the effort is more accurately captured by the heart rate [44 , 50] or by VO2max [41, 49]. This is generally a moderate intensity, with the maximum reported to 80%. To intensify the effect on cognitive abilities when walking, talking with a patient is usually performed as well [43 , 48]. It seems that these studies do not put emphasis on the performance, but on the movement as such. Frequency of exercise is most often 3 times a week, in the range of 30–60 min. The choice of walking as a means is a logical step; it is a natural compound movement and is a sign of some patient’s self-sufficiency. Therefore, it is also used for testing (ADL, 2-min or 6-min walking test, up-and-go test). Winchester et al. [109] confirm this as the most common activity. It is not possible to state an absolute positive influence of aerobic load on the monitored cognitive and functional parameters. Nevertheless, there is evidence that an independent aerobic activity may affect cognitive functions in AD patients. On the other hand, there is evidence that the measurements also worsened the measured values: MMSE [42], neuropsychiatric symptoms [45], and chair-test [47].

Like aerobic activities, resistance exercises are generally appropriate. The resistance/strengthening exercises of the AD has different forms: body weight exercises [61], exercises on machines [52], exercises with dumbbells [55], exercises with expander [73], with the ball [56]. Only Yáguèz et al. [58] and partly Francese at al. [56] use isometric muscle exercise, in other cases isotonic movements are conducted. Furthermore, the balance exercises are used in Roach et al. [53]. This is not a direct effect on the strength development, but these coordination abilities are related to strength assumptions. The interventions were mostly 3–5x per week. An interesting exception is the study by Lindenmuth and Moose [54], who themselves did the exercises with patients daily. Unfortunately, the lack of detail in the exercise in this study makes it difficult to interpret. This is also true for Holthoff et al. [59] and Francese et al. [56] The form of exercise is not presented. The expected positive results in tests with a strength component such as chair test, stairway walking were confirmed by Ahn and Kim [57], Garuffi et al. [55], or Frances et al. [56]. However, cognitive and AD-specific tests such as ADL and MMSE were chosen to verify the effectiveness of the intervention. In the vast majority of studies, progress can be reported in some of the measured parameters (2-min walking test, hand grip strength, or up-and-go test). As with the aerobic load, there are studies in which the authors either did not achieve statistically significant deviations from the control group or even worsened, for example, in chair test, 400 m walking test [52 , 59]. In addition, it appears that it is not easy for certain patients in advanced AD who have experienced significant degradation of exercise functions to accurately define the load. In these cases, the caregiver’s work is very important since s/he can regulate resistance for the patient.

In therapeutic interventions, the use of mixed physical activities is no exception. This category includes activities where aerobic and strengthening exercises were also used. Their ratio varies, but mostly it is 20–30 minutes of aerobic activity combined with a resistance exercise [60 , 112]. Unfortunately, in some cases the description of activities is too superficial; there is no numerical expression or a specific selection of exercises [61 , 65]. Only in one study by Pitkälä et al. [64] was there worsened results or insignificant deviations from the control group. However, this is a longitudinal study where degressivity in the traits of interest can be expected due to the age of the patients and the nature of the disease. In addition, in Nascimento et al. [66], both female groups worsened; the control group, however, was found to be worse than the experimental one. Other studies always show some improvement in the chosen test [53 , 67].

Compared to the usual procedures in the selection of physical activities, there exist alternative approaches which, due to the results, may represent other suitable pathways for patients with AD. Abreu and Hartley [71] used Salsa as a medium; Myers et al. [74] used aquatic therapy; both were case studies. Sanatana-Sosa et al. [73] use simultaneously with resistance training and walking, exercises accompanied by music. Similarly, Öhman et al. [69] applies dance as one of the methods. In the study by Sobel et al. [72], bingo was selected for one of the groups. Again, in terms of outputs, the results were mixed, but in each study, there were some improvements in the monitored tests. Thus, research shows that it is advisable to choose a holistic approach to the health of the individual in order to affect a greater number of factors influencing wellness and general fitness. Thanks to music, the environment or the suitably chosen attitude of nurses, the emotional and social component of the healing process will be significantly influenced.

Table 9 summarizes the possible limitations of the findings of individual studies dealing with the relationship between the physical activity and AD.

Table 9

Limitations of the findings in the detected studies

Connection with the disease	Connection with the physical activity
Small sample sizes in some studies	a lack of the analysis of the previous movement activities
Short duration of the intervention	for different stages of AD, the same intervention cannot be applied and comparable results cannot be expected
Large age variation of the research sample, or age not shown	stable results can be seen as a positive effect at an advanced age
Different AD stages (sometimes not even mentioned in the study)	slowing down cognitive degradation can also be considered a positive outcome in AD

Despite the lack of human studies (but enough data from animal models), physical activity appears to be significantly modulating the gut microbiome [71]. It can thus be concluded that the state of physical activity in humans seems to correlate with the composition of gut microorganisms [113 –115]. In general, it has been found that greater microbial diversity is associated with “excess health". A more diverse microbiome is also able to respond better to repeated slight fluctuations [116]. In this context, exercise was observed to induce a more diverse composition of human gut microbiome [117]. The diversity of microbiome was also associated with cardiovascular condition in studies. Microbiomes of individuals with higher VO2max levels tend to produce more butyrate [78], which belongs to SCFA with anti-inflammatory effect [118]. Barton et al. [79] report that the gut microbiome of athletes promoted a more intense metabolism of macronutrients (especially carbohydrates and proteins) and higher SCFA concentrations were found compared to the sedentary control group.

SCFA is believed to serve as a source of energy for various tissues, to improve insulin sensitivity, and to alter central nervous system morphology [119 –121]. Inflammation plays a very important role in the human body in connection with AD. In animal models of older age, a decrease in the expression of inflammatory mediators and apoptotic markers in intestinal lymphocytes is described by physical exercise [122].

The intestinal microbiome is influenced by many lifestyle factors and by the environment in which we live [123]. One of the components is a movement activity, which acts on the organ system and has an overlap into the function of the gastrointestinal tract. In view of the focus of this article, research studies that have used similar interventions as those found in AD patients have been explored. Bressa et al. [80] observed a group of premenopausal women for 6 weeks and found a clear difference between the active and control groups in the positive microbiome change. The active group had to meet the minimum requirements of 3 hours of physical activity per week. The effect of exercises on the structure of microbiome in 18–70 women who have had breast cancer is described by Paulsen et al. [81]. The analyzed group had to undergo at least 60 minutes of moderate intensity physical activity per week for 6 months. The result was a correlation in microbiome structure and cardiorespiratory fitness of the research group. On another sample of 19 obese women, microbiome modifications were demonstrated during a 6-week intervention. The activity was to ride a stationary bike 3 times a week with low to medium intensity for 40–50 minutes [124]. Allen et al. [16] also selected moderate intensity and aerobic load. After a 6-week program (3 times a week, 30–60 minutes of walking on a belt or riding a stationary bike), she notes changes in SM composition and retrograde development after exercise. In summary, regular aerobic physical activity has a confirmed effect on the composition and function of SM [76].

Overall, research shows that exercise can increase the number of beneficial bacteria, generally enhance the diversity of microbiomes, and also increase the amount of commensal species. All these effects are clearly beneficial to the host and improve his health. The available data summarized in this paper strongly support the fact that, among other well-known internal and external factors, exercise appears to be a significant factor that can cause changes in terms of both qualitative and quantitative composition of the gut microbiome. It is well known that a stable and diverse microbiome is indispensable for the normal function of the gastrointestinal tract, which in turn positively affects the gut-brain axis and contributes overall to a healthy person’s condition.

A major limitation of studies monitoring the effect of exercise on the gut microflora is their cross-sectional design, factors that can temporarily alter the intestinal microflora (diet, antibiotics, obesity, impaired bowel barrier function, etc.); however, they are not evaluated in most of the detected studies.

Conclusion

AD is one of the most common neurodegenerative diseases of the central nervous system. It occurs primarily in the elderly and leads to incurable cognitive impairment and dementia. It is estimated that there are currently around 50 million people living in the world suffering from AD. However, the real assumptions are expected to reach 152 million by 2050. The medical condition of most patients at an advanced stage requires professional care that burdens national budgets. For example, direct health care costs are estimated to be EUR 14, 236 million in Europe between 2050 and 616 million euros in direct non-medical care costs [3]. With a slight exaggeration, one can argue that the professional public is alert and a large number of research teams are trying to find a solution.

One of the great issues of coexistence is the human intestinal microbe. After entering the general “microbiome” in database Pubmed, 57,002 publications can be found, of which 1,515 are clinical trials and 1,345 are on humans (as of July 6, 2019). There is no doubt that the composition of the human intestinal microbiome correlates with the neurological functions due to the gut-brain axis and therefore, in many articles, microbiome appears to be a promising target for anti-aging therapeutic interventions. As the number of patients grows, public budget administrators try to reduce the cost of potential treatment. On a general level, most medical recommendations can see a return to human nature, i.e., a healthy lifestyle that includes appropriate nutrition and movement. From the evidence we have provided on AD, movement, and microbiome, it can be seen that the trends of diversion from consumerism have their own merits, and human intestinal microbiota could be the link. Microbiome is associated with AD. AD is positively influenced by physical activity. And physical activity has a beneficial effect on the human intestinal microbiome. It is a comprehensive complex of interactions, which could result in benefits for AD patients, but also for the professional public and national budgets.

This study separately presents everything that has been done to humans in these areas, but it does not have an experimental character; its purpose is to serve as a theoretical basis for the future implementation of adequate human research that is still lacking. It might seem like speculation, but the opposite is true. Recent experimental studies in animal models strongly support the link between cognitive defect, exercise, and microbiome. Research published by Abraham et al. [125, 126] clearly demonstrates through experiments that “exercise and probiotic treatment can decrease the progress of AD and the beneficial effects could be mediated by alteration of the microbiome". Similar statements can be found in a review by Ticinesi et al. [127], which also uses the term “muscle-gut axis". In fact, Ticinesi et al. [127] and our study are the first two studies discussing these links.

Based on the positive results of these research studies, it is possible to propose specific procedures that should be applied when working with AD patients. Due to the large differences between patients (stage of AD, age, fitness level, or economic background), it is not possible to determine the exact procedure, but the following general points can be recommended:

long-term intervention, at least 3-4 times a week;

activity both aerobic (30–60 minutes mean intensity, including walking), and

strength (20–30 minutes containing exercises with own body, resistance exercise with

expander or light external load), they can be combined;

include dual task (collection of items, walking and talking, stand/walk with full

glass, etc.);

create socially (family members, trained caregivers) and emotionally (music,

movement in nature, decoration) pleasant environment;

creatively use the possibilities (material, financial, etc.) for activities such as dance,

rhythmic activities, bingo, or similar games.

In conclusion, the interdisciplinary approach, i.e., the relationship between patient, doctor, and physiotherapist/personal trainer should be paramount in these situations. The research indicates that the complexity of AD patient-microbiome interactions and the potential for affecting them have a profound effect on AD therapy, respectively prevent the development of this disease.

Footnotes

ACKNOWLEDGMENTS

This work was supported by MH CZ - DRO (UHHK, 00179906) - by the grant projects of the Ministry of Health of the Czech Republic (FN HK66400179906) and of the Charles University in Prague, Czech Republic (PROGRES Q40), by the project IT4Neuro (degeneration), reg. no. CZ.02.1.01/0.0/0.0/18_069/0010054, and by the SPEV project 2104/2019, run at the Faculty of Informatics and Management of the University of Hradec Kralove, Czech Republic. The authors thank Josef Toman for his help with data collection.

Authors’ disclosures available online ().

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