Biomedicine & Pharmacotherapy 153 (2022) 113430

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Microbiota alteration and modulation in Alzheimer’s disease by

gerobiotics: The gut-health axis for a good mind
Duygu Ağagündüz a, Betül Kocaadam-Bozkurt b, Osman Bozkurt b, Heena Sharma c,
Renata Esposito d, Fatih Özoğul e, Raffaele Capasso f, *
a
Department of Nutrition and Dietetics, Gazi University, Emek, Ankara 06490, Turkey
b
Department of Nutrition and Dietetics, Erzurum Technical University, Yakutiye, Erzurum, Turkey
c
Dairy Technology Division, ICAR-National Dairy Research Institute, Karnal, Haryana 132001, India
d
Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L.Vanvitelli”, Via Vivaldi 43, 81100 Caserta, Italy
e
Department of Seafood Processing Technology, Faculty of Fisheries, Cukurova University, 01330 Adana, Turkey
f
Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici, NA, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: The role of the gut microbiota in human health is one of the most important research topics. There is a strong
Gerobiotics relationship between the microbiota-gut-brain axis and cognitive functions. Since Alzheimer’s disease (AD) is a
Probiotics disease characterized by cognitive impairment, the influence of the gut microbiota in the development and
Alzheimer’s disease
treatment of the disease attracts considerable attention. Gerobiotics is a new concept that includes probiotics or
Gut-brain axis
Nutrition
derived postbiotics involved in delaying the aging process. Increasing evidence in the literature suggests that
gerobiotics has important roles in the pathogenesis and progression of AD, and even in its treatment, through
various mechanisms of action. Several researchers have established the linkage between ingestion of gerobiotics
and improved gut dysbiosis and cognitive functions, nevertheless the dose and duration of treatment differ based
on strain. Furthermore, oxidative-inflammatory pathways are mainly involved in the neuroprotective effects
caused by gerobiotics. This review provides the effects of gerobiotics on microbiota alteration and modulation in
AD.

1. Introduction
Alzheimer’s disease (AD), a progressive neurological disorder, was
discovered more than a century ago by German psychiatrist Alois Alz­
heimer [1]. Recently in the last few decades, researchers have focused
on exploring the epidemiology of AD and dementia, one of the most
common clinical signs manifested by AD. Dementia is described as a
clinical syndrome characterized by loss of memory, impaired language
and related cognitive functions and day-to-day activities. It has been
reported that dementia affects more than 25 million people worldwide,
and most these suffer from AD while total dementia cases are 50%−
70%. [2] All these cases have more serious implications due to the
globally increasing elderly population (>65 years). The US Centers for
Disease Control and Prevention (CDC) estimates an increase of 7–12% in
the elderly population from 2000 (420 million in numbers) to 2030 (1
billion). Since the occurrence of AD is more positively correlated with
the aging process and in addition to this, developing countries are wit­
nessing a huge propionate increase in the absolute numbers of elderly
persons, therefore, this disorder would be a challenging task to ensure
public health systems in the future. Figures indicate that around 5–6
million AD cases are reported every year and the population suffering
from dementia doubles after every 5 years among people aged more than
65 years [3].
AD has a significant impact on both individuals and society as a
whole. It is often associated with reduced life expectancy, and physical-
functional disability and may lead to death in some cases. The popula­
tion is more prone to stroke, musculoskeletal disorders and cardiovas­
cular diseases due to AD [4]. Besides, decreased diversity and disturbed
microbial ecology in microbiota are reported in AD and thus may be
associated with pathogenesis of AD and related metabolic outputs in AD
[5,6]. Moreover, due to the disease involving multiple factors, AD de­
mands certain interventions (protective factors) that might result in

* Corresponding author.
E-mail addresses: duyguturkozu@gazi.edu.tr (D. Ağagündüz), betulkocaadam@gmail.com (B. Kocaadam-Bozkurt), dytosmanbozkurt@gmail.com (O. Bozkurt), s.
heenavet@gmail.com (H. Sharma), renataesposito21@gmail.com (R. Esposito), fozogul@cu.edu.tr (F. Özoğul), rafcapas@unina.it (R. Capasso).

https://doi.org/10.1016/j.biopha.2022.113430
Received 22 June 2022; Received in revised form 14 July 2022; Accepted 14 July 2022
Available online 18 July 2022
0753-3322/© 2022 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
D. Ağagündüz et al.
stabilized cognitive functions, controlled neurological symptoms and
improved quality of life. One such intervention strategy is to target the
diet of people containing health-potentiating biotics, such as probiotics
and their metabolites. International Scientific Association for Probiotic
and Prebiotic (ISAPP) are defined probiotics as “living microorganisms
that create health benefits in the host when taken in sufficient amounts”
and prebiotics as “inanimate food ingredients that support health in the
host through microbiota modulation” [7,8]. On the other hand, ISAPP
has recently described postbiotics as “the preparation of non-viable
microorganisms and/or components that provide health benefits to
the host” and underlined that postbiotics must contain microbial cells or
cellular components that have been inactivated with or without me­
tabolites, contributing to the observed health benefits [9]. Several re­
searchers have demonstrated the development and health beneficial
aspects of fermented foods using probiotics, prebiotics and/or the
combination of both (synbiotics) [10–13]. However, gerobiotics, a new
concept, specifically includes those probiotics (and/or derived post­
biotics) which are mainly involved in delaying the aging process and
enhancing the health span of the host [14]. Several probiotic strains
have conferred the status of gerobiotics, including B. longum BB68,
L. fermentum MBC2, L. gasseri SBT2055, B. infantis ATCC15697,
L. paracasei PS23 L. brevis OW38, and others [15–18]. These bacterial
strains modulate gut homeostasis and hamper the progression of AD,
including inflammatory reactions and oxidative stress. Thus, the gut
microbiota composition plays a significant role in regulating the path­
ways directly involved in the pathogenesis of AD and blood-brain barrier
permeability [19]. Increased permeability of blood-brain barrier (BBB)
might result in neuronal degradation, neuronal cell loss and, subse­
quently, AD [20]. In this way, gerobiotics in the diet can be one of the
most significant intervention to prevent the occurrence of AD by
modulating the microbiota composition and consequential response of
physiological processes in the brain. Therefore, this article focuses on
the impact and significance of AD and the possible mechanisms by
which gerobiotics can modulate the gut-health axis. Additionally, it also
covers the recent animal and clinical studies supporting the counter-act
Fig. 1. The relationship between the microbiota-gut-brain axis and Alzheimer’s Disease.
2
Biomedicine & Pharmacotherapy 153 (2022) 113430
of dysbiosis by gerobiotics and resulting in reduced pathogenesis of AD.
2. Microbiota-gut-brain axis and Alzheimer’s disease
AD is a progressive neurodegenerative disease and extracellular
amyloid-beta (Aß) plaques composed of amyloid and intracellular
neurofibrillary tangles composed of hyperphosphorylated tau play a role
in its development [21]. It is thought that with aging, genetic and
environmental factors become influential in the development of AD.
Especially recently, the idea that AD is a “systemic disease” has signif­
icantly become widespread [22].
The role of the gut microbiota on human health is one of the most
important research topics today [23]. Recent studies point to a signifi­
cant relationship between the microbiota-gut-brain axis and cognitive
functions [19,24,25]. Since AD is a disease characterized by cognitive
impairment, the influence of the gut microbiota on the development of
the disease has become of a popular interest [26]. Simultaneously, many
recent studies have shown that AD can start in the gut and is closely
related to dysbiosis in the gut microbiota [27–29] (Fig. 1).
The microbiota-gut-brain axis contains a complex, multi-directional
interconnection system, through which the microbiota and brain have
bidirectional communication. This system includes neural (enteric ner­
vous system, sympathetic and parasympathetic system), immune (in­
testinal and neural-immune system), neuroendocrine (hypothalamus-
pituitary-adrenal axis (HPA)) and metabolic systems. Metabolites, neu­
rotransmitters, and hormones produced by the microbiota via nervous
and humoral pathways, cytokines and other immune signals reach the
brain [30,31]. Microbiota produces some important metabolites asso­
ciated with changes in brain functions, including neurotransmitters such
as serotonin, dopamine, γ-aminobutyric acid (GABA), and short-chain
fatty acids (SCFAs) [32,33]. It has also been stated that microbiota is
effective in microglia maturation and functions [34].
It is noted that oxidative stress and some changes that occur in the
microbiota influence amyloid plaque formation with neuro­
inflammation activation in the cause of AD [35]. The effect of
D. Ağagündüz et al.
microbiota on the pathogenesis of AD is associated with the capacity of
the microorganisms. It hosts secrete neurotransmitters, metabolites, and
high amounts of amyloid and lipopolysaccharides (LPS), which trigger
the central nervous system (CNS) inflammation and cerebrovascular
degeneration [36]. It was reported that patients with AD have three
times higher plasma LPS levels compared with healthy controls [26].
Besides, it was revealed that plasma LPS concentration was negatively
correlated with the viable count of intestinal Bifidobacterium, which
retains the integrity of the intestinal barrier and shows
anti-inflammatory effects by preventing bacterial/endotoxin trans­
location [37].
It was further stated that there was a relationship between amyloid
plaque formation and pro-inflammatory gut bacteria (e.g., Proteobac­
teria). These bacterial species induce the secretion of proinflammatory
cytokines by producing high amounts of amyloid, which may lead to the
deterioration of cognitive functions [38]. The brain-derived neuro­
trophic factor (BDNF) regulated by the microbiota plays a neuro­
protective role. In patients with AD, intestinal homeostasis changes with
oxidative stress, and a significant decrease is observed in BDNF levels
[39]. It is believed that this may contribute to the decrease in cognitive
function and progressive neurodegeneration of hippocampal neurons.
For these reasons, studies on the relationship between the
microbiota-gut-brain axis and the progression of AD have become a
popular interest [23].
3. Recent evidence for gerobiotics and Alzheimer’s disease
In this section, animal and human studies with gerobiotic strains that
are considered important in the development of AD are discussed and
some current shreds of evidence are displayed in Table 1 and Table 2.
3.1. Animal studies
The effects of different bacterial strains on the pathogenesis and
prognosis of AD have been shown in different animal models using
different strain types and dose interventions. Thus, in a study conducted
on Wistar rats with Alzheimer’s, moderate-intensity interval training
was applied daily for 8 weeks with L. plantarum and B. bifidum. It was
found that choline acetyltransferase (ChAT) and BDNF increased
significantly in the Hippocampus in the group that received exercise
together with probiotics. It has been reported that the increase in ChAT
levels also increases probiotic-induced cholinergic transmission. Exer­
cise and these probiotic strains significantly repair tissue damage and
improve short-term memory in AD [40].
Song et al. (2021) reported that the L. plantarum DP189 strain was
applied to mice with AD for 10 weeks, and it was seen that this inter­
vention improved dysbiosis by modulating the gut microbiota; increased
serotonin, dopamine, and GABA levels; and improved neuronal damage,
Aß deposition, and tau pathology and thus influenced the pathological
processes positively [42]. Additionally, it was revealed that L. plantarum
DP189 regulated the PI3 K/Akt/GSK-3β pathway and prevented tau
hyperphosphorylation. Therefore, L. plantarum DP189 may be a thera­
peutic strategy in AD.
Huang et al. (2022) worked on mice with streptozotocin-accelerated
cognitive dysfunction and reported that L. plantarum PS128 supplements
regulated gliosis, propionic acid levels, and glycogen synthase kinase 3 ß
activity, and thus prevented damage caused by intracerebroventricular
streptozotocin injection. The authors showed that they proposed PS128
supplementation as a potential strategy for preventing and/or delaying
the progression of AD [43].
Supplementing Bifidobacterium bifidum TMC3115 (5 ×108 colony-
forming unit [cfu]) and L. plantarum 45 (LP45) (5 × 108 cfu) on mice
with AD for 22 weeks reversed intestinal dysbiosis by reducing Bacter­
oides species and increasing the density of Acetatifactor and Millionella.
These results suggest that these strains repair spatial memory impair­
ment and modify the gut microbiome, which may have potential
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Biomedicine & Pharmacotherapy 153 (2022) 113430
benefits for AD [44]. Another study on mice with AD revealed
improvement in memory loss and learning abilities in the group
receiving probiotics (B. lactis, B. longum, L.fermentum, L. acidophilus)
compared with the control group. Additionally, the improvement in
malondialdehyde (MDA) and superoxide dismutase levels in the pro­
biotic group reduced the increased oxidative stress resulting from AD.
Consequently, this study revealed that probiotics have effects on the
pathogenesis of AD by improving memory impairment and regulating
the microbiota [47].
A biochemical pathway seen in AD focused on acetylcholine, a
neurotransmitter with an important role in the hippocampus. Normally,
the enzyme acetylcholinesterase inactivates acetylcholine. In AD,
metabolically low acetylcholine levels and high acetylcholinesterase
levels are frequently reported. Considering this information, in a study,
rodents were given scopolamine (1 mg/kg/day) for 10 days to cause
forgetfulness (to create an AD-like condition), L. rhamnosus and curcu­
min affected the acetylcholine level by regulating the acetylcholines­
terase level and improving memory loss [46]. In another study, mice
were injected D-Galactose intraperitoneally and were induced AD. It was
seen that the administration of L. plantarum MTCC1325 had a positive
effect on the entire ATPase system in the mouse brain and delayed
neurodegeneration as it stabilizes the structural and functional integrity
of the biological membranes by regulating the ionic concentration
gradient, and thus protects neurons [48]. Moreover, some studies have
been conducted in the mouse model to improve LPS-induced cognitive
impairment-like behaviors. For example, one study examined the effects
of L. plantarum NK151 and B. longum NK173 on cognitive impairment
caused by LPS. L. plantarum NK151 and B.longum NK173 prevent LPS
production by E. coli in mice. The study revealed that upregulating BDNF
expression through Nuclear Factor kappa B (NF-κB) and suppressing
fecal and blood bacterial LPS levels reduced IL-1β, IL-6, and TNF-α ex­
pressions. In this way, an improvement was achieved in cognitive
impairment-like behavior caused by E. coli K1 or LPS and colitis. Thus, it
has been reported that these probiotic strains may be effective in the
development and treatment of AD and dementia [41].
In a recent study on aged mice conducted with Akkermansia muci­
niphila strain which is named as a gerobiotic, it was observed that this
strain increased the phagocytic activities of macrophages and the ac­
tivities of neutral killer (NK) cells as another mechanism. It was also
found to improve oxidative stress parameters (glutathione peroxidase,
reductase activity, lipid peroxidation level). It was stated that Akker­
mansia muciniphila strain could transform into short-chain fatty acids,
reach the hypothalamus through the blood-brain barrier and affect
neurotransmitters. In this way, it positively affects the central nervous
system and immune system [45]. Similarly, in a different study, aged
mice (18 months) were administered L. brevis OW38 strain (a gerobiotic)
orally for 8 weeks (1 ×109 cfu). It was reported that the expression of
inflammatory markers such as Tumor Necrosis Factor (TNF), NF-kB,
interleukin (IL)− 1β, and LPS was inhibited, which can improve colitis
and memory loss
BDNF, which is among the neurotrophic factors, plays an important
role in neuronal growth, differentiation, survival and plasticity. It is used
as a marker for a decrease observed in BDNF levels because of deterio­
ration in cognitive functions with aging. Long-term supplementation (43
weeks) of L. paracasei K71 strain in aged rodents was observed to in­
crease c-AMP response element binding protein (CREB) and BDNF
expression in the hippocampus, thereby improving cognitive function
[51].
Nuclear factor erythroid 2-related factor 2 (Nrf-2), which is a tran­
scription factor regulating antioxidant and detoxifying enzymes, pro­
tects against oxidative stress. A study conducted on aged rodents
revealed that the L. plantarum AR501 strain increased the expression of
antioxidant genes (GCLm: Glutamate-cysteine-ligase regulatory sub-
unit, GCLc: Glutamate cysteine-ligase catalytic subunit, GST: Gluta­
thione S-Transferase) by affecting the activation pathways of Nrf-2 [53].
TNF-α, which is a cytokine that indicates inflammation, may increase
D. Ağagündüz et al.
Table 1
Animal studies evaluating the relationship between gerobiotics and Alzheimer’s disease (a summary).
Strains Subjects and Procedures
Lactiplantibacillus Forty male Wistar rats
plantarum Five groups (n = 8 in
Bifidobacterium bifidum each)
1. Control,
2. AD models receiving Aβ
3. Aβ + MIIT (AD rats undergoing
MIIT)
4. Aβ + Probiotics (AD rats fed
Lactobacillus plantarum and
Bifidobacterium bifidum),
5. Aβ + MIIT + Probiotics (AD rats
receiving both treatments).
8 weeks
Bifidobacterium longum C57BL (n = 6) mice (6-week old)
NK173 Bifidobacterium longum NK173 and
Lactiplantibacillus Lactobacillus plantarum NK151 from a
plantarum NK151 human fecal bacteria
Lactiplantibacillus AD mice
plantarum DP189 10 weeks
Lactiplantibacillus PS128 (1010 (cfu/mL) was
plantarum PS128 administered via oral gavage to 6-
month-old male AD mice that
received an intracerebroventricular
injection of streptozotocin (3 mg/kg)
Lactiplantibacillus The APP/PS1 mice
plantarum 45 (LP45) Four groups:
Bifidobacterium bifidum 1. Alzheimer’s disease (AD)
TMC311 2. TMC3115 group (1 × 109 cfu),
3. LP45 group (1 × 109 cfu) and
4. A mixture group of TMC3115 (5 ×
108 cfu) and LP45 (5 × 108 cfu)
22 weeks
Akkermansia muciniphila Old rodent group (Control)
(AKK) Old rodent group (Experiment)
2 × 108 cfu
4 weeks
Lacticaseibacillus Rodents were separated into 5 groups
rhamnosus UBLR-58 for 10 days:
Group 1: Saline (1 mL/kg/day)
Group 2: Scopolamine (1 mL/kg/
day)
Group 3: Scopolamine (1 mL/kg/
day) +Donepezil (2 mg/kg/day)
Group 4: Curcumin (205 mg/kg/day)
+ Scopolamine (1 mL/kg/day)
Group 5: Curcumin (205 mg/kg/day)
+ Scopolamine (1 mL/kg/day)
+ Lactobacillus rhamnosus (1 ×106
cfu/day)
Lactobacillus acidophilus Mice were separated into 5 groups for
Bifidobacterium longum 8 weeks:
Bifidobacterium lactis Group 1: Control group
Limosilactobacillus Group 2: Control-Probiotic group
fermentum Group 3: Saline
Group 4: AH Group
Group 5: AH- Probiotic group (2 g
(1 × 1010 cfu /day))
Lactiplantibacillus 48 healthy Wistar rats:
plantarum MTCC1325 1. Control group,
2. AD model
3. Normal control rats+ Lactobacillus
plantarum MTCC1325
4. AD-induced rats+ Lactobacillus
plantarum MTCC1325 (10 mL/kg
body weight, 12 × 108 cfu /mL)
Physiological effects
Short-term memory was improved in Aβ
+ MIIT + Probiotics group
Alleviated Escherichia coli K1- or LPS-induced
cognitive
impairment-like behaviors and colitis
Prevented cognitive dysfunction
Neuronal damage, tau pathology, and
amyloid-beta deposition were recovered.
Gut dysbiosis was improved.
Prevents cognitive dysfunction caused by
intracerebroventricular streptozotocin
infection
Combined TMC3115 and LP45
supplementation alleviated gut dysbiosis
İmproved spatial memory impairment
Akkermansia muciniphila can reach the
hypothalamus by passing through the blood-
brain barrier by being reduced to short-chain
fatty acids. It affects behavior by acting on
neurotransmitters in the hypothalamus.
Its positive effects on the central nervous
system and immune system are also thought
to be effective in improving life expectancy.
There was improvement in memory loss in the
group that received Lactobacillus rhamnosus
and curcumin.
Probiotic intake has been shown to provide
improvement in memory loss and learning in
mice with AD. In addition, it has been
observed that probiotics reduce neurologic
inflammation by reducing increased
oxidative stress.
Rats induced by AD were treated with
Lactobacillus plantarum MTCC1325 and all
ATPase enzyme components turned to near
normal levels within 30 days.
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Biomedicine & Pharmacotherapy 153 (2022) 113430
Mechanism of Actions References
(Aβ + MIIT + Probiotics group) [40]
Increase in ChAT↑
BDNF level↑
NF-κB-mediated BDNF expression was [41]
upregulated by suppressing the fecal and
blood bacterial LPS levels.
IL-1β↓
IL-6↓
TNF-α↓
Serotonin↑ [42]
Dopamine↑
GABA↑
Tau hyperphosphorylation was prevented
with the regulation of PI3 K/Akt/GSK-3β
Regulates glycogen synthase kinase 3 beta [43]
activity, propionic acid levels, and glucose
Abundance of Bacteroides↓ [44]
The abundance of Acetatifactor↑
The abundance of Millionella.↑
Provides positive effects on anxiety. [45]
Phagocytic activities of macrophages↑
NK cells activities↑
Provides improvement in oxidative stress
parameters (glutathione peroxidase,
reductase activity, lipid peroxidation level)
Lactobacillus rhamnosus and curcumin affect [46]
the acetylcholine level by regulating the
acetylcholinesterase level.
Oxidative stress↓
Oxidative stress↓ [47]
Improvement in MDA and SOD levels
The activities of the membrane transport [48]
ATPases system were improved.
Lactobacillus plantarum MTCC1325 stabilizes
the structural and functional integrity of
biological membranes and regulates the
ionic concentration gradient, thereby
protecting the neurons.
(continued on next page)
D. Ağagündüz et al. Biomedicine & Pharmacotherapy 153 (2022) 113430

Table 1 (continued )
Strains Subjects and Procedures Physiological effects Mechanism of Actions References

Levilactobacillus brevis
OW38
Lacticaseibacillus paracasei
PS23
Lacticaseibacillus paracasei
K71
Lactobacillus helveticus
KLDS1.8701
Lactiplantibacillus
plantarum AR501
Lactiplantibacillus pentosus
var. plantarum C29
Lactiplantibacillus
plantarum NDC 75017
8 weeks
Old mice (18 months old) Colitis formation↓ TNF↓ [49]
8 weeks (1 × 109 cfu/rodent, orally) Memory impairment↓ Interleukin (IL) − 1β↓
Nuclear factor Kappa β (NF-K β)↓
Lipopolysaccharide↓
Group of non-aged mice The decrease in muscle mass and muscle Mitochondrial Function↑ [50]
Old mouse group (control) strength decreased in the mouse group IL10↑
Old mouse group (LPPS23) receiving LPPS23 compared to the control ROS↓
orally for 12 weeks group.
(1 × 109 cfu/ rodent) It has been found to slow the development of
sarcopenia.
Old group (LPK71) Cognitive function↑ BDNF↑ [51]
Old group (control) Memory impairment↓ CREB↑
for 43 weeks
Old control group It has been found to reduce aging-related liver NRF-2↑ [52]
Old group (LHKLDS1.8701) damage by decreasing oxidative stress in the
liver.
Old rodents Antioxidant level↑ Regulates the activity of SOD, CAT and GPX [53]
6 weeks It has been found to reduce aging-related liver Regulates the expression of antioxidant
1010 cfu /mL damage by decreasing oxidative stress in the genes (GST, GCLc, GCLm)
liver. NRF-2↑
Memory Impairment↓ Oxidative stress↓ [54]
Age-related inflammation↓ BDNF level↑
CREB↑
M1 macrophages↓
(TNF-α, Arginine II)
Old mice were separated into 5 Learning ability↑ Mitochondrial Functions↑ [55]
groups of 10. Memory ability↑
7 weeks
(1 × 108, 1 × 109, 1 × 1010 cfu /mL)

AD: Alzheimer’s disease; MIIT: Moderate-intensity interval training; Aβ: Amyloid beta-peptide; ChAT: choline acetyltransferase; BDNF: Brain derived neurotrophic
factor; LPS: Lipopolysaccharides; CFU: Colony forming unit; NF-kB: Nuclear Factor kappa B; IL-1B: Interleukin 1 beta; IL- 6: Interleukin 6; TNF- α: Tumor Necrosis
Factor-alfa; GABA: Gamma-aminobutyric acid; PI3K: Phosphoinositide 3-kinase; GSK-3β: Glycogen synthase kinase-3- beta; NK cells: Natural Killer Cells; SOD: Su­
peroxide dismutase; CAT: Catalase; GPX: Glutathione Peroxidase; GST: Glutathione S-Transferase; GCLc: Glutamate cysteine ligase catalytic subunit; GCLm:
Glutamate-cysteine ligase regulatory subunit; NRF-2: Nuclear factor erythroid-2; CREB: c-AMP response element binding protein. RBANS: Repeatable Battery for the
Assessment of Neuropsychological Status.

with aging. Woo et al. (2014) reported that TNF-α levels increase due to
aging in old rodents. These old rodents were administered the L. pentosus
var. plantarum C29 strain for 5 weeks. At the end of the intervention, it
was found that TNF-α expression and inflammation due to aging
decreased [54]. Additionally, it was reported that BDNF and CREB levels
increased, memory impairment decreased, and cognitive function
improved. Similarly, in a study conducted with the L. plantarum NDC
75017 strain, an increase was found in memory ability [55].
3.2. Human studies
Similar to animal models, the potential effects of gerobiotics in AD
have been investigated in human clinical studies, although compara­
tively limited. For example, in a study, L. plantarum C29 strain was given
to the elderly with mild cognitive impairment for 12 weeks and it was
observed that serum BDNF level increased, and cognitive function and
attention level improved (Hwang et al., 2019). In similar studies using
the Bifidobacterium breve A1 strain in elderly individuals with mild
cognitive impairment, it was reported that cognitive performance
improved at the end of the intervention although the intervention times
varied (12–24 weeks) [62–64].
The effects of gerobiotics vary depending on the strain used, the
dose, and the severity of AD and show their effects through different
mechanisms. A study conducted with patients with AD revealed that
microbiota dysbiosis and the immune system improved when various
Bifidobacterium and Lactobacillus strains were applied for 4 weeks [61].
Consistent with this finding, it was found that IL-10 levels and the ac­
tivity of natural killer (NK) cells increased when the L. casei shirota strain
was given to elderly individuals for 4 weeks [56]. In a randomized
controlled study conducted with individuals with AD (n = 79), a
decrease in CRP levels, an increase in the total antioxidant capacity, and
an increase in cognitive functions were observed because of selenium
and probiotic co-supplementation (B. longum, B.bifidum, L. acidophilus)
for 12 weeks [59]. In a different study on B. longum BB536, B. infantis
M-63, B. breve M-16 V, and B. breve B-3 strains, it was reported that
BDNF levels increased, cognitive function improved, and
depression-anxiety level decreased even in healthy elderly individuals
[58]. In another randomized controlled study with B. longum BORI and
B. bifidum BGN4 strains, it was found that the gut microbiota signifi­
cantly changed, mental flexibility was promoted, and stress was allevi­
ated in the group receiving probiotics during a 12-week intervention
[66].
In another randomized controlled study, probiotic milk containing
(200 mL/day) B. bifidum, L. casei, L. acidophilus, and L. fermentum
(2 ×109 cfu/g for each) was administered to patients with AD for 12
weeks, and similarly, it was found that cognitive functions increased and
CRP levels decreased. Additionally, it was seen that the MDA levels
decreased [60]. A study conducted with probiotic-fermented milk with
kefir grains revealed that oxidative stress, systemic inflammation, and
blood cell damage decreased in patients with AD because of the 90-day
intervention, and cognitive performance increased [65]. These studies
show that some special probiotic strains, which are not only in their
nutraceutical form but also in the food matrix, may have a gerobiotic
effect and lead to improvements in patients with AD.
A 12-week randomized controlled study with Bifidobacterium and
Lactobacillus strains revealed that probiotic supplementation was inef­
fective against cognitive and biochemical parameters in severe AD. It
was shown that not only the formulation and dosage of probiotic bac­
teria but also the severity of the disease and the duration of adminis­
tration might influence the outcomes of treatment [67].

5
D. Ağagündüz et al. Biomedicine & Pharmacotherapy 153 (2022) 113430

Table 2
Human studies evaluating the relationship between gerobiotics and Alzheimer’s disease (a summary).
Strains Subjects and procedure Physiological Effect Mechanism of Actions References

Lacticaseibacillus casei Shirota Older adults (n = 30) Improve immune system The activity of neutral killer cells↑ [56]
Every day (1.3 × 1010 cfu beverage Level of Serum interleukin (IL)− 10↑
containing probiotic/placebo group
milk)
4 weeks
Lactiplantibacillus plantarum C29 Older adults (n = 100) Cognitive function↑ BDNF level↑ [57]
(800 mg supplementation/ Attention level↑
placebo)
800 mg a day
12 weeks
Bifidobacterium infantis M-63 Older adults (n = 38) Cognitive function↑ BDNF level↑ [58]
Bifidobacterium longum BB536 20 supplement Level of depression-anxiety↓ Gastrointestinal System Function↑
Bifidobacterium breve B-3 Every day (1.25 × 1010 cfu/day) Body Mass Index↓
Bifidobacterium breve M-16V placebo (n = 18) Frequency of defecation↑
12 weeks
Selenium and probiotic co- Patients with AD (n = 79) Cognitive function↑ hs-CRP↓ [59]
supplementation 12 weeks total antioxidant capacity↑
Bifidobacterium longum (2 × 109 cfu/day each) TNF-α↑
Lactobacillus acidophilus PPAR-γ↑
Bifidobacterium bifidum
Lactobacillus acidophilus Patients with AD (n = 60) Cognitive function↑ MDA↓ [60]
Limosilactobacillus fermentum 12 weeks CRP↓
Lacticaseibacillus casei (2 × 109 cfu/g)
Bifidobacterium bifidum
Lactococcus lactis W19 AD patients (n = 20) Modulate gut microbiota↑ Modulate tryptophan metabolism in serum [61]
Lacticaseibacillus casei W56 4 weeks Immune system and the activation of macrophages and/or
Lactobacillus acidophilus W22 dendritic cells
Lacticaseibacillus paracasei W20
Lactiplantibacillus plantarum W62
Bifidobacterium lactis W52
Bifidobacterium lactis W51
Bifidobacterium bifidum W23
Ligilactobacillus salivarius W24
Bifidobacterium breve A1 Older adults (n = 27) with mild Cognitive function ↑ MMSE scores↑ [62]
cognitive impairment
24 weeks
Bifidobacterium breve A1 Probiotic group (n = 59) elderly Cognitive function↑ RBANS score↑ [63]
with memory complaints and control MMSE score
group (n = 58)
12 weeks
Bifidobacterium breve A1 Probiotic group (n = 40) and control Memory functions↑ Increased Repeatable Battery for the [64]
group (n = 40) Assessment of Neuropsychological Status
16 weeks scores
Probiotic-fermented milk with kefir AD patients (n = 13) Improve cognitive deficits Inflammatory cytokine markers↓ [65]
grains 12 weeks Improvement of serum protein oxidation,
mitochondrial dysfunction, DNA damage/
repair, and apoptosis
Oxidative stress markers↓
NO↑
Probiotic containing Bifidobacterium Probiotic group (n = 27) and control Mental flexibility↑ BDNF level↑ [66]
longum BORI and Bifidobacterium group (n = 26) Alleviate stress The gut microbiome significantly shifted
bifidum BGN4 12 weeks (Eubacterium and Clostridiales)
Multi-strain probiotics containing Probiotic group (n = 25) and 23 in In severe AD patients, cognitive and Not defined [67]
three bacteria including either control group (n = 23) biochemical functions were not
Lactiplantibacillus plantarum, 12 weeks influenced by probiotics
Limosilactobacillus fermentum, and
Bifidobacterium lactis or
Bifidobacterium longum,
Lactobacillus acidophilus, and
Bifidobacterium bifidum

AD: Alzheimer’s disease; BDNF: Brain-derived neurotrophic factor; hs-CRP: high sensitivity C-reactive protein; TNF-α: Tumor necrosis factor - alfa; PPAR-γ: Peroxisome
proliferator-activated receptor-gamma; NO: Nitric oxide; CFU: Colony forming unit; MDA: Malondialdehyde; NO: Nitric oxide; MMSE: Mini Mental State Examination

4. The mechanisms of action of gerobiotics on Alzheimer’s
disease
Studies on the significance of the microbiota-gut-brain axis in the
pathogenesis of AD show this axis as an important target in preventing
and slowing the development of the disease [31,35]. Recent evidence
has revealed that gut microbiota is important in gut-brain interactions
[68]. Changes in the gut microbiota composition may lead to the
development of various neurological disorders such as AD. Thus,
probiotics are considered both protective and promising therapeutic
agents in AD due to their effects on the gut microbiota [23].
Probiotics are known as “live microorganisms that affect the health
of the host positively when taken in sufficient quantities” [69]. Gero­
biotics include probiotics or derived postbiotics involved in delaying the
aging process [14]. However, this concept is usually used to meet the
concept of probiotics than postbiotics in the literature. Increasing evi­
dence in the literature suggests that gerobiotics has important roles in
the development and progression of AD, and even in the treatment,

6
D. Ağagündüz et al.
through various mechanisms of action [68].
4.1. Mechanisms of action on the central nervous system
The microbiome plays a major role in synaptic transmission at the
molecular mechanism levels. Numerous studies have revealed that
probiotics can produce neuromodulators and neurotransmitters,
including norepinephrine, GABA, serotonin, dopamine, acetylcholine,
and BDNF [42,48,70]. It has also been stated that probiotics improve
neuronal damage, Aß accumulation, and tau pathology in AD, thereby
improving pathological processes and cognitive functions [42,71].
Gerobiotics affect the acetylcholine level by regulating the acetyl
cholinesterase level and improving memory and cognitive functions [40,
46]. It was revealed that memory loss can be improved by inhibiting the
expression of inflammatory markers such as TNF, IL-1β, NF-kB and LPS
[49]. Additionally, the inhibition of the expression of inflammatory
markers increased the expression of c-AMP response element binding
protein (CREB) and BDNF in the hippocampus, thereby improving
cognitive function [51,54,66]. It was also reported that it had glycogen
synthase kinase 3 β activity and gliosis regulatory effects [43].
Human studies revealed that with gerobiotic supplementation,
serum BDNF levels increase and cognitive function and attention
improved [57,58].
4.2. Antioxidant and anti-inflammatory mechanisms of action
Antioxidant and anti-inflammatory effects have been mentioned
among the positive roles of probiotics. Oxidative stress is a significant
factor in the development of AD, which suggests that probiotics may
have important protective effects against neurodegenerative diseases
[35].
It was reported that some Lactobacillus and Bifidobacterium strains
reduce the level of pro-inflammatory cytokines and neutralized ROS
[68,72,73]. It has also been argued that the structural and functional
integrity of biological membranes could be stabilized by gerobiotics
through the regulation of the ionic concentration gradient [48]. It was
further shown that gerobiotics reduced the elevated oxidative stress due
to AD by improving glutathione peroxidase, superoxide dismutase and
lipid peroxidation levels such as MDA levels [45,47,53].
Human studies revealed that gerobiotics increase the total antioxi­
dant capacity with a decrease in C-reactive protein (CRP) and MDA
levels, thereby regulating cognitive functions [59,60]. It has also been
reported that gerobiotics reduce various cytokine markers effective in
inflammation, increase NO bioavailability, improve serum protein
oxidation, DNA damage/apoptosis and mitochondrial dysfunction, and
thus improve cognitive functions [65].
4.3. Mechanisms of action on microbiota and immune system
The gut microbiota can influence brain activity via humoral activity
or the vagus nerve. Therefore, the deterioration in the gut microbiota
may cause brain dysfunction. At this point, it is stated that gerobiotics
increase the phagocytic activities of macrophages and the activities of
NK cells and thus have positive effects on the immune system [45,56]. It
has also been reported that with the modulation of tryptophan meta­
bolism in serum and the activation of macrophages and/or dendritic
cells, probiotics modulate the microbiota and immune system [61].
Intestinal dysbiosis causes increased inflammation, activation of the
HPA axis, and changes in neurotransmitter and bacterial metabolite
levels, which may lead to abnormal signaling through the vagus nerve.
Bacterial migration (leaky gut) and inflammation occur as the integrity
of the gastrointestinal barrier decreases. Inflammation disrupts the
integrity of the blood-brain barrier. Probiotics may normalize all of
these processes. Studies have shown that some probiotics, called gero­
biotics, also modulate dysbiosis by modulating gut microbiota [42,47].
Consistent with this, it was found that by suppressing blood and fecal
7
Biomedicine & Pharmacotherapy 153 (2022) 113430
bacterial LPS levels and with the NF-kB mediated upregulation of BDNF
expression, gerobiotics decrease TNF-α, IL-1β, and IL-6 expressions. In
this way, it contributes to an improvement in cognitive impairment-like
behavior and colitis [41,49].
With the above-mentioned mechanisms of action, probiotics are
thought to play a significant role in the gut-brain axis and modulate
brain functions (Fig. 2). Although the aim is to explain how probiotics
modulate the gut-brain axis, the precise and concrete mechanisms have
not yet been fully elucidated [23].
5. Potential therapeutic effects of probiotics on Alzheimer’s
disease
There is a debate on whether the current treatments applied to AD
cause positive or negative influences on the gut microbiota due to a few
interesting findings in the literature [74]. For example, similar to AD
drugs, it has been reported that some pesticides have inhibitory effects
on acetylcholinesterase and can modulate the gut microbiota composi­
tion in animals [75]. The treatment of rats with high doses of tacrine led
to some negative effects on the gut microbiota [76]. In this respect, AD
drugs may worsen the course of the disease in the long term due to their
negative effects on the gut microbiota. Accordingly, intestinal dysbiosis
can be prevented and/or improved when treated with pre/probiotics
and AD drugs. A paper reviewing the therapeutic effects of probiotics in
AD reported that probiotic supplementation could produce neuro­
protective effects, increase cognitive function and modulate gut micro­
biota dysbiosis, which is associated with oxidative-inflammatory
pathways [77].
Supporting this view, probiotics affect normal brain activity as well
as improve the cognitive functions of patients with AD [60]. It was also
found that mice with AD treated with pre-and probiotics had higher
cognitive performance and fewer Aβ plaques in their hippocampus [78].
In conclusion, the latest data show that pre/probiotic therapy in AD is an
important area of research considering its relationship with conven­
tional drug therapies. It must be investigated whether administering
pre/probiotics and currently available drugs at the same time produces
synergistic beneficial effects.
6. Conclusion and future directions
AD is a neurological disorder manifested by clinical symptoms and
affects the elderly population. Clinical evidence suggests that dietary
interventions can be a strategic measure to prevent the occurrence of
such disorders. Probiotics and/or postbiotics, noticeably gerobiotics,
significantly influence the fundamental aging process by modulating the
interaction between gut microbiota and neuronal network via the
microbiota-gut-brain axis. Several researchers have established the
linkage between ingestion of gerobiotics and improved gut dysbiosis and
cognitive functions, nevertheless the dose and duration of treatment
differ based on strain. However, we may comment that a minimum of 4
weeks of some gerobiotics ingestion appears to be beneficial for AD and
related symptoms in some human studies according to literature, but the
range of intervention time of gerobiotics to observe AD prognosis in
animal studies is quite wide (4–24 weeks) and it is not easy to reach a
general judgment. Besides, oxidative-inflammatory pathways are
mainly involved in the neuroprotective effects caused by gerobiotics.
Since the pathogenesis of AD is quite complex, other pathways that
evaluate the effect of probiotics need to be unveiled. Moreover, most of
the investigations have been conducted on animal models and clinical
studies are limited to a small sample size. Therefore, it becomes
imperative to conduct longitudinal human studies with a larger sample
for stringent validation of the results. It is worth noting that a single
mechanism or pathway would never yield promising results, thus the
interactive pathways may be deduced to a reasonable explanation
behind the role of gerobiotics and their bioactive components in the
improvement of AD.
D. Ağagündüz et al.
Fig. 2. The mechanism of action of gerobiotics on Alzheimer’s Disease. TNF: Tumor Necrosis Factor; NF-kB: Nuclear Factor kappa B; LPS: Lipopolysaccharides; ROS:
Reactive Oxygen Species; CRP: C-reactive protein; MDA: Malondialdehyde; NK cells: Natural Killer cells; GABA: γ-aminobutyric acid; BDNF: brain-derived neuro­
trophic factor; CREB: c-AMP Response Element Binding Protein; NO: Nitric oxide.
CRediT authorship contribution statement
Duygu Ağagündüz: Conceptualization, Writing – review & editing.
Heena Sharma, Betül Kocaadam-Bozkurt, Renata Esposito, Osman
Bozkurt: Writing – original draft. Fatih Özoğul, Raffaele Capasso:
Supervision. All authors read and approved the final manuscript.
Conflict of interest statement
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Data availability
No data were used in the research described in this article.
Acknowledgments
Fig. 1 and Fig. 2 were created with BioRender.com.
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