ISSN 0006-2979, Biochemistry (Moscow), 2024, Vol. 89, No. 3, pp. 523-542 © Pleiades Publishing, Ltd., 2024.
523
REVIEW
Role of the Gut Microbiome and Bacterial Amyloids
in the Development of Synucleinopathies
Nina P. Trubitsina
1
, Anton B. Matiiv
1
, Tatyana M. Rogoza
1,2
, Anna A. Zudilova
1
,
Mariya D. Bezgina
1
, Galina A. Zhouravleva
1,3
, and Stanislav A. Bondarev
1,3,a
*
1
Department of Genetics and Biotechnology, Saint Petersburg State University, 199034 Saint Petersburg, Russia
2
St. Petersburg Branch of the Vavilov Institute of General Genetics, 198504 Saint Petersburg, Russia
3
Laboratory of Amyloid Biology, Saint Petersburg State University, 199034 Saint Petersburg, Russia
a
e-mail: s.bondarev@spbu.ru, stanislavspbgu@gmail.com
Received September 18, 2023
Revised January 16, 2024
Accepted January 24, 2024
Abstract— Less than ten years ago, evidence began to accumulate about association between the changes in the
composition of gut microbiota and development of human synucleinopathies, in particular sporadic form of Par-
kinson’s disease. We collected data from more than one hundred and thirty experimental studies that reported
similar results and summarized the frequencies of detection of different groups of bacteria in these studies. It is
important to note that it is extremely rare that a unidirectional change in the population of one or another group
of microorganisms (only an elevation or only a reduction) was detected in the patients with Parkinson’s disease.
However, we were able to identify several groups of bacteria that were overrepresented in the patients with Par-
kinson’s disease in the analyzed studies. There are various hypotheses about the molecular mechanisms that ex-
plain such relationships. Usually, α-synuclein aggregation is associated with the development of inflammatory
processes that occur in response to the changes in the microbiome. However, experimental evidence is accumulat-
ing on the influence of bacterial proteins, including amyloids (curli), as well as various metabolites, on the α-synu-
clein aggregation. In the review, we provided up-to-date information about such examples.
DOI: 10.1134/S0006297924030118
Keywords: amyloids, alpha-synuclein, Parkinson’s disease, microbiome, dysbiosis, neurodegenerative diseases,
bacterial amyloids, curli
Abbreviations: Aβ,β-amyloid; AD,Alzheimer’s disease; aSyn,α-synuclein; CNS,central nervous system; ENS,enteric nervous
system; GIT,gastrointestinal tract; LPS,lipopolysaccharides; NS, nervous system; PD,Parkinson’s disease; PNS,peripheral
nervous system; SCFA,short-chain fatty acids; sPD,sporadic Parkinson’s disease.
* To whom correspondence should be addressed.
INTRODUCTION.
αSyn PROTEIN AND SYNUCLEINOPATHIES
Interest in synuclein proteins increased signifi-
cantly after discovery of genetic and neuropathological
association between α-synuclein (αSyn, encoded by the
SNCA gene) [1] and Parkinson’s disease (PD). Protein
αSyn is a major component of the pathological pro-
tein aggregates inside neurons, Lewi bodies. Presence
of such aggregates is one of diagnostic signs of PD [2].
At present, β- and γ-synucleins have also been identi-
fied[3,4]. Similar to αSyn, they are small soluble pro-
teins present predominantly in the nervous tissue cells
and in some tumors in vertebrates[3]. The αSyn pro-
tein consists of 140 aa[5,6]. There are three domains
in its composition: N-terminal region (1-60 aa), which is
bound to a cell membrane; hydrophobic region known
as non-amyloid component (NAC, 61-95 aa), and C-ter-
minal hydrophilic region (96-140 aa)[6-8]. It is known
that αSyn facilitates decrease of apoptosis in dopami-
nergic neurons [9], prevents oxidation of unsaturated
fatty acids [10], regulates transport of synaptic vesicles
at presynaptic terminals [11], participates in formation
of the SNARE complex (soluble NSF (N-ethylmaleimide-
TRUBITSINA et al.524
BIOCHEMISTRY (Moscow) Vol. 89 No. 3 2024
sensitive factor) attachment receptor) [12] and in the
clathrin-mediated endocytosis [13]. Nevertheless, all
functions of the αSyn protein have not been eluci-
dated yet.
Aggregation of the αSyn protein. Despite the
numerous existing studies, structure of αSyn under
physiological conditions has not been fully elucidat-
ed yet. It is assumed that in cytosol this protein exists
predominantly as an unfolded monomer [14]. Aggre-
gation propensity has been shown for the αSyn pro-
tein; therefore, it can form both oligomers and fibrils
[15]. These complexes could have typical cross-β-struc-
ture and exhibit other properties common to amy-
loids [16, 17].
Various factors could affect the process of αSyn
aggregation including acidity [18], temperature [19],
molecular crowding (effect of reduction of free cyto-
plasmic volume in the cell and increase of concentra-
tion of molecules [20], metal ions (such as aluminum,
copper, iron, cobalt, and manganese)[19], organic sol-
vents [21], pesticides[19], αSyn-binding proteins [22-24],
exosome lipids [25], and others. Moreover, neurotoxici-
ty of αSyn and its aggregation could be affected by post-
translational modifications, such as phospho rylation
[26, 27], ubiquitination [28], nitration [29], SUMOyla-
tion [30], proteolysis [31], and N-terminal acetylation
[32]. Most of the aggregates of αSyn (90%) found in
Lewi bodies contain protein phosphorylated at the
S129 residue [33]. However, it is still unclear whether
the αSyn phosphorylation stimulates its aggregation or
prevents this as well as whether it affects αSyn neuro-
toxicity [34]. Role of glycation in the development of
synucleinopathies is also seems controversial. On the
one hand, the protein with this modification has been
identified in the frontal cortex of the patients with
PD [35, 36], while its level is elevated in the blood of
these patients [37]. On the other hand, the glycated
monomeric or oligomeric αSyn do not form fibrils on
its own, prevent aggregation of non-modified protein
[38,39], as well as are incorporated into the αSyn fi-
brils to a lesser degree [40].
Different chaperons, including the ones from bac-
teria, also affect αSyn aggregation. The CsgC and DnaK
proteins from Escherichia coli inhibit this process [41,
42], while the SlyD and DnaJ proteins, on the contrary,
stimulate aggregation [42, 43]. The human chaperon
FKBP12, belonging to the same protein family as SlyD,
also accelerates formation of the αSyn amyloid aggre-
gates [43].
The results of experiments with animal models
and cell cultures, including neuronal cell cultures, in-
dicate pathogenic role of αSyn aggregation that caus-
es disruption of synaptic transmission, functioning of
mitochondria and endoplasmic reticulum, initiates de-
fective autophagy, neuroinflammation, and oxidative
stress [44,45]. It has been also suggested that the αSyn
aggregation in presynaptic terminals affects assembly
of the SNARE complexes, thus reducing efficiency of
dopamine release [46]. Moreover, some synaptic pro-
teins and receptors of neurotransmitters, such as, for
example, N-methyl-D-aspartic acid receptors (NMDA),
were identified as presumed αSyn partners [47]. Inpar-
ticular, it was shown that αSyn co-aggregated with
thenitric oxide synthase 1 (neuronal) adaptor protein
(NOS1AP or CAPON), which indirectly interact with the
NMDA-receptors[24].
Prion-like properties of the αSyn protein. In the
strict sense mammalian prions are infectious agents in
which the PrP
Sc
protein with altered conformation re-
cruits and transforms its normal analogue PrP
C
, thus
creating self-propagating protein particles with mis-
folded structure, which could be transmitted from cell
to cell [48, 49]. It has been suggested that some amy-
loid proteins have the similar prion-like propagation
mechanism. In addition to αSyn, existence of prion
properties has been suggested for other known amy-
loids such as β-amyloid (Aβ)[50], Tau[51], and hun-
tingtin [52].
Prion mechanism of neurodegeneration develop-
ment in PD was first suggested in the studies by
Braaketal.[53,54] based on the distribution of patho-
logical changes associated with αSyn aggregation in
the brain of the patients with PD. Later the proof of
prion-like propagation of αSyn was obtained as a re-
sult of observation of this protein aggregation in the
transplanted tissues several years after surgery; in
particular, transfer of the Lewy pathology from the
host to transplant was detected [55, 56]. Since then, it
was shown in different studies that the αSyn fibrils
obtained from the recombinant protein or from the
lysates isolated from the disease-affected brain could
propagate in a prion-like manner in the different types
of human cell cultures [57-59] and in the rodent brains
[60-63]. Several mechanisms of αSyn propagation have
been suggested in response to the question how the
transfer of αSyn between the cells occurs. For example,
there are indications that the αSyn monomers, oligo-
mers, and fibrils could be transported with the help of
vesicles from the donor cell via exocytosis followed by
release into the extracellular space and capture by the
acceptor cells [64,65].
Synucleinopathies are a group of neurodegener-
ative diseases characterized by the presence of inclu-
sions in neurons and/or glia consisting of aggregated
αSyn [66]. From the point of view of pathomorpholo-
gy synucleinopathies could be divided into two main
groups: multiple system atrophy (MSA) and diseases
associated with formation of Lewy bodies [67,68].
MSA could be subdivided into two main subtypes:
olivopontocerebellar atrophy and striatonigral degen-
eration. MSA is an impaired movement disease charac-
terized with various combinations of vegetative state,
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BIOCHEMISTRY (Moscow) Vol. 89 No. 3 2024
parkinsonism, cerebellar ataxia, pyramidal signs, and
non-motor symptoms [69].
Pathologies with Lewy bodies are subdivided into
three main clinical pathological subtypes: PD, PD de-
mentia, and Lewy body dementia. However, Lewy bod-
ies and αSyn aggregates are found also in a number
of neurometabolic diseases such as PLA2G6-associated
neurodegeneration, POLG-associated neurodegenera-
tion, Niemann–Pick typeC disease, and Krabbe disease
[70], as well as in the patients with Alzheimer’s disease
(AD) [71]. Moreover, αSyn amyloid aggregates have
been observed in axonal spheroids in neuroaxonal
dystrophies [72]. PD symptomatic will be considered
below, but it is worth mentioning that in the majority
of PD patients (around 83%) at the later stages it devel-
ops into PD dementia [73]. The symptoms of dementia
with Lewy bodies include dementia, neurocognitive
changes, parkinsonism, visual hallucinations, and dis-
ruption of behavior in the rapid eye movement phase
of sleep [74].
There are two forms of PD: sporadic PD (sPD) with
unknown etiology and familial PD with known genetic
etiology[75]. In the latter case replacements in amino
acid sequence of αSyn have been identified (e.g., A53T,
A30P, E46K, A53E), which are associated with autoso-
mal dominant forms of PD [76-79]. In addition, famil-
ial PD is caused by duplication and triplication of the
SNCA gene [80,81]. Some mutations in other genes are
also considered as risk factors for PD development.
Among these the LRRK2 gene (encodes leucine-rich re-
peat kinase 2, LRRK2) has been identified, expression
of which increases in the inflamed colon tissues of the
patients with PD and Crohn’s disease, as well as in the
cells of peripheral immune system [82]. Other genes
mutations in which are associated with PD are PINK1
(encodes phosphatase and tensin homolog-induced
kinase 1, PINK1) and PRKN (encodes ubiquitin ligase
parkin, parkin), which play a key role in adaptive im-
munity repressing presentation of mitochondrial anti-
gens, i.e., are repressor of autoimmune mechanisms.
Mutations in these genes cause mitochondrial dysfunc-
tions in some forms of PD [83].
PD is accompanied by a number of symptoms,
which are subdivided into movement (motor) and non-
movement. Motor symptoms include tremor and limb
rigidity, slowness of movement (bradykinesia), and
gait impairment. Non-motor symptoms are manifested
as neuropsychic disorders, problems with sleeping, de-
pression, physical and mental fatigue, as well as sen-
sory disorders: vision dysfunction associated with rap-
id movements of eyeballs, hyposmia (decreased sense
of smell) [84-86]. In the majority of cases non-motor
symptoms are manifested much earlier than the mo-
tor symptoms, which raises the question on where ex-
actly development of synucleinopathies starts: in the
peripheral (PNS) or central nervous system (CNS) [87].
It must be mentioned in the context of this review
that some gastrointestinal disorders are observed in
the patients with PD (with sPD, in particular) such as
excessive salivation, dysphagia, difficulties with gas-
tric emptying, constipation, and problems with defe-
cation [84]. These symptoms are often accompanied
by changes in the gut microbiome (dysbiosis) [88-90].
Examples of association between dysbiosis and devel-
opment of synucleinopathies will be discussed in more
detail further in the review. The term “dysbiosis” will
be used in a broader sense for the cases when either
increase or decrease of certain groups of microorgan-
isms occurs. Otherwise, a particular effect will be men-
tioned. The term “microbiome” will be used for the mi-
crobial community (microbiota) in the certain habitat
with particular physicochemical properties. Itmust be
noted that this notion includes not only live objects,
but also products of their metabolism [91].
CHANGES IN MICROBIOME
ASSOCIATED WITH THE DEVELOPMENT
OF SYNUCLEINOPATHIES
Human gut microbiome. In order to elucidate
what changes occur in microbiome of gastrointestinal
tract (GIT) of the patients with PD, it is necessary to
consider first composition of gastrointestinal micro-
biota in healthy individuals. It is currently recognized
by the scientists that human microbiota is a set of all
microorganisms populating human body [92]. It in-
cludes bacteria, archaea, single-cell eukaryotes (fungi
and protozoa), and viruses; and it is directly involved
in maintenance of healthy functioning of an organism,
which allows considering it as a ‘hidden organ’ in a
human organism [93].
Two methods are currently used for investigation
of the human microbiome. The first one is amplicon
sequencing of the variable region V3-V4 of the 16S
ribosomal RNA (rRNA), which allows characterizing
composition of bacteria and archaea at the taxonomic
level and identifying structural changes in the microbi-
al communities. However, this method does not allow
one to determine differences at the species level. Shot-
gun metagenomic sequencing allows more detailed
assessment of the microbiome composition as well as
to achieve accurate taxonomic classification and deter-
mine functions of bacteria[94]. Various strategies used
for analysis of metagenomics data sets are based on
the reference databases; hence, there is a need in large
well-characterized collections of the reference micro-
bial genomes. At present results of numerous large-
scale studies devoted to deciphering composition of
the human gut microbiota have been reported[94-98].
Microbiota can be subdivided into oral, skin, gut,
and respiratory microbiota; it has been considered that
TRUBITSINA et al.526
BIOCHEMISTRY (Moscow) Vol. 89 No. 3 2024
the gut microbiota is the most important in the context
of maintenance of health of the whole organism and
has the most diverse species composition [93, 97]. Cur-
rent understanding of the human gut microbial com-
munity is primarily limited by the taxonomic features
at the genus level[97]. Nevertheless, according to var-
ious estimates, human gut microbiota includes from
200 to more than 1000 bacterial species [99-101]. It has
been shown that the healthy human gut microbiota
mainly consists of the representatives of the follow-
ing bacterial phyla: Bacillota (Firmicutes), Bacteroi-
dota (Bacteroidetes), Actinomycetota (Actinobacteria),
Pseudomonadota (Proteobacteria), Fusobacteriota (Fu-
sobacteria), and Verrucomicrobiota (Verrucomicrobia)
[102], among which Bacillota and Bacteroidota are pre-
dominant [99, 102, 103] or, according to other studies,
Bacillota and Actinomycetota [104]. Fungi species such
as Candida, Saccharomyces, Malassezia, and Clado-
sporium[105] and archaea (primarily methanogenic),
among which the Methanobrevibacter smithii species is
predominant [100, 106, 107], have been also found in
the composition of human gut microbiota.
Despite the existence of numerous studies devot-
ed to investigation of the ‘healthy’ microbiome, there is
no exact definition of this notion [108]. It is commonly
recognized that under normal conditions microbiome
is characterized with a wide diversity of microorgan-
isms and persistent predominance of two key phyla:
Bacillota and Bacteroidota[109]. In a number of cases
description of the ‘healthy’ microbiome with the help
of sequencing reveals also diversity of the genes in-
volved in maintenance of symbiosis with the host or-
ganism [93, 110]. It must be mentioned that relative
distribution of microorganisms is unique for every
individual, and could be subjected to changes within
the individual under effects of various factors. Human
microbiome could be affected by the following factors:
sex, age, diet, antibiotics, state of the environment, eth-
nic background, and many other factors [93, 110, 111].
Understanding composition of the healthy human mi-
crobiota could facilitate development of effective strat-
egies for microbiome manipulation for therapeutic
purposes. At present several methods are used includ-
ing the most popular transplantation of gut microbiota
and administration of prebiotics, probiotics, or symbi-
otic [92].
Gut microbiota participates in a number of bio-
logical processes. First of all, it allows effective extrac-
tion of energy and nutrients from food due to the
presence of universal ‘metabolic’ genes, products of
which participate in different enzymatic reactions and
biochemical pathways [112]. Gut microbiota is capable
of metabolizing polysaccharides and short-chain fatty
acids (SCFA), majority of which are represented by ac-
etates, butyrates, or propionates. They serve as an en-
ergy source for gut epithelium and liver[93, 113, 114].
Synthesis of biologically active molecules such as vi-
tamins, amino acids, and lipids is realized with direct
participation of gut microbiota [93].
Gut microbiota plays protective role in the human
organism. It protects not only from external pathogens
by producing antimicrobial substances but also serves
as an important component in the development of gut
mucus and immune system [93]. It is important to note
in the context of this review that gut microbiota also
is directly involved in immunomodulation, such as in
regulation of inflammation processes. For example, mi-
crobiota mediates neutrophil migration, which further
affects differentiation of T-lymphocytes into different
types of regulatory and helper T-cells [115]. Dysbalance
of gut microflora could result in the development of
autoimmune diseases [116]. In addition, microorgan-
isms themselves are able to produce a number of mole-
cules, such as defensins, which facilitate enhancement
of inflammation processes [117]. The data are also avail-
able indicating role of microbiota in supporting func-
tions of the CD8
+
T-lymphocytes[118].
No less important role of microbiota is mainte-
nance of the constant state of the internal environment
via interaction with the brain. This interaction has
been termed gut-brain axis and is a bidirectional sys-
tem of signaling pathways involving the vagus nerve,
immune system, and bacterial metabolites [119]. SCFA
produced by the gut microbiota are capable of affect-
ing release of mucosa neurotransmitters [120], modu-
lation of neurotransmitters [121], and functioning of
parasympathetic nervous system (NS) [122]. In addi-
tion, gut microbiota could affect functioning of affer-
ent sensory neurons by, for example, increasing their
excitability through inhibition of calcium-dependent
channels as observed in the case of Lactobacillus reu-
teri[123].
Microbiota and neurodegenerative diseases.
There are numerous examples of association of micro-
biome changes with different diseases including neu-
rodegenerative ones. The examples include Crohn’s
disease [124], irritable bowel syndrome [125], colon
cancer [126], AD [127], diabetes [128], obesity [129],
and rheumatoid arthritis [130]. Further, we will pres-
ent several examples of association of microbiome and
development of neurodegenerative diseases.
AD is a neurodegenerative disease leading to pro-
gressive cognitive dysfunction [131]. Microbiome of the
AD patients is enriched with bacteria of the Escherichia
and Shigella genera, which cause proinflammatory
state and decrease concentration of Eubacterium rec-
tale exhibiting anti-inflammatory activity [132]. It is
also known that bacterial lipopolysaccharides (LPS)
could initiate formation of Aβ fibrils [133, 134]. These
and other data allowed suggesting that some bacteria
could secrete a large amount of LPS and amyloid pro-
teins, which are capable of crossing gut- and blood-
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BIOCHEMISTRY (Moscow) Vol. 89 No. 3 2024
brain barriers, which are weakening with aging or in
disease, as well as indirectly affect crossing of these
protective physiological barriers by the pro-inflamma-
tory cytokines leading to AD development [131,135].
Gut dysbiosis is considered as an important factor
affecting pathogenesis of multiple sclerosis, which is
an immune-mediated chronic neurological disease as-
sociated with demyelination, axon damage, and neu-
rodegeneration [136]. Decrease of the number of bac-
teria associated with anti-inflammatory response has
been observed in the patients with relapsing-remitting
multiple sclerosis, as well as increase of the number
of bacteria responsible for pro-inflammatory reac-
tions [137].
Amyotrophic lateral sclerosis (ALS) is a progres-
sive neurodegenerative disease associated with the
death of neurons in the brain and spinal cord, as well
as motor neurons. Decrease of the level of various bac-
teria producing butyrate (such as Butyrivibrio fibrosol-
vens, Oscillibacter, Anaerostipes) has been observed in
the gut of the ALS patients and of the transgenic mice
used for modeling this disease [138-140]. Moreover, it
was shown that addition of butyrate to drinking wa-
ter of the mice used as a model for studying ALS slows
down the disease development [141].
Hence, many examples are known demonstrat-
ing the role of microbiome or its metabolites in the
development of neurodegenerative diseases. Various
hypotheses have been suggested for the possible mech-
anisms underlying these phenomena. In the following
sections the role of microbiome in the development of
synucleinopathies will be considered in more details as
well as hypotheses explaining these interconnections.
Association between gut microbiome and synu-
cleinopathies. The relationship between the changes
in gut microbiome and PD has been first reported in
the literature in 2015[142]. It was shown in this study
that the patients with PD have reduced content of
bacteria from the Prevotellaceae family, and it was
concluded that gut microbiome changes in PD, which
leads to motor dysfunction. Later two more studies
have been published: in one study the authors demon-
strated that the patients with PD have reduced amount
of ‘anti-inflammatory’ bacteria producing butyrates
from the Blautia, Coprococcus, and Roseburia genera
[143]. In another study the authors demonstrated as-
sociation of PD with other groups of bacteria; in par-
ticular the amount of bacteria of Lactobacillus genus
was higher, while the total amount of analyzed bacte-
ria Clostridium coccoides and Bacteroides fragilis was
lower than in the control. Furthermore, increased gut
permeability was assumed for the patients with PD
based on the analysis of the levels of LPS-binding pro-
tein and diamine oxidase in the blood serum. Suppos-
edly, this could either promote development of dysbio-
sis and progression of PD, or be the result of dysbiosis
[144]. These studies laid foundation for the hypothesis
implying that dysbiosis could be the cause of neuroin-
flammation, which results in misfolding of αSyn and
development of PD. After that for almost 10 years inter-
est in this hypothesis was increasing steadily: a large
amount of scientific studies with the results of metag-
enomic investigation of GIT of the patients with PD
and other synucleinopathies was published. Search of
PubMed revealed more than 130 experimental studies
devoted to PD (date of access:04.12.2022).
Apparently, the number of studies will continue
to grow, especially considering the fact that certain
contradictions are often being reported. For example,
there is a difference in indicators of microbiome di-
versity within one group– PD or control (the so-called
α-diversity): some studies report decrease of diversity
in the patients with PD in comparison with the con-
trol group of healthy individuals [145, 146]; in oth-
ers, on the contrary, either increase of diversity was
demonstrated [147] or absence of differences [148].
Atthe same time, at the level of β-diversity (difference
in composition of microbiota between the samples or
groups) majority of the microbiome studies of the pa-
tients with PD are characterized with the significant
change of composition in comparison with the control.
In order to summarize current results on the issue, we
analyzed the literature and presented all reported as-
sociations of the changes in microbiome composition
with PD as a phylogenetic tree (Fig.1). Despite the fact
that there were significant differences between the an-
alyzed studies investigating changes in the gut micro-
biome in PD including study design, ratio of sexes, age,
duration of the disease, and others, in our analysis
we did not concentrate on the cited differences, and
used all statistically reliable association in our analysis.
According to these data, representatives of the phyla
Bacillota and Bacteroidota are most often associated
with PD, moreover, for both cases associations were
demonstrated both for the decrease and for the in-
crease of the number of these microorganisms. In gen-
eral, this could be expected, because the investigated
groups form the basis of the human microbiome.
We also analyzed associations at the level of bac-
terial families in order to analyze potential causes of
dysbiosis in PD (Fig. 1). Typically, multidirectional as-
sociations have been shown for many families, as
well as for the larger taxonomic groups. Both reduc-
tion and increase of population of a particular group
have been associated with PD development. The fol-
lowing families have been reported most often to have
changed population (either elevated or reduced) in the
patients with PD: Lactobacillaceae, Bifidobacteriaceae,
Desulfovibrionaceae, Akkermansiaceae, Rikenellaceae,
Verrucomicrobiaceae, Porphyromonadaceae, Tanner-
elaceae, and Enterobacteriaceae. The reduced popu-
lation in composition of microbiome is typical for the
TRUBITSINA et al.528
BIOCHEMISTRY (Moscow) Vol. 89 No. 3 2024
Fig. 1. Known associations between the changes of microbiome and development of PD. Taxonomic tree of bacterial families in
human microbiome (according to NCBI Taxonomy database) with marked numbers of the cases of described associations (pub-
lications) or representatives of the respective family with PD. Cases in which increase or decrease of the population of particu-
lar groups of bacteria are observed are considered separately. Search of publications was conducted in the PubMed database
(accessed on 04.12.2022; search query was similar to the one in the study by Tohetal., 2022: (“Microbiota” OR “Microbiome” OR
“Microflora” OR “Dysbiosis”) AND (“Parkinson” OR “Parkinsonism”) [149]. 138 experimental papers from the total list of 1061
publications were analyzed. Classes with two or more identified families are shown, as well as most represented bacterial phyla.
GUT DYSBIOSIS IN SYNUCLEINOPATHY DEVELOPMENT 529
BIOCHEMISTRY (Moscow) Vol. 89 No. 3 2024
representatives of the Oscillospiraceae, Lachnospir-
aceae, Clostridiaceae, and Prevotellaceae families.
It must be noted that unidirectional changes of pop-
ulation (only elevated or reduced) of any particular
group have been observed rarely in the patients with
PD. The families Eggerthellaceae, Desulfovibrionaceae,
Porphyromonadaceae, Rikenellaceae, Akkermansiace-
ae, and Verrucomicrobiaceae (shown only the families
with representatives in a large number of independent
studies) are the exception.
According to the literature data, reduction of bacte-
rial taxa associated with anti-inflammatory/neuropro-
tective effects was shown in general for PD, especially
in the Lachnospiraceae family and the key members
such as Butyrivibrio, Pseudobutyrivibrio, Coprococcus,
and Blautia [150]. Changes in representation of the
Lachnospiraceae family correlate with the changed
rate of metabolism in PD[150]. Several members of the
Lachnospiraceae family attract attention due to their
ability to produce SCFA [151].
Summarizing available information on the chang-
es in microbiome composition in PD allowed us to re-
veal general pattern, in particular, to identify key taxa,
which presumably contribute to the development of
intestinal symptoms. At the same time there are many
bacterial species for which association with PD have
been shown only in few publications, therefore, fur-
ther studies of human gut metagenome are needed,
especially the ones using shotgun sequencing, which
allow elucidating strain-level composition of microbial
community. This could facilitate deciphering mecha-
nisms of dysbiosis development in PD and to develop
treatment methods.
POSSIBLE MECHANISMS
OF SYNUCLEINOPATHIES DEVELOPMENT
ASSOCIATED WITH DYSBIOSIS
Braak’s hypothesis on misfolding of αSyn in a gut.
αSyn aggregates have been detected not only in CNS,
but also in PNS, such as, for example, in the part in-
nervating gut. The hypothesis on the sPD development
occurring as a result of aggregation of αSyn in the in-
testine neurons followed by propagation of the pathol-
ogy to CNS was first suggested by Braaketal.[53,54].
In their study the authors investigated localization of
αSyn aggregates in different parts of NS of the patients
with sPD. In particular, the samples of enteric nervous
system (ENS), dorsal motor nuclei of the vagus nerve,
substantia nigra, temporal mesocortex, and neocortex.
One of the important observations was the fact that
in all cases accumulation of αSyn was detected in ENS
and in vagus nerve, while correlation between the
presence of aggregates and stage of the disease was
observed in the remaining zones. The αSyn aggre-
gates in neocortex were found only in the patients at
the latest stage of the disease development [54]. This
hypothesis is in good agreement with the results of a
number of publications. Lewy bodies have been found
in myenteric and submucosal plexus of the intestine
in the patients with PD [152,153]. Presence of αSyn in
the vagus neurons innervating intestine also has been
demonstrated experimentally [154]. For example, accu-
mulations of αSyn are found in the biopsy samples of
the intestine from the patients with PD including those
at the early stages of the disease, as well as prior to the
development of symptoms [155-157]. The data are also
available demonstrating that vagotomy decreases the
risk of PD development [158]. Experimental proof of
the αSyn aggregates transfer from the gut to brain has
been obtained in rats. The animals were injected with
the protein lysates derived from the PD patients or
recombinant human αSyn into the intestine wall. Af-
ter that presence of this protein was analyzed in dif-
ferent parts of the vagus nerve at different intervals
[159]. Inthe experiments with mice, it was possible to
achieve aggregation of αSyn in the gut by administra-
tion of rotenone (isoflavone used as a broad-spectrum
insecticide and pesticide), as well as to demonstrate
that the aggregates appear with time in the spinal cord
and brain [160]. Different variants of the factors trig-
gering aggregation of αSyn in the gut have been consid-
ered including presence of pathogens or viruses [161].
Prion-like properties of αSyn discussed in detail in the
subsection “Prion-like properties of the αSyn protein”
also support the notion that synucleinopathies could
start in PNS followed by the transfer to CNS.
The data are available that contradict the Braak’s
hypothesis. In particular, examination of the patients
with Lewy pathology did not reveal any cases with only
PNS affected (place of the start of pathology according
to the Braak’s hypothesis), i.e., accumulation of αSyn
is also found both in ENS and CNS[162]. On the other
hand, there is an opinion that such observations could
be false-negative due to insufficient sample size [87].
Another hypothesis has been proposed after the
Braak’s hypothesis suggesting that the first stages of sy-
nucleinopathy development could affect olfactory sys-
tem and start there, in the olfactory bulbs. This was the
start of expansion of the Braak’s hypothesis develop-
ment recognized as a dual-hit hypothesis [161]. Atpres-
ent there is no consensus on where and when aggre-
gation of αSyn begins, although the Braak’s hypothesis
remains to be the one most often cited [87].
Relationship between αSyn and GIT symptoms.
In the last 20 years since introduction of the Braak’s
hypothesis various molecular mechanisms have been
suggested explaining development of synucleinopathy
in ENS or emergence of the respective symptoms. One
of them is associated with the presumed role ofαSyn
as an immunomodulator. It was shown in several stud-
TRUBITSINA et al.530
BIOCHEMISTRY (Moscow) Vol. 89 No. 3 2024
ies that this protein can stimulate microglia cells or
monocytes to produce inflammatory cytokines (TNFα,
IL-1β) [163,164]. Monomeric or oligomeric αSyn stimu-
lated attraction of neutrophils and monocytes, as well
as maturation of dendritic cells. Positive correlation
between the intestine inflammation and αSyn expres-
sion has also been established. It has been suggested
in the study that the αSyn secretion served as a stim-
ulus for initiation of inflammatory processes [165]. In-
crease of the αSyn expression is a factor promoting de-
velopment of PD, which previously was shown for the
patients with several copies of the SNCA locus [80, 81];
this could explain development of synucleinopathy.
On the other hand, overexpression of αSyn could in-
hibit release of neurotransmitters and neuromediators
(dopamine, acetylcholine, noradrenaline, and others),
and, due to this affect functioning of the intestine [166].
αSyn protein could induce increased expression
of the genes of Toll-like receptor(TLR) and pro-inflam-
matory cytokine in microglia cells. TLRs participate in
innate immune response and recognize the most abun-
dant bacterial LPS. Activation of TLR-signaling could
result in apoptosis of dopaminergic neurons. More-
over, activation of microglia, in turn, increases produc-
tion of nitrogen oxide(NO), and, further development
of synucleinopathy could proceed due to nitration of
αSyn in the neighboring neurons and their apoptosis
[167]. This modification also potentially stimulates for-
mation of αSyn oligomers, and protein with such mod-
ification has been found in Lewy bodies in the patients
with PD [168]. Increased content of NO-synthase has
been demonstrated in the model mice with induced
inflammation, which results in enhanced aggregation
ofαSyn[169].
Various compounds appearing in GIT could pro-
voke PD development; among the examples different
xenobiotics (herbicides, pesticides) could be mentioned
[170,171]. It was shown in the mouse model that these
compounds could lead to the death of dopaminergic
neurons and development of PD [172]. Indirect con-
firmation of this hypothesis could be provided by the
fact that activation of the pathway of degradation of
xenobiotics in the gut of the patients with PD has been
demonstrated [173]. Supposedly, some antibiotics af-
fect PD pathogenesis helping bacteria producing cur-
li. Antibiotics in general decrease microbial diversity
in the gut, modulate the Bacillota/Bacteroidota ratio,
which results in the excessive growth of opportunistic
pathogens [174]. Some bacterial metabolites such as
β-N-methylamino-L-alanine could also promote PD de-
velopment [175]. SCFA produced by bacteria also could
cause PD symptoms. This was demonstrated with the
transgenic mice overproducing αSyn and lacking their
own microbiota. Administration of these compounds
to animals with feed was observed to activate mi-
croglia, aggregation of αSyn, as well as development
motor symptoms typical for PD. The authors suggest
that in this case microglia activation is a key element
of the cascade leading to the development of the dis-
ease [176]. This is in agreement with the earlier data
indicating that the inflammatory processes induced by
injection of LPS stimulate aggregation of αSyn in trans-
genic mice producing human αSyn with A53T replace-
ment [169].
Gastrointestinal mucosa located under the epithe-
lial layer, which is part of the blood-brain barrier, is
an important factor protecting against the PD devel-
opment. Normal gut microflora and its metabolites
are also components of this barrier; hence, dysbiosis
could facilitate penetration of pathogenic bacteria
through the tight junctions into Peyer’s patches. As a
result, intestine becomes inflamed, which could result
in the inflammatory process in PNS and emergence of
PD symptoms [177]. On the other hand, as mentioned
above, inflammation could cause overproduction
ofαSyn.
αSyn aggregation in the presence of amyloids.
The hypothesis of synucleinopathy development
through GIT has been considered above. However, the
question remains how αSyn aggregates are formed in
the intestine neurons. The reason for this, likely, lies
in the possibility to induce αSyn aggregation with the
help of other amyloid aggregates, which could be pres-
ent on the surface of bacteria inhabiting intestinal lu-
men, as has been mentioned above.
The phenomenon of protein co-aggregation in
composition of amyloid aggregates has been demon-
strated for numerous cases, number of which contin-
ues to increase [178]. The pair of proteins Rip1 and
Rip3 could serve as an example of functional co-aggre-
gation of proteins in compositions of amyloids. Their
aggregation is one of the signals for necrolysis initi-
ation [179], moreover, 3D-structure of heterofibrils of
these proteins has been obtained [180]. The key role
in this process belongs to the receptor-interacting pro-
tein kinase (RIP) homotypic interaction amino acid
motifs (RHIM), which were also found in the Het-s
protein (Podospora anserina) capable of forming am-
yloid aggregates [181]. Moreover, numerous examples
of protein co-aggregation associated with different
human amyloids are known, in particular, co-aggrega-
tion of the following proteins has been demonstrated:
Aβ and Tau [182]; Aβ and amylin [183]; Aβ and PrP
[184,185].
There are evidences in the literature on co-aggre-
gation of αSyn with different human proteins. Its ag-
gregation could be induced in vitro by the Aβ fibrils
(1-40 and 1-42) [186], IAPP[187], lysozyme, as well as
GroES[188]. αSyn and Aβ physically interact in the pa-
tients with PD and AD [189]. It has also been demon-
strated recently that αSyn co-aggregate with the
NOS1AP protein [190].
GUT DYSBIOSIS IN SYNUCLEINOPATHY DEVELOPMENT 531
BIOCHEMISTRY (Moscow) Vol. 89 No. 3 2024
The data have been accumulated recently that the
proteins from other organisms could stimulate αSyn ag-
gregation. Peptides of the PSMαs protein, which forms
amyloid-like aggregates in Staphylococcus aureus, are
capable of accelerating αSyn aggregation in vitro [191].
The similar effect was demonstrated for the SARS-
CoV-2 N-protein [192], but no information on its am-
yloid properties is available. The most investigated
example of interactions of amyloids from different
organisms is the pair of proteins CsgA and aSyn. CsgA
is the main component of extracellular fibrils, named
curli, in E. coli and other bacteria [24, 193]. The results
reported in two recent studies with model animals in-
dicate that curli stimulate αSyn aggregation and devel-
opment of synucleinopathies [194, 195]. Investigations
were conducted with the rats prone to synucleinop-
athy development [194], or mice lacking microbiota
and with enhanced production of αSyn [195]. In the
course of experiments animals were perorally infect-
ed with E. coli strains containing curli, which resulted
in the development of synucleinopathy. This was not
observed in the animals from the control group infect-
ed with bacteria without aggregates. In the rats, an
increase of the number of αSyn plaques in the intes-
tine ganglion cells (Auerbach’s plexus and submucosa)
as well as in the hippocampus striatum neurons was
observed. The authors also detected development of
the innate immunity response in the brain. In the pro-
cess, the experimental group of animals did not differ
from the control group in weight, as well as in the lev-
el of cellular inflammatory processes in the mouth tis-
sues, kidneys, eyes, and stomach [194]. It was shown
in experiments with mice that only administration of
bacteria containing curli causes impairment of motor
functions and increase of the amount of aggregated
and phosphorylated αSyn (S129) in various parts of
the brain, as well as development of inflammatory
processes in GIT and NS. In the in vitro experiments
CsgA of E. coli and its orthologs from other organisms
accelerate aggregation of αSyn[195, 196]. Although the
question of the role of amyloid aggregates of CsgA in
this process remains unresolved so far. Bacteria that
produce non-amyloidogenic variant of CsgA, termed
“SlowGo” cause the described symptoms less often
[195]. Injection of the amyloidogenic CsgA peptides
into the intestine wall of model mice results in the
impairment of motor functions, as well as accelerates
αSyn aggregation. These effects were not observed
in the experiments with non-amyloid CsgA peptides
[195]. On the other hand, there are indications that the
slowed down aggregation of CsgA leads to acceleration
of αSyn aggregation, i.e.,it is the monomeric CsgA that
plays a key role [196].
Accelerated aggregation of αSyn fused with yellow
fluorescent protein (YFP) was observed in the Caenor-
habditis elegans nematodes, which were fed with bac-
teria containing curli [194, 197]. In the process, the
αSyn aggregation in nematodes correlated with the
amount of curli, and colocalization of αSyn and CsgA
in the muscles and neurons was observed [198]. And,
finally, the genes csgA and csgB were identified in the
screening aiming at identification of bacterial genes
responsible for neurodegeneration in C. elegans pro-
ducing αSyn(A53T) prone to aggregation. These nem-
atodes exhibited degeneration of motor neurons and
characteristic disruptions of behavior, when they were
fed with E. coli K-12 bacteria normally producing cur-
li. In the course of screening, derivatives of this strain
were also analyzed with deletions of the non-essential
genes. It was found out that the absence of exactly CsgA
and CsgB in the bacterial cells facilitated decrease of
pathogenesis in nematodes. Altogether 38 genes have
been identified in the screening with the similar ef-
fects [198].
Potential role of CsgA in the development of PD
in humans has been suggested by the recent clinical
data. Proteins reacting with the antibodies against the
CsgA peptide were found in the blood of patients with
PD [199]. Moreover, it has been demonstrated recently
that that the enteroendocrine cells, components of the
intestine epithelium and, hence, are in direct contact
with microbiota, produce αSyn[200,201].
CONCLUSIONS
According to the most popular theory, develop-
ment of PD begins in the gastrointestinal tract under
the effect of external factors [54, 202]. Nevertheless,
what exactly facilitates αSyn aggregation in ENS, and
what molecular mechanisms underlie these processes
remain unclear.
Currently numerous associations between the dis-
balance in gut microbiota and development of PD and
other synucleinopathies have been described. In the
presented review we attempted to summarize the most
significant and relevant information on this topic. Sev-
eral hypotheses have been suggested explaining how
bacteria could cause development of synucleinopa-
thies (Fig.2). One of the most popular is the hypothesis
associated with development of inflammation, which,
in turn, causes aggregation of αSyn. This hypothesis is
supported by the existence of positive correlation be-
tween the degree of inflammation caused by viral in-
fection and amount of αSyn in the axons of gut neuron
[65]. Although, even in this case, this association could
be explained by different molecular mechanisms. The
most plausible mechanism involves overproduction of
αSyn during inflammation as well as its nitration [29,
165, 167]. On the other hand, there are a number of
suggestions on the role of bacterial proteins or their
metabolites in the development of synucleinopathies.
TRUBITSINA et al.532
BIOCHEMISTRY (Moscow) Vol. 89 No. 3 2024
Fig. 2. Possible mechanisms of αSyn aggregation in the gut. Question mark indicated the fact that there are no exact data on the
type of cells in which the processes presented in the inset occur.
Amyloid proteins from bacteria are the newest candi-
dates for the role of the triggers of αSyn aggregation
(Fig.2). A whole range of studies discussed above sup-
ports this idea and demonstrates induction of αSyn
aggregation by the CsgA fibrils[194-196, 198]. Similar
effect could be promoted by the bacterial chaperons
[42, 43]. Finally, PD development could be caused by
bacteria metabolites (such as SCFAs) (Fig. 2), however,
particular molecular mechanisms of this process, con-
trary to the previous cases, are not known yet. Exis-
tence of a barrier function in the gut epithelium is one
of the counterarguments against the hypothesis of in-
duction of αSyn aggregation by the factors of bacterial
origin. However, its efficiency decreases significantly
with aging, and permeability of the barrier for large
molecules increases [154,203,204].
Acknowledgments. This paper is dedicated to
300th anniversary of the St. Petersburg State Univer-
sity. The authors are grateful to Olga Mikhailovna
Zemlyanko for critical reading of the paper.
Contributions. N.P.T. writing the section “Associa-
tion between gut microbiome and synucleinopathies”,
processing of the final version of the publication, ed-
iting of the paper; A.B.M. writing the section “αSyn
protein and synucleinopathies” and subsection “Micro-
biota and neurodegenerative diseases”, editing of the
paper; T.M.R. writing the subsection “Relationship be-
tween αSyn and GIT symptoms”, editing of the paper;
A.A.Z. and M.D.B. writing the subsection “Human gut
microbiome”; G.A.Z. editing of the paper; S.A.B. writing
the section “Possible mechanisms of synucleinopathies
development associated with dysbiosis”, preparation
of illustrations, editing of the paper.
Funding. The work was financially supported by
the Russian Science Foundation, grant no.22-74-10042.
Ethics declarations. This work does not con-
tain any studies involving human and animal sub-
jects. Theauthors of this work declare that they have
noconflicts of interest.
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