International Journal of Cardiovascular Sciences.

2020; 33(5):528-536
528

REVIEW ARTICLE

The Gut Brain-Axis in Neurological Diseases

Pedro Melo Barbosa and Egberto Reis Barbosa
Departamento de Neurologia, Universidade de São Paulo, São Paulo, SP – Brazil

Abstract evident when the digestive tract is considered. Commensal

bacteria, which colonize the human gut shortly after birth,
Recent evidence suggests that dysfunction of the gut- acquire nutrients from their hosts. In exchange, they assist
brain axis may be an important factor contributing to many the digestive process and the production of metabolites
diseases of the nervous system. Increased gut permeability that contribute to the host’s survival. The collective of host-
associated with chronic gastrointestinal dysfunction, as associated microbes is denominated microbiota, and its
well as changes in the composition of the gut microbiota genomic constitution, microbiome.1
could contribute to exposure of the enteric and central The enteric nervous system consists of approximately
nervous system to pathogens and its metabolites, 200 million neurons that control the function of the
including endotoxins and pro-inflammatory cytokines. entire digestive tract. It is composed of an intrinsic
As a consequence, dysfunction of the host’s immune network of nervous fibers and ganglia, the myenteric
system could contribute to an abnormal immunological and submucosal plexus. The myenteric plexus controls
response leading to auto-immune conditions, such as mainly the motility of the digestive tract (peristalsis) and
multiple sclerosis. So far, gut dysbiosis has been reported is located deeply between the longitudinal and circular
in association with Parkinson’s disease, Alzheimer’s layers of the entire digestive tract. It is composed mainly
disease, multiple sclerosis, neurodevelopmental and of a network of ganglia linked by unmyelinated fibers
neuropsychiatric conditions, and cerebrovascular disease. connected to the vagus nerve and sympathetic ganglia.
These findings suggest that the possibility of targeting the The submucosal plexus (Meissner plexus) is located more
gut microbiota could become a future therapeutic option superficially and closer to the intestinal lumen from the
to treat these conditions. However, before this knowledge stomach to the colon. It is composed mainly by nervous
can be useful in the clinical setting, more data is needed to fibers and ganglia, and controls the mucosal secretions,
establish clear causal relationships between dysfunction vascular flow and absorption.2
of the gut-brain axis and neurological diseases. The gut-brain axis is an information exchange platform
which allows two-way communication between the gut
Introduction and the host nervous system. Information can be exchanged
via neural network, hormones and the immune system.3
Hundreds of millions of years of co-evolution have resulted Disruption of the delicate balance between host and gut
in a complex symbiotic relationship between multicellular bacteria could be a contributing factor behind many diseases.
life and bacteria. While it is very likely that more aggressive Following publications that have reported changes in the
interactions predominated in the early days, survival in composition of the gut microbiome, in association with many
the long run demanded a more harmonic relationship. digestive and non-digestive conditions, research interest in
For modern humans, the benefits of this relationship are the gut-brain axis has significantly increased making it a
research hot topic. This review will explore the physiology
and pathophysiology of the gut-brain axis and its role in
Keywords neurological diseases.
Gastrointestinal Tract; Brain; Nervous System;
Microbiome Gastrointestinal/complications;
Neurobehavioral Manifestations. Egberto Reis Barbosa
Assistant Doctor at Universidade de São Paulo
Mailing Address: Egberto Reis Barbosa Universidade de São Paulo
Av Dr. Arnaldo, 455. Postal Code: 05508-900, São Paulo, SP – Brazil. egbertob@8415.com.br
E-mail: egbertob@8415.com.br

DOI: https://doi.org/10.36660/ijcs.20200039 Manuscript received on March 08, 2020, revised manuscript on April 03, 2020, accepted on April 03, 2020.
 Barbosa & Barbosa Int J Cardiovasc Sci. 2020; 33(5):528-536
529 The Gut-Brain Axis Review Article

Pathophysiology to affect the production of neurotransmitters, such

as gamma-aminobutyric acid (GABA), acetylcholine
and the serotonin precursor tryptophan.1 Commensal
Normal functioning of the gut-brain axis gut bacteria are also capable of producing important
nutrients, such as choline and SCFA, as well as the
The intestinal epithelial barrier relies on tight
hormones ghrelin and leptin. They are also able to alter
junctions between cells to keep its integrity and to
brain function through changes in the expression of
separate the external (the gut microbiota) from the
CNS receptors.9 Animal research using murine models
internal environment (the gut immune and nervous
have highlighted the importance of the gut bacteria,
systems). The composition of the gut microbiota is
not only for preserving the health of the brain, but also
regulated by both extrinsic factors, such as diet, lifestyle
for contributing to its normal development. Collins
and early microbiota exposure; and intrinsic factors,
et al.,10 have reported a decrease in nerve density, a
such as genetic background, metabolism, and activity
decrease in neuronal density in ganglia, and an increase
of the host’s hormonal and immune systems.4
in the prevalence of nitrergic neurons in the myenteric
One of the most studied extrinsic factors that is
plexus of the jejunum and ileum of germ-free mice,
able to alter the gut microbiota composition is diet.
highlighting the importance of the gut microbiota in the
Dietary fibers are degraded by commensal bacteria in
normal development of the enteric nervous system.10
the gut and lead to the production of short-chain fatty
Worse cognition and increased stress response have
acids (SCFA), which are beneficial to the brain. On the
been reported in germ-free mice, a different behavioral
other hand, epidemiological studies have reported a
phenotype compared to control animals.11 The gut
positive correlation between increased risk of cognitive
microbiota can also affect brain circuits responsible for
decline and consumption of high-saturated-fat food,
motor and behavioral control.12 Increased microbiota
high intake of animal protein and refined sugars.5
diversity has been associated with improved structural
The Mediterranean diet, known for its association with
organization of the hippocampus, hypothalamus and
longevity, is also able to influence the composition of the
caudate nucleus.13
gut microbiome, resulting in higher levels of fecal SCFA
and predominance of Prevotella and Firmicutes species,
a composition that appears to be more favorable to the Dysfunction of the gut-brain axis
host.6 SCFAs are important bacterial metabolites that A complex immune interplay is in place allowing
can reduce inflammatory response and promote CNS the gut microbiota to co-exist peacefully with the host’s
plasticity. A diet high in fructose has been associated cells. The gut immune system needs to be finely tuned
with an exacerbated inflammatory response in the to maintain its vital defensive function in the presence
hippocampus, which could be a consequence of changes of commensal bacteria. Diverse pathological forces
in the gut bacteria.7 could break this delicate and complex relationship
Patients with refractory epilepsy can benefit from a resulting in diseases.
ketogenic diet. Olson et al8 have studied how this type The composition of the gut microbiota appears to be an
of diet can influence the gut microbiota. Higher levels important factor contributing to diseases. An unbalanced
of hippocampal GABA have been reported alongside composition of the gut microbiota, known as dysbiosis,
an increase in Akkermansia and Parabacteroides species. has been implicated not only in diseases of the gut,
This change appears to confer seizure protection, as it does but also in pathologies of distant organs/systems. The
not occur if germ-free mice were fed with a ketogenic diet.8 immune system can be affected by dysbiosis in many
The vagus nerve is an important gut-brain axis ways. Activation of T-cells by changes in gut microbiota
pathway that allows for direct connection between these has been associated with auto-immune uveitis14 and
two organs. By controlling gut motility and secretion, the could have a role in other auto-immune conditions.
vagus nerve is able to change the gut environment and Furthermore, systemic levels of pro-inflammatory
to control the enteric immune system response with a cytokines can be affected by commensal gut bacteria
direct consequence to the gut microbiota. Conversely, gut and could be implicated in different conditions.
bacteria produce metabolites that are able to influence Lastly, allergies have also been associated with changes
both the enteric and the central nervous system and in the composition of the gut microbiota.15
Int J Cardiovasc Sci. 2020; 33(5):528-536 Barbosa & Barbosa
Review Article The Gut-Brain Axis 530

Another possible factor connecting dysbiosis to Neuropsychiatric symptoms and neurodevelopmental

diseases is an increase in gut permeability (‘leaky conditions
gut’), caused by local pathological processes. This Inducing gut dysbiosis by antibiotic use in animal
could allow gut bacteria and/or its metabolites to models, researchers have reported that anxiety and
reach the host’s circulatory system and the brain other cognitive abilities, such as motor control, memory
(provided they are capable of crossing the blood-brain and learning can be influenced by gut bacteria. The
barrier), interfering with the normal functioning of ability of commensal bacteria to influence the stress
distant structures. Furthermore, absence of normal gut response by modulating the activity of the hypothalamic-
microbiota in mice has been associated with increased pituitary axis, and to produce neurotransmitters and
permeability of the blood-brain-barrier, which can be neuromodulating substances is a possible explanation
reduced by exposure to pathogen-free microbiota.16 for the reported association between gut microbiota
It is likely that, in many conditions, both gut dysbiosis and stress and depression. Dysbiosis could
dysbiosis and a leaky gut are required to cause diseases, also explain the higher prevalence of psychiatric
as seen in patients with hepatic encephalopathy. As a comorbidities in individuals with inflammatory bowel
consequence of increased permeability of the gut wall diseases and irritable bowel syndrome.17
in the context of hepatic dysfunction, plasma levels of Research interest in the connection between gut
cytokines and bacterial endotoxins increase, leading bacteria and neurodevelopmental disorders, such as
to cognitive dysfunction. Gut dysbiosis appears to autism, followed the initial reports on the importance
be an important pathophysiological phenomenon of the gut microbiome for the normal development of
as well. Not only a predominance of Alcaligenaceae the central nervous system. A different composition
and Porphyromonadaceae has been reported in these of the gut microbiota has been reported in animal
patients, but it has also been correlated with cognitive models of autism spectrum disorders. Children with
dysfunction.3 autism appear to have a distinct composition of the
gut microbiota, with lower levels of Bifidobacterium,
Neurological conditions Firmicutes, Bacteroidetes, Akkermansia and higher levels
of Lactobacillus, Clostridium, Suterella and Bacteroidetes.4
This section focuses on the latest advances on the A specific bacterial metabolite, propionic acid,
influence of the gut-brain axis in neurological disease. appears to be important to the development of autism
A summary is presented in Table 1. spectrum disorders in animal models. Intraventricular

Table 1 – Dysfunction of the gut-brain axis in neurological diseases

Bacterial
Immune
Condition Dysbiosis metabolites/ Leaky gut Inflammation
dysfunction
endotoxins

Autism spectrum
X X
disorders

Amyotrophic lateral
X X X
sclerosis

Parkinson’s disease X X X X X

Alzheimer’s disease X X X

Multiple system atrophy X X X X

Multiple sclerosis X X X X

Cerebrovascular disease X X

Different mechanisms leading to dysfunction of the gut-brain axis, which have been reported in association with neurological conditions.
 Barbosa & Barbosa Int J Cardiovasc Sci. 2020; 33(5):528-536
531 The Gut-Brain Axis Review Article

injection of this substance has been reported to induce molecular changes in alpha-synuclein initially occur
autism-like behaviour. Furthermore, treatment with in the gut and spread to vulnerable areas of the CNS,
Bacteroidis fragilis, can reduce the levels of propionic via retrograde axonal and transneural transport.20
acid and improve behavioral symptoms.18 This theory is compatible with Braak’s model of PD
progression, according to which the disease enters the
Neurodegenerative diseases CNS via the olfactory or the vagus nerve.22 The finding
by Svensson et al. that patients submitted to truncal
The pathophysiological processes driving many vagotomy earlier in life are less likely to develop PD
neurodegenerative conditions and leading to neuronal supports this theory.23
death remain elusive. Such processes are varied
In PD, there is increased permeability of the
and complex and beyond the scope of this review.
intestinal barrier, which could be the consequence
However, shared pathophysiological features of
of chronic gastrointestinal dysfunction. A leaky gut
neurodegeneration, such as aggregation of misfolded
results in exposure of enteric neurons to bacterial
proteins and inflammation have recently been studied
endotoxins and local inflammation. Local aggregation
from the perspective of the gut-brain axis.
of alpha-synuclein could occur as a consequence
of exposure to yet unknown environmental factors
Parkinson’s disease associated with alpha-synuclein pathology.24
Parkinson’s disease (PD) appears to be the There is evidence to support an immune role for
consequence of a complex interplay between alpha-synuclein, such as expression of this protein
environmental and genetic factors associated with age- in the human gut after viral infections, the ability to
related neuronal loss. These factors, either isolated or attract macrophages and stimulate dendritic cells,
in combination, lead to dysfunction of diverse neuronal and the increased propensity of alpha-synuclein
structures/systems and, consequently, to neuronal knockout mice to develop infections. Considering
death.19 In PD, insoluble forms of alpha-synuclein (a this putative role in immunity, alpha-synuclein could
synaptic protein found in healthy neurons) aggregate also accumulate in the enteric nervous system due to
and accumulate in neurons, resulting in damage to production rates far greater than the clearance rate
critical cell processes such as mitochondrial activity in the presence of chronic gastrointestinal infection
and axonal flux. Alpha-synuclein is one of the main and inflammation. 25 However, the presence of gut
components of Lewy bodies, inclusions routinely microbiota may be required for the aggregation and
found in patients with idiopathic PD. spread of alpha-synuclein. In an alpha-synuclein
Clinical data, showing that digestive symptoms overexpression mice model, germ-free animals
are ubiquitous in PD, and anatomopathological show reduced alpha-synuclein pathology. Reduced
studies confirming deposition of alpha-synuclein in pathology has also been achieved by treatment with
the enteric nervous system suggest that the gut may antibiotics.26
play an important role in the pathophysiology of Further exploring the relationship between the gut
PD. PD can affect all levels of the digestive tract, and microbiome and PD, Scheperjans et al., 27 reported
gastrointestinal symptoms are well known nonmotor a reduction in Prevotellaceae species compared with
symptoms of the disease. Constipation, specifically, is the controls, and a correlation between an excess of
the most frequent nonmotor symptom, affecting 50 to Enterobacteriaceae species and the severity of postural
80% of patients. Not only it can manifest early in the instability and gait dysfunction.27 Other researchers
disease course, but it can also precede motor symptoms have reported a higher prevalence of bacterial species
by many years, which is why it is considered one of associated with bacterial lipopolysaccharides and
the prodromal symptoms of PD.20 inflammation in PD patients and a decrease in species
Lewy pathology (alpha-synuclein aggregates, Lewy associated with a reduced inflammatory response.4
neurites and Lewy bodies) is found in the myenteric, Intestinal inflammation in PD can also be influenced by
submucosal plexus and mucosal fibers of patients bacterial metabolites, such as SCFA. Lower fecal SCFA
with PD in territories innervated by the vagus nerve. levels have been reported in PD patients, who also
The finding that Lewy bodies are also present in the exhibited increased levels of intestinal inflammation.28
dorsal nucleus of the vagus 21 led to the theory that
Int J Cardiovasc Sci. 2020; 33(5):528-536 Barbosa & Barbosa
Review Article The Gut-Brain Axis 532

Considering the heterogeneous findings reported in of H.pylori appears to improve cognitive function. 35
the literature on the composition of the gut microbiota A possible explanation has been given by Wang and
in PD, consistent data were reported for abundance of colleagues who have demonstrated that H.pylori can
Verrucomicrobiaceae and Akkermansia and for decreased contribute to neurodegeneration by inducing tau
Prevotellaceae, whereas inconsistent findings were hyperphosphorylation.36
reported for Lactobacillaceae and Bacteroidetes.29 A peripheral inflammatory state has been described
Specific compositions of the gut microbiota have also in individuals with cognitive impairment in the context
been studied in atypical parkinsonism. Barichella et al.,30 of amyloidosis. Gut microbiota could play an important
compared 193 PD patients with 113 healthy controls, 22 role in this phenomenon, since it has been associated
progressive supranuclear palsy and 22 multiple system with an increase in pro-inflammatory bacterial species,
atrophy (MSA) patients. The only consistent finding such as Escherichia and Shigella, and a decrease in anti-
between PD and healthy controls was abundance of inflammatory species of bacteria, such as E.rectale.37
Lachnospiraceae. A clinical profile of worse cognitive The role of the gut microbiome in AD is strengthened
impairment, gait dysfunction and postural instability by studies showing cognitive function improvement
was associated with decreased Lachnospiraceae and through the use of probiotics, both in animal models
increased Lactobacillaceae and Christensenellaceae. MSA and in patients with the disease.4
patients had similar PD profiles, with the exception
of a reduction in Prevotellaceae and no decrease in Multiple sclerosis
Lachnospiraceae, whereas PSP Lactobacillaceae were
The availability of an animal model of multiple
similar, and Streptococcaceae were reduced.30
sclerosis (MS) and a surge in research interest in this
Similarly to what has been reported in PD, a small
condition, associated with the development of novel
study of six MSA patients showed dysfunction of the
immunomodulatory treatments, have led many authors
intestinal barrier and signs of intestinal inflammation
to study the influence of the gut-brain axis in the
associated to bacterial endotoxins. Furthermore, there
development of MS.
was abundance of Bacteroidetes and Proteobacteria
As stated previously, auto-immune diseases could
(pro-inflammatory bacteria) and a reduction in butyrate-
be triggered by activation of T-cells by gut commensal
producing bacteria (anti-inflammatory).31
bacteria, a phenomenon that has been shown to occur
in an animal model of relapsing-remitting MS. The
Alzheimer’s disease importance of gut bacteria in activating T-cells is
Alzheimer’s disease (AD) is the most common highlighted by the finding that germ-free mice do not
neurodegenerative condition and one of the main public develop encephalomyelitis, unless they receive fecal
health issues worldwide due to ageing of the population transplant.38
and the lack of a curative treatment. Its pathological This abnormal immune response appears to be
signature is the deposition of neurofibrillary tau tangles modulated by bacterial metabolites. In the same
and amyloid-β plaques in specific areas of the central animal model, long-chain fatty acids are associated
nervous system. with exacerbation of the disease, whereas SCFA
The formation of amyloid plaques could be influenced improves symptoms.39 Tryptophan is a precursor of
by gut bacteria. Amyloid metabolites can be produced serotonin and its levels can be regulated by the gut
by the intestinal microbiota, which could contribute microbiota. This substance appears to be beneficial to
to inflammation and increase vascular permeability, a mouse model of MS,4 probably as a consequence of
resulting in amyloidogenesis.32 Furthermore, bacterial its ability to control microglial activation and reduce
endotoxins are also able to increase the formation of inflammation in the CNS .40
amyloid plaques by influencing amyloid-β peptide The role of the gut microbiota in the development
fibrillogenesis.33 of multiple sclerosis is also supported by studies with
An additional piece of the puzzle comes from human subjects. Similar to other conditions, increased
studies showing that individuals with AD infected by gut permeability has been reported in individuals
H.pylori have a more severe AD phenotype compared with MS. While there is still no specific gut microbiota
to non-infected controls. 34 Furthermore, eradication composition associated with MS, similarities with
 Barbosa & Barbosa Int J Cardiovasc Sci. 2020; 33(5):528-536
533 The Gut-Brain Axis Review Article

non-neurological auto-immune pathologies and Treatment with C butyricum decreases neuronal injury
inflammatory bowel disease have been reported, such and improves cognitive function in brain injury induced
as an increase in Archea and reduction in Clostridium by ischemia/reperfusion after bilateral carotid common
and Bacteroidete.1 artery occlusion.47
Dysbiosis has been shown to occur after stroke
Cerebrovascular disease and influence its outcome by negatively affecting the
size of the lesion and contributing to inflammation.
Cerebrovascular disease is an important cause of
Reduced diversity and abundance of Bacteroidetes have
morbidity and mortality worldwide. Commensal gut
been reported after stroke (46). Stroke and transient
bacteria could be connected to the development of stroke
ischemic attack patients have been reported to harbor
by diverse factors. Diet contributes to atherosclerosis
more opportunistic pathogens, such as Enterobacter,
and other risk factors of cerebrovascular disease, such as
Megasphaera, Oscillibacter, and Desulfovibrio, and fewer
arterial hypertension, dyslipidemia and diabetes. It can
commensal or beneficial genera, including Bacteroides,
also have a direct effect on the composition of the gut
Prevotella, and Faecalibacterium. 42 Furthermore, an
microbiota, making any correlations between dysbiosis
abundance of Peptococcaceae and Prevotellaceace has been
and atherosclerosis susceptible to many confounding
correlated with stroke severity.48
factors. However, recent research suggests that the
gut microbiota may have a more direct role to play in
atherosclerosis and cerebrovascular disease. Amyotrophic lateral sclerosis
Trimethylamine n-oxide (TMAO) is a metabolite Amyotrophic lateral sclerosis is a neurodegenerative
produced by gut bacteria from dietary choline and is condition which affects primarily the motor neuron. It
extensively found in body tissues and fluids. It has been is an aggressive condition that commonly leads to death
implicated in both cardiovascular and cerebrovascular a few years after diagnosis. Changes of the gut-brain
diseases. In a large prospective study involving more axis have also been reported in animal models of this
than 4,000 people, plasma levels of TMAO were condition, such as dysfunction of the gut epithelium
correlated with cardiovascular events. The importance of and of the gut immune system, and a reduction in the
gut bacteria in producing TMAO was highlighted by the prevalence of bacterial species that produce butyrate.49
fact that treatment with antibiotics reduced its levels.41 Interestingly, butyrate supplementation can increase
Furthermore, individuals with stroke and transient survival in the same animal model.50
ischemic attack have lower levels of TMAO compared to
individuals with asymptomatic atherosclerosis.42
Conclusions
Animal models show that supplementation of
phosphatidylcholine metabolites (including TMAO The gut-brain axis is an exciting research topic, which
and choline) can increase the expression of macrophage has received a great deal of attention from the scientific
receptors associated with atherosclerosis. This effect community in recent years. However, the role of the gut-
appears to require the presence of gut bacteria. In germ- brain axis in the development of neurological diseases
free mice, choline supplementation is not associated is far from established. Evidence that the gut microbiota
with an increase in atherosclerosis and leads to a and its metabolites interfere with the host’s immune and
reduction in aortic plaque size.43,44 These findings need endocrine systems, affecting neurological function and
to be interpreted with caution since both choline and its vasculature, derives mainly from studies showing
TMAO can be influenced by diet, and gut microbiota has correlations, not causality.4 More prospective studies
so far been associated with both protective and harmful are needed to demonstrate a causal relationship. When
effects in the origin and course of atherosclerosis.11 studying neurodegenerative conditions with disease
Normal microbiota appears to be important for progression spanning several years, one also needs to
recovery following vascular lesions. Depletion of consider that changes in microbiota occur much faster,
microbiota by broad spectrum antibiotics after occlusion complicating even more the interpretation of causality.
of the middle cerebral artery results in decreased Another important issue is that the majority of studies
survival in an animal model. 45 Furthermore, stroke published so far have used animal models, limiting
outcomes can be improved by fecal transplant. 46 extrapolation of their findings to humans.
Int J Cardiovasc Sci. 2020; 33(5):528-536 Barbosa & Barbosa
Review Article The Gut-Brain Axis 534

Furthermore, it is also important to consider the if this knowledge can be useful in the clinical
many confounding factors associated with human setting. Future research needs to establish more
fecal experiments that are likely to contribute to the clear causal relationships between the gut bacteria
heterogeneity of findings, such as diet, demographic, and different neurological conditions and whether
clinical and socioeconomic factors, as well as sample targeting the microbiota is a safe and beneficial
collection, laboratory procedures and genetic sequencing therapeutic option.
techniques. Ideally, control populations should be selected
with a similar risk profile. For example, using controls Author contributions
from households could help minimize dietary variations.29
Conception and design of the research: Barbosa PM,
The potential benefits that could derive from research
Barbosa ER. Acquisition of data: Barbosa PM, Barbosa
on the gut-brain axis in neurological disease are the
ER. Writing of the manuscript: Barbosa PM, Barbosa
identification of biomarkers of neurodegeneration
ER. Critical revision of the manuscript for intellectual
and the development of novel treatments, such as the
content: Barbosa ER.
use of probiotics and fecal transplant. However, there
is still no good quality evidence to support clinical
use. Administration of the probiotics Lactobacillus and Potential Conflict of Interest
Bifidobacterium to PD patients can improve constipation, but No potential conflict of interest relevant to this article
it does not affect other symptoms of the disease.51 More data was reported.
is needed, particularly after reports of worse outcomes
with the use of probiotics in immunocompromised Sources of Funding
patients and in individuals with pancreatitis.11
There were no external funding sources for this study.
Considering the influence of the gut microbiota
in several modifiable risk factors of cerebrovascular
Study Association
disease and its influence in post stroke complications,
in theory many benefits could derive from targeting This study is not associated with any thesis or
the gut microbiota. More data is needed to address dissertation work.
the feasibility of targeting the gut microbiota by using
antibiotics, probiotics or fecal transplant .11 Ethics approval and consent to participate
Despite recent advances in our understanding of This article does not contain any studies with human
the gut-brain axis, more data is needed to address participants or animals performed by any of the authors.

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