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The gut-brain axis: Interactions between enteric microbiota, central and enteric nervous systems


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The gut-brain axis (GBA) consists of bidirectional communication between the central and the enteric nervous system, linking emotional and cognitive centers of the brain with peripheral intestinal functions. Recent advances in research have described the importance of gut microbiota in influencing these interactions. This interaction between microbiota and GBA appears to be bidirectional, namely through signaling from gut-microbiota to brain and from brain to gut-microbiota by means of neural, endocrine, immune, and humoral links. In this review we summarize the available evidence supporting the existence of these interactions, as well as the possible pathophysiological mechanisms involved. Most of the data have been acquired using technical strategies consisting in germ-free animal models, probiotics, antibiotics, and infection studies. In clinical practice, evidence of microbiota-GBA interactions comes from the association of dysbiosis with central nervous disorders (i.e. autism, anxiety-depressive behaviors) and functional gastrointestinal disorders. In particular, irritable bowel syndrome can be considered an example of the disruption of these complex relationships, and a better understanding of these alterations might provide new targeted therapies.
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© 2015 Hellenic Society of Gastroenterology
Annals of Gastroenterology (2015) 28, 203-209
The gut-brain axis: interactions between enteric microbiota,
central and enteric nervous systems
Marilia Carabotti
, Annunziata Scirocco
, Maria Antonietta Maselli
, Carola Severi
University Sapienza, Rome; S. De Bellis, Castellana Grotte, Bari, Italy
Insights into the gut-brain crosstalk have revealed a complex
communication system that not only ensures the proper
maintenance of gastrointestinal homeostasis, but is likely to
have multiple eects on aect, motivation, and higher cognitive
functions. e complexity of these interactions is enclosed in
the denomination of “gut-brain axis” (GBA) [1]. Its role is to
monitor and integrate gut functions as well as to link emotional
and cognitive centers of the brain with peripheral intestinal
functions and mechanisms such as immune activation,
intestinal permeability, enteric reex, and entero-endocrine
signaling. e mechanisms underlying GBA communications
involve neuro-immuno-endocrine mediators.
is bidirectional communication network includes the
central nervous system (CNS), both brain and spinal cord,
the autonomic nervous system (ANS), the enteric nervous
system (ENS) and the hypothalamic pituitary adrenal (HPA)
axis (Fig.1). e autonomic system, with the sympathetic and
parasympathetic limbs, drives both aerent signals, arising from
the lumen and transmitted though enteric, spinal and vagal
pathways to CNS, and eerent signals from CNS to the intestinal
wall. e HPA axis is considered the core stress eerent axis that
coordinates the adaptive responses of the organism to stressors
of any kind [2]. It is a part of the limbic system, a crucial zone
of the brain predominantly involved in memory and emotional
responses. Environmental stress, as well as elevated systemic
pro-inammatory cytokines, activate this system that, through
secretion of the corticotropin-releasing factor (CRF) from
the hypothalamus, stimulates adrenocorticotropic hormone
(ACTH) secretion from pituitary gland that, in turn, leads
to cortisol release from the adrenal glands. Cortisol is a major
stress hormone that aects many human organs, including the
brain. us, both neural and hormonal lines of communication
combine to allow brain to inuence the activities of intestinal
functional eector cells, such as immune cells, epithelial cells,
enteric neurons, smooth muscle cells, interstitial cells of Cajal and
enterochroman cells. ese same cells, on the other hand, are
under the inuence of the gut microbiota [3] whose contributing
role in brain-gut reciprocal communications has recently been
assessed. e concept of a microbiome GBA is now emerging.
e enteric microbiota is distributed in the human
gastrointestinal tract and, although each persons microbiota
prole is distinct, relative abundance and distribution along the
Department of Internal Medicine and Medical Specialties, University
Sapienza, Rome (Marilia Carabotti, Annunziata Scirocco, Carola
Experimental Pharmacology Laboratory, Scientic Institute of
Gastroenterology S. de Bellis, Castellana Grotte, Bari (Maria Antonietta
Maselli), Italy
Conict of Interest: None
Correspondence to: Marilia Carabotti, Viale del Policlinico 155, 00161
Rome, Tel.: +390649 978376, Fax: +390644 63737,
Received 5September 2014; accepted 7December 2014
e gut-brain axis (GBA) consists of bidirectional communication between the central and the
enteric nervous system, linking emotional and cognitive centers of the brain with peripheral intestinal
functions. Recent advances in research have described the importance of gut microbiota in inuencing
these interactions. is interaction between microbiota and GBA appears to be bidirectional, namely
through signaling from gut-microbiota to brain and from brain to gut-microbiota by means of
neural, endocrine, immune, and humoral links. In this review we summarize the available evidence
supporting the existence of these interactions, as well as the possible pathophysiological mechanisms
involved. Most of the data have been acquired using technical strategies consisting in germ-free animal
models, probiotics, antibiotics, and infection studies. In clinical practice, evidence of microbiota-
GBA interactions comes from the association of dysbiosis with central nervous disorders (i.e.autism,
anxiety-depressive behaviors) and functional gastrointestinal disorders. In particular, irritable bowel
syndrome can be considered an example of the disruption of these complex relationships, and a
better understanding of these alterations might provide new targeted therapies.
Keywords Gut-brain axis, enteric microbiota, central nervous system, enteric nervous system,
irritable bowel syndrome
Ann Gastroenterol 2015; 28 (2): 203-209
204 M. Carabotti et al
Annals of Gastroenterology 28
intestine of these bacterial phylotypes is similar among healthy
individuals. e two more prominent phyla are Firmicutes and
Bacteroides accounting for at least ¾ of the microbiome[4].
is microbial community has important metabolic and
physiological functions for the host and contributes to its
homeostasis during life.
Role of microbiota in GBA
Both clinical and experimental evidence suggest that enteric
microbiota has an important impact on GBA, interacting not
only locally with intestinal cells and ENS, but also directly with
CNS through neuroendocrine and metabolic pathways.
In humans, the most compelling evidence of a
gastrointestinal microbe-brain interaction arose more than
20 years ago from the observation of the oen dramatic
improvement in patients with hepatic encephalopathy, aer the
administration of oral antibiotics [5]. In the meantime, emerging
data support the role of microbiota in inuencing anxiety and
depressive-like behaviors [6,7] and, more recently, of dysbiosis
in autism. In fact, autistic patients present specic microbiota
alterations according to the severity of the disease [8,9].
Dysbiosis occurs also in functional gastrointestinal disorders
(FGID) that are highly associated with mood disorders and
are linked to a disruption of GBA [10-12]. Data have been
provided that both brain-gut and gut-brain dysfunctions
occur, the former being dominant particularly in irritable
bowel syndrome (IBS) [13]. e disruption occurring in the
GBA determines changes in intestinal motility and secretion,
causes visceral hypersensitivity and leads to cellular alterations
of the entero-endocrine and immune system. Microbiota may
interplay with multiple of these dierent pathophysiological
IBS targets [14] and its role is supported by varying lines
of evidence: the presence in IBS patients of alterations in
microbiota composition with defects both in its stability and
diversity, the development of post-infectious IBS, the possible
coexistence with small intestinal bacterial overgrowth and the
ecacious treatment of certain probiotics and non-systemic
antibiotics [15-17]. Furthermore, the visceral hypersensitivity
phenotype, characteristic of IBS, can be transferred via the
microbiota of IBS patients to previously germ-free rats [18]. e
concomitant dysregulation of both GBA and gut microbiota in
the pathogenesis of IBS has lead to the proposal of considering
this FGID as a disorder of the microbioma-GBA [19].
From gut microbiota to brain
In the last years there has been a proliferation of
experimental works, conducted mainly on animals, aimed to
explore the contribution of the microbiota in modulating GBA.
Dierent technical strategies have been used, consisting in the
use of germ-free (GF) animals, probiotics, antibiotics and
infection studies [20].
Studies on GF animals have shown that bacterial
colonization of the gut is central to development and
maturation of both ENS and CNS [21,22]. e absence of
microbial colonization is associated to an altered expression
and turnover of neurotransmitters in both nervous
systems [21,23,24] and also to alterations of gut sensory-motor
functions, consisting in delayed gastric emptying and intestinal
transit [25,26] reduced migrating motor complex cyclic
recurrence and distal propagation [27,28] and enlarged cecal
size [29]. Neuromuscular abnormalities resulted associated
to a reduction in gene expression of enzymes involved in the
synthesis and transport of neurotransmitters, as well as in
that of muscular contractile proteins [30]. All these anomalies
are restored, aer animal colonization in a bacterial species-
specic manner.
$0* +,33
Figure1 Microbiome gut-brain axis structure
e central nervous system and in particular hypothalamic pituitary
adrenal (HPA) axis (in dashed line) can be activated in response to
environmental factors, such as emotion or stress. HPA is nalized to
cortisol release and is driven by a complex interaction between amygdala
(AMG), hippocampus (HIPP), and hypothalamus (HYP), constituting
the limbic system. HYP secretion of the corticotropin-releasing factor
(CRF) stimulates adrenocorticotropic hormone (ACTH) secretion from
pituitary gland that, in turn, leads to cortisol release from the adrenal
glands. In parallel, central nervous system communicate along both
aerent and eerent autonomic pathways (SNA) with dierent intestinal
targets such as enteric nervous system (ENS), muscle layers and gut
mucosa, modulating motility, immunity, permeability and secretion of
mucus. e enteric microbiota has a bidirectional communication with
these intestinal targets, modulating gastrointestinal functions and being
itself modulated by brain-gut interactions
Microbiota and gut-brain axis interactions 205
Annals of Gastroenterology 28
Studies conduced on GF animals have also demonstrated
that microbiota inuences stress reactivity and anxiety-like
behavior, and regulates the set point for HPA activity. ese
animals generally show a decreased anxiety [23,24,31-33] and
an increased stress response with augmented levels of ACTH
and cortisol [31,34]. Microbial colonization of the gut leads to
a normalization of the axis in an age-dependent manner, with
reversibility of the exaggerated stress response being observed
aer GF colonization only in very young mice, supporting the
existence of a critical period during which the plasticity of
neural regulation is sensitive to input from microbiota [34].
In parallel, in GF animals, also memory dysfunction
has been reported [35] probably to be ascribed to an altered
expression of brain-derived neurotrophic factor (BDNF),
one of the most important factors involved in memory. is
molecule is a neurotrophic factor, mainly located in the
hippocampus and cerebral cortex, which regulates dierent
aspects of brain activities and cognitive functions as well as
muscle repair, regeneration, and dierentiation [36]. Finally,
the presence of the microbiota results also to modulation of the
serotoninergic system, since an increase in serotonin turnover
and altered levels of related metabolites have been reported in
the limbic system of GF animals [24].
e impact of microbiota on GBA has been further
supported by studies nalized to the manipulation of gut
microbiota through the use of probiotics and/or antibiotics.
ese studies also conrm that microbiota aects anxiety
and HPA system by inuencing brain neurochemistry [37].
Chronic treatment with Lactobacillus rhamnosus JB-1 induced
region-dependent alterations in GABA mRNA in the brain.
In comparison to mice with controlled diet, GABA
increased in cortical cingulate and prelimbic regions while
concomitantly decreased in the hippocampus, amygdala, and
locus coeruleus. In turn GABA
mRNA expression was
reduced in the prefrontal cortex and amygdala, but increased
in the hippocampus. e probiotics, in parallel, reduced stress-
induced release of cortisol, anxiety- and depression-related
behavior [38]. Similarly, transient alteration of microbiota
composition, obtained by administration of oral antimicrobials
(neomycin, bacitracin, and pimaricin) in specic-pathogen-
free mice, increased exploratory behavior and hippocampal
expression of BDNF [39]. Furthermore, change in microbiota
composition with the probiotics association VSL#3 leads to
an increase in BDNF expression, attenuation of age-related
alterations in the hippocampus [40], and reversion of neonatal
maternal separation-induced visceral hypersensitivity in a rat
model of IBS [41]. In this latter model of stress, a change in the
expression of subsets of genes involved in pain transmission
and inammation has also been described, that was reset by the
early life administration of probiotics.
Evidence indicates that microbiota communication with the
brain involves the vagus nerve, which transmits information
from the luminal environment to CNS. In fact, neurochemical
and behavioral eects were not present in vagotomized mice,
identifying the vagus as the major modulatory constitutive
communication pathway between microbiota and the
brain [38]. In a model of chronic colitis associated to anxiety-
like behavior, the anxiolytic eect obtained with a treatment
with Bidobacterium longum, was absent in mice that were
vagotomized before the induction of colitis [42].
Microbiota may interact with GBA through dierent
mechanisms (Table 1), the principal one likely being
modulation of the intestinal barrier, whose perturbation can
inuence all the underlying compartments. Probiotic species-
specic central eects are indeed associated with restoration
of tight-junction integrity and the protection of intestinal
barrier, as recently reported in an animal model of water
avoidance stress [43]. Pre-treatment of animals with probiotic
combined formulation of Lactobacillus helveticus R0052
and Bidobacterium longum R0175 restored tight junction
barrier integrity and attenuated HPA axis and autonomic
nervous system activities, assessed through plasma cortisol
and catecholamine measurements. Probiotics also prevented
changes in hippocampal neurogenesis and expression in
hypothalamic genes involved in synaptic plasticity.
Microbiota can interact with GBA also through the
modulation of aerent sensory nerves as reported for
Lactobacillus reuteri that, enhancing their excitability by
inhibiting calcium-dependent potassium channels opening,
modulates gut motility and pain perception [44]. Furthermore,
microbiota can inuence ENS activity by producing molecules
that can act as local neurotransmitters, such as GABA,
serotonin, melatonin, histamine and acetylcholine [45] and by
generating a biologically active form of catecholamines in the
lumen of the gut [46]. Lactobacilli also utilize nitrate and nitrite
to generate nitric oxide [47] and to produce hydrogen sulde
that modulates gut motility by interacting with the vanilloid
receptor on capsaicin-sensitive nerve bers [48].
e ENS represents also the target of bacterial metabolites.
One of the main product of bacterial metabolism are short-chain
fatty acid (SCFAs), such as butyric acid, propionic acid and acetic
acid, that are able to stimulate sympathetic nervous system [49],
mucosal serotonin release [50] and to inuence memory and
learning process [51,52]. In this context, it is interesting to report
that diet manipulation of microbiota may inuence behavior.
Mice fed with a diet containing 50% lean ground beef, have a
greater diversity of gut bacteria than those receiving standard
rodent chow, and presented an increase physical activity,
reference memory and less anxiety-like behavior [53].
Given the ability of gut microbiota to alter nutrient
availability and the close relationship between nutrient sensing
Table 1 Main principal mechanisms of the bidirectional brain-gut-
microbiota axis
From gut microbiota to brain:
Production, expression and turnover of neurotrasmitters
(i.e. serotonin, GABA) and neurotrophic factor (BDNF)
Protection of intestinal barrier and tight junction integrity
Modulation of enteric sensory aerents
Bacterial metabolites
Mucosal immune regulation
From brain to gut microbiota:
Alteration in mucus and biolm production
Alteration in motility
Alteration of intestinal permeability
Alteration in immune function
206 M. Carabotti et al
Annals of Gastroenterology 28
and peptide secretion by enteroendocrine cells, the interaction
of microbiota and GBA might also occur through the release
of biologically active peptides from enteroendocrine cells that
can aect the GBA [54]. For example, galanin stimulates the
activity of the central branch of the HPA axis (i.e.the release of
CRF and ACTH), thereby enhancing glucocorticoid secretion
from the adrenal cortex. Galanin also is able to stimulate
directly cortisol secretion from adrenocortical cells, and
norepinephrine release from adrenal medulla [55]. Ghrelin too
possesses a marked ACTH/cortisol-releasing eect in humans
and it is probably involved in the modulation of the HPA
response to stress and nutritional/metabolic variations [56].
Last but not least, microbiota aects mucosal immune
activation. e enhanced mucosal inammation induced
in mice aer treatment with oral antimicrobials, increases
substance P expression in ENS, an eect normalized by the
administration of Lactobacillus paracasei which also attenuates
antibiotic-induced visceral hypersensitivity [57]. e eects of
microbiota on immune activation might be in part mediated
by proteases. ese enzymes are upregulated in intestinal-
immune mediated disorders and become the end-stage
eectors of mucosal and enteric nervous damage [58-59].
Increased concentration of proteases have been detected in
fecal samples of IBS patients associated to specic intestinal
bacterial species [60,61]. e current working hypothesis in
IBS is that an abnormal microbiota activates mucosal innate
immune responses, which increase epithelial permeability,
activate nociceptive sensory pathways inducing visceral pain,
and dysregulates the enteric nervous system [62,63].
Similar mechanisms may be involved in the eects
induced by the gastric mucosa-colonizing microorganism,
Helicobacter pylori (H. pylori) on the GBA. e eects induced
by this microorganism may arise through both activation
of neurogenic inammatory processes and microelements
deciency secondary to functional and morphological
changes in the digestive tract [64]. Nevertheless, unequivocal
data concerning the direct and immediate eects of H.pylori
infection on the GBA are still lacking, and in clinical
practice the relationship between functional dyspepsia and
H. pylori infection is not well dened. In fact, the number
needed to treat to cure one case of dyspepsia is 14(95%CI
10-25 [65] suggesting a multifactorial etiology for the increase
in H.pylori-related upper FGID.
From brain to gut microbiota
Dierent types of psychological stressors modulate the
composition and total biomass of the enteric microbiota,
independently from duration. In fact, also the use of short
stressors impact the microbiota, being the exposure to
social stressor for only 2 h signicantly able to change the
community prole and to reduce the relative proportions of
the main microbiota phyla [66]. ese eects may be mediated,
through the parallel neuroendocrine output eerent systems
(i.e. autonomic nervous system and HPA), both directly via
host-enteric microbiota signaling and indirectly via changes in
the intestinal milieu (Table1). ese eerent neural pathways,
associated to the pain-modulator endogenous pathways,
constitute the so-called “emotional motor system” [1].
e direct inuence is mediated by the secretion, under
the regulation of brain, of signaling molecules by neurons,
immune cells and enterocroman cells, which might aect
microbiota. Communication between CNS eectors and
bacteria relies on the presence of neurotransmitter receptors
on bacteria. Several studies have reported that binding sites
for enteric neurotransmitters produced by the host are present
on bacteria and can inuence the function of components
of the microbiota, contributing to increase predisposition
to inammatory and infection stimuli [67]. High anity for
GABA system has been reported in Pseudomonas uorescens
with binding properties similar to those of a brain receptor [68].
Escherichia coli O157:H7 possesses a receptor for host-derived
epinephrine/norepinephrine that can be blocked specically
by adrenergic antagonists [69].
Besides, brain has a prominent role in the modulation of
gut functions, such as motility, secretion of acid, bicarbonates
and mucus, intestinal uid handling and mucosal immune
response, all important for the maintenance of the mucus
layer and biolm where individual groups of bacteria grow in
a multiplicity of dierent microhabitats and metabolic niches
associated with the mucosa [70]. Adysregulation of GBA can
then aect gut microbiota through the perturbation of the
normal mucosal habitat.
Stress induces variation in size and quality of mucus
secretion [71]. Acoustic stress aects gastric and intestinal
postprandial motility in dogs, delaying the recovery of the
migrating motor complex pattern and inducing a transient
slowing of gastric emptying [72]. Mental stress too increases
the frequency of cecocolonic spike-burst activity through
the central release of CRF [73]. Regional and global changes
in gastrointestinal transit can have profound eects on the
delivery of important nutrients, mainly prebiotics and dietary
bers, to the enteric microbiota.
Brain might also aect microbiota composition and
function by alteration of intestinal permeability, allowing
bacterial antigens to penetrate the epithelium and stimulate
an immune response in the mucosa. Acute stress increased
colonic paracellular permeability involving overproduction of
interferon-γ and decrease in mRNA expression of ZO-2 and
occluding [74]. Brain, through the ANS, may also modulate
immune function. e sympathetic branch modulates number,
degranulation and activity of mast cells with consequent
imbalance in tryptase and histamine release in stress-related
muscle dysfunction [75]. Other mast cell products, such as
CRF, in turn, can increase epithelial permeability to bacteria,
which facilitates their access to immune cells in the lamina
propria [1]. Also corticotropin releasing hormone receptors
are involved in colonic barrier dysfunction in response to mild
stress in neonatal maternal separation in adult rats that [76]
leads to depression and enhanced vulnerability to colitis [77].
Bilateral olfactory bulbectomy induced depression-like
behavior associated to elevated central CRF expression and
serotonin levels, associated to alterations in colonic motility
and intestinal microbial prole in mice [78]. Another possible
perturbation in the microbiota habitat induced by stress
Microbiota and gut-brain axis interactions 207
Annals of Gastroenterology 28
occurs through the enhancement in secretion of α-defensin,
an antimicrobial peptide, from Paneth cells [79].
Finally, it is important to remark that gut alterations
associated to stress facilitate the expression of virulent
bacteria. Norepinephrine released during surgery induces the
expression of Pseudomonas aeruginosa, which might result
in gut sepsis [80]. Besides, norepinephrine can also stimulate
proliferation of several strains of enteric pathogens and increase
the virulent properties of Campylobacter jejuni [81] and might
favor overgrowth of non-pathogenic isolates of Escherichia coli,
as well as of pathogenic Escherichia coli 0157:H7:3 [82,83].
Concluding remarks
Strong evidence suggests that gut microbiota has an important
role in bidirectional interactions between the gut and the nervous
system. It interacts with CNS by regulating brain chemistry and
inuencing neuro-endocrine systems associated with stress
response, anxiety and memory function. Many of these eects
appear to be strain-specic, suggesting a potential role of certain
probiotic strains as novel adjuvant strategy for neurologic
disorders. In addition, the eects of CNS on microbiota
composition are likely mediated by a perturbation of the normal
luminal/mucosal habitat that can also be restored by the use of
probiotics and possibly by diet. In clinical practice, an example
of this interaction is constituted by FGID, in particular IBS, now
considered a microbiome-GBA disorder.
e authors kindly thank Dr Laura Carabotti for the
artwork of the gures.
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... Studies have demonstrated that microbiota performs a variety of roles in brain health, with the Gut-Brain Axis (GBA) showing a close relationship between the digestive system and the brain (Carabotti et al., 2015). Various studies have demonstrated the mechanisms underlying the GBA. ...
... The presence and diversity of microbiota in the gut greatly influences the GBA mechanism, ultimately affecting cognitive function and signifying that cognitive function does not merely rely on an internal relationship through neuronal mechanisms. The gut microbiota (GM) influences both brain structure and cognition (Carabotti et al., 2015;Fernandez-Real et al., 2015;Chen et al., 2021;Feng et al., 2022). Modifying gut probiotic composition by probiotic supplementation might contribute to a prevention and therapy methods of Alzheimer's Disease (AD) (Kowalski and Mulak, 2019). ...
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Introduction: Oral consumption of probiotics can alter Gut Microbiota by causing changes in the production of probiotic derivatives. Therefore, by utilizing Gut-Brain-Axis (GBA), probiotics could provide an opportunity for central nervous system (CNS) modulation, including cognitive function. Tempeh is a traditional Indonesian food rich in probiotics and beneficial for cognitive function. However, the type of probiotics that play a role in cognitive improvement and the number of probiotics needed for the benefits of increasing cognitive function was unknown. Method: This experimental study involved a total of 93 subjects, divided into 3 groups: A, B and C/control (n: 33, 32, and 28), who were provided with probiotic supplementation isolated from tempeh for 12 weeks intervention. Inclusion criteria were age > 60 years, and memory impairment with the third repetition value of Word List Memory Immediate Recall (WLMIR) < 7. Subjects with diabetes were excluded. Cognitive function examinations were carried out before and after treatment. The tempeh-derived probiotics were prepared trough several processes. Genomic isolation, detection of GABA-encoding genes, and species identification using the 16S-rRNA gene encoding were performed. Results: The probiotics isolate used in the intervention was identified as Limosilactobacillus fermentum. We assigned this isolate as L. fermentum A2.8. The presence of the gene encoding GABA was found on this isolate. There was an increase in the cognitive domains of memory, learning process, and verbal fluency (p < 0.05) in group A (probiotics at concentration of 108 CFU/mL). Memory function, visuospatial, and verbal fluency improved (p < 0.05) in group B (probiotics at concentration of 107 CFU/mL). Only an increase in the memory domain was observed in the control group. Improvement of the learning process occurred only in group A (p = 0.006). Conclusion: Administration of probiotics derived from L. fermentum A2.8 increased the cognitive domains of memory, language and visuospatial function. However, probiotic supplementation at a concentration of 108 CFU/mL was better in improving the learning process. This study succeeded in detecting Lactic Acid Bacterial isolates L. fermentum A2.8 that enclosed gene encoding glutamate decarboxylase (gad) which is involved in the synthesis of -aminobutyric acid (GABA), a neurotransmitter vital for cognitive function.
... The gut-brain axis encompasses the CNS, the autonomic and enteric nervous system, and peripheral nerves and is vital for maintaining homeostasis. Signals from the brain control the secretory and sensory function of the gut, whilst the brain and gut communicate via physiological channels including the neuroendocrine, autonomic nervous system, neuroimmune pathways and molecules synthesised from gut microbes [51]. Since the gut microbiota is integral to the modulation of this communication at different levels (from the gut lumen to the CNS) and chronologically as we age, many have broadened the term to 'microbiota-gut-brain axis' [52]. ...
A consequence of our progressively ageing global population is the increasing prevalence of worldwide age-related cognitive decline and dementia. In the absence of effective therapeutic interventions, identifying risk factors associated with cognitive decline becomes increasingly vital. Novel perspectives suggest that a dynamic bidirectional communication system between the gut, its microbiome, and the central nervous system, commonly referred to as the microbiota-gut-brain axis, may be a contributing factor for cognitive health and disease. However, the exact mechanisms remain undefined. Microbial-derived metabolites produced in the gut can cross the intestinal epithelial barrier, enter systemic circulation and trigger physiological responses both directly and indirectly affecting the central nervous system and its functions. Dysregulation of this system (i.e., dysbiosis) can modulate cytotoxic metabolite production, promote neuroinflammation and negatively impact cognition. In this review, we explore critical connections between microbial-derived metabolites (secondary bile acids, trimethylamine-N-oxide (TMAO), tryptophan derivatives and others) and their influence upon cognitive function and neurodegenerative disorders, with a particular interest in their less-explored role as risk factors of cognitive decline.
... Nutraceuticals as a Therapeutic Promise in Healthy Aging and Neurocognitive Disorders DOI: gut microbiota, often improving the diversity of gut microbiota, regulating immune function of the host, and improving the integrity of the intestinal barrier, which may have a beneficial role in the prevention and treatment of various neuropsychiatric and neurocognitive disorders[68][69][70][71]. ...
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The world is facing a rapid population ageing. Noncommunicable disorders (NCDs) form the bulk of present-day morbidity. Besides dealing with neurodegeneration and neurocognitive disorders, modern-day therapeutics have also geared toward healthy ageing and preventive approaches. Several chemical substances belonging to classes of natural dietary origin display protective properties against some age-related diseases, including neurodegenerative ones. These compounds, known as nutraceuticals, differ structurally, acting on different pathways. There has been a paradigm shift in the understanding of dementias toward neuroinflammation, oxidative stress, immunomodulation, and gut-brain axis dysregulation. This offers promise for the nutraceuticals as a novel approach in the field of neurocognitive disorders and healthy ageing. However, the collective evidence is still evolving and as of yet not robust enough for nutraceuticals to be a part of clinical guidelines. The other caveats are lack of subjective understanding of use, and individual constituents of a product showing differential effects, which lead to ambiguous outcomes in clinical trials. This chapter critically looks at the role of various nutraceuticals in promoting healthy aging and management of neurodegenerative conditions (especially Alzheimer’s disease). The evidence so far is highlighted with the challenges in their use and future directions of research.
... First, neuroscientists agree that there is a connection between what's in our digestive systems and how our brains work (e.g. Carabotti et al., 2015). For example, there is evidence that lactobacillus -a strain of bacteria found in yogurt -when present in sufficiently large quantities in the gut are capable of affecting mood. ...
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In this paper, we describe causal powers realism as a conjunction of four claims: causal powers are not reducible to counterfactuals; they are empirically-discoverable; they manifest effects in conjunction with partners; and their manifestations empower further manifestations. We describe four challenges to extended mind theory and for each show how an ontology of causal powers realism either avoids or dissolves the problem. We close by suggesting that causal powers realism isn’t a competitor with extended mind theory but rather a new way to understand what it means for minds to be extended.
... Previous studies have suggested that healthy lung is sterile, but NGS sequencing has confirmed that there are complex and diverse bacterial communities in the mucosa of the lower respiratory tract (Wypych et al. 2019). In brain-gut axis, some studies showed that owing to the increased permeability of the intestinal barrier and microbial-driven proinflammatory state, intestinal microorganisms could activate the HPA axis, indicating that microorganisms in the lung may be able to activate the HPA axis through a mechanism similar to the brain-gut axis (Carabotti et al. 2015). However, more reliable and direct evidence is needed to demonstrate this mechanism. ...
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The brain has many connections with various organs. Recent advances have demonstrated the existence of a bidirectional central nervous system (CNS) and intestinal tract, that is, the brain-gut axis. Although studies have suggested that the brain and lung can communicate with each other through many pathways, whether there is a brain–lung axis remains still unknown. Based on previous findings, we put forward a hypothesis: there is a cross-talk between the central nervous system and the lung via neuroanatomical pathway, endocrine pathway, immune pathway, metabolites and microorganism pathway, gas pathway, that is, the brain–lung axis. Beyond the regulation of the physiological state in the body, bi-directional communication between the lung and the brain is associated with a variety of disease states, including lung diseases and CNS diseases. Exploring the brain–lung axis not only helps us to understand the development of the disease from different aspects, but also provides an important target for treatment strategies.
The prevalence of obesity, diabetes, non-alcoholic fatty liver disease, and related metabolic disorders has been steadily increasing in the past few decades. Apart from the establishment of caloric restrictions in combination with improved physical activity, there are no effective pharmacological treatments for most metabolic disorders. Many scientific-studies have described various beneficial effects of probiotics in regulating metabolism but others questioned their effectiveness and safety. Postbiotics are defined as preparation of inanimate microorganisms, and/or their components, which determine their safety of use and confers a health benefit to the host. Additionally, unlike probiotics postbiotics do not require stringent production/storage conditions. Recently, many lines of evidence demonstrated that postbiotics may be beneficial in metabolic disorders management via several potential effects including anti-inflammatory, antibacterial, immunomodulatory, anti-carcinogenic, antioxidant, antihypertensive, anti-proliferative, and hypocholesterolaemia properties that enhance both the immune system and intestinal barrier functions by acting directly on specific tissues of the intestinal epithelium, but also on various organs or tissues. In view of the many reports that demonstrated the high biological activity and safety of postbiotics, we summarized in the present review the current findings reporting the beneficial effects of various probiotics derivatives for the management of metabolic disorders and related alterations.
The imbalance of intestinal microbiota can cause the accumulation of endotoxin in the main circulation system of the human body, which has a great impact on human health. Increased work and life pressure have led to a rise in the number of people falling into depression, which has also reduced their quality of life. The gut–brain axis (GBA) is closely related to the pathological basis of depression, and intestinal microbiota can improve depressive symptoms through GBA. Previous studies have proven that prebiotics can modulate intestinal microbiota and thus participate in human health regulation. We reviewed the regulatory mechanism of intestinal microbiota on depression through GBA, and discussed the effects of prebiotics, including plant polysaccharides and polyphenols on the regulation of intestinal microbiota, providing new clues for the prevention and treatment of depression.
Type 2 diabetes and obesity have reached pandemic proportions throughout the world, so much so that the World Health Organisation coined the term “Globesity” to help encapsulate the magnitude of the problem. G protein-coupled receptors (GPCRs) are highly tractable drug targets due to their wide involvement in all aspects of physiology and pathophysiology, indeed, GPCRs are the targets of approximately 30% of the currently approved drugs. GPCRs are also broadly involved in key physiologies that underlie type 2 diabetes and obesity including feeding reward, appetite and satiety, regulation of blood glucose levels, energy homeostasis and adipose function. Despite this, only two GPCRs are the target of approved pharmaceuticals for treatment of type 2 diabetes and obesity. In this review we discuss the role of these, and select other candidate GPCRs, involved in various facets of type 2 diabetic or obese pathophysiology, how they might be targeted and the potential reasons why pharmaceuticals against these targets have not progressed to clinical use. Finally, we provide a perspective on the current development pipeline of anti-obesity drugs that target GPCRs.
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The acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of many immune and metabolic systems integral to health and well-being. Recent research has shown that the presence of gut microbiota regulates the set point for hypothalamic-pituitary-adrenal (HPA) axis activity.1 Accordingly, we sought to investigate if there were other changes of brain function such as behavioral alterations in germ free (GF) mice, and if so, to compare these to behavior of mice with normal gut microbiota. Our recent paper showed reduced anxiety-like behavior in the elevated-plus maze (EPM) in adult GF mice when compared to conventionally reared specific pathogen-free (SPF) mice.2 Here, we present data collected when we next colonized the adult GF mice with SPF feces thereby introducing normal gut microbiota, and then reassessed anxiety-like behavior. Interestingly, the anxiolytic behavioral phenotype observed in GF mice persisted after colonization with SPF intestinal microbiota. These data show that gut-brain interactions are important to CNS development of stress systems and that a critical window may exist after which reconstitution of microbiota and the immune system does not normalize the behavioral phenotype
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Irritable bowel syndrome (IBS) is an extremely prevalent but poorly understood gastrointestinal disorder. Consequently, there are no clear diagnostic markers to help diagnose the disorder and treatment options are limited to management of the symptoms. The concept of a dysregulated gut-brain axis has been adopted as a suitable model for the disorder. The gut microbiome may play an important role in the onset and exacerbation of symptoms in the disorder and has been extensively studied in this context. Although a causal role cannot yet be inferred from the clinical studies which have attempted to characterise the gut microbiota in IBS, they do confirm alterations in both community stability and diversity. Moreover, it has been reliably demonstrated that manipulation of the microbiota can influence the key symptoms, including abdominal pain and bowel habit, and other prominent features of IBS. A variety of strategies have been taken to study these interactions, including probiotics, antibiotics, faecal transplantations and the use of germ-free animals. There are clear mechanisms through which the microbiota can produce these effects, both humoral and neural. Taken together, these findings firmly establish the microbiota as a critical node in the gut-brain axis and one which is amenable to therapeutic interventions.
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The intestinal microbiota is increasingly recognized as a complex signaling network that impacts on many systems beyond the enteric system modulating, among others, cognitive functions including learning, memory and decision-making processes. This has led to the concept of a microbiota-driven gut-brain axis, reflecting a bidirectional interaction between the central nervous system and the intestine. A deficit in synaptic plasticity is one of the many changes that occurs with age. Specifically, the archetypal model of plasticity, long-term potentiation (LTP), is reduced in hippocampus of middle-aged and aged rats. Because the intestinal microbiota might change with age, we have investigated whether the age-related deficit in LTP might be attenuated by changing the composition of intestinal microbiota with VSL#3, a probiotic mixture comprising 8 Gram-positive bacterial strains. Here, we report that treatment of aged rats with VSL#3 induced a robust change in the composition of intestinal microbiota with an increase in the abundance of Actinobacteria and Bacterioidetes, which was reduced in control-treated aged rats. VSL#3 administration modulated the expression of a large group of genes in brain tissue as assessed by whole gene expression, with evidence of a change in genes that impact on inflammatory and neuronal plasticity processes. The age-related deficit in LTP was attenuated in VSL#3-treated aged rats and this was accompanied by a modest decrease in markers of microglial activation and an increase in expression of BDNF and synapsin. The data support the notion that intestinal microbiota can be manipulated to positively impact on neuronal function.
The effect of a mental stress model corresponding to conditioned fear on cecocolonic motility was evaluated electromyographically in intact and hypophy-sectomized rats equipped with electrodes implanted in the cecum and proximal colon over a long period and a small polyethylene catheter inserted into the right lateral ventricle of the brain. Intact fasted and fed rats showed an increase of 82.3% and 67.2%, respectively, in colonic spike-burst frequency when placed for 30 minutes in a box in which they had previously received electrical shocks in their feet. Intracerebroventricular administration of corticotropin-releasing factor (0.5 μg/kg) mimicked the effects of mental stress and increased cecocolonic spikeburst frequency by 75.8%. The specific corticotropin-releasing factor receptor antagonist α-helical CRF9–41 given intracerebroventricularly (5 μ/kg) prevented both the effects of mental stress and corticotropin-releasing factor (0.5 μg/kg intracerebroventricularly) on colonic spike-burst frequency. In contrast, diazepam (0.5 mg/kg IM) suppressed colonic hypermotility induced by mental stress but not that resulting from intracerebroventricular injection of corticotropin-releasing factor (0.5 (μg/kg). Increased colonic spike-burst frequency induced either by stress or by central administration of corticotropin-releasing factor was not prevented by hypophysectomy. It was concluded that mental stress increases the frequency of cecocolonic spike-burst activity and that these effects are related to the central release of corticotropin-releasing factor because they are blocked by a corticotropin-releasing factor antagonist and reproduced by intracerebroventricular administration of corticotropin-releasing factor. Moreover, mental stress-induced colonic motor alterations are mediated by the autonomic nervous system rather than by the hypothalamopituitary axis because they are not abolished by hypophysectomy.
The last ten years' wide progress in the gut microbiota phylogenetic and functional characterization has been made evidencing dysbiosis in several gastrointestinal diseases including inflammatory bowel diseases and irritable bowel syndrome (IBS). IBS is a functional gut disease with high prevalence and negative impact on patient's quality of life characterized mainly by visceral pain and/or discomfort, representing a good paradigm of chronic gut hypersensitivity. The IBS features are strongly regulated by bidirectional gut-brain interactions and there is increasing evidence for the involvement of gut bacteria and/or their metabolites in these features, including visceral pain. Further, gut microbiota modulation by antibiotics or probiotics has been promising in IBS. Mechanistic data provided mainly by animal studies highlight that commensals or probiotics may exert a direct action through bacterial metabolites on sensitive nerve endings in the gut mucosa, or indirect pathways targeting the intestinal epithelial barrier, the mucosal and/or systemic immune activation, and subsequent neuronal sensitization and/or activation.
The concept that alterated communications between the gut microbiome and the brain may play an important role in human brain disorders has recently received considerable attention. This is the result of provocative preclinical and some clinical evidence supporting early hypotheses about such communication in health and disease. Gastrointestinal symptoms are a common comorbidity in patients with autism spectrum disorders (ASD), even though the underlying mechanisms are largely unknown. In addition, alteration in the composition and metabolic products of the gut microbiome has long been implicated as a possible causative mechanism contributing to ASD pathophysiology, and this hypothesis has been supported by several recently published evidence from rodent models of autism induced by prenatal insults to the mother. Recent evidence in one such model involving maternal infection, that is characterized by alterations in behavior, gut physiology, microbial composition, and related metabolite profile, suggests a possible benefit of probiotic treatment on several of the observed abnormal behaviors.