ArticlePDF AvailableLiterature Review

On communication between gut microbes and the brain

Abstract

Interest in the microbiota-gut-brain axis is increasing apace and what was, not so long ago, a hypothetical relationship is emerging as a potentially critical factor in the regulation of intestinal and mental health. Studies are now addressing the neural circuitry and mechanisms underlying the influence of gut bacteria on the central nervous system and behavior. Gut bacteria influence development of the central nervous systems (CNS) and stress responses. In adult animals, the overall composition of the microbiota or exposure to specific bacterial strains can modulate neural function, peripherally and centrally. Gut bacteria can provide protection from the central effects of infection and inflammation as well as modulate normal behavioral responses. Behavioral effects described to date are largely related to stress and anxiety and an altered hypothalamus-pituitary-adrenal axis response is a common observation in many model systems. The vagus nerve has also emerged as an important means of communicating signals from gut microbes to the CNS. Studies of microbiota-gut-brain communication are providing us with a deeper understanding of the relationship between the gut bacteria and their hosts while also suggesting the potential for microbial-based therapeutic strategies that may aid in the treatment of mood disorders.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
C
URRENT
O
PINION
On communication between gut microbes and
the brain
Paul Forsythe
a,b
, Wolfgang A. Kunze
a,c
, and John Bienenstock
a,d
Purpose of review
Interest in the microbiotagut– brain axis is increasing apace and what was, not so long ago, a
hypothetical relationship is emerging as a potentially critical factor in the regulation of intestinal and mental
health. Studies are now addressing the neural circuitry and mechanisms underlying the influence of gut
bacteria on the central nervous system and behavior.
Recent findings
Gut bacteria influence development of the central nervous systems (CNS) and stress responses. In adult
animals, the overall composition of the microbiota or exposure to specific bacterial strains can modulate
neural function, peripherally and centrally. Gut bacteria can provide protection from the central effects of
infection and inflammation as well as modulate normal behavioral responses. Behavioral effects described
to date are largely related to stress and anxiety and an altered hypothalamus–pituitary adrenal axis
response is a common observation in many model systems. The vagus nerve has also emerged as an
important means of communicating signals from gut microbes to the CNS.
Summary
Studies of microbiota–gut brain communication are providing us with a deeper understanding of the
relationship between the gut bacteria and their hosts while also suggesting the potential for microbial-based
therapeutic strategies that may aid in the treatment of mood disorders.
Keywords
behavior, brain, commensal bacteria, microbiota, probiotic, vagus
INTRODUCTION
There is increasing interest in bidirectional signaling
between the intestine and brain and the potential
impact of this communication on intestinal and
mental health. Most recently has come recognition
that the gut microbiota influences these signaling
pathways leading to the concept of a microbiota–
gutbrain axis.
This review will highlight recent evidence that
changes in the gut microbiota or intestinal exposure
to specific commensal bacteria can modulate the
peripheral and central nervous systems (CNS) with
subsequent alterations in brain functions. There will
also be a discussion of the emerging mechanisms
through which signals from gut bacteria are com-
municated to the brain.
EVIDENCE FOR A MICROBIOTAGUT
BRAIN AXIS
Recent investigations have taken a number of
approaches in an attempt to understand the influ-
ence of gut bacteria on the brain and behavior.
These include the study of germ-free animals, dis-
ruption of the existing microbiota and exposure to
specific microorganisms. All have provided insight
into the microbiomegutbrain axis and it is clear
that the field is moving beyond purely descriptive
studies to now trying to understand the neural
circuitry and mechanisms underlying the influence
of the microbiota on the central nervous system.
The microbiota influences central nervous
systems development
Two recent studies have indicated that the com-
plete absence of gut bacteria results in decreased
a
The McMaster University Brain-Body Institute St. Joseph’s Healthcare,
b
Respiratory Division, Department of Medicine,
c
Department of Psychia-
try and
d
Department of Pathology and Molecular Medicine, McMaster
University, Hamilton, Ontario, Canada
Correspondence to Paul Forsythe, The Brain-Body Institute, 50 Charlton
Avenue East, T3302, Hamilton, Ontario L8N 4A6, Canada. Tel: +1 905
522 1155/35890; fax: +1 905 540 6593; e-mail: forsytp@mcmaster.ca
Curr Opin Gastroenterol 2012, 28:557– 562
DOI:10.1097/MOG.0b013e3283572ffa
0267-1379 ß2012 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-gastroenterology.com
REVIEW
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
anxiety-like behavior, in a number of testing para-
digms, compared with conventional animals
[1
&
,2
&
]. In one of these studies, Heijtz et al. [1
&
]
demonstrated that colonization of germ-free mice
early in life, but not as adults, could normalize
several germ-free behavioral patterns. This suggests
that the gut microbiota contributes to developmen-
tal programming, as previously proposed by Sudo
et al. [3], and there is a ‘window of vulnerability’
within which the gut microbiota can impact on
physiological function with potentially life-long
consequences [4].
In assessing the changes in neural circuitry of
germ-free animals that potentially underly the
reduction in anxiety, Heijtz et al. [1
&
] demonstrated
significantly lower brain derived neurotrophic fac-
tor (BDNF) mRNA expression in brain areas that
contribute to the neural circuitry underlying
anxiety and fear including the hippocampus, amyg-
dala and cingulate cortex [5,6]. A reduction in BDNF
expression levels in the cortex and hippocampus
relative to conventional mice was also described
previously by Sudo et al. [3].
In contrast, Neufeld et al. [2
&
] identified that
reduced anxiety in germ-free mice was associated
with an upregulation, rather than decrease, in the
expression of BDNF mRNA in the dentate gyrus of
the hippocampus. The reasons underlying the con-
flicting findings are unclear; however, given existing
evidence that the neurochemical and behavioral
consequences of stress are sex dependent [7] it
may be significant that both studies describing
decreased BDNF expression were conducted in male
mice [3], whereas Neufeld et al. [2
&
] exclusively used
female animals.
Disruption of the microbiota
In a study of adult Balb/c mice Bercik et al. [8
&&
]
demonstrated that oral administration of the
nonabsorbable antibiotics neomycin and bacitracin
along with the antifungal agent primaricin led to a
change in the composition, but not overall
quantity, of the gut microbiota. Specifically, there
was an increase in Actinobacteria and Lactobacilli
species and decrease in g-proteobacteria and bacter-
oidetes. The antibiotics also induced changes in
behavior. Treated animals demonstrated increased
exploratory drive and decreased apprehension in
the step-down and light/dark preference tests. The
effects of antibiotic treatment on the composition of
the intestinal microbiota and on behavior were
transient with treated mice appearing similar to
controls after a 2-week washout period. As has been
described in comparisons between germ-free and
conventional animals, behavioral changes in anti-
biotic treated animals were associated with altered
BDNF levels in the brain, being decreased in the
amygdala, although increased in the hippocampus
[8
&&
]. Evidence of a causal relationship between the
microbiota changes and behavioral effects was
provided by the fact that intraperitoneal treatment
did not influence behavior and antibiotic treat-
ment had no effect on the behavior of germ-free
animals [8
&&
]. This study did not attempt to
address whether the behavioral changes could be
attributed to specific alterations in the microbiota.
However, it is now becoming clear that exposure to
a single specific organism can influence brain
and behavior.
Exposure to specific organisms
Noninvasive bacterial pathogens of the rodent
intestine have emerged as useful tools with which
to investigate the gut-brain axis. In one study of
Citrobacter rodentium-infected mice, Gareau et al.
[9
&
] observed no behavioral abnormalities either
at the height of infection or following bacterial
clearance. However, when infected mice were
exposed to acute stress, known to increase intestinal
permeability [10,11] and influence gut bacterial
function [12], memory dysfunction became appa-
rent both during infection and following clearance
[9
&
]. The impairment of nonspatial and working
memory,assessedbythenovelobjectandT-maze
tests, respectively, could be prevented by daily treat-
ment of infected mice with a probiotic preparation
containing stains of Lactobacillus rhamnosus and
Lactobacillus helveticus [9
&
]. This probiotic pretreat-
ment also attenuated stress induced serum corticos-
teronelevels,aswellaspreventingC. rodentium
induced reductions in hippocampal BDNF and
c-fos expression [9
&
].
Bercik et al. [13
&
] demonstrated that chronic,
mild, chemically induced colitis, were associated
KEY POINTS
The gut microbiota is involved in developmental
programming of the brain and stress response systems.
There is now good evidence from studies of adult
animals that gut bacteria influence brain chemistry
and behavior.
Change in the HPA axis response to stress is a common
effect of modifying the gut microbiota.
The vagus nerve plays a critical role in mediating
effects of certain gut microorganisms on the brain and
subsequently, behavior.
Immunology
558 www.co-gastroenterology.com Volume 28 Number 6 November 2012
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
with increased latency in the step-down test,
indicative of anxiety-like behavior. Treatment with
the probiotic bacteria Bifidobacterium longum nor-
malized the behavior but did not alter intestinal
inflammation as assessed by histological score and
MPO levels. Previous studies from the same inves-
tigators [14] examined behavior and brain chemistry
in mice following mild gut inflammation induced
by infection with Trichuris muris. Here they also
observed increased anxiety-like behavior as assessed
by step-down and light/dark preference tests
together with an associated decrease in mRNA
message for hippocampal BDNF [14]. As with find-
ings in the DSS colitis model, B. longum normalized
behavior and BDNF mRNA without modulating
specific measures of inflammation, in this case intes-
tinal levels of inflammatory cytokines TNF or IFNg
[14]. However, limited inflammatory parameters
were assessed in these studies and it is clear that
cytokine production and other immune changes
can modulate the peripheral and central nervous
system and are associated with altered mood and
behavior [15]. Thus, given the well described immu-
nomodulatory and anti-inflammatory effects of the
commensal and probiotic bacteria [16], it is difficult
to rule out attenuation of components of the inflam-
matory response being responsible for normaliza-
tion of behavior in models wherein anxiety is
associated with inflammation. Nevertheless, such
studies provide good evidence for gut-brain com-
munication being altered following exposure to
commensal or probiotic strains and are highly
relevant to inflammatory bowel disease and other
inflammatory conditions that are strongly associ-
ated with mood disorders or depression. However, it
is now evident that certain nonpathogenic bacteria
can alter brain chemistry and behavior in normal
animals.
Long-term (28 day) oral administration of a
L. rhamnosus strain (JB1) has been demonstrated
to alter the normal behavior of adult balb/c mice
[17
&&
]. Treatment with the bacteria reduced anxiety-
like behavior as assessed in an elevated and maze
and decreased the time spent immobile in a forced
swim test. In addition, stress-induced plasma corti-
costerone levels were lower in treated mice. Overall,
changes induced with L. rhamnosus JB-1 were indica-
tive of reduced anxiety and decreased depression-
like behavior [17
&&
].
Assessment of neural correlates to behavioral
changes determined that mice receiving L. rhamno-
sus had alterations in central GABA receptor subunit
mRNA expression. L. rhamnosus administration
decreased expression of GABA type B (GABAB) sub-
unit 1 isoform b (GABAB1b) mRNA in the amygdala
and hippocampus, while increasing expression in
cortical areas. Expression of GABAAa2 receptor
mRNA was reduced in the amygdala and cortical
areas, whereas levels were increased in the hippo-
campus [17
&&
]. It is difficult to attribute a causal
relationship between behavioral effects observed
and neural correlates. However, reduced expression
of GABAB1b mRNA, in the amygdala, hippocampus
and locus ceruleus is consistent with the anti-
depressant-like effect of GABAB receptor antagonists
[18] and with studies of GABAB1b-deficient animals,
indicating an important role of this subunit in the
development of cognitive processes, including those
relevant to fear [19,20]. It is also interesting to note
that in a recent study of transcriptomes from the
mucosa of the proximal small intestines of healthy
human participants following treatment with
different Lactobacillus species, there was a strong
correspondence between in-vivo transcriptional
networks altered after consumption of one of the
strains, Lactobacillus casei, and the response of
human cells to the anxiolytic GABA A receptor
modulator, tracazolate [21].
ELEMENTS OF MICROBIOTAGUTBRAIN
SIGNALING
Analysis of recent studies reveals that certain com-
mon elements are emerging that suggest they may
play key roles in communicating microbial signals
from the gut to the CNS and in mediating sub-
sequent behavioral changes.
Neural correlates
As described above a number of studies have dem-
onstrated that gut bacteria influence BDNF levels,
particularly in the hippocampus [1
&
,2
&
,3,14]. BDNF
is involved in the regulation of multiple aspects
of cognitive and emotional behaviors being a key
promoter of neuronal survival and growth as well
as differentiation of new neurons and synapses
[2224]. Serum levels of BDNF are significantly
decreased in the plasma of depressed patients
[25,26] and in postmortem hippocampal tissue from
depressed suicide patients [27,28].
Little is currently understood regarding how
specific changes in brain chemistry contribute to
observed effects on behavior. However, the central
neural circuits influenced by the changes in the gut
microbiota or exposure to specific commensal
strains are wide ranging and have been reported
to include the GABAergic [17
&&
], glutaminergic
[2
&
,3], serotonergic [1
&
], dopaminergic [1
&
], histami-
nergic [29] and adrenergic [30] systems.
Intriguingly, a recent study suggests that the
influence of certain probiotic strains on the brain
On communication between gut microbes and the brain Forsythe et al.
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may not be limited to traditional neurotransmitters
and neurotrophins. Wall et al. [31] observed that
treatment with a specific strain of B. breve (NCIMB
702258) led to significantly higher concentrations
of arachidonic acid (ARA) and docosahexaenoic acid
(DHA) in the brain. This observation of increased
ARA and DHA in the brain of mice administered
B. breve was consistent with previous findings com-
bining B. breve with a-linolenic acid supplement-
ation [32]. ARA and DHA play important roles in
neurogenesis, neurotransmission and protection
against oxidative stress [33,34] and their concen-
trations in the brain influence cognitive processes
such as learning and memory [33].
The hypothalamuspituitaryadrenal axis
In one of very few studies of the effect of probiotic
treatment on psychological parameters in humans,
healthy volunteers were treated for 30 days with
L. helveticus R0052 and B. longum R0175 in combi-
nation or placebo in a double-blind, randomized
parallel group study [35
&&
]. This treatment alleviated
psychological distress in volunteers, as determined
by the Hopkins Symptom Checklist (HSCL-90) scale,
the Hospital Anxiety and Depression Scale and by
the Coping Checklist (CCL). This treatment also
led to a reduction in urinary free cortisol levels
suggesting a reduction in the hypothalamus
pituitaryadrenal axis (HPA) response to daily stres-
sors. An altered HPA axis response to stress is a
common effect of gut bacteria in many model sys-
tems [2
&
,3,17
&&
,30,36] and may likely contributes
to behavioral changes. Psychological stress is a com-
mon risk factor for the development of major
depression and an identifiable stressor precedes
most initial depressive episodes [37]. Furthermore,
hyperactivity of the HPA axis has been found in
some psychiatric disorders, especially in older
patients with severe depression [38]. It is, therefore,
possible that changes in gut microbiota or exposure
to specific commensal bacteria may alter the HPA
axis or other stress response systems and in turn
modulate stress-related mood or behavioral dis-
orders.
In an attempt to understand how the gut micro-
biota influences the HPA response Ait-Belgnaoui
et al. [39] demonstrated that a 2-week treatment
with L. farciminis attenuated the HPA axis response
to acute restraint stress in rats. L. farciminis
also prevented stress-induced colonic hyper-
permeability and uptake of lipopolysaccharides
(LPS) in the portal blood. An antibiotic treatment
aimed to reduce luminal LPS and subsequent
circulating LPS following stress, resulted in
reduced endotoxemia, central neuroinflammation
and neuroendocrine response to stress suggesting
that LPS may play a role in regulating the stress
response. These results led to the suggestion that
the mechanism of action involved in the L. farcimi-
nis-induced prevention of stress-induced central
effects depends of the ability of the bacteria to
enhance the intestinal epithelial barrier, thus,
reducing circulating LPS [39].
The neural pathway to the brain
Evidence that gut bacteria and their products influ-
ence the enteric nervous system (ENS) is now strong,
and such effects may, in addition to regulating gut
motility, contribute to afferent signaling to the
brain [4042]. The mechanism of effects of probi-
otics on neurons and the signaling pathways
involved are largely unknown. However, it has been
identified that chemosensitive intrinsic primary
afferent neurons (IPANs) are cellular target of neuro-
active bacteria. Myenteric IPANs within colon seg-
ments taken from rats that were fed L. rhamnosus
JB-1 were more excitable than those from controls. It
is suggested that the underlying molecular mech-
anism involved an intermediate conductance
calcium dependent potassium (IK
Ca
) (Gardos type)
[43] channel because application of the IK
Ca
chan-
nel blocker TRAM-34 mimicked the effects of
L. rhamnosus, namely, reducing the IPAN slow after
hyperpolarization [40,41]. On the basis of such
observations it has been suggested that the ENS acts
as a critical relay between gut bacteria and extrinsic
afferent neurons [13
&
,17
&&
].
Given the key role of the vagus in communi-
cating visceral and immune signals to brain and
particularly to neural circuitry associated with
mood and anxiety, many investigations of com-
munication between gut bacteria and the CNS
have focused on the vagus. There is now good
evidence, from animal studies, to support a critical
role of the vagus nerve in mediating effects of gut
microorganisims on the brain and subsequently
behavior.
The effect of C. rodentium infection on the cen-
tral nervous system of mice was accompanied by
increased neuronal activation in the hippocampus
and vagal ganglia, suggesting gut to brain signaling
was mediated through the vagus nerve [9
&
,44]. This
supports previous key studies indicating that the
anxiogenic effect of orally administered subclinical
doses of Campylobacter jejuni, in mice was associated
with a significant increase in c-Fos expression in
neurons bilaterally in the vagal ganglia and acti-
vated visceral sensory nuclei in the brainstem that
are responsible for autonomic neuroendocrine and
behavioral responses [45].
Immunology
560 www.co-gastroenterology.com Volume 28 Number 6 November 2012
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Strikingly, subdiaphragmatic vagotomy blocked
the anxiolytic and antidepressant effects of chronic
L. rhamnosus ingestion in normal adult Balb/c mice
while also preventing the associated alterations in
GABA receptor mRNA expression in the amygdala
[17
&&
]. Similarly, the ability of B. longum to attenuate
DSS colitis induced anxiety was abolished by
vagotomy [13
&
].
Overall, studies indicate that the vagus can
differentiate between nonpathogenic and poten-
tially pathogenic bacteria even in the absence of
overt inflammation and correspondingly, depend-
ing on the nature of the stimulus, vagal signals can
induce both anxiogenic and anxiolytic effects. How-
ever, although it appears that the vagus is critical to
mediating gut-brain communication by specific
bacteria in some model systems, it is by no means
the only potential signaling method. Indeed, behav-
ioral changes induced through disruption of the
microbiota by antibiotic treatment have been dem-
onstrated to be independent of vagal signaling [8
&&
].
This clearly suggests that the bacteria in the gut
can communicate to the brain through multiple
pathways.
CONCLUSION
There is now strong evidence supporting a relation-
ship between the gut microbiota and behavior from
studies using animal models [46,47]. However,
major questions remain regarding the relationship
between gut bacteria and the brain in human health
and indeed, human studies in this area have been
limited [35
&&
,48,49]. It is an intriguing idea that
composition of the gut microbiota may be associ-
ated with psychiatric conditions or something anal-
ogous to the hygiene [50] or microbiota [51]
hypothesis for immune diseases may also be applied
to mood disorders.
Acknowledgements
None.
Conflicts of interest
The authors have no conflicts of interest.
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562 www.co-gastroenterology.com Volume 28 Number 6 November 2012
... Bacteria produce their metabolites and can trigger signals that affect the synthesis and conduction of neurotransmitters. This information can be transmitted locally in the gut or routed to the brain through the vagus nerve [43]. Serotonin, gamma-aminobutyric acid (GABA), glutamate, and dopamine are neurotransmitters that do not cross the blood-brain barrier but are synthesized thanks to local precursors in the central nervous system [44]. ...
... However, the vagus nerve is not the only communication between the gut microbiota and the central nervous system. Behavioral changes following the use of broad-spectrum antibiotics were also observed in vasectomized mice [2,17,43,45,56]. ...
... In turn, supplementation with probiotic Bifidobacterium breve strain (NCIMB 702258) led to an increase in the concentration of arachidonic acid (ARA) and docosahexaenoic acid (DHA) in the brain. They play an important role in neurogenesis and nerve conduction, protect against oxidative stress, and impact memory and learning ability [43]. ...
Article
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Along with the increase in life expectancy in the populations of developed and developing countries resulting from better access and improved health care, the number of patients with dementia, including Alzheimer’s disease (AD), is growing. The disease was first diagnosed and described at the beginning of the 20th century. However, to this day, there is no effective causal therapy, and symptomatic treatment often improves patients’ quality of life only for a short time. The current pharmacological therapies are based mainly on the oldest hypotheses of the disease—cholinergic (drugs affecting the cholinergic system are available), the hypothesis of amyloid-β aggregation (an anti-amyloid drug was conditionally approved by the FDA in 2020), and one drug is an N-methyl-D-aspartate receptor (NMDAR) antagonist (memantine). Hypotheses about AD pathogenesis focus on the nervous system and the brain. As research progresses, it has become known that AD can be caused by diseases that have been experienced over the course of a lifetime, which could also affect other organs. In this review, we focus on the potential association of AD with the digestive system, primarily the gut microbiota. The role of diet quality in preventing and alleviating Alzheimer’s disease is also discussed. The problem of neuroinflammation, which may be the result of microbiota disorders, is also described. An important aspect of the work is the chapter on the treatment strategies for changing the microbiota, potentially protecting against the disease and alleviating its course in the initial stages.
... Changes in the intestinal microbiota or exposure to certain specific bacteria can modulate a response at the CNS level and the peripheral nervous system (PNS), resulting in alterations in the brain's functioning. This relationship between systems is given by the microbiota-gut-brain (MGB)-axis (Bienenstock et al., 2015;Forsythe et al., 2012). Gut bacteria can influence brain chemistry and development the so-called ENS, including neural signaling through the sensory vagus nerve (Forsythe et al., 2012) in vivo. ...
... This relationship between systems is given by the microbiota-gut-brain (MGB)-axis (Bienenstock et al., 2015;Forsythe et al., 2012). Gut bacteria can influence brain chemistry and development the so-called ENS, including neural signaling through the sensory vagus nerve (Forsythe et al., 2012) in vivo. The products of the microbiota (i.e., short-chain fatty acids (SCFA)), also have metabolic benefits, such as reducing body weight, reducing adiposity, improving glucose control and insulin sensitivity via the neural circuits of the MGB-axis (De Vadder et al., 2014). ...
Chapter
In mammals, there is an excellent autonomous regulation between the nervous system and the intestinal microbiota, which arises at the level of the immune system, neuroendocrine system and the vagus nerve. The gut-brain axis allows the intestinal microbiota to affect brain function through different pathways such as an immune regulatory, a neuroendocrine and a vagus nerve pathway. The information generated by these systems is bidirectional, affecting, regulating, and controlling the central nervous system and enteric nervous system, as well as gut microbiota. On the other hand, in mammals, there is a complex system of circadian rhythms, which regulates the integration of information generated abroad through the retinohypothalamic pathway and the consequent rhythm of endogenous circadian clocks, which govern physiology, cognition and behavior in humans, other mammals and microorganisms. This chapter aims to summarize literature reports on the role of intestinal microbiota in circadian rhythms and the influence of internal and external factors in the bidirectional communication between them. Also, mechanisms underlying stress and circadian cycles are reviewed to understand the components and pathways that participate in gut microbiota's modulatory activity over brain function.
... Animal studies have observed that probiotics improved depression by increasing monoamine neurotransmitters levels or by reducing proinflammatory cytokine levels (8,18,19). More importantly, studies have increasingly reported that the intestinal microbiota may influence the inflammatory responses and in so doing may modulate mood and depression-like behaviors (7,20). Lactobacillus rhamnosus HN001 (HN001) and Bifidobacterium animalis subsp. ...
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Increasing evidence indicated that probiotics can be effective in improving behaviors similar to depression and anxiety disorders. However, the underlying mechanisms remain unclear, as is the effects of single vs. combined probiotics on depression and anxiety. This study aimed to determine whether combined probiotics could attenuate depressive-like and anxiety-like behavior induced by chronic unpredictable mild stress (CUMS) and its potential mechanisms. Rats underwent CUMS treatment and then administered Lactobacillus rhamnosus HN001 (HN001) or Bifidobacterium animalis subsp. lactis HN019 (HN019), alone or in combination. Levels of neurotransmitters, inflammatory factors, and the gut microbiota were measured. HN001 and (or) HN019 treatment improved depressive-like and anxiety-like behavior in rats, including increased moving distance and exploratory behavior (p < 0.05). In addition, altered gut microbiota structure induced by CUMS was amended by HN001 and/or HN019 (p < 0.05). HN001 and/or HN019 intervention also remarkably normalized levels of 5-HT, DA, NE, HVA, DOPAC, HIAA, TNF-α, IL-6, IL-18 and IL-1β in CUMS rats (p < 0.05). Furthermore, the effects of combined probiotics on decreasing inflammation and improved gut microbiota (Chao1 index and ACE index, p < 0.05) were superior to the single probiotics. Moreover, spearman analysis showed a certain correlation between the different microbiota, such as Firmicutes, Bacteroidetes, Verrucomicrobias, Proteobacterias and Actinobacterias, and inflammation and neurotransmitters. These findings suggested that CUMS induced depressive and anxiety-like behaviors can be alleviated by the combination of probiotics, which was possibly associated with the alterations in the gut microbiota composition and increased neurotransmitters and decreased inflammatory factors.
... The vagus nerve is identified as a major way of signaling, mediated from the gut to the brain (Forsythe et al., 2012). Via this route, the gut microbiome can directly influence the brain, especially in PD where patients have higher pro-inflammatory gene profiles and increased inflammatory markers in the gut (Dumitrescu et al., 2021;Li et al., 2021). ...
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Immune-related alterations in Parkinson's disease (PD) can be monitored by assessing peripheral biological fluids that show that specific inflammatory pathways contribute to a chronic pro-inflammatory status. This pro-inflammatory activity is hypothesized to be already present in the prodromal stages of PD. These pathways maintain and reinforce chronic neurodegeneration by stimulating cell activation and proliferation what triggers the pro-inflammatory status as well. The gut microbiome possibly contributes to inflammatory pathways and shows specific differences in fecal samples from PD compared to healthy controls. In PD, Bacteroides abundance correlates with inflammatory markers in blood and motor impairment. Increased pro-inflammatory and decreased anti-inflammatory bacterial colonization can lead to changes in the metabolic pathways of amino acids, inducing increased membrane permeability, described as a leaky gut, enabling advanced contact between immune cells and gut microbiome and potentially a spreading of neuroinflammation through the body via the blood. Increased cytokine blood levels in PD are correlated with disease severity, motor symptoms, and clinical phenotypes. α-synuclein is a central player in PD-associated inflammation, inducing specific T-cell activity and triggering microglial activation in the central nervous system (CNS). Misfolded α-synuclein propagation possibly results in the spreading of aggregated α-synuclein from neuron to neuron leading to a sustained neuroinflammation. This is supported by age-dependent defects of protein uptake in microglia and monocytes, so-called “inflammaging”, including α-synuclein oligomers, as the key pathological protein in PD. Genetic risk markers and inherited forms of PD are also associated with inflammation, which is highly relevant for potential therapeutical targets. The documented associations of inflammatory markers and clinical phenotypes indicate a pro-inflammatory concept of specific PD pathophysiology here. An in-depth understanding of inflammatory mechanisms in PD from bottom (gut) to top (CNS) and vice versa is needed to design novel immunomodulatory approaches to delay or even stop PD. Future studies focusing on structured protocols in large patient cohorts with appropriate control groups and comparative analysis among studies will aid the discovery of novel candidate biomarkers.
... Additionally, gut microbiota-derived mediators in the central nervous system may modulate induction and maintenance of central sensitization via regulating neuroinflammation, which involves the activation of blood-brain barrier cells, microglia, and infiltrating immune cells [91,93,94]. Animal models have shown that gut microbes can stimulate the vagus nerve, which controls brain and behavior, and that changes in gut microbial composition are linked to significant changes in mood, pain, and cognition behaviors [95]. Preclinical and clinical findings suggest that communication between the gut microbiome, inflammation and microglia is involved in the development of chronic pain, implying that manipulating the gut microbiome in chronic pain sufferers could be an effective way to improve pain outcomes [96]. ...
Article
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Evidence for the relationship between chronic pain and nutrition is mounting, and chronic pain following cancer is gaining recognition as a significant area for improving health care in the cancer survivorship population. This review explains why nutrition should be considered to be an important component in chronic pain management in cancer survivors by exploring relevant evidence from the literature and how to translate this knowledge into clinical practice. This review was built on relevant evidence from both human and pre-clinical studies identified in PubMed, Web of Science and Embase databases. Given the relationship between chronic pain, inflammation, and metabolism found in the literature, it is advised to look for a strategic dietary intervention in cancer survivors. Dietary interventions may result in weight loss, a healthy body weight, good diet quality, systemic inflammation, and immune system regulations, and a healthy gut microbiota environment, all of which may alter the pain-related pathways and mechanisms. In addition to being a cancer recurrence or prevention strategy, nutrition may become a chronic pain management modality for cancer survivors. Although additional research is needed before implementing nutrition as an evidence-based management modality for chronic pain in cancer survivors, it is already critical to counsel and inform this patient population about the importance of a healthy diet based on the data available so far.
... In addition, soil also plays key role in developing and regulating human immune system through continuous exposure to soil-borne microorganisms and their products. This can be related to the idea of the microbiome-gut-brain axis, which highlights the importance of gut microbiome in modulating immune signalling pathways and even human behaviour (Forsythe et al., 2012;Stilling et al., 2016). Medical research, is exploring the influence of natural environment, including soil, on microbially driven immune-regulatory responses that positively influence mental and physical wellbeing in humans. ...
Article
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Plant nutrition is essential for animal welfare, animal health and quality of animal products. Soil physical and biochemical properties are the indicators of soil-nutrient status which are directly correlated with crop-production potential. With the increasing population, which is expected to further touch 1.6 billion by 2050, the load on the available cultivable soil is going to increase further with little scope for the horizontal increase in the crop area. The over-exploitation of the soil system has resulted in micronutrient deficiencies for zinc, iron, manganese, copper and bo-ron, ranging from 5-50% in different states of the country. Recycling organics, integrated nutrient management (INM), site-specific nutrient management, foliar nutrition, mulch cum manuring, integrated farming systems help in soil health restoration, reduce nutrient stress to maximize the availability of nutrients to crop plants and healthy fodder which in turn contribute to human and animal health. Thus, healthy soil is key for overall healthy food and healthy human capital of the country and seen as soil-plant-animal and human continuum. Efficient genotypes, microbial culture, modifying rhizosphere characters of soil are equally important for soil-nutrient mobilization for human and animal nutrition. Positive impacts include enhancement of human health by providing nutrient supplies through food production and enhancement of the immune system. Soil, being an ecosystem has numerous interconnected components where each component is influencing the other. A balance of all these functioning components forms the healthy soil, where animal and human health also benefit.
... Melatonin treatment significantly changed the composition of the gut microbiota in mice fed a HFD (18). Gut microbiota, directly affects the gastrointestinal (GI) tract, liver, skin, and central nervous system, and participates in the digestion and absorption of nutrients (21,22). Due to the interrelationship between melatonin and the gut microbiota, melatonin has been hypothesized to be involved in communication between the gut tissue and the intestinal microbiota (15). ...
Article
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Background: Intermittent fasting (IF) can reduce energy intake and body weight (BW). Melatonin has many known functions, which include reducing appetite and preventing excessive weight gain. Objective: This study aimed to investigate the effects of IF on body fat and the gut microbiota and metabolome as well as a potential interaction with melatonin. Methods: Male C57BL/6J mice (23.0 ± 0.9 g, 6 wk old) were randomly assigned into four groups (12 mice/group): control (C), intermittent fasting (F), melatonin (M), and intermittent fasting plus melatonin (MF). The C and M groups mice were provided with ad libitum access to food and water, while the F and MF groups underwent alternative-day feed deprivation (15 cycles total). Melatonin was administered in the drinking water of the M and MF groups. Blood, epididymal fat, liver tissue, and intestinal tissue and contents were collected for lab measurements, histology, and microbiota and metabolome analysis. Main effects and interactions were tested by 2-factor ANOVA. Results: IF significantly reduced BW gain and serum glucose, total cholesterol (TC) and triglyceride (TG) levels. Adipocyte size significantly decreased with IF, then the number of adipocytes per square millimeter significantly increased ( P < 0.05). Compared to the C group, the M and MF groups had significantly higher serum melatonin levels (17 and 21%, respectively), although melatonin monotherapy had no effect on serum parameters and adipocytes. There was no interaction between IF and melatonin on BW gain and serum parameters except for on adipocyte area and number per square millimeter, Bacteroidetes and Akkermansia bacterial abundance, and the levels of the intestinal metabolites alanine, valine and isoleucine. IF changed the intestinal microbiota structure, with the F and MF groups clearly separating from the C and M groups. Metabolomic analysis showed that there was obvious separation between all four groups. Conclusions: IF, but neither melatonin nor the interaction between IF and melatonin, could alter intestinal microbiota and metabolism and prevent obesity by reducing BW gain, serum glucose, TC, and TG, and adipocyte size in mice.
... A large number of neuro-metabolites are secreted directly by gut microbiota, or by secretory epithelial cells due to the stimulation of microbiota. These neuro-metabolites include neurotransmitters that act directly on the central nervous system (CNS), signaling cascades or other signaling pathways and exerting direct or indirect influences on the regular function of the CNS [111,112]. For example, Lactobacillus and Bifidobacterium strains can produce large amounts of GABA when a suitable substrate is present [113]. ...
Article
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In recent years, human gut microbiota have become one of the most promising areas of microorganism research; meanwhile, the inter-relation between the gut microbiota and various human diseases is a primary focus. As is demonstrated by the accumulating evidence, the gastrointestinal tract and central nervous system interact through the gut–brain axis, which includes neuronal, immune-mediated and metabolite-mediated pathways. Additionally, recent progress from both preclinical and clinical studies indicated that gut microbiota play a pivotal role in gut–brain interactions, whereas the imbalance of the gut microbiota composition may be associated with the pathogenesis of neurological diseases (particularly neurodegenerative diseases), the underlying mechanism of which is insufficiently studied. This review aims to highlight the relationship between gut microbiota and neurodegenerative diseases, and to contribute to our understanding of the function of gut microbiota in neurodegeneration, as well as their relevant mechanisms. Furthermore, we also discuss the current application and future prospects of microbiota-associated therapy, including probiotics and fecal microbiota transplantation (FMT), potentially shedding new light on the research of neurodegeneration.
... Numerous studies have shown that bacteria normally present in the gut (eg, Streptococcus, Escherichia, Lactococcus, and Lactobacillus) are able to directly synthesize neurotransmitters (eg, serotonin [77][78][79][80][81] ) and produce metabolites that stimulate neurotransmitter production by host cells. 82 Studies have also shown that gut microorganisms can activate the vagal nerve 83,84 to influence autonomic nerve system function and behavior. 57 Furthermore, a growing body of literature demonstrates the important role of gut bacteria in the development of chemotherapy-induced toxicities, including diarrhea, inflammation, and mucositis. ...
Article
Uncontrolled chemotherapy-induced nausea and vomiting can reduce patients' quality of life and may result in premature discontinuation of chemotherapy. Although nausea and vomiting are commonly grouped together, research has shown that antiemetics are clinically effective against chemotherapy-induced vomiting (CIV) but less so against chemotherapy-induced nausea (CIN). Nausea remains a problem for up to 68% of patients who are prescribed guideline-consistent antiemetics. Despite the high prevalence of CIN, relatively little is known regarding its etiology independent of CIV. This review summarizes a metagenomics approach to the study and treatment of CIN with the goal of encouraging future research. Metagenomics focuses on genetic risk factors and encompasses both human (ie, host) and gut microbial genetic variation. Little work to date has focused on metagenomics as a putative biological mechanism of CIN. Metagenomics has the potential to be a powerful tool in advancing scientific understanding of CIN by identifying new biological pathways and intervention targets. The investigation of metagenomics in the context of well-established demographic, clinical, and patient-reported risk factors may help to identify patients at risk and facilitate the prevention and management of CIN.
... There is strengthening evidence that: (i) the ability of GI-tract microbiome resident bacteria to influence neuro-immune functions well beyond the confines of the GI-tract; (ii) that changes are communicated to the brain and CNS through a GI-tract-CNS network, sometimes called the 'gut-brain-axis', in part via small signaling molecules such as SCFAs or other chemical messenger signaling systems; (iii) that microbial components of the GI-tract microbiome such as BF-LPS and/or the microbes themselves can transverse biophysical barriers without too much difficulty and contribute to AD-type change; and (iv) that specific GI-tract microbiome-derived neurotoxins have a strong pathological role in eliciting an up-regulation of ROS and pro-inflammatory NF-kB-miRNA-directed gene expression that is both AD-relevant and propagates the AD process [7,12,15,16,27]. Established pathways of gut-brain axis communication currently include the autonomic nervous system (ANS), the enteric nervous system (ENS), the neuroendocrine system, the immune system, the systemic circulation and vesicular trafficking [9,13,15,43,[124][125][126][127]. Surprisingly, neuronal signaling pathways along the bidirectional gut-brain axis remain an understudied research area despite their important roles: (i) in coordinating metabolic-, nutritive-and neurobiological-functions, and (ii) in their functional disruption in chronic diseases such as metabolic syndrome, diabetes, obesity, anxiety, autoimmune-disease and stress-induced neuropsychiatric disease and neurodegenerative brain diseases such as AD [7,12,15,37,43,119,117,[128][129][130][131][132]. ...
Article
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The human gastrointestinal (GI)-tract microbiome is a rich, complex and dynamic source of microorganisms that possess a staggering diversity and complexity. Importantly there is a significant variability in microbial complexity even amongst healthy individuals-this has made it difficult to link specific microbial abundance patterns with age-related neurological disease. GI-tract commensal microorganisms are generally beneficial to human metabolism and immunity, however enterotoxigenic forms of microbes possess significant potential to secrete what are amongst the most neurotoxic and pro-inflammatory biopolymers known. These include toxic glycolipids such as lipopolysaccharide (LPS), enterotoxins, microbial-derived amyloids and small non-coding RNA. One major microbial species of the GI-tract microbiome, about ~100-fold more abundant than Escherichia coli in deep GI-tract regions is Bacteroides fragilis, an anaerobic, rod-shaped Gram-negative bacterium. B. fragilis can secrete: (i) a particularly potent, pro-inflammatory and unique LPS subtype (BF-LPS); and (ii) a zinc-metalloproteinase known as B. fragilis-toxin (BFT) or fragilysin. Ongoing studies indicate that BF-LPS and/or BFT disrupt paracellular-and transcellular-barriers by cleavage of intercellular-proteins resulting in 'leaky' barriers. These barriers: (i) become defective and more penetrable with aging and disease; and (ii) permit entry of microbiome-derived neurotoxins into the systemic-circulation from which they next transit the blood-brain barrier and gain access to the CNS. Here LPS accumulates and significantly alters homeostatic patterns of gene expression. The affinity of LPS for neuronal nuclei is significantly enhanced in the presence of amyloid beta 42 (Aβ42) peptides. Recent research on the appearance of the brain thanatomicrobiome at the time of death and the increasing likelihood of a complex brain microbiome are reviewed and discussed. This paper will also highlight some recent advances in this extraordinary research area that links the pro-inflammatory exudates of the GI-tract microbiome with innate-immune disturbances and inflammatory-signaling within the CNS with reference to Alzheimer's disease (AD) wherever possible.
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The probiotic Bifidobacterium longum NCC3001 normalizes anxiety-like behavior and hippocampal brain derived neurotrophic factor (BDNF) in mice with infectious colitis. Using a model of chemical colitis we test whether the anxiolytic effect of B. longum involves vagal integrity, and changes in neural cell function. Methods  Mice received dextran sodium sulfate (DSS, 3%) in drinking water during three 1-week cycles. Bifidobacterium longum or placebo were gavaged daily during the last cycle. Some mice underwent subdiaphragmatic vagotomy. Behavior was assessed by step-down test, inflammation by myeloperoxidase (MPO) activity and histology. BDNF mRNA was measured in neuroblastoma SH-SY5Y cells after incubation with sera from B. longum- or placebo-treated mice. The effect of B. longum on myenteric neuron excitability was measured using intracellular microelectrodes. Chronic colitis was associated with anxiety-like behavior, which was absent in previously vagotomized mice. B. longum normalized behavior but had no effect on MPO activity or histological scores. Its anxiolytic effect was absent in mice with established anxiety that were vagotomized before the third DSS cycle. B. longum metabolites did not affect BDNF mRNA expression in SH-SY5Y cells but decreased excitability of enteric neurons. In this colitis model, anxiety-like behavior is vagally mediated. The anxiolytic effect of B. longum requires vagal integrity but does not involve gut immuno-modulation or production of BDNF by neuronal cells. As B. longum decreases excitability of enteric neurons, it may signal to the central nervous system by activating vagal pathways at the level of the enteric nervous system.
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There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA(B1b) mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA(Aα2) mRNA expression in the prefrontal cortex and amygdala, but increased GABA(Aα2) in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.
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Microbial colonization of mammals is an evolution-driven process that modulate host physiology, many of which are associated with immunity and nutrient intake. Here, we report that colonization by gut microbiota impacts mammalian brain development and subsequent adult behavior. Using measures of motor activity and anxiety-like behavior, we demonstrate that germ free (GF) mice display increased motor activity and reduced anxiety, compared with specific pathogen free (SPF) mice with a normal gut microbiota. This behavioral phenotype is associated with altered expression of genes known to be involved in second messenger pathways and synaptic long-term potentiation in brain regions implicated in motor control and anxiety-like behavior. GF mice exposed to gut microbiota early in life display similar characteristics as SPF mice, including reduced expression of PSD-95 and synaptophysin in the striatum. Hence, our results suggest that the microbial colonization process initiates signaling mechanisms that affect neuronal circuits involved in motor control and anxiety behavior.
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In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers. In the preclinical study, rats were daily administered PF for 2 weeks and subsequently tested in the conditioned defensive burying test, a screening model for anti-anxiety agents. In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P < 0·05) and alleviated psychological distress in volunteers, as measured particularly by the HSCL-90 scale (global severity index, P < 0·05; somatisation, P < 0·05; depression, P < 0·05; and anger-hostility, P < 0·05), the HADS (HADS global score, P < 0·05; and HADS-anxiety, P < 0·06), and by the CCL (problem solving, P < 0·05) and the UFC level (P < 0·05). L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.
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The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established. To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation. Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated. No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota. The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.
Article
Background & AimsAlterations in the microbial composition of the gastrointestinal tract (dysbiosis) are believed to contribute to inflammatory and functional bowel disorders and psychiatric comorbidities. We examined whether the intestinal microbiota affects behavior and brain biochemistry in mice.Methods Specific pathogen–free (SPF) BALB/c mice, with or without subdiaphragmatic vagotomy or chemical sympathectomy, or germ-free BALB/c mice received a mixture of nonabsorbable antimicrobials (neomycin, bacitracin, and pimaricin) in their drinking water for 7 days. Germ-free BALB/c and NIH Swiss mice were colonized with microbiota from SPF NIH Swiss or BALB/c mice. Behavior was evaluated using step-down and light preference tests. Gastrointestinal microbiota were assessed using denaturing gradient gel electrophoresis and sequencing. Gut samples were analyzed by histologic, myeloperoxidase, and cytokine analyses; levels of serotonin, noradrenaline, dopamine, and brain-derived neurotropic factor (BDNF) were assessed by enzyme-linked immunosorbent assay.ResultsAdministration of oral antimicrobials to SPF mice transiently altered the composition of the microbiota and increased exploratory behavior and hippocampal expression of BDNF. These changes were independent of inflammatory activity, changes in levels of gastrointestinal neurotransmitters, and vagal or sympathetic integrity. Intraperitoneal administration of antimicrobials to SPF mice or oral administration to germ-free mice did not affect behavior. Colonization of germ-free BALB/c mice with microbiota from NIH Swiss mice increased exploratory behavior and hippocampal levels of BDNF, whereas colonization of germ-free NIH Swiss mice with BALB/c microbiota reduced exploratory behavior.Conclusions The intestinal microbiota influences brain chemistry and behavior independently of the autonomic nervous system, gastrointestinal-specific neurotransmitters, or inflammation. Intestinal dysbiosis might contribute to psychiatric disorders in patients with bowel disorders.
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