See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/331152198

The Gut-brain Axis

Chapter · February 2019

CITATIONS READS
0 9,519

3 authors:

Ravi K Anadure Shankar Subramanian

Army Research and Referral Hospital Armed Forces Medical College
42 PUBLICATIONS 65 CITATIONS 153 PUBLICATIONS 3,768 CITATIONS

SEE PROFILE SEE PROFILE

Ajay Shankar Prasad

12 PUBLICATIONS 65 CITATIONS

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Intracranial Hemorrhage View project

Extracranial dissections in a Indian population View project

All content following this page was uploaded by Ravi K Anadure on 16 February 2019.

The user has requested enhancement of the downloaded file.

 Author Queries:
• Kindly verify and confirm the correctness of the highlighted text.
139B
CHAPTER The Gut-brain Axis
RK Anadure, S Shankar, AS Prasad
INTRODUCTION
This axis refers to a two-way communication between central
nervous system (CNS) and enteric nervous system (ENS),
linking emotional and cognitive centers of the brain with
peripheral intestinal functions. The gut microbiota plays a
very important role in the gut-brain axis (GBA). The human
body is a super-complex ecosystem containing trillions
of bacteria and other microorganism, which inhabit skin,
mouth, sexual organs, and intestines. These commensals and
microorganisms are vital for maintaining body homeostasis
and may also be involved in the etiology of several metabolic,
immune and mental disorders. This bidirectional interaction
between microbiota and brain appears to be by means of a
complex neural, endocrine, immune, and humoral network.
In clinical practice, evidence of microbiota and brain
interactions comes from the association of gut dysbiosis with
central nervous disorders (e.g., autism, anxiety-depressive
behaviors) and functional gastrointestinal (GI) disorders like
irritable bowel syndrome (IBS).
FUNCTIONAL NEUROANATOMY (FIG. 1)
Langley first postulated about the ENS as a distinct entity,
and through animal experiments revealed that even when
the gut is completely denervated from CNS, it can function
CNS, central nervous system.
FIG. 1: Neural substrates of gut-brain axis (GBA).
by itself. The ENS has about 100 million neurons and is a
part of CNS that is separated during development; however,
it retains a two-way communication pathway with the CNS.
Gut is controlled by the autonomic nervous system (ANS)
consisting of parasympathetic and sympathetic systems,
and also by the local enteric nervous system consisting
of the myenteric (Auerbach plexus) and Meissner’s
(submucosal plexus). Parasympathetic control of the CNS is
through vagal nerve with efferent cholinergics acting on the
myenteric plexus (motor movements) and Meissner plexus
(submucosal glands secretions). The sympathetic control is
through the splanchnic nerves which decrease motility of
gut and blood supply of splanchnic circulation.
GUT MICROBIOTA
The term “microbiota” refers to an ecological community
of commensals, symbiotic and pathogenic microorganisms
that literally share our body space. Friedrich Escherich first
cultured Escherichia coli from healthy people and Joshua
Lederberg suggested the term microbiota. There exists a
symbiotic relationship between the host organisms and
the microbiota which are co-dependent on each other
for survival. Total microbial cells in the gut are actually
more than the human cells in the body. Total weight of
these gut microbes is 1–2 kg (similar to the weight of the
human brain).1 Cumulative number of genes in the pool of
microorganism in the gut is larger than that in the human
genome. The gut has about 100 trillions of microbes—
bacteria, yeasts, helminthes, viruses, and protozoa. The
phylogenetic composition of the microbiota in various parts
of the gut is as shown in the diagram below (Fig. 2).
The colonization of the gut microbiota commences
at birth and the factors deciding microbiota composition
include, mode of delivery, breastfeeding, infection, anti­
biotics, diet and stress.2
GUT-BRAIN SIGNALING
There are four main signaling pathways in the GBA, the
neural pathway, enteroendocrine signaling, serotonin and
tryptophan pathway and finally immune signaling (Fig. 3).3
SECTION 5
Neurology

FFAs, free fatty acids; SCFAs, short-chain fatty acids.

FIG. 2: Composition of the gut microbiome.

GABA, gamma-aminobutyric acid; SCFA, short-chain fatty acid; PYY, peptide YY; CCK, cholecystokinin; IL, interleukin;
GLP-1, glucagon-like peptide 1; TNF, tumor necrosis factor.
2 FIG. 3: Gut-brain axis signaling pathways.
Neural Pathways gastric emptying and intestinal transit. 12 Lactobacilli

CHAPTER 139
generate nitric oxide and hydrogen sulfide that modulates
Central nervous system control over the ENS is important
gut motility by interacting with vanilloid receptors in the gut
for adaptive gut responses during stressful events that signal
mucosa.1 Microbiota influences stress reactivity and anxiety-
homeostatic threat to the organism. Vagal nerve transmits
like behavior by regulating the set point of hypothalamic-
signals from gut microbiota like Lactobacillus rhamnosus
pituitary axis (HPA). They also modulate the serotonergic
which alters central gamma-aminobutyric acid (GABA)
pathways in the limbic system.13 The micrbiome influences
receptor expression and results in reduced anxiety and

The Gut-brain Axis

depressive behavior.4 In a colitis model, Bifidobacterium
longum caused an anxiolytic effect again through an intact
vagus nerve.5
Enteroendocrine Signaling
The bacterial byproducts on coming in contact with the
gut epithelium stimulate enteroendocrine cells to secrete
neuropeptides. These peptides diffuse throughout the
lamina propria to produce local effects on intrinsic ENS,
and also enter the bloodstream to act on CNS.6 Various
neuropeptides involved in enteroendocrine signaling are
peptide YY (PYY), neuropeptide Y (NPY), glucagon-like
peptide (GLP 1 and 2) and substance P.7
Serotonin and Tryptophan Pathway
Serotonin (5-HT) is an important neurotransmitter within
the brain and ENS. About 95% of 5-HT in the body is
produced by gut mucosal enterochromaffin cells and ENS
neurons.8 Peripherally, 5-HT is involved in the regulation
of GI secretion, motility (smooth muscle contraction and
relaxation), and pain perception. In brain 5-HT signaling
pathways are implicated in regulating mood and cognition.
Spore-forming bacteria in the gut promote 5-HT biosynthesis
from colonic enterochromaffin cells and seem to play a role
in GI disorders (IBD) and mood disorders (depression).9
gut motility by maintenance of the mucous layer and biofilm
through secretion of various acids, bicarbonates and mucus.
This helps in intestinal fluid handling and in mucosal
immune responses.14
ROLE OF GUT-BRAIN AXIS IN DISEASE
Role of microbiota in disease was noticed several years back
when gut antibiotics were given for hepatic encephalopathy.
Role of microbiota is rapidly emerging in gut-brain
communication and alterations in the composition of gut
microbiota have been observed in several diseases (Fig. 4).
Depression
Major alteration in the gut population of Acinetobacter and
Bacteroides has been observed in patients with depression.
Mice receiving microbiota from patients with depression,
developed depressive behavior and disturbances in
hippocampal gene activation.15 Depressed patients have
abnormal immune system and brain anomalies resulting
in decreased levels of 5-HT and brain-derived neurotrophic
factor along with changes in neuronal morphology in the
amygdale. Microbial metabolites like short-chain fatty acids,
butyrate, propionate and acetate are key products of the

Immune Signaling
Gut-associated lymphoid tissues form the largest immune
organ of the human body, and it comprises more than 70%
of the total immune system. It provides a vital defensive
barrier between externally-derived pathogens and the
internal biological environment. Infectious microorganisms
cause behavioral problems through activation of the
immune pathways in the gut that influence the brain.
C. jejuni administration to mice at subclinical doses
results in anxiety like behavior.10 Microbiota metabolites
upregulate T regulatory cells synthesis and secretion of
the anti-inflammatory cytokine, IL-10. Oral consumption
of Bifidobacterium infantis in humans is associated with
enhanced IL-10 expression in peripheral blood.11 Therefore,
the balance of gut microbes may closely regulate host
inflammatory responses.

ROLE OF GUT-BRAIN AXIS IN HEALTH

Bacterial colonization of the gut is central to development
and maturation of both ENS and CNS. Absence of microbial
colonization results in altered gene expression and turnover
of neurotransmitters in CNS and ENS. It also causes IBS, irritable bowel syndrome.

alterations of gut sensory-motor functions and delayed FIG. 4: Disorders associated with impaired gut-brain axis (GBA).
3
 gut microbiota. Increased acetate by altered gut microbiota
SECTION 5
results in activation of the parasympathetic nervous system.
This increases glucose-stimulated insulin and ghrelin
secretion causing hyperphagia, obesity and related sequelae
associated with depression.16
Irritable Bowel Syndrome
Neurology
Alterations in gut microbiota result in HPA axis abnorma­
lities, causing increased corticotropin releasing hormone
(CRH) synthesis, which is associated with IBS. CRH affects
motility and sensitivity in the gut causing diarrhea.17 ANS
dysfunction with impaired parasympathetic function causes
alternating diarrhea/constipation, which is easily influenced
by social stressors. Altered GBA is associated with low-
grade inflammation or immune activation in the gut, which
causes alterations in intestinal motility and sensations.18
Functional MRI studies reveal heightened metabolic activity
in the anterior cingulated, prefrontal cortex, and the insula
in patients with IBS. These areas are again closely associated
with the GBA.19
Autism Spectrum Disorders
This is a neurodevelopmental disorder characterized by
difficulty with social interaction and communication skills
with restricted activities, repetitive behaviors and varied levels
of intellectual disability. GI symptoms, feeding difficulties
are very common and usually proportional to severity
of autism spectrum disorder (ASD). Among the various
etiologies invoked, apart from genetics and environmental
factors, altered gut microbiota and oxidative stress have
also been implicated.20 Increased levels of Ruminococcus
and Bacteroides and decreased levels of firmicutes have
been associated with ASD in different studies. 21 Stool
samples of children with ASD show low levels of short-chain
fatty acids (SCFA), acetic acid, propionic acid and butyric
acid which points to alterations on the gut microbiota.22
Bacteria like Clostridium tetani and Desulfovibrio have been
observed to directly aggravate autism.23 Probiotics and
gluten-free diet modulate the gut microbiota composition
and improve intestinal immune system, resulting in better
symptom control in children with ASD.24 Some of the other
neurological disorders associated with alterations in GBA
include multiple sclerosis (MS), stroke, Parkinson’s disease
and Alzheimer's dementia, where research is still ongoing.
FUTURE THERAPEUTIC DIRECTIONS
There are two main strategies for manipulating gut micro­
biota. One is a targeted approach by clearly defining the
offending microorganism and eliminating it directly or
by inducing an immune response to it by vaccination. The
second approach is by manipulating the whole microbiome
by a combination of antibiotics, probiotics or fecal transplant.
Fecal microbiota transplantation (FMT) is well established
in the treatment of patients with severe Clostridium difficile
(C. difficile) colitis.25 It is now approved in USA by the Food
and Drug Administration when pseudo-membranous colitis
4 is not responsive to antibiotics like metronidazole and
vancomycin. However, this therapy still has some limitations
like the optimal way of delivering the transplant to the gut is
not yet clear, and the standards for identifications of persons
who qualify as healthy donors are also not yet fully established.
Another novel therapeutic approach includes bacteriophage
therapy, targeting bacterial genes to suitably modify the
microbiome.26 However, there are some unexpected side
effects with these therapies, like peripheral neuropathy in
some cases given FMT, and accelerated atherosclerosis
in experimental mice undergoing manipulation of GBA.
Therefore, more long-term safety data is needed in this
promising but challenging field.
CONCLUSION
Current 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 influencing neuroendocrine systems
associated with stress response, anxiety and memory
function. Stress and indiscriminate usage of antibiotics
strongly influence the microbiota, and can cause disease
states. Judicious use of antibiotics and a healthy lifestyle
with a healthy diet shall go a long way in helping the GBA.
Controlled manipulations or alterations in the microbiome
is a promising new area of research, that may give solutions
to some chronic functional disorders like IBS, inflammatory
disorders like MS and degenerative conditions like
Parkinson’s disease and dementia.
REFERENCES
1. Stilling RM, Dinan TG, Cryan JF. Microbial genes, brain and behaviour-epigenetic
regulation of the gut-brain axis. Genes Brain Behav. 2014;13:69-86.
2. Donnet-Hughes A, Perez PF, Doré J, et al. Potential role of the intestinal
microbiota of the mother in neonatal immune education. Proc Nutr Soc.
2010;69:407-15.
3. Mertz HR. Overview of functional gastrointestinal disorders: dysfunction of the
brain-gut axis. Gastroenterology Clin N Am. 2003;32:463-76.
4. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates
emotional behavior and central GABA receptor expression in a mouse via the
vagus nerve. Proc Natl Acad Sci. 2011;108:16050-5.
5. Bercik P, Park AJ, Sinclair D, et al. The anxiolytic effect of Bifidobacterium
longum NCC3001 involves vagal pathways for gut-brain communication.
Neurogastroenterol Motil official J Eur Gastrointest Motil Soc. 2011;23:1132-9.
6. Kunze WA, Mao YK, Wang B, et al. Lactobacillus reuteri enhances excitability of
colonic AH neurons by inhibiting calcium-dependent potassium channel opening.
J Cell Mol Med. 2009;13:2261-70.
7. Cani PD, Everard A, Duparc T. Gut microbiota, enteroendocrine functions and
metabolism. Curr Opin Pharmacol. 2013;13:935-40.
8. Yano JM, Yu K, Donaldson GP, et al. Indigenous bacteria from the gut microbiota
regulates host serotonin biosynthesis. Cell. 2015;161:264-76.
9. Costedio MM, Hyman N, Mawe GM. Serotonin and its role in colonic function and
in gastrointestinal disorders. Dis Colon Rectum. 2007;50:376-88.
10. Bilbo SD, Schwarz JM. The immune system and developmental programming of
brain and behavior. Front Neuroendocrinol. 2012;33:267-86.
11. Dinan TG, Cryan JF. Melancholic microbes: a link between gut microbiota and
depression? Neurogastroenterol Motil. 2013;25:713-9.
12. Barbara G, Stanghellini V, Brandi G, et al. Interactions between commensal
bacteria and gut sensorimotor function in health and disease. Am J Gastroenterol.
2005;100:2560-8.
13. Clarke G, Grenham S, Scully P, et al. The microbiome-gut-brain axis during early
life regulates the hippocampal serotonergic system in a sex-dependent manner.
Mol Psychiatry. 2013;18:666-73.
14. Husebye E, Hellström PM, Sundler F, et al. Influence of microbial species on
small intestinal myoelectric activity and transit in germ-free rats. Am J Physiol
Gastrointest Liver Physiol. 2001;280:G368-80.
15. Kelly JR, Borre Y, Patterson E, et al. Transferring the blues: depression associated
gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res.
2016;82:109-18.
16. Luna RA, Foster JA. Gut brain axis: diet microbiota interactions and implications
for modulation of anxiety and depression. Curr Opin Biotechnol. 2015;32:35-41.
17. Mayer EA, Savidge T, Shulman RJ. Brain-gut microbiome interactions and
functional bowel disorders. Gastroenterology. 2014;146:1500-12.
18. Mayer EA, Naliboff BD, Chang L, et al. Stress and irritable bowel syndrome,
American journal of physiology. Gastrointest Liver Physiol. 2001;280:G519-24.
19. Moloney RD, Johnson AC, O'Mahony SM, et al. Stress and the microbiota-gut-
brain Axis in visceral pain: relevance to irritable bowel syndrome. CNS Neurosci
Ther. 2016;22:102-17.
20. Fakhoury M. Autistic spectrum disorders: a review of clinical features, theories
and diagnosis. Int J Dev Neurosci. 2015;43:70-7.
View publication stats
21. Finegold SM, Dowd SE, Gontcharova V, et al. Pyrosequencing study of fecal
CHAPTER 139
microflora of autistic and control children. Anaerobe. 2011;6:444-53.
22. Wang L, Christophersen CT, Sorich MJ, et al. Elevated fecal short chain fatty
acid and ammonia concentrations in children with autism spectrum disorder. Dig
Dis Sci. 2012;57:2096-102.
23. Parracho HM, Bingham MO, Gibson GR, et al. Differences between the gut
microflora of children with autistic spectrum disorders and that of healthy
children. J Med Microbiol. 2005;54:987-91.
24. Sanders ME. Probiotics: definition, sources, selection, and uses. Clin Infect
The Gut-brain Axis
Dis. 2008;46:S58-61.
25. Brandt LJ, Reddy S. Fecal microbiota transplantation for recurrent clostridium
difficile infection. J Clin Gastroenterol. 2011;45:S159-67.
26. Motlagh AM, Bhattacharjee AS. Biofilm control with natural and genetically-
modified phages. World J Microbiol Biotechnol. 2016;32:67-70.