can gut microbiota be the newer approach for treatment in psychiatric disorders??

1. The Gut Microbiota–Brain
Axis In
Behaviour And Brain
Disorders And Newer
Approach To Treatment??
Dr. Subodh Sharma
Resident
Department of Psychiatry, NMCTH, Birgunj, Nepal

4. Introduction
In a striking display of trans- kingdom symbiosis, gut bacteria cooperate with
their animal hosts to regulate the development and function of the immune,
metabolic and nervous systems through dynamic bidirectional communication
along the ‘gut–brain axis’.
These processes may affect human health, as certain animal behaviours appear
to correlate with the composition of gut bacteria, and disruptions in microbial
communities have been implicated in several neurological disorders.
Most insights about host–microbiota interactions come from animal models,
which represent crucial tools for studying the various pathways linking the gut
and the brain. However, there are complexities and manifest limitations inherent
in translating complex human disease to reductionist animal models.

5. Introduction
Historically, mental illness has been viewed as driven solely by defects in brain
processes; however, this brain- centric perspective neglects the fact that the
development and function of the nervous system is affected by the metabolic and
immune state of the body.
Contemporary research is starting to appreciate how microorganisms influence the
brain through their ability to produce and modify many metabolic, immunological
and neurochemical factors in the gut that ultimately impact the nervous system.

7. Mammalian behaviour arises from
the activity of a complex network
of highly specialized cells (for
example, microglia, astrocytes,
oligodendrocytes and glial
progenitors) that communicate
through synapses.
Some aspects of brain
development depend on signals
from the gut microbiota.
• As an example, germ- free (GF) mice
exhibit alterations in neurogenesis and
colonization of GF mice with preterm
human faecal samples affects early neuron
and oligodendrocyte development.
Furthermore, appropriate myelin
patterns in the brain are disrupted
in GF mice and perturbations to
the microbiota with antibiotics
during the postnatal period alter
myelination.

8. Discovery of the enteric nervous
system (eNs), a branch of the
autonomic nervous system, marked a
major scientific advance in better
understanding the bidirectional
communication between the CNs and
the gastrointestinal tract.
Known as the ‘second brain
of the body’, the eNs is
crucial for stable gut health
and is maintained through a
collaborative effort between
enteric neurons and
connections to the CNS.
Communication between the CNs and
the eNs travels through different
signalling pathways, including both
direct neuronal and endocrine
pathways.
Importantly, this
communication can be
modulated by the gut
microbiota.

9. The ‘gut–microbiota–brain axis’ refers
to the network of connections involving
multiple biological systems that allows
bidirectional communication between
gut bacteria and the brain, and is
crucial in maintaining homeostasis of
the gastrointestinal, central nervous and
microbial systems of animals.
The communication pathways in these
biological networks include both direct
and indirect signalling via chemical
transmitters, neuronal pathways and the
immune system.

10. Bacteria found in the gut microbiota equal the number of human
cells in the body and the genetic repertoire found in the collective
gut microbiome is estimated to include a staggering 232 million
genes, which greatly expand the metabolic potential of humans
(the microbiota has equivalent metabolic capacity to the human
liver).
The gut microbiota acts as a
filter and biological rheostat
for sensing, modifying and
tuning vast amounts of
chemical signals from the
environment that then circulate
throughout the body.
As such, gut bacterial
communities lie at the
intersection of the host and the
environment, and may directly
influence human health.

11. Communication
between
Gut and Brain
Chemical Signalling
Neuronal Pathway
Immune System
Signalling

12. • Short Chain Fatty acids >>>Neuroplasticity and Epigentic and Genetic
expression
• Example: SCFA (Na-Butyrate altered the level of BDNF)
Direct Chemical
Signalling
• Microbial regulation of the neuroendocrine system
• Appettite and feeding behaviour modulating by production of endocrine
signals
• GF mice eats less than conventional mice.
• ?GLP responsible
Indirect Chemical
Signalling
• Modulation of concentration of neurotransmitters
• Direct synthesis (Bacteroids, Bifidobacterium, parabacteroides and E.
Coli can produce GABA)
• Serotonin production is affected by microbial metabolites (Indole,
SCFAs, α-tocopherol, tyramine, p-aminobenzoate)
• Spore forming bacteria (human gut) affects tryptophan metabolism.
Classic signalling

13. Chemical
Signalling

14. Neuronal pathways for Gut-Brain
Interaction
• Brain stem to Enteric Nervous System (ENS)
• The transmission of signals from the peripheral ends of the vagus nerve to the
CNS occurs though activation of mechanoreceptors or chemoreceptors
triggered by chemical stimuli produced by EECs, which may themselves be
influenced by the gut microbiota.
• For example, a study in cultured intestinal organoids demonstrated that EECs
can act as chemosensors for SCFAs, resulting in calcium signalling that could
be relayed to specialized vagus nerve fibres that innervate the gut epithelium.
• These factors, in turn, may alter the gut microbiota by affecting the
environment of the gut, which implicates the vagus nerve as an important
mediator of bidirectional communication both to and from the brain.
Vagus
Nerve

15. Neuronal pathways for Gut-Brain
Interaction
Microbiota–brain communication via the vagus nerve is also important in
modulating host behaviour.
For example, administration of
Lactobacillus rhamnosus JB-1alters
the expression of GABA receptors in
brain regions associated with fear and
emotions, such as the amygdala and
hippocampus, and modulates anxiety-
like behaviours in mice.
Most effects of L. rhamnosus JB-1
on behaviour and changes in GABA
receptor expression are abrogated in
vagotomized mice where the vagus
nerve has been surgically severed,
suggesting that the effects of the
bacteria depend on neuronal
communication to the brain.

16. Moreover, the vagus nerve is crucial to the beneficial effects of Lactobacillus reuteri in promoting
social behaviour in animal models of ASD.
These findings point to the possibility of activating the vagus nerve as a method of treating human
disease.
For example, vagus nerve stimulation, which is performed through surgical implantation of an
electrical device that activates the vagus nerve, is an approved therapy for treatment- resistant
epilepsy and depression.
It may be possible to avoid this surgery if appropriate microbial stimulation of the vagus nerve
can be achieved.
Although proof of concept and elucidation of mechanism will need to be demonstrated in animal
models, owing to the technical challenges of studying the vagus nerve in people, the translatability
of these findings to humans remains promising.

19. Gut-Microbiota-Brain Signalling through the
Immune System
Both CNS and Gut microbiota are affected by the immune system.
The microbiota is also necessary for healthy development, maturation and activation
of the microglia, innate immune cells of the brain.
GF mice and Antibiotic treated mice have immature microglial cells and were
restored when treated by SCFA i.e. metabolites of gut microbiota.
Complex if not specific taxa may be necessary for the proper functioning and
development of microglia.
Impact of gut microbiota seems to occur in sex and time specific manner.

20. Gut-Microbiota-Brain Signalling through the
Immune System
Alteration in microglia function have been linked to stress, behavioural and
neurodegenerative disorders.
Peripheral cytokines and chemokines from systemic inflammations or brain resident
immune cells alters the immune signalling within the brain.
BBB has higher permeablity in GF mice due to reduces expression of tight junction
protein.
Infections, autoimmune diseases and injuries may alter the permeability of BBB
increasing the susceptibility of brain to the microbial products and subsequent
pathology.

21. ALTERED GUT MICROBIAL
PROFILE
IN
BRAIN DISORDERS
• Noted in Alzheimer’s disease, Parkinson’s disease and in patients with
depression, autism, and post-traumatic stress disorder.
• Fecal microbiota transplant (FMT) from patients with depression resulted in
a transfer of the depressive phenotype from patient into preclinical models.

23. • Acute stress - Appropriate HPA axis activation
• Chronic stress - Inappropriate HPA axis
activation.
• Changing the early-life microbial profile
through antibiotic , lack of breastfeeding, birth
by C-section, host genetics and other
environmental factors, can impact stress-
related physiology and behaviour.
• Prenatal stress exposure in women lead to
infant GI symptoms and allergic reactions.
STRESS

24. • Anxiety and depression often are comorbid
conditions in patients with IBS.
• Preclinical studies have shown the microbiota’s
capacity to modulate emotional behaviors.
• Depressed human-to-rodent fecal microbial
transplants have induced depressive behaviors in
the animal models.
• Coprococcus and Dialister species - Positively
associated with quality of life scores.
Depression
and
Anxiety

25. • Risk of Parkinson's disease development
increases with infrequency of bowel movement
and constipation severity.
• FMT from PD patients into mouse models of
PD resulted in both motor deficits and
neuroinflammation.
• A full truncal vagotomy for treatment of peptic
ulcer disease have a diminished risk of PD.
Parkinson’s
Disease

26. • ASD patients frequently present with gut-related
comorbidities and unusual dietary patterns.
• Bifidobacterium – Reduced abundance
• Clostridia – Increased abundance
• Treatment with vancomycin resulted in positive
alterations in behavioural symptoms.
• FMT from healthy individuals into ASD patients
resulted in improvements in both gut
comorbidities and behaviours.
Autism
spectrum
disorder

27. • Limited studies on the impact of gut
microbiota.
• Presence of Candida albicans is associated
with worse psychiatric symptoms in males.
• Specific taxa, including Veillonellaceae and
Lachnospiraceae were associated with
schizophrenia severity.
Schizophrenia

28. • Gut microbiota and its metabolites play an crucial role
in the modulation of satiety signals and eating
behaviors.
• Preclinical studies - Fecal transplantation from
hyperphagic obese mice to germ-free mice; induce
hyperphagic behavior and weight gain.
• Gut microbiome has been associated with changes in
brain microstructure in obesity.
• Dramatic change in gut microbial composition after
bariatric surgery.
Obesity/Food
Addiction

29. • Significant microbial shifts in fecal microbial
community composition between healthy
people and IBS patients.
• Dysbiotic IBS subgroup also differed in
regional brain volumes from the eubiotic group.
• Decreased relative abundance of the genera
Bifidobacterium and Lactobacillus and an
increased Firmicutes : Bacteroidetes ratios.
Functional
Intestinal
Disorders

30. Therapeutically Targeting The Microbiota-gut- Brain Axis
• The term psychobiotic was coined in 2013 by Dinan et al. as a novel class of
psychotropic, defined as a “live organism that, when ingested in adequate
amounts, produces a health benefit in patients suffering from psychiatric
illness.”
• Psychobiotics includes probiotics, prebiotics, synbiotics, and postbiotics.
• These substances can be delivered through supplements, functional foods and
improvements to dietary intake.

31. • First described over 100 years ago in the work of Elie
Metchnikoff - Consumption of lactic acid bacteria in
fermented milk in a population of poor Bulgarians.
• Probiotics are defined as “live microorganisms that,
when administered in adequate amounts, confer a
health benefit on the host”.
• Health benefits of probiotics are entirely strain-
dependent.
• Strains of Lactobacillus and Bifidobacterium have
well-defined safety profiles.
• Require daily consumption to maintain positive
effects.
Probiotics: Live
Biotherapeutics

36. • Prebiotics are defined as a “substrate that is
selectively utilized by host microorganisms
conferring a health benefit”.
• Prebiotics consist of fibers such as inulin,
fructo- oligosaccharides, galacto-
oligosaccharides (GOSs) and resistant starch.
• Prebiotics are found in fruits, vegetables,
grains and human milk.
Prebiotics

37. • Synbiotics are a combination of probiotics and
prebiotics.
• Mild to moderate MDD - GOS and a dual-strain
probiotic (L. helveticus and B. longum) ; reduction in
depression scores and positively impacted tryptophan
signalling.
• Positive results of a fermented soy drink in a PTSD
cohort.
• Functional GI symptoms were improved in a PD cohort.
• Synbiotic (Bifidobacterium infantis plus
oligosaccharides) reduced gut-related comorbidities
related to ASD.
Synbiotics

38. • Postbiotics are nonviable entities that are
metabolites of bacterial fermentation and include
bioactives such as SCFAs.
• General impacts of the gut microbiome and SCFAs
on metabolic traits and disease have recently been
described.
• Inulin-proprionate ester; increases proprionate
production in the colon, brain imaging (via
functional MRI) showed a reduction in anticipatory
reward responses in the striatum.
• Gut peptides: Role in stress, anxiety and depression.
Postbiotics

39. • nonviable probiotics, e.g., heat-killed
probiotics, may exert biological activity in the
host.
• Heat-killed, washed, paraprobiotic CP2305:
Reduces stress due to university exams in
medical students.
• Heat-killed Lactobacillus paracasei PS23:
Benefits in a corticosterone-induced depressive
phenotype, reversing hippocampal and
prefrontal cortex reductions in dopamine levels.
Para-
probiotics

40. • Lactobacillus delbreuckii subsp. bulgaricus
and S. thermophilus.
• Dairy products - Bifidobacterium and
Lactobacillus are commonly used. •
• Fermented milk drinks - Positive benefits in
emotional processing and stress.
• Mediterranean diets - Decreased risk of
depression and cognitive impairment.
• SMILES trial - Benefit in moderate to severe
depression, with an economic evaluation.
Fermented
Foods
and Diet

41. References
• The gut microbiota–brain axis in behaviour and brain disorders Livia H. Morais
Et. Al. 2020, Nature reviews
• Microbiota gut brain axis: a new therapeutic oppurtunities. CL smith et al 2020,
annual review of pharmacology and toxicology.

42. Thank You!