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Molecular + Cellular Neuro > Gut brain Axis > Flashcards

Gut brain Axis Flashcards

1
Q

Define Gut Microbiota + give some background info (1 +3))

A

microorganisms in an individual’s gastrointestinal system

  • Microbiota consists mainly of bacteria, viruses and yeast
  • microbes account for 1-3% of human body weight ( as skin, oral cavity + lungs have their own)
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2
Q

Define Gut Microbiome (1)

A

combined genetic material of the microorganisms in an individual’s gut

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3
Q

What are the dominant bacterial phyla in adult gut? (4+1)

A

these are just the main ones for healthy functioning:
➢ Actinobacteria
➢ Bacteroidetes
➢ Firmicutes
➢ Proteobacteria

BUT
Composition varies amongst individuals and over life-course - diet, antibiotics, aging etc.

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4
Q

Why is it necessary to learn about bacteria? (1)

A

Bacteria and their metabolites/by-products influence numerous physiological functions

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5
Q

Define Dysbiosis + state its clinical relevance (1 + 1)

A

The disbalance of organisms present in a system

It has been associated with a range of physical and mental conditions (GI disorders -> neurological diseases)

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6
Q

What is the Microbiota-Gut-Brain Axis (MGBA)? (3)

A
  • A bidirectional link between the brain and gut microbiota
  • Involves direct and indirect pathways between brain and gut (b/w cognitive + emotional centres in brain and periphery intestinal functions)
  • Also called: gut-brain axis, brain-gut axis, gut-brain connection
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7
Q

Explain the neuronal pathway (The Vagus nerve) (4)

A

Vagus nerve = longest bundle of nerves in ANS

  • provides the central communication pathway of MGBA
  • Bi-directional: Afferent fibres from GUT to BRAIN, Efferent fibres from BRAIN to GUT
  • No direct contact with microbiota but can…
    ➢ detect microbial compounds
    ➢ convey information to/from microbiota via intestinal cells e.g. neurotransmitters because vagus nerve terminals are scattered throughout intestinal wall + mucosa
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8
Q

Explain the relationship b/w Gut microbiota and neurotransmitter production using an example (4)

A
  • Numerous gut microbiota have been linked w/ neurotransmitter production

Serotonin (5-HT):
- largest endogenous pool of serotonin resides in gut (because primary function of enterochromaffin cells = synthesise + secrete)

  • Peripherally: Regulation of GI secretion & motility
  • Centrally: Mood & cognition
  • Gut microbiota can influence 5-HT levels by:
    ➢ Impacting 5-HT release (eg E.coli = increased sero. = vomiting)
    ➢ Influencing 5-HT production (microbes alter availability of tryptophan, or can be altered indirectly via metabolites using Short chain fatty acids (SCFA)
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9
Q

Explain the significance of SCFA and neurotransmitter release (3)

A
  • microbes alter availability of tryptophan (needed for sero production)
  • can also be influenced more indirectly via metabolites (by fermenting complex carbohydrates -> dietary fibre) = produces SCFA (eg acetate + butyrate)

=> enhance sero production in enterochromaffin buy regulating tryptophan hydroxylase (RLS)
–> same for Glutamate/mine, GABA, DA

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10
Q

explain the HPA axis in response to stress (4 +1)

A

1) Hypo

—- CRH——

2) Anterior pituitary

— ACTH—–

3)Adrenal Cortex

—- CORT——

= fluid + salt retention -> impairs inflammation ( good for ST but X for LT)

  • Affects gut immune cell activity, gut permeability & gut microbiota composition
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11
Q

Define enteroendocrine cells (2)

A

specialised cells in the GI Tract, stomach, and pancreas that produce and release hormones in response to stimuli.

  • over 20 types of gut peptides or hormones they release
    = stim hypo = neuropeptide release
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12
Q

explain how bacterial products (SCFA) and enteroendocrine cells release neuropeptides - endocrine pathway (4)

A

1) SCFA stim. enteroendocrine cells

2) = Production of several gut hormones (e.g. PYY, GLP-1)

3) either
a) travel directly to brain
b) activate locla vagal nerve terminals

4) neuropeptide release

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13
Q

immune pathways facts (3)

A
  • A complex interaction exists b/w immune system and MGBA -> constant = maintains gut homeostasis ==> ALL homeostasis in the body
  • Gut microbiota influence and modulate microglial maturation and function of innate and active immunity -eg modulate a-Beta function, microbiota colonisation in GIT tract during early life = affects dev. of T cells into T helper cells
  • Microbial metabolites modulate astrocyte activity -> SCFA influence neuroinflam response by activating microglia, the astrocytes detect danger signals = respond with chemokines + cytokines
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14
Q

How do you make a germ-free rodent? (5)

A

1.Create an embryo via in vitro fertilization

2.Transplant into a GF mother (Alternative = sterilize mum & do c-section)

  1. Any pups = germ-free
  2. All progeny will = germ-free unless contaminated
  3. Each rodent = housed separately in sterile isolator( looks for diff’s in brain/other organs in rodents w/o microbiome) with sterilized food & water
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15
Q

What are the main 4 things researching GF rodent MGBA shows us? (4)

A
  • stress response: Immune defects (IgA, T cells), increased stress-induced ACTH + CORT
  • decreased neuroprotection: increased BBB permeability + altered microglial function + homeostasis
  • disrupted neural function: chemical neural alterations eg structural changes, increased hippocampal neurogenesis, neurotrans expression + turnover etc.
  • impaired behavioural profile: reduced anxiety like behaviour, cognitive deficits, altered sociability + increased stereotyped and repetitive behaviour
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16
Q

Are GF rodents a useful way to study MGBA? (for + against) (2 +3)

A

Yes:
* Can test role of microbial colonisation from early life
* Can provide ‘proof of concept’

No:
* No real clinical relevance
* Neurodevelopmental changes can mean GF model is of limited use
* Is a rodent’s gut a good comparator for a human gut?

17
Q

Define prObiotics AND prEbiotics (2)

A

prO: giving bacterial strains in mixture

prE: giving substances that resident microbiota ferment + activity and amount of bacteria in the gut

18
Q

Give an example that displays alteration of resident gut microbiota by Probiotics/prebiotics (2)

A

Example: B. pseudocatenulatum

=
Decreased stress response in maternal separation mouse model

19
Q

Give a controversial example that displays alteration of resident gut microbiota by antibiotics (3)

A

Example: Broad-spectrum ABX in water (= wide-spread dysbiosis)

=
Reduced anxiety-like behaviours (Desbonnet et al, 2015)

BUT
Frohlich et al, 2016 = no ABX effect on anxiety (but this might differ due to the type of antibiotics used or the amount given or species of animal)

20
Q

Give an example that displays alteration of resident gut microbiota by FMT (2)

A

Example: Healthy mice receiving FMT from PD mouse model (usually rectally but sometimes enteral)

=
Deteriorated motor function + decreased striatal neurotransmitters

21
Q

Why and how might Faecal microbiota transplantation (FMT) be useful? (3)

A

infusion of stool from healthy individual into patient w/ presumed gut dysbiosis

via colonoscopy (rectally) or endoscopy/ capsules (enterally)

= successful treatment for
- c. Difficile infection
- IBS
- MGBA studies in animals

22
Q

How do you determine microbiota composition? (2 +6)

A

sample types:
➢ Faeces - most common in animal and human studies (proxy for gut microbiota)
➢ Intestinal tissue - often not suitable in human studies with healthy participants (Post mortem tissue used in animals)

then use techniques to generate information about the sample’s microbiota/microbiome:
- Metabolomics
- Metaproteomics
- Shotgun Sequencing
- Amplicon sequencing
- PCR panels
- Culture

23
Q

What are the gastrointestinal (GI) symptoms associated with stress? (4)

A

➢ Intestinal fluttering sensation (aka ‘butterflies in the stomach’)
➢ Diarrhoea (less common = constipation)
➢ Indigestion
➢ Nausea and vomiting

24
Q

Why do we even have stress induced GI symptoms? (5+1)

A

1) Brain perceives a potential threat

2) = Activates stress response

3)
a) Sympathomedullary pathway -> Adrenaline & noradrenaline release (paradoxically = relaxation of external anal sphincter = diarrhoea)
b) HPA Pathway-> Cortisol release (inc. BP, HR, Resp. rate)

4) Blood flows away from stomach

5) = Reduced gastric emptying, Butterfly’ sensation, Nausea, GI upset (contraction = slows down digestions)

  • Bi-directional link exists between stress response and microbiota
25
Q

Explain a condensed version of the stress response (7)

A

1) Stress

2) - Reduces amount and diversity of bacterial species in gut
- Increases colonic colonization of pathogenic bacteria
- Upregulates colonic expression of pro-inflammatory cytokines (INFLAM)

3) - Exacerbates intestinal inflammation
- Increases intestinal permeability

4) Allows bacteria to move across intestinal mucosa

5) Direct activation of immune cells by microbiota and its by-products/metabolites

6) Stimulation of HPA axis (hyperactivated = prolonged response)

7) Stress response

26
Q

stress naive vs restraint stressed mice results (2)

A

alterations in gut motility:

  • upper gut (stomach + intestine) = decreased activity
    –> may be defence mechanism to promote vomiting + reduce oral intake)
  • but in contrast: large bowel = increased activity in stool output + transit speed ( also defence mechanism to eliminate toxins)
27
Q

GF mice vs Establishment of microbiota in GF mice (4)

A
  • Hyperactive HPA stress response (Sudo et al, 2004)
  • Alteration in microglia activity and morphology (Enry et al, 2015)

vs

  • Reduces HPA hyperactive stress response
  • Microglia activity and morphology becomes similar to non-GF rodents
28
Q

What effects does stress have on WT rodents and what might mitigate it? (2)

A
  • stress alters microbiota = dysbiosis
  • also specific probiotic mixtures have been shown to weaken the response of HPA + endocrine response to chronic stress (but not for all probiotics)
29
Q

Stress bacteria response in humans (3)

A
  • Human studies limited
  • Currently appears Lactobacillus = often reduced in the gut during stress
  • Example: Undergraduates undergoing exams = reduced Lactobacilli concentrations (saliva + faecal)
30
Q

Can altering your gut microbiota help you cope with stress? (3)

A
  • Probiotic administration in humans study (limited studies in general) - taken in milk containing lactobacilli 8 wks prior to exams
  • = Lactobacillus probiotic reduced exam related stress (Takada et al, 2016)
  • Prebiotics have been shown to reduce basal cortisol levels and reaction to negative stimuli
31
Q

Parkinson’s Disease (PD) overview - clinical signs + pathology (6)

A
  • Clinical features:
    ➢ Bradykinesia
    ➢ Rigidity
    ➢ Resting tremor
  • Main neurotransmitter involved:
    ➢ Dopamine (DA)
  • Pathology:
    ➢ Alpha-synuclein accumulation
    ➢ Neuroinflammation (microglia but guts + neuro)
32
Q

PD and microbiota research - animal studies eg’s (4)

A
  • PD mice = increased expression of microglia (Iba-1), elevated IL-6, IL-1 (both inflam) and decreased IL-10 (antiinflam)
  • Healthy mice given PD FMT = PD pathology
  • PD mouse given ‘healthy’ FMT = reduced pathology
  • Bacillus subtilis inhibits α-synuclein aggregation + clears preformed aggregates - in ringworm
33
Q

PD and microbiota research - human studies background (4)

A
  • ‘Leaky gut’ (increased intestinal permeability because of injury, inflam or dysbiosis) & bowel inflammation affect PD progression
  • alpha-synuclein GI levels = higher in PD (prior to brain)
  • Sequencing of gut microbiota
    => dec, Prevotellaceae, Lactobacillaceae
    => inc. Enterobacteriaceae
34
Q

Alzheimer’s Disease (AD) overview - clinical signs + pathology (4)

A
  • Clinical features:
    ➢ Decline in cognitive skills
  • Main neurotransmitter involved:
    ➢ Acetylcholine
  • Pathology:
    ➢ Amyloid-beta (Aβ) plaque & neurofibrillary tau tangles
    ➢ Neuroinflammation
35
Q

AD and microbiota research - animal studies eg’s (2)

A
  • Microbiota
  • APP-transgenic mice = shift in gut microbiota
  • GF APP mice = reduced Aβ pathology
    = Microbiota = increased Aβ pathology
  • Microbiota metabolites:
  • SCFA regulate microglia homeostasis in vitro
  • # SCFA obstruct Aβ protein aggregation in vivoPossible role of SCFA on microglial function in AD pathogenesis
36
Q

AD and microbiota research - human eg’s (2)

A
  • AD patients = different gut microbiota composition BUT study results vary
  • Bacteria-derived amyloid may initiate + cross seed host amyloid aggregation
37
Q

Multiple Sclerosis (MS) overview - clinical signs + pathology (6)

A

A chronic immune-mediated inflammatory disease

Clinical features:
* Fatigue
* Difficulty with walking, balance, coordination
* Visual disturbances
* Bladder/bowel dysfunction
* Numbness/tingling, muscle spasms
* Cognitive impairment
Note: Symptoms vary widely from person to person

Pathology:
* Demyelination - multiple focal areas of myelin loss within CNS (plaques/lesions)

38
Q

MS and microbiota research - animal studies eg’s (2)

A
  • Experimental autoimmune encephalomyelitis (EAE) = MS animal model
  • EAE mice = alterations in microbiome and increased cases of “leaky gut”
39
Q

MS and microbiota research - human studies eg’s (2)

A
  • Antibodies to C. perfringens toxin = more prevalent in MS
    BUT
    Others = no association of C. perfringens gut dysbiosis with MS
  • Sequencing of MS gut microbiota show alterations
    BUT
    Microbiota composition varies between studies

Molecular + Cellular Neuro (21 decks)

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