Gut brain Axis Flashcards
Define Gut Microbiota + give some background info (1 +3))
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)
Define Gut Microbiome (1)
combined genetic material of the microorganisms in an individual’s gut
What are the dominant bacterial phyla in adult gut? (4+1)
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.
Why is it necessary to learn about bacteria? (1)
Bacteria and their metabolites/by-products influence numerous physiological functions
Define Dysbiosis + state its clinical relevance (1 + 1)
The disbalance of organisms present in a system
It has been associated with a range of physical and mental conditions (GI disorders -> neurological diseases)
What is the Microbiota-Gut-Brain Axis (MGBA)? (3)
- 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
Explain the neuronal pathway (The Vagus nerve) (4)
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
Explain the relationship b/w Gut microbiota and neurotransmitter production using an example (4)
- 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)
Explain the significance of SCFA and neurotransmitter release (3)
- 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
explain the HPA axis in response to stress (4 +1)
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
Define enteroendocrine cells (2)
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
explain how bacterial products (SCFA) and enteroendocrine cells release neuropeptides - endocrine pathway (4)
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
immune pathways facts (3)
- 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
How do you make a germ-free rodent? (5)
1.Create an embryo via in vitro fertilization
2.Transplant into a GF mother (Alternative = sterilize mum & do c-section)
- Any pups = germ-free
- All progeny will = germ-free unless contaminated
- Each rodent = housed separately in sterile isolator( looks for diff’s in brain/other organs in rodents w/o microbiome) with sterilized food & water
What are the main 4 things researching GF rodent MGBA shows us? (4)
- 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
Are GF rodents a useful way to study MGBA? (for + against) (2 +3)
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?
Define prObiotics AND prEbiotics (2)
prO: giving bacterial strains in mixture
prE: giving substances that resident microbiota ferment + activity and amount of bacteria in the gut
Give an example that displays alteration of resident gut microbiota by Probiotics/prebiotics (2)
Example: B. pseudocatenulatum
=
Decreased stress response in maternal separation mouse model
Give a controversial example that displays alteration of resident gut microbiota by antibiotics (3)
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)
Give an example that displays alteration of resident gut microbiota by FMT (2)
Example: Healthy mice receiving FMT from PD mouse model (usually rectally but sometimes enteral)
=
Deteriorated motor function + decreased striatal neurotransmitters
Why and how might Faecal microbiota transplantation (FMT) be useful? (3)
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
How do you determine microbiota composition? (2 +6)
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
What are the gastrointestinal (GI) symptoms associated with stress? (4)
➢ Intestinal fluttering sensation (aka ‘butterflies in the stomach’)
➢ Diarrhoea (less common = constipation)
➢ Indigestion
➢ Nausea and vomiting
Why do we even have stress induced GI symptoms? (5+1)
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
Explain a condensed version of the stress response (7)
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
stress naive vs restraint stressed mice results (2)
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)
GF mice vs Establishment of microbiota in GF mice (4)
- 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
What effects does stress have on WT rodents and what might mitigate it? (2)
- 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)
Stress bacteria response in humans (3)
- Human studies limited
- Currently appears Lactobacillus = often reduced in the gut during stress
- Example: Undergraduates undergoing exams = reduced Lactobacilli concentrations (saliva + faecal)
Can altering your gut microbiota help you cope with stress? (3)
- 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
Parkinson’s Disease (PD) overview - clinical signs + pathology (6)
- Clinical features:
➢ Bradykinesia
➢ Rigidity
➢ Resting tremor - Main neurotransmitter involved:
➢ Dopamine (DA) - Pathology:
➢ Alpha-synuclein accumulation
➢ Neuroinflammation (microglia but guts + neuro)
PD and microbiota research - animal studies eg’s (4)
- 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
PD and microbiota research - human studies background (4)
- ‘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
Alzheimer’s Disease (AD) overview - clinical signs + pathology (4)
- Clinical features:
➢ Decline in cognitive skills - Main neurotransmitter involved:
➢ Acetylcholine - Pathology:
➢ Amyloid-beta (Aβ) plaque & neurofibrillary tau tangles
➢ Neuroinflammation
AD and microbiota research - animal studies eg’s (2)
- 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
AD and microbiota research - human eg’s (2)
- AD patients = different gut microbiota composition BUT study results vary
- Bacteria-derived amyloid may initiate + cross seed host amyloid aggregation
Multiple Sclerosis (MS) overview - clinical signs + pathology (6)
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)
MS and microbiota research - animal studies eg’s (2)
- Experimental autoimmune encephalomyelitis (EAE) = MS animal model
- EAE mice = alterations in microbiome and increased cases of “leaky gut”
MS and microbiota research - human studies eg’s (2)
- 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
