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Neuroanatomy & -physiology > 07 The Gut-Brain Axis > Flashcards

07 The Gut-Brain Axis Flashcards

1
Q

Gut Microbiata

A
  • microbial community colonising Gastrointestinal Tract
  • resides in symbiosis with host organism, unless alteration in normal distribution of species (dysbiosis, potentially harmful)
  • 100 trillion microorganisms, hence 50% human 50% bacteria
  • 200 - 1,000 bacterial species
  • 90% of gut microbiata: Firmicutes and Bacteriodetes
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2
Q

gut microbiome

A
  • collection of genomes from all microorganisms in environment
  • human: 20,000 - 25,000 genes
  • gut microbiome: 2,000,000 genes
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3
Q

3 main categories of bacteria according to potential impact

A

commensal bacteria
- non-harmful bacterial species not associated with infections
probiotic bacteria
- produce anti-inflammatory products in the gut
potentially pathogenic bacteria
- form colonies
- contribute to local and systemic inflammation
- associated with clinical infections or outbreaks

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4
Q

History of gut-brain connection

A
  • Hippocrates: all disease begins in the gut
  • Senator (1860s): systemic disease (incl. mental disorders) could be rooted in intestinal self-infective processes
  • Metchnikoff (1910): orally consumed lactic acid reverses autointoxication
  • Stokes and Pillsbury (1930s): overlapped systemic inflammation with intestines
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5
Q

gut microbiate and host metabolism

A
  • germ-free mice maintained healthy weight despite high caloric intake
  • conventionally raised mice: obesity and change in microbiate
  • transplantation of microbiata drove germ-free mice to develop phenotype of donor
  • gut microbiate decide phenotype of host
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6
Q

gut microbiata and microglia

A

gf mice and mice treated with antibiotics showed
- abnormal microglia: ramified (unable to initiate immune response), increased cell volume and dendrite length, increased branching
- immature state
-> impairing immune activation and brain development
-> lack of microbes diminishes microglia immune response
detrimental effects were corrected by administration of short-chain fatty acids (SCFAs)
-> gut microbial products enter CNS and affect function

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7
Q

Gut-Brain Axis

A
  • bidirectional connection
  • brain controls parasympathetic aspects of gut by vagus nerve, modifies intestinal functions via HPA axis
  • enteric system communicates with brain via gut metabolites (e.g. SCFAs), gut hormones (e.g. Ghrelin), neuroactive substances (e.g. Serotonin, GABA, dopamine), inflammatory factors (cytokines)
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8
Q

gut metabolites

A
  • SCFAs most critical, produced by fermentation of dietary fiber and resistant starch, key roles in anti-inflammatory responses and integrity of BBB, major products: Acetate, Propionate, Butyrate
  • LCFAs enhance expression of pro-inflammatory cytokines
  • Lipopolysaccharides (LPS) component of pathogenic bacteria, induce chronic inflammation in gut and CNS when secreted
  • Tryptophan metabolised to produce serotonin and melatonin
  • Vitamins D and B6 maintain gut epithelial integrity and modulate immune responses
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9
Q

effects of gut metabolites

A

SCFAs (cross BBB, product of commensal and probiotic microbiota) and Tryptophan
- upregulate gene expression of tight junction proteins (BBB integrity)
- reduce neuroinflammation
- enhance brain development, cognitive functions, learning, memory
- elevate BDNF and NMDA receptor expression
LPS and LCFA (both cross BBB)
- downregulate gene expression of tight junction proteins (BBB permeability)
- induce inflammasome pathway, chronic activation and proliferation of microglia
- provoke impairments in spatial memory, stress-induced cognitive decline, depression
- depress BDNF and NMDA receptor expression

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10
Q

effects of gut metabolites in mice

A
  • increased BBB permeability in germ-free mice compared to pathogen-free mice
  • significant reduction in expression of tight junction proteins
  • implementation of SCFAs in germ-free mice reconstituted BBB integrity
  • significant increase in expression of previously suppressed proteins
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11
Q

gut microbiata as immune modulators

A
  • 70-80% of immune cells scattered along intestinal mucosa
  • separated from microbiome by epithelial cells, reside mainly in nodes in epithelium
  • symbiosis in gut ensures that chronic inflammation is not reached through commensal species that induce anti-inflammatory cytokines
  • Firmicutes and Bifidobacterium (both producing SCFAs) activate Tregs
  • Bateriodetes and pathogenic species induce inflammatory cytokines and proliferation of immune cells
    gut dysbiosis favors pathogenic species -> chronic unattenuated inflammation -> leaky gut, LPS, LCFAs and toxic substances into circulation and reach brain -> neuroinflammation
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12
Q

gut hormones

A
  • central regulation of gut motility, apetite, food intake
  • contributions to inflammation, psychiatric and neurological anomalies
  • some species able to secrete hormones (Lactobacillus dopamine)
  • enteroendocrine cells (EEC) secrete hormones in response to microbiata products
  • EEC express receptors for SCFAs and LCFAs
  • secrete into gut lumen affecting microbiata and into blood stream affecting vagus nerve signaling
  • all gut hormones have receptors in amygdala, hippocampus, hypothalamus, thalamus, brain stem nuclei and cortical areas
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13
Q

Ghrelin (gut hormone)

A
  • increase associated with obesity
  • decrease associated with autism and cognitive decline
  • induces hunger and increases food intake
  • inhibts vagal afferent firing and insulin release
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14
Q

Leptin (gut hormone)

A
  • stimulates vagal afferent firing
  • reduces appetite
  • increases insulin release
    weight loss
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15
Q

CCK (gut hormone)

A
  • increase associated with anxiety and panic disorder
  • functions as neurotransmitter
  • digestion
  • inhibits gastric emptying
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16
Q

dopamine (gut hormone)

A
  • 50% secreted in gut
  • mediated by SCFAs
  • functions as neurotransmitter
  • increase associated with anxiety, increase in competition and aggression
  • decrease associated with depression and Parkinson’s
17
Q

serotonin (gut hormone)

A
  • 90-95% secreted in gut
  • mediated by SCFAs
  • functions as neurotransmitter
  • decrease associated with depression and mood disorders
18
Q

Ghrelin and dentate gyrus

A
  • dentate gyrus center of neurogenesis in hippocampus, contributes to learning
  • Ghrelin increases cell proliferation in dentate gyrus and is thus involved in hippocampal neurogenesis
19
Q

gut microbiata and HPA axis

A

stress -> dysbiosis, dysbiosis in offspring’s microbiota -> influences gene expression in hippocampus and hypothalamus and corticosterone levels -> dysregulation of HPA axis development

stress -> gut dybiosis -> dysregulation of HPA axis -> stress

20
Q

Enteric nervous system and gut neurotransmitters

A
  • Enteric nervous system called “second brain” (more neurons than spine, similar structure, function and chemical coding)
  • mainly interacts with vagus nerve by cholinergic activation
  • secretes over 30 neurotransmitters (GABA, Serotonin, dopmaine, Acetylcholine, Glutamate)
  • glutamate and dopamine can cross BBB
  • all act on vagus nerve activating neural pathway
  • evidence of decreased GABA in gastrointestinal tract and CNS infers gut dysbiosis increases risk for AD
21
Q

Vagus Nerve - Modulator of Gut-Brain Axis

A
  • neurotransmitters and certain metabolites signal to brain via VN
  • main contributor to parasympathetic nervous system
  • gut is major sensory input for brain (a lot more afferent fibers than efferent vibers)
  • projects to nucleus track solitary (NTS) that projects to limbic system (amygdala) followed by cortical areas
22
Q

gut microbiata and Alzheimer’s pathogenesis

A
  • recent studies implicated gut dysbiosis as vital factor for AD etiology
  • metabolites of gut were traced in CSF of AD patients
  • western (high fat) diets induce gut dysbiosis and systemic inflammation eventually triggering neuroinflammation and AD (cognitive impairments and hippocampus memory disorder)
  • mediterranean diets rich in Omega 3 (DHA) enhance gut symbiosis and protect against AD
  • decrease in SCFAs -> increase LPS -> neuroinflammation -> increased AD risk
23
Q

pathway gut microbiate and Alzheimer’s

A

lactobacillus and bifidobacterium decrease in gut -> overgrowth of pathogenic microbes inducing chronic inflammation -> decreased GABA and Glutamate in CNS -> leaky gut induces BBB permeability -> neuroinflammation and inhibition of BDNF in hippocampus -> misfolding and amyloidogenic splicing of APP -> amyloid plaques accumulate increasing neuroinflammation -> hyperphosporelation of tau proteins -> AD progression

24
Q

inflammation, AD and dementia

A

only in AD, inflammation leads to:
- increased APP mRNA and protein expression
- beta and gamma secretase
- increased amyloid beta accumulation in brain of AD patients
and more

inflammation -> Abeta plaques -> tau fibrils

25
Q

AD therapeutic insights

A
  • one study highlights impact of microbiata on development of Abeta plaques and cognitive skills
    -> amelioration of AD status by antibiotics
  • one study highlights potential remedial impact of butyrate (major SCFAs from gut) on increasing BDNF expression
    -> reversing neurodegeneration and cognitive decline by means of probiotic species

Neuroanatomy & -physiology (14 decks)

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