07 The Gut-Brain Axis Flashcards
Gut Microbiata
- 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
gut microbiome
- collection of genomes from all microorganisms in environment
- human: 20,000 - 25,000 genes
- gut microbiome: 2,000,000 genes
3 main categories of bacteria according to potential impact
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
History of gut-brain connection
- 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
gut microbiate and host metabolism
- 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
gut microbiata and microglia
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
Gut-Brain Axis
- 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)
gut metabolites
- 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
effects of gut metabolites
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
effects of gut metabolites in mice
- 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
gut microbiata as immune modulators
- 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
gut hormones
- 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
Ghrelin (gut hormone)
- increase associated with obesity
- decrease associated with autism and cognitive decline
- induces hunger and increases food intake
- inhibts vagal afferent firing and insulin release
Leptin (gut hormone)
- stimulates vagal afferent firing
- reduces appetite
- increases insulin release
weight loss
CCK (gut hormone)
- increase associated with anxiety and panic disorder
- functions as neurotransmitter
- digestion
- inhibits gastric emptying
dopamine (gut hormone)
- 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
serotonin (gut hormone)
- 90-95% secreted in gut
- mediated by SCFAs
- functions as neurotransmitter
- decrease associated with depression and mood disorders
Ghrelin and dentate gyrus
- dentate gyrus center of neurogenesis in hippocampus, contributes to learning
- Ghrelin increases cell proliferation in dentate gyrus and is thus involved in hippocampal neurogenesis
gut microbiata and HPA axis
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
Enteric nervous system and gut neurotransmitters
- 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
Vagus Nerve - Modulator of Gut-Brain Axis
- 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
gut microbiata and Alzheimer’s pathogenesis
- 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
pathway gut microbiate and Alzheimer’s
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
inflammation, AD and dementia
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
AD therapeutic insights
- 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
