Lecture 14: Neuropsychiatry and the Gut Microbiota 1 Flashcards
What is the most common neuropsychiatric disease?
schizophrenia
What are the types of symptoms of schizophrenia?
positive (psychosis), cognitive and negative
What are symptoms of autism spectrum disorder?
stereotyped or repetitive motor movements, use of objects, or speech
highly restricted, fixated interests
hyper- or hypo-reactivity to sensory input
What are examples of neuropsychiatric diseases with gastrointestinal involvement?
parkinson’s disease, ASD and schizophrenia
What is Parkinson’s disease associated with?
persistent constipation or delayed gastric emptying can appear up to 10 years
before motor or cognitive symptoms
one theory is that pathology begins in neurons of GI tract
What is ASD associated with?
up to 90% report GI symptoms ranging from constipation to diarrhoea
What is schizophrenia associated with?
significant evidence of GI inflammatory issues in > 30% of patients
What is evidence of neuropsychiatric diseases being genetic disorders?
twin studies show a high degree of concordance between monozygotic twins
but significant environmental component determines penetrance and severity
What are examples of the environment playing a major role?
brothers with the same ASD producing mutation have markedly different presentations
some individuals with disease producing mutations never show symptoms
What is an essential part of the environment for any animal?
the GI microbiota
Why are the microbiota relevant to neuroscience?
disturbances in the balance of microbes in the gut can cause long term effects on behaviour
several disorders associated with mood are correlated with alterations in gut microbes
What does probiotic bacteria cause altered activity of?
enteric neurons in rodents
What have various studies indicated that ASD symptoms may be related to?
composition of the microbiota
What can stress and anxiety modulate?
the microbiota and vice versa
What can stress/disease of the normal microbiota and CNS lead to?
alterations in behaviour, cognition, emotion, nociception
altered levels of inflammatory cells and / or mediators
intestinal dysbiosis
How many more distinct genes are there in the microbiome than in the human genome?
150x to 300x more distinct genes
diversity has been correlated with health
How many more bacteria are there in the gut than there are cells in the human body?
the gut contains about 10x more bacteria than there are cells in the human body
What type of bacteria are present in the colon?
almost exclusively anaerobic
Why type of bacteria are present in the caecum?
about 20% aerobic
What can change the proportions of normal microbiota?
diet, stress, probiotics and antibiotics can change proportions, but species mix remains relatively constant
What does bacteria in mucus associated with epithelium differ from?
those in the lumen itself
What is a tool for study of gut microbiome?
16S ribosomal RNA sequencing and next generation whole genome sequencing methods for identifying presence of different species
What is metabolomics?
identification of the metabolic products produced by colonic bacteria
What are germ-free mice used for?
behavioural studies
functional studies at single neuron level
can introduce whole microbiota (faecal transplant) or single bacterial strains (probiotic)
How does what we eat change the microbiota?
what we eat and how often determines the competitive advantage of different microbes
Why are prebiotics used?
to favour specific species at the expense of others
How does exercise change the microbiota?
by altering blood flow to the gut and thus changing the balance between secretion and absorption of water
How does diarrhoea or constipation each alter the microbial system?
by altering transit through the colon thereby disrupting turnover of the faecal microbiota
What are basic experimental approaches for determining whether the microbiota change behaviour or not?
germ-free studies, infection studies, faecal-transplantation studies, antibiotic studies, probiotic studies
What is JB-1?
a type of bacteria which has the same effect upon an intrinsic sensory neuron with Bactericides fragilis
What does JB-1 excite as well as intrinsic sensory neurons?
vagal afferent axons and has psychogenic effects in germ free mice
What is a key characteristic of bacterial metabolites?
many metabolic products of microbiome have direct actions on nervous system
What are key bacterial metabolites?
GABA, serotonin, histamine, LPS and short chain fatty acids
What is the role of GABA released by bacteria in the gut?
excites enteric and extrinsic primary afferent neurons
What is the role of serotonin released by bacteria in the gut?
excites enteric neurons and terminals of extrinsic primary afferent neurons
What is the role of histamine released by bacteria in the gut?
inflammatory mediator, excites enteric neurons
What is the role of LPS released by bacteria in the gut?
neuroactive cell wall component, acts on enteric neurons via toll-like receptors, enteroendocrine cells, enters blood stream
What is the role of short chain fatty acids released by bacteria in the gut?
can excite intrinsic sensory neurons and EE cells via specific G-protein-coupled receptors
How does stress modify the microbiome?
via cortisol
probably also via CRF receptors on enteric neurons
How does the microbiome modify central mood?
via cytokines, tryptophan metabolites
probably also via primary afferent neurons
How are germ-free mouse produced?
delivered under sterile conditions -> caesarian delivery, isolated from dams, reared and held in germ free conditions
Can antibiotics be used to achieve germ free status?
no
What happens to germ-free mice in terms of their development?
changes in ENS development and these mice are metabolically handicapped
Are germ free mice more or less anxious than mice with gut microbiota? How does this change following faecal transplant?
germ free mice are less anxious
anxiety measures increased by faecal transplant or instillation of a single probiotic strain
