Lecture 14: Neuropsychiatry and the Gut Microbiota 1

Question 1

What is the most common neuropsychiatric disease?

Answer 1

schizophrenia

Question 2

What are the types of symptoms of schizophrenia?

Answer 2

positive (psychosis), cognitive and negative

Question 3

What are symptoms of autism spectrum disorder?

Answer 3

stereotyped or repetitive motor movements, use of objects, or speech
highly restricted, fixated interests
hyper- or hypo-reactivity to sensory input

Question 4

What are examples of neuropsychiatric diseases with gastrointestinal involvement?

Answer 4

parkinson’s disease, ASD and schizophrenia

Question 5

What is Parkinson’s disease associated with?

Answer 5

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

Question 6

What is ASD associated with?

Answer 6

up to 90% report GI symptoms ranging from constipation to diarrhoea

Question 7

What is schizophrenia associated with?

Answer 7

significant evidence of GI inflammatory issues in > 30% of patients

Question 8

What is evidence of neuropsychiatric diseases being genetic disorders?

Answer 8

twin studies show a high degree of concordance between monozygotic twins
but significant environmental component determines penetrance and severity

Question 9

What are examples of the environment playing a major role?

Answer 9

brothers with the same ASD producing mutation have markedly different presentations
some individuals with disease producing mutations never show symptoms

Question 10

What is an essential part of the environment for any animal?

Answer 10

the GI microbiota

Question 11

Why are the microbiota relevant to neuroscience?

Answer 11

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

Question 12

What does probiotic bacteria cause altered activity of?

Answer 12

enteric neurons in rodents

Question 13

What have various studies indicated that ASD symptoms may be related to?

Answer 13

composition of the microbiota

Question 14

What can stress and anxiety modulate?

Answer 14

the microbiota and vice versa

Question 15

What can stress/disease of the normal microbiota and CNS lead to?

Answer 15

alterations in behaviour, cognition, emotion, nociception
altered levels of inflammatory cells and / or mediators
intestinal dysbiosis

Question 16

How many more distinct genes are there in the microbiome than in the human genome?

Answer 16

150x to 300x more distinct genes

diversity has been correlated with health

Question 17

How many more bacteria are there in the gut than there are cells in the human body?

Answer 17

the gut contains about 10x more bacteria than there are cells in the human body

Question 18

What type of bacteria are present in the colon?

Answer 18

almost exclusively anaerobic

Question 19

Why type of bacteria are present in the caecum?

Answer 19

about 20% aerobic

Question 20

What can change the proportions of normal microbiota?

Answer 20

diet, stress, probiotics and antibiotics can change proportions, but species mix remains relatively constant

Question 21

What does bacteria in mucus associated with epithelium differ from?

Answer 21

those in the lumen itself

Question 22

What is a tool for study of gut microbiome?

Answer 22

16S ribosomal RNA sequencing and next generation whole genome sequencing methods for identifying presence of different species

Question 23

What is metabolomics?

Answer 23

identification of the metabolic products produced by colonic bacteria

Question 24

What are germ-free mice used for?

Answer 24

behavioural studies
functional studies at single neuron level
can introduce whole microbiota (faecal transplant) or single bacterial strains (probiotic)

Question 25

How does what we eat change the microbiota?

Answer 25

what we eat and how often determines the competitive advantage of different microbes

Question 26

Why are prebiotics used?

Answer 26

to favour specific species at the expense of others

Question 27

How does exercise change the microbiota?

Answer 27

by altering blood flow to the gut and thus changing the balance between secretion and absorption of water

Question 28

How does diarrhoea or constipation each alter the microbial system?

Answer 28

by altering transit through the colon thereby disrupting turnover of the faecal microbiota

Question 29

What are basic experimental approaches for determining whether the microbiota change behaviour or not?

Answer 29

germ-free studies, infection studies, faecal-transplantation studies, antibiotic studies, probiotic studies

Question 30

What is JB-1?

Answer 30

a type of bacteria which has the same effect upon an intrinsic sensory neuron with Bactericides fragilis

Question 31

What does JB-1 excite as well as intrinsic sensory neurons?

Answer 31

vagal afferent axons and has psychogenic effects in germ free mice

Question 32

What is a key characteristic of bacterial metabolites?

Answer 32

many metabolic products of microbiome have direct actions on nervous system

Question 33

What are key bacterial metabolites?

Answer 33

GABA, serotonin, histamine, LPS and short chain fatty acids

Question 34

What is the role of GABA released by bacteria in the gut?

Answer 34

excites enteric and extrinsic primary afferent neurons

Question 35

What is the role of serotonin released by bacteria in the gut?

Answer 35

excites enteric neurons and terminals of extrinsic primary afferent neurons

Question 36

What is the role of histamine released by bacteria in the gut?

Answer 36

inflammatory mediator, excites enteric neurons

Question 37

What is the role of LPS released by bacteria in the gut?

Answer 37

neuroactive cell wall component, acts on enteric neurons via toll-like receptors, enteroendocrine cells, enters blood stream

Question 38

What is the role of short chain fatty acids released by bacteria in the gut?

Answer 38

can excite intrinsic sensory neurons and EE cells via specific G-protein-coupled receptors

Question 39

How does stress modify the microbiome?

Answer 39

via cortisol | probably also via CRF receptors on enteric neurons

Question 40

How does the microbiome modify central mood?

Answer 40

via cytokines, tryptophan metabolites | probably also via primary afferent neurons

Question 41

How are germ-free mouse produced?

Answer 41

delivered under sterile conditions -> caesarian delivery, isolated from dams, reared and held in germ free conditions

Question 42

Can antibiotics be used to achieve germ free status?

Answer 42

no

Question 43

What happens to germ-free mice in terms of their development?

Answer 43

changes in ENS development and these mice are metabolically handicapped

Question 44

Are germ free mice more or less anxious than mice with gut microbiota? How does this change following faecal transplant?

Answer 44

germ free mice are less anxious | anxiety measures increased by faecal transplant or instillation of a single probiotic strain