The Human Microbiome: Role in Obesity & Diabetes (7/8)

Question 1

Describe the fibre content of ultra-processed food and how this affects the gut.

Answer 1

Lacks fibre
Fibre itself is not digestible by humans but is for gut microbiome
Ultra-processed food can alter the microbiome profile and cause inflammation

Question 2

Suggest why the same exercise is not equally beneficial for different people.

Answer 2

The benefits of exercise are affected by factors such as diet and the gut microbiome profile.

Question 3

What is the gut microbiome?

Answer 3

Ecological community of commensal, symbiotic and pathogenic microorganisms within the gut
It makes up 1-3% of total body mass

Question 4

What is the gut microbiome made up of?

Answer 4

Generally non-pathogenic made up of bacteria (mainly), viruses, protozoa, fungi
Symbiotic with host

Question 5

How is the gut microbiome studied?

Answer 5

Using 16S rRNA (small subunit of prokaryotic ribosomes) which is highly conserved in bacteria and archaea
Hyper-variable species specific sequences
No horizonal gene transfer - not transferred between species

Question 6

What is dysbiosis?

Answer 6

An imbalance between the types of organism present in a person’s natural gut microflora
Contributes to a range of conditions of ill health

Can involve and increase in potentially pathogenic bacteria (e.g. campylobacter or salmonella) causing acute illness or a relatively subtle alteration in the richness and/or diversity of bacterial species present in the gut

Question 7

What is richness in relation to the gut microbiome?

Answer 7

The total number of bacterial species in your gut microbiome

Question 8

What is diversity in relation to the gut microbiome?

Answer 8

The amount of individual bacteria from each of the bacterial species present in your gut microbiome

Question 9

How do diversity and richness of the gut microbiota change over time?

Answer 9

Increases during development
Remains stable in adulthood

Can decrease with ageing: inflammation or immunosenescence
Also decreases with chronic poor diet

Question 10

How can biased diets affect the gut microbiome?

Answer 10

Alteration of the microbiome species

A high fat diet -> alkaline environment tolerance
A high protein diet is the least dangerous
Atkins diet: high carbohydrates and proteins, no fat

Question 11

How can the gut microbiota affect the brain?

Answer 11

Bacteria communicate with each other by releasing GABA, which is a neurotransmitter that affects the brain

Other microbiota secretions include 5-HT (serotonin) precursors.

There is 2-way communication between the brain and the gut.
- Dysbiosis affects the brain
- Mental issues (stress, anxiety etc.) affect the gut

Question 12

How do adipose tissue and the liver cope with obesity?

Answer 12

Triglycerides are normally stored in adipose tissue
In obesity, adipose tissue can only cope up to a point
The liver copes with the excess triglycerides
Liver increases in size, becomes fatty
It can also cope up to a point

Question 13

What happens when the liver can’t cope with excess triglycerides in obesity?

Answer 13

Fatty liver disease will develop due to the build-up of excess triglycerides in the liver

Question 14

How does microbial dysbiosis contribute to fatty liver disease?

Answer 14

Increased production of intestinal ethanol can be toxic to the liver and can damage the gut permeability by destroying tight junctions

Leaky gut (loss of tight junctions between epithelial cells)

Question 15

How do pathogen-associated molecular patters (PAMPs) contribute to fatty liver disease?

Answer 15

PAMPs can bind to toll-like receptors in the liver and activates pro-inflammatory pathways. This causes hepatic inflammation and fibrosis

Question 16

How does choline metabolism contribute to fatty liver disease?

Answer 16

Gut microbiota hydrolyse choline to form dimethylamine and trimethylamine

Increased choline metabolism may cause choline deficiency, which prevents the excretion of very low-density lipoprotein (VLDL)
Initiates the accumulation of triglycerides in liver

Question 17

How does fasting-induced adipocyte factor (FIAF) contribute to fatty liver disease?

Answer 17

FIAF inhibits endothelial lipoprotein lipase (LPL) which releases triglycerides from VLDLs into the liver

Altered gut microbiota can inhibit the secretion of FIAF

Fasting-induced adipocyte factor (FIAF) = Angiopoietin-related protein 4 (ANGPTL4)

Question 18

What are the net effects of FIAF inhibition in fatty liver disease?

Answer 18

Inhibition of lipid β-oxidation and increased storage of hepatic triglycerides

Question 19

What are short chain fatty acids (SCFAs)?

Answer 19

Microbial metabolites that play a critical role in host metabolism and immunity through both local and systemic actions on multiple targets

They have different mechanisms in different organs

Question 20

How do short-chain fatty acids (SCFAs) contribute to fatty liver disease?

Answer 20

Excessive SCFAs are substrates for gluconeogenesis and fat synthesis in liver
They promote the accumulation of hepatic free fatty acids (FFAs) by inhibiting the activity of adenosine monophosphate activated protein kinase (AMPK)

Question 21

How do short-chain fatty acids (SCFAs) relate to the gut microbiota health?

Answer 21

A healthy gut microbiome increases the number of SCFAs through the fermentation of fibre
Overproduction of SCFAs is not good

Question 22

How are short-chain fatty acids (SCFAs) taken in by organs?

Answer 22

Through G-protein coupled receptors

Question 23

What is the mechanism of GLP-1?

Answer 23

Stimulated by SCFAs
Receptors in gut, liver, pancreas and hypothalamus

Improve insulin sensitivity, decrease gastric emptying, increase glucose uptake/oxidation etc.

Question 24

What effect does GLP-1 have in the hypothalamus?

Answer 24

It acts on the same neurones as leptin
Decreases gastric emptying to increase satiety signals

Question 25

How does the gut microbiome affect the response to exercise?

Answer 25

By generating FAA metabolites that trigger CB1 receptors on TRPV1+ sensory neurones (endocannabinoid receptors)
Exercise induced signal to brain promotes downregulation of MAO expression
This contributes to higher levels of dopamine and enhances exercise capability

Question 26

How does a “wiped out” gut microbiome affect exercise response (e.g., pre-diabetic)?

Answer 26

Decreased SCFAs and GABA
This reduces insulin sensitivity and glycaemic control

Question 27

How do CB1 antagonists affect exercise response/gut microbiome?

Answer 27

Increases AEA and 2-AG to increase exercise response
Anti-satiety

Question 28

Which taste receptors heterodimerise to detect which tastes?

Answer 28

T1R1-T1R3: Umami
T1R2-T1R3: Sweet
T2R Family (25 members): Bitter

Question 29

Which receptors detect medium- and long-chain fatty acids?

Answer 29

Free fatty acid receptor 1 (FFAR1) and G-protein coupled receptor 120 (GPR120)

Question 30

What signalling events occur after taste receptor binding/ heterodimerisation?

Answer 30

Gustatory G-proteins are activated, releasing intracellular Ca2+

This activated TRPM5 channels, allowing Na+ to enter the cell, depolarising it.
Further depolarisation after VGNC are activated (voltage-gated Na+).

Release of ATP through PX-1 activates purinergic receptors (P2X2/3) on afferent fibres leading to taste perception

Question 31

What is a proposed mechanism of the underlying effects of artificial/non-nutritive sweeteners?

Answer 31

NNS interact with the T1R2-3 and activate G protein α-gustducin

Increase of intracellular cAMP levels and increased neurotransmitter release

NNS also interfere with gut microbiota composition, with short-chain fatty acids (SCFAs) from dietary intake acting as ligands for GPCRs in the gastrointestinal tract, regulating NNS permeability and gut microbiota composition

Additionally, NNS are associated with insulin and other hormone secretion, which ultimately impact learned behaviour and response to sweetness