Gut Microbiota in Disease Pathology

Question 1

Define dysbiosis.

Answer 1

When changes to the amount and quantity of microbiota causes pathology. Affected by interactions between food, bacteria and the immune system.

Question 2

What is the effect of large fibre molecules in the diet?

Answer 2

Digested by specific types of microbiota that break them down to give SCFAs, e.g. acetate and butyrate.

Question 3

Give the effects of butyrate on the gut immune system.

Answer 3

Binds the GPR43 receptor on Tregs - promotes Treg survival and results in increased IL-10 production.

Question 4

Give evidence of diet influencing the presence of certain bacteria.

Answer 4

High fat diets significantly increase colitis incidence in IL-10 KO mice, more than lower fat diets. High fat diet increased presence of B.wasdsworthia - causes increased colitis.

Question 5

How does the immune system affect the microbiota composition?

Answer 5

Through the production of IgA that is specific to certain bacteria.

Question 6

How do segmented filamentous bacteria (SFB) affect immune cells?

Answer 6

Increases number of Th17 - healthy homeostasis.

Question 7

How do clostridia affect immune cells?

Answer 7

Increases number of Tregs - healthy homeostasis.

Question 8

How do prevotella affect immune cells?

Answer 8

Increases number of Tregs, when found above the mucus layer. Increases number of Th1/Th17 cells when found at the epithelial cell layer during dysbiosis.

Question 9

How do klebsiella affect immune cells?

Answer 9

Increases the number of Th1 and Th17 cells - causing inflammation.

Question 10

Describe IBD.

Answer 10

Includes ulcerative colitis and Crohn’s disease. Complex diseases with many factors involved, including defects in autophagy, and the roles of miRNAs.

Question 11

What does the increased incidence of IBD in western countries suggest?

Answer 11

Suggests that lifestyle is influencing incidence - but it is hard to tell to what extent this is due to improved diagnostic methods.

Question 12

How many susceptibility genes have been identified for IBD?

Answer 12

> 200, e.g. the NOD2 NLR.

Question 13

Give the features of dysbiosis in IBD.

Answer 13

• reduced microbiota diversity.
• decrease of SCFA-producing bacteria.
• increase of mucolytic bacteria.
• increase of sulfate-reducing bacteria.
• increase of pathogenic bacteria, e.g. E. coli.

Question 14

What is the result of reduced microbiota diversity in dysbiosis?

Answer 14

Decrease energy sources available for epithelial cell growth - pathogens can pass barrier more easily.

Question 15

What is the result of a decrease of SCFA-producing bacteria during dysbiosis?

Answer 15

Decreased Treg survival and increased inflammation.

Question 16

What is the result of an increase of mucolytic bacteria during dysbiosis?

Answer 16

Degradation of mucus layer - pathogens can pass barrier more easily.

Question 17

What is the result of an increase of sulfate-reducing bacteria in dysbiosis?

Answer 17

Increased epithelial cell damage and inflammation.

Question 18

What does an increase in pathogenic bacteria during dysbiosis affect?

Answer 18

Alters mucosal permeability.

Question 19

Give evidence for a change in microbiota composition in IBD.

Answer 19

Mice fed TNBS (chemically damages the epithelium and induces colitis) could be rescued by addition of F. prausnitzii. Reported that F.prauznitzii is depleted in IBD patients.

Question 20

What effect does regular antibiotic treatment have on gut microbiota?

Answer 20

Kills microbiota, enabling colonisation of pathogenic bacteria that are normally kept out by the commensal bacteria.

Question 21

How is C. difficile infection prevented in the gut?

Answer 21

Primary bile acids produced in the gut are converted to secondary bile acids which have negative effects on the growth of C. difficile.

Question 22

What effect does antibiotic treatment have on C.difficile infection?

Answer 22

When commensal bacteria are lost due to antibiotic treatment, there is an imbalance in the production of primary bile acids -> secondary bile acids not produced.
This promotes the presence of succinate -> aids growth of C.difficile.

Question 23

What is an effective treatment for recurring C.difficile infection?

Answer 23

Transplant of healthy donor faeces into the lower parts of the stomach of patients - faeces contains microbiota. Not yet common practice.

Question 24

Give an example of a disease where other organs are affected by gut microbiota.

Answer 24

Rheumatoid arthritis.

Question 25

What is rheumatoid arthritis?

Answer 25

Chronic autoinflammatory disease affecting joints and other tissues.

Question 26

How many candidate gene have been identified for rheumatoid arthritis?

Answer 26

100 - where HLA is the most important genetic risk factor.

Question 27

Give examples of host proteins that auto-antibodies are produced against in rheumatoid arthritis.

Answer 27

Rheumatoid factor and anti-citrullinated proteins.

Question 28

Where can auto-reactive antibodies be found in rheumatoid arthritis?

Answer 28

In the synovial fluid.

Question 29

Describe changes to gut microbiota in rheumatoid arthritis patients.

Answer 29

- Decreased Bifidobacteria. - Decreased Bacteroidetes. - Increased Prevotella.

Question 30

Give evidence that rheumatoid arthritis originates at mucosal surfaces.

Answer 30

IgA anti-citrullinated protein antibody (ACPA) is detectable before the onset of arthritis.

Question 31

Give evidence that rheumatoid arthritis is influenced by microbiota.

Answer 31

IL-1Ra -/- mice develop arthritogenic disease - does not occur in germ free mice. Addition of lactobacillus to germ free mice - disease incidence increases.

Question 32

Give evidence that the TLR4 pathway is involved in bacterial recognition and development of arthritis.

Answer 32

TLR4 KO mice had decreased disease severity.

Question 33

Describe the hygiene hypothesis.

Answer 33

If an individual grows up in a family environment or day care centres, they are less likely to develop allergies. Children living in a more sterile environment, from single-child families, are more likely to develop allergies, asthma and eczema.

Question 34

What is the relationship between the western world and allergy incidence?

Answer 34

We no longer encounter enough antigens in the western world to give the correct microbiota and immune system development, giving enhanced onset of allergies and autoimmune disease.

Question 35

Why has there been evidence that farm environments lowered incidence of allergy in children?

Answer 35

Pregnant mothers encounter more microbial products and xenogenic signals when living in farm environments -> activates Th1 responses. Without this, there is activation of Th2 (in competition with Th1), and development of allergies and autoimmune disease.

Question 36

What is a potential danger of farm lifestyles?

Answer 36

Potential to encounter dangerous pathogenic pathogens which require treatment with high doses of antibiotics, which negatively affects the microbiome.

Question 37

Give evidence that the microbiota are required for development of the gut immune system.

Answer 37

Germ free mice have poorly developed MLNs, PPs, cryptopatches and isolated lymphoid follicles. Colonisation with a single bacterial species can reverse this.

Question 38

What is needed in future research in mucosal immunology?

Answer 38

To look at it as a global organ, to understand the relationships between different mucosal sites.

Question 39

Give an example of cross-talk between mucosal sites.

Answer 39

Use of antibiotics in neonatal mice is associated with a greater risk of developing asthma - suggesting that fut microbiota can affect the lung.