Lecture 18 - Microbiota Immune Response

Question 1

What are 2 tools for analyzing Microbiota-Immune

System Relationships?

Answer 1

1. High through-put DNA sequencing
   
   • Microbiome
2. Germfree animals

Question 2

What do commensal gut bacteria contribute to health?

Answer 2

1. Provide energy by metabolizing dietary polysaccharides
2. Provide vitamins
3. Required for development of the immune system
4. Protect from pathogenic bacteria

Question 3

Lack of GALT or if no exposure to commensals means no _____

What bacteria is useful?

Which isn’t?

Answer 3

Secondary lymphoid organs

1. B subtilis is useful

(not fragilis)

Question 4

How do antibiotics affect the commensals?

Answer 4

Cause C. Difficile

• gains a foothold and produces toxins that cause mucosal injury
• neutrophils and red blood cells leak into gut between injured epithelial cells
• connective tissue degradation leads to COLITIS and pseudomembrane formation

Question 5

Probiotic _______ protects
from enteric pathogen (like E. Coli)

How Can Commensals
Protect from
Intestinal Inflammation?

What increases the level of FOXP3?

Answer 5

Bacillus subtilis

2. Balance pro - and anti-inflammatory
   immune reactions
   Th vs Treg
3. B. Fragilis!
   - increases Tregs

Question 6

Dysbiosis can favor pro-inflammatory
(TH17 and TH1) over
anti-inflammatory (Treg) state

Answer 6

Dysbiosis

Question 7

IBD (Crohn’s Disease and Ulcerative Colitis)

What response is stimulated by microbial antigens?

Likely due to changes in what?

What is the initiating factor?

Answer 7

T cell-mediated inflammatory response due to stimulation by microbial antigens

IBD likely due to changes in development or
composition of intestinal microbiota (dysbiosis)

Commensal bacteria thought to be initiating factor
(not pathogen)

Question 8

What happens when feces from Tbet, Rag KO mouse are transplanted to a wild type?

Answer 8

Develop IBD in wild type mouse

Question 9

What can protect and treat IBD?

How?

What are some other diseases that can be causes by disruption of the gut microbes?

Answer 9

Bacteroides Fragilis

• via Treg anti-inflammatory responses

1. Allergy
2. Autoimmunity (MS/EAE)
3. Metabolic Syndrome (Obesity

Question 10

What happened to allergy in the following:

Children growing up on farms

Children attending day care during 1st 6 months of life

East German children compared to children in more developed West Germany

CHILDREN GIVEN ANTIBIOTICS FIRST YEAR OF LIFE

Answer 10

Decreased for all except children given antibiotics the first year of life

Question 11

As infectious diseases decline, what increases?

What is the hygiene hypothesis?

Answer 11

IMMUNE DISORDERS

• increase in allergy due to DECREASED EXPOSURE to microbes during childhood

Question 12

Balance between Th1 and Th2:

Bacteria and viruses elicit what response?

This down regulates what response which produces allergy?

Insufficient amounts of Th1 response due to decreased bacteria would increase what?

Answer 12

1. Elicit Th1 response
   (Il-2 and INF gamma)
2. Th1 down regulates Th2
3. Insufficient Th1 response due to decreased bacteria and viral infections would increase Th2 (Ige)

Question 13

What can protect from EAE (autoimmune disease)

Answer 13

Intestinal bacteria

• induction of Tregs

No many microbes = no signaling through MyD88  often only get IgE!!!! ONLY ALLERGY

**B. Fragilis  can end up generating toleragenic DCs  activating FOXP3 = protect from EAE

Question 14

TLR5 KO mouse have increased what?

What is altered?

What reverses this?

What can intestinal microbiota cause?

Answer 14

1. increased food intake, insulin resistance, hypertension and are obese
2. altered gut microbiota
3. Antibiotic treatment reverses it

• • can cause metabolic syndrome ** (obesity)
• transfer feces from TLR5 - mouse(obese) to antibiotic treated wild type = obese mouse

Question 15

How can microbiota promote obesity?

What can human intestinal bacteria do?

Answer 15

Induces changes in microbiota due to HIGH FAT DIET

PROTECT FROM OBESITY

ex: twin study –> fat/lean feces transplanted to mice

Question 16

Gut bacteria from thin humans can protect mice from what?

If given low-fat diet, lean-associated microbiota can
prevent _____

With high-fat diet, lean microbiota _____

Answer 16

OBESITY

obesity in mice with obese-associated microbiota.

did not prevent obesity.

Question 17

What are the 4 main causes of Dysbiosis?

Answer 17

1. Antibiotics
2. Diet, especially high-fat diet
3. Early childhood experience
   (hygiene hypothesis)
4. Model of delivery: Vaginal vs. Cecarean

Question 18

What decreases when antibiotics are administered?

Answer 18

Anti-microbial peptides

• which accounts for the homeostasis of the microbiota

Question 19

Antibiotic Treatment Impairs ____

Therapy

Answer 19

Cancer

• decrease survival of those who receive both the drug AND the antibiotics compared to those on the drug alone

Question 20

Commensals can suppress _____ responses and protect from diseases in intestine and other organs.

Protection is mediated by balancing __(what Th response?)___ and _____(anti- inflammatory) cells

Dysbiosis of gut commensals likely contributes to what?

Antibiotics that kill commensals effect ______

Answer 20

Inflammatory

2. TH (TH1 & TH17, pro-inflammatory)

and Treg

3. chronic inflammatory diseases, e.g., IBD, autoimmunity, allergy and obesity
4. cancer drug effectiveness

Question 21

Causes of dysbiosis are?

Answer 21

Dysbiosis caused by

1. diet,
2. antibiotics
3. stress, and
4. possibly by early childhood exposure to commensals