6. Bacteria-mucosal immunity

Question 1

Although colonization of the gut and other tissues by commensal bacterial is common to all metazoans, its extend increased during evolution particularly in vertebrates. Why? What happened?

Answer 1

Due to the emergence of new organs that could be colonized
- With this increase in colonization, metazoans developed an increasingly elaborate relationship with their gut flora

Question 2

What is the gastrointestinal tract the site of?

Answer 2

Where divergent needs of nutrient absorption and host defense collide
- Efficient nutrient absorption requires a larger surface area and a thin epithelium
- Efficient host defense requires the ability to discriminate btw the continuously resident microbiota with which it actively maintains a homeostatic balance, and the invasive pathogens to which it must respond

Question 3

Many commensals are SYMBIONTS that provide a benefit to the host. They are adapted to a state of MUTUALISM rather than adopting a niche that requires damage to host tissues. What are 3 major benefits to the host?

Answer 3

1. Metabolism of nutrients and organic substrates
2. Development of intestinal epithelium, vasculature and lymphoid tissue
3. Colonization resistance (i.e. formation of a barrier against pathogens)

Question 4

Immune ignorance

Answer 4

Suggests that physical or physiological barriers maintain a segregation btw tissues and immune cells and antibodies
- i.e. PASSIVE MECHANISM where host is unaware of this antigen

Question 5

Immune privilege

Answer 5

Indicates that certain sites in the body (ex. gut) are able to tolerate the introduction of antigen without eliciting an inflammatory immune response. But unlike ignorance, these are active mechanisms where the host is aware of its presence

Question 6

Why does immune privilege exist?

Answer 6

An evolutionary adaption to protect vital structures from the damaging effects of an inflammatory immune response
- Inflammation in the brain or eye can lead to loss of organ fxn, gut to inefficiency in nutrient absorption, while immune responses directed against a fetus can lead to the loss of progeny

Question 7

What does the epithelium overlying organized gut-associated lymphoid tissue (GALT) contain?

Answer 7

1. Specialized M cells that constantly transport gut bacteria and antigens from the gut lumen into the lymphoid tissue
2. DC in the LP reach through epithelial cells and also sample gut bacteria
3. The epithelium is filled with CD8+ T cells, and the LP contains many CD4+ T cells, macrophages, and IgA antibody-producing plasma cells
4. Potentially tissue-damaging T cell responses may be inhibited by immunosuppressive cytokines and regulatory T cells

Question 8

Gut-associated lymphoid tissue (GALT)

Answer 8

Mucosa-associated lymphoid tissue. Includes Peyer’s patches, appendix, and solitary lymphoid nodules in the submucosa

Question 9

M cells (or microfold cells)

Answer 9

Cells found in the follicle-associated epithelium of the Peyer’s patch that have the unique ability to sample antigen from the lumen of the SI and deliver it via transcytosis to APCs and lymphocytes located in a unique pocket-like structure on their basolateral side

Question 10

Lamina Propria

Answer 10

A thin layer of loose connective tissue beneath the epithelium and together with the epithelium constitutes the mucosa. Contains capillaries and a central lacteal (lymph vessel) in the SI, as well as lymphoid tissue. Also contains glands with the ducts opening on to the mucosal epithelium, that secrete mucus and serous secretions

Question 11

Peyer’s patches

Answer 11

Aggregations of lymphoid tissue that are usually found in the lowest portion of the SI (ileum) in humans; as such, they differentiate the ileum from the duodenum and jejunum in that the number of Peyer’s patches increase further down the intestine (ie. terminal ileum contains most Peyer’s patches). Located in the lamina propria of the mucosa and extending into the submucosa of the ileum

Question 12

How does the gut differentiate between pathogens and commensal bacteria?

Answer 12

Bacterial ligands (PAMPs) are shared and very good at activating NODs and TLRs

Question 13

Does sequestration of indigenous microflora by surface epithelia play a role in how the gut differentiates btw pathogens and commensal bacteria?

Answer 13

Commensals could be sequestered within the lumen while pathogenic bacteria equipped with virulence factors would be able to overcome barrier
- Bacterial flagellin activates basolaterally expressed TLR5 to induce epithelial proinflammatory gene expression

CONCLUSION: Basolateral flagellin activates epithelial chemokine secretion via an NF-kappaB-mediated mechanism
- TLR5 is expressed on model epithelia and polarized to the basolateral surface

Question 14

Does that mean that a single layer of gut epithelia is the only thing that separates 10^13 TLR inducing bacteria, which would surely cause septic shock?

Answer 14

NO!

Question 15

The gut epithelial layer is a highly dynamic structure that limits BUT…

Answer 15

Does not exclude antigens from entering the tissues
- Antigens can cross epithelial surface through breaks in tight jxns (villous tips where epithelial cells are shed)
- Intact food proteins have been detected in plasma
- A few gut bacteria have been detected in mesenteric lymph nodes draining the gut of healthy animals

Question 16

How do commensal bacterial contribute to the pathogenesis of inflammatory bowel diseases via inappropriate activation of the TLR system?

Answer 16

• TLRs fxn as sensors of microbial infection and are critical for the initiation of inflammatory and immune defense responses
• Bacterial ligands recognized by TLRs are not unique to pathogens, but rather are shared by entire classes of bacteria (ie. commensal microorganisms)

Question 17

In addition to proinflammatory responses, what else do TLRs contribute to?

Answer 17

Gut epithelial homeostasis (ie the integrity of gut epithelial layer

Question 18

Probiotics

Answer 18

Live microorganisms which when administered in adequate amounts confer a health benefit on the host’. Lactic acid bacteria (LAB) are the most common type of microbes used. LAB low food pH which may create fewer opportunities for spoilage organisms to grow. Also, probiotic bacterial cultures can assist naturally occurring gut flora to reestablish themselves. Strains of the genera Lactobacillus and Bifidobacterium, are the most widely used probiotic bacteria.

Question 19

Prebiotics

Answer 19

Non-digestible functional food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, and thus improve host health. Most are carbohydrates (such as oligosaccharides). Is not limited to a specific bacterial group. Often, however, it is assumed that a prebiotic should increase the number and/or activity of bifidobacteria and lactic acid bacteria.