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BIOM30001 - Frontiers in Biomedicine > Lecture 8 - Microbiota > Flashcards

Lecture 8 - Microbiota Flashcards

1
Q

Describe the trends of human disease in the Western world since 1950

A

Decreased incidence of:
• Infectious disease

Increase incidence of:
 • Autoimmune and allergic disease:
 • Asthma
 • Allergy
 • MS
 • Crohn's disease
 • T1DM
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2
Q

Describe the hygiene hypothesis for increased incidence of allergic and autoimmune disease

A

The increased sanitation has meant that we are not exposed to the same pathogens:
• Increased cleanliness
• Vaccination
• Antibiotic use

Our immune system becomes dysregulated

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3
Q

Describe the role of microbes in the development and function of the immune system

A

We know this through studying germ free mice:

• Underdeveloped Peyer’s patches

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4
Q

Describe the ‘Old Friends’ hypothesis

A

The vital microbial exposure is not infectious, rather our natural commensal microbiota

Humans co-evolved with these harmless organisms

Microbes are vital for the development and function of the immune system

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5
Q

What is the most important factor in the composition of the microbiota?

A

Diet; esp. fibre

There has been a profound transition in diet in the last 50 years

This is leading to profound changes in the microbiota, and hence in disease

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6
Q

Describe the presence of the microbes along the alimentary canal

A

Non-uniform presence

Increased density as one progresses from stomach to colon

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7
Q

Describe the Human Microbiome Project

A
  1. First phase
    • 2007-2012
    • Characterisation of composition of various locations (nose, mouth, skin, GIT, UGT)
    • Evaluation of genetic metabolic potential
  2. Second phase:
    • 2013-2015
    • Creation of integrated dataset of biological properties from microbiome and host
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8
Q

Describe the genetic implications of the microbiome

A

Human genome: 23,000 genes

Human microbiome: > 1 million genes

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9
Q

Is there such thing as a healthy microbiome?

A

Each person has a unique microbiome

Two individuals may have different micro biomes, but still have a ‘healthy’ microbiome

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10
Q

Describe the variability of the microbiome and the implications of this

A

The gut microbiota is highly variable (on a phylum level)

However, the metabolic capacity does not vary that much

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11
Q

Describe the study of microbiota in children from Burkina Faso and Florence

A

Diet:
Burkina faso:
• Pre-industrialisation diet

Florence:
• Modern, western diet

Composition of microbiota:
• Vastly different composition of microbiome

Conclusion:
• Diet is a dominant driver of the composition of the microbiome

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12
Q

Compare dominant bacteria genera found in children from Burkina Faso and Florence

A

Burkina faso:
• Predominantly Bacteroidetes

Florence:
• Predominantly Firmicutes

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13
Q

Define the following:
• Probiotics
• Autobionts
• Pathobionts

Give examples of each

A

Probiotics:
• Transient
• Beneficial bacteria consumed
• e.g. Lactobacillus spp., Bifidobacterium spp.

Autobionts:
 • Permanent
 • Symbiotic
 • Immunomodulatory
 • e.g. Bacteriodetes fragilis
Pathobionts:
 • Permanent
 • Parasitic / infectious
 • Cause opportunistic infections
 • e.g. C. difficile
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14
Q

Describe the role of autobionts in digestion

A

Autobionts are adapted to life in the gut

Express PUL (polysaccharide utilisation loci) when there is polysaccharide present in the diet

PUL products are capable of digesting many plant polysaccharides present in dietary fibre

Humans do not have enzymes that can break down dietary fibre

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15
Q

Describe Bacteroides ovatus’ break down of xyloglucan

A

B. ovatus expresses a PUL capable of breaking down xyloglucan

Xyloglucan PUL:
• 8 glycosyl hydrolyses
• 2 glycan transporters
• 2 glycan chaperones

Xyloglucan is a complex carbohydrate present in dietary fibre that humans cannot digest on their own

B. ovatus has a complex system of breaking down xyloglucan:
• Chaperones on outer membrane capture sugar
• Endoglycosylases on OM that cleave within the polysaccharide
• Transporter on OM moves oligosaccharides into periplasmic space
• Further digestion
• Monosaccharides move through transporter on inner membrane into bacterial cell

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16
Q

Which molecules are largely produced in the break down of dietary fibre?

Give specific examples

What happens then to these breakdown products?

A

SCFA: short chain fatty acids

Examples:
• Acetate (Bacteroides)
• Propionate (Bacteroides)
• Butyrate (Firmicutes)

SCFAs move into host cells through a variety of mechanisms:
• Passive diffusion
• Transporters
• Binding to GPRC

17
Q

List some roles of SCFAs

A
  • Stimulation of mucous secretion
  • IgA production
  • Tissue repair & epithelial integrity
  • Inhibition of inflammation (through inhibition of NFKB)
  • Promotion of Tregs
18
Q

List the various roles of gut microbiota

A
  • Digestion of dietary fibre
  • Production of vitamins (B and K)
  • Gut epithelial development
  • Immune system development, tolerance development
  • Barrier function (occupation of niche)
19
Q

Describe the observations in the gut microbiota in obesity and T2DM

A

Significant changes in gut microbiota
(this could underlie increased chronic inflammation)

  • Low diversity
  • Dysbiosis
  • Reduced butyrate production
  • Increased opportunistic pathogens
20
Q

Describe studies in microbiota transplant studies in mice, looking at obesity, T2DM and pregnancy

A

Obesity & T2DM:
• Gut microbiota from obese/lean human twins transferred to mice
• Mice who received ‘obese’ microbiota had greater body mass and adiposity than those who received ‘lean’ microbiota

Pregnancy:
• Gut microbiota from pregnant women in first and third trimester transferred to mice
• ‘Third trimester’ microbiota mice had increased body mass and insulin insensitivity than ‘first trimester’ microbiota

NB Women in third trimester of pregnancy experience:
 • Weight gain
 • Insulin insensitivity
 • Dysbiosis
 • Increased inflammation
21
Q

Describe bacteria can modulate host metabolism

A

SCFA products from bacteria can signal in a variety of mechanisms to lead to changes in host metabolism:

1. GPRC41
 • SCFA binds GPRC41 on enterocytes
 • S-T pathway
 • Enterocytes release PYY
 • PYY regulates gut motility and suppresses hunger
  1. GPCR43
    • SCFA binds GPRC43 on enterocytes and adipocytes
    • Results in release of GLP1 from enterocytes
    • Inhibits insulin signalling in adipocytes → inhibits uptake and storage of glucose in adipocytes
  2. Intestinal gluconeogenesis
    • SCFA diffuse into enterocytes and are used as a carbon source for intestinal gluconeogenesis
  3. Fiaf (fasting induced adipose factor
    • Dietary fibre inhibits Fiaf (?*)
    • Fiaf normally inhibits lipoprotein lipase and fat accumulation in adipocytes
22
Q

What is PYY?
What are its actions?
What triggers its release?

A

PYY: peptide-YY

Actions:
• Regulation of gut motility & intestinal transit time
• Suppresses hunger

23
Q

What is GLP1?

What triggers its release?

A

Glucagon-like peptide 1

Released by enterocytes through GPRC43 signalling

Function:
• Potent anti-hyperglycaemic hormone
• Stimulates insulin secretion
• Inhibits glucagon secretion

24
Q

What is the effect of signalling through GPRC43 on adipocytes?

A

Inhibition of insulin signalling, inhibiting glucose uptake and storage in adipocytes

25
Q

What is IGN?

What is the role of SCFAs in IGN?

A

Intestinal gluconeogenesis

SCFAs are used as a carbon source for IGN

26
Q

Describe the action of Fiaf

A

Inhibits lipoprotein lipase

i.e. inhibits fat digestion in intestine

27
Q

Describe the importance of GPRC43

What happens when it is KO’d or over expressed?

A

GPRC43:
• SCFAs signal through this receptor on enterocytes and adipocytes
• Leads to release of GLP-1 in enterocytes
• Leads to inhibition of insulin in adipocytes

KO:
• Mice are obese on lean diet

Over-expression:
• Mice are lean on high calorie diet

28
Q

Describe the effects of dysbiosis on inflammation and immunity

A

Changes during dysbiosis:
• Increased local and systemic inflammation

  • Preponderance of Th17 over Tregs
  • Increased presence of pathobionts and release of LPS
  • Decreased barrier function
  • Increased gut bacteria in blood
29
Q

Describe how the gut microbiota regulates Treg / Th17 balance

What are the effects of both of these subtypes?

A

Treg:
• Stimulated by butyrate
• ‘Immunosuppressive’
• Releases IL-10

Th17:
• Stimulated by pathobionts
• Inflammatory
• Releases IL-17

30
Q

Compare the following in children from Burkina Faso and Florence:
• SCFA
• Pathogenic bacteria

A

Burkina Faso:
• Increased SCFA levels
• Decreased pathobiont levels

Florance:
• Decreased SCFAs
• Increased pathobionts

Pathobionts:
 • Escherichia spp.
 • Salmonella
 • Shigella
 • Klebsiella
31
Q

Compare healthy and disrupted microbial communities in the gut

A 
Healthy:
 • Substantial microbiota population occupying the niche
 • IgA production
 • Maintenance of epithelial integrity
 • Mucous production
Disrupted:
 • Depleted microbiota
 • Overgrowth of pathiobionts
 • Epithelial amage
 • Dissemination of pathogens and commensals into blood
32
Q

Describe the effect of dysbiosis on systems around the body

A

Brain:
• Decreased satiety
• Behavioural problems

Lungs:
• Asthma

Liver:
• Development of NAFLD

Pancreas:
• Diabetes

Allergy

Joints:
• Autoimmune arthritis

33
Q

Describe ways that microbiota can be used as immunotherapy

A

Diet:
• Less fat, more fibre

Prebiotics:
• Compounds that are good for microbiota

Probiotics:
• Beneficial bacteria

Faecal transplant

Targeted manipulation

34
Q

Describe trends in fibre intake currently

A

Both men and women consume roughly half of recommended fibre

Women require less, but still aren’t getting enough

35
Q

Describe the importance of early life in terms development of immunoallergic diseases

A

Early life is the most important phase of life

Evidence:
• Populations moving from regions of low risk of these diseases to regions of high risk (e.g. India to Europe / US)
• The earlier an individual moves, the more likely they are to develop the disease

Rationale:
• The interaction between microbiota and host immune system is established early in
life

Implications:
• Antibiotic use early in life is v. risky

36
Q

Describe the use of faecal transplants to treat C. difficile infections

A

Faecal transplants from healthy donors are effective at treating C. difficile infections

37
Q

What is the trouble with faecal transplant?

How could this be averted?

A

Must be certain that there are no pathogens in the transplant

Other approaches:
• Cultured autobionts
• Inclusion of microbiota small molecules in diet

BIOM30001 - Frontiers in Biomedicine (35 decks)

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