Lecture 8 - Gut Microbiota Flashcards Preview

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1

Broad change in prevalence of diseases between 1950 and 2000

Reduction in incidence of infectious diseases
Increase in autoimmune, allergic, inflammatory disease

2

Hygiene hypothesis

Increased cleanliness associated with increased levels of autoimmune disease.
Reduced exposure to infectious agents leads to immune dysregulation

3

Hypotheses for why autoimmune diseases are increasing in prevalence in the Western world

1) Hygiene hypothesis
2) Microbiota hypothesis (human gut evolved to have bacteria)
3) Diet hypothesis (human microbiome changes according to diet)

4

Factors leading to altered diet in developed world

Economic
Demographic
Epidemiological

5

Aspects of Western diet that could lead to dysbiota

High in fat, sugar
Highly refined and processed
Low in fibre (important)

6

Factors potentially affecting microbiota composition

Host genetics
Maternal transfer, early colonisation
Antibiotics, medications
Infection
Inflammation
Stress
Hygiene
Age

7

Is the microbiome uniform through the GIT?

No. Increases in bacterial density/g from the stomach to the colon.

8

Human vs microbial genome in human body

Human genome has ~23,000 genes.
Microbiome has over 100,000 genes

9

Advances in studying GIT microbiome
1)
2)
3)
4)

1) Generation of germ-free mice
2) High throughput DNA sequencing
3) Transcriptional and metabolomic tools, with which to measure microbiota impact on host physiology, immunity, development
4) Development of tractable experimental systems (C. elegans, drosophila)

10

Germ-free mice

Mice raised in a germ-free environment. Can be from different genetic lines, clonal, non-clonal.
Can selectively restore bacteria in microbiome

11

High throughput DNA sequencing effect on studying microbiome

Can generate metagenomic analyses to compare metabolic and taxonomic data from different microbiota

12

What is the human microbiome project?
1)
2)
3)

1) NIH
2) First phase (2007-2012). Characterised composition and diversity of human microbiome in skin, nose, mouth, GIT, UGT. Evaluated metabolic potential.
3) Second phase (2013-2015). Create the first integrated dataset of biological properties of host and microbiome from cohort studies of microbiome-associated diseases

13

What is a healthy microbiome?

1) Varies a lot between individuals
2) Predictions can be made loosely based on country, breast feeding, level of education
3) No core microbiotal genome, but broad metabolic characteristics are shared

14

Study into the diversity of microbiota
1)
2)
3)

1) 16S rRNA sequences compared in mono- and dizygotic twins
2) No core genome shared. High variability in species/phylum composition
3) Analysis of genes showed a similarity in metabolic capacities

15

Two major phyla in GIT microbiome

Firmicutes
Bacteroidetes

16

Study into diet-induced changes in GIT microflora
1)
2)
3)
4)
5)

1) Microbiota of children from Burkina-Faso and Florence were compared.
2) Bacteroidetes dominated in Burkina-Faso
3) Firmicutes dominated in Italy
4) Diet has a larger role in shaping microbiome than ethnicity, climate, sanitation, hygiene
5) More pathogenic bacteria, lower SCFA levels in Italian children

17

Functional members of non-pathogenic GIT microbiome

1) Probiotics
2) Autobionts
3) Pathobionts

18

Probiotics

Transiently-present bacteria.
Can be beneficial.
EG: bifidobacterium spp, lactobacillus spp

19

Autobionts

Permanent, symbiotic, immunomodulatory.
Part of normal microbiome.
Direct influence on host immune function
EG: Bacteroidetes fragilis, clostridium XIV

20

Pathobionts

Permanent, parasitic/infectious.
Don't cause disease normally, unless microbiome is perturbed.
EG: Clostridium difficile, helicobacter

21

How are autobionts adapted to life in the GIT?

Express polysaccharide utilisation loci
Allows them to digest polysaccharides from plants.
Necessary for humans to be able to get nutrition from certain sugars (humans can only digest starch, maltose, sucrose).

22

Example of a polysaccharide utilisation locus in bacteroidetes ovatus

Xyloglucan PUL

23

Digestion of dietary fibre

1) Gut bacteria digest dietary fibre into short-chain fatty acids.
Bacteroidetes make acetate (2C), propionate (3C)
Firmicutes make butyrate (4C).
2) Short-chain fatty acids diffuse across lumen, are taken up by host transporters or bind to GPCR

24

Roles of short-chain fatty acids in GIT
1)
2)
3)
4)
5)

1) Stimulate mucus production by epithelial cells
2) Stimulate B cells to make IgA
3) Promote differentiation of Treg, leading to tolerance
4) Maybe lead to inflammosome activation, IL-18 release. This promotes epithelial integrity
5) Inhibition of inflammaroty NF-kB

25

Only source of nutrition for colonic cells

Short-chain fatty acids

26

Importance of the GIT microbiome
1)
2)
3)
4)
5)

1) ~10% of calorific intake
2) Vitamins B and K
3) GIT epithelial development
4) Immune system development and tolerance
5) Competition for pathogenic bacteria

27

Results of metagenome-wide association studies into microflora in T2DM patients
1)
2)

1) Decreased microbiome diversity associated with weight gain, insulin resistance, fatty liver, low-grade inflammation
2) Reduced butyrate products, increased pathogenic bacteria

28

Evidence for GIT microflora influencing adiposity
1)
2)
3)
4)

1) Gut microflora from obese/lean human twins transferred to mice
2) Tranfer of 'obese' microbiome resulted in greater adiposity
3) Presence of lean mice with a high-fibre diet or 'lean' microbiome led to decreased adiposity in obese mice (from coporophagy)

4) Transfer of microbiome from first trimester/third trimester pregnant women to mice. Mice that received first trimester remained lean. Mice that received third trimester became obese.

29

Modulation of host metabolism by short-chain fatty acid synthesis
1)
2)
3)

1) GPRC41 and GPRC43 stimulated. GPRC41 stimulation leads to peptide YY release. GPRC43 stimulation leads to hormone glucagon-like peptide release
2) Intestinal gluconeogenesis uses short-chain fatty acids as a carbon source
3) Inhibits fasting-induced adipose factor (FIAF).

30

Fasting induced adipose factor role

Inhibits lipoprotein lipase. Lipoprotein lipase leads to VLDL and chylomicron release of free fatty acids, leading to their storage in adipocytes.
Inhibiting FIAF might lead to increased adiposity