The number of microorganisms residing in our intestines is
10 times the number of our somatic and germ cells.
The number of microorganisms residing in our intestines is
10 times the number of our somatic and germ cells.
But the bugs are not
distributed equally
http://en.wikipedia.org
Stomach: relatively few
Small Intestine: more
Cecum & colon: lots & lots
What’s the cecum all about?
•
material undigested by the host (coarse, fibrous
foods) passes slowly through the cecum
•
longer residence time = more complete microbial
degradation = nutritional benefit to the host
•
animals which lack a cecum are largely able to use
their own enzymes to digest their food
http://en.wikipedia.org
Herbivores
Source:
Carnivores
Omnivores
Herbivores
Source:
Carnivores
Omnivores
Herbivores
Source:
Carnivores
Omnivores
Herbivores
Source:
Carnivores
Omnivores
Herbivores
Source:
Carnivores
Omnivores
Herbivores
Source:
Carnivores
Omnivores
Herbivores
Source:
Carnivores
Omnivores
Who makes up our intestinal microbiota?
-
Bacteria, archaea and eukarya
-
Only 8 of 55 bacterial divisions
-
-
Cytophaga-Flavobacterium-Bacteroides (CFB), Firmicutes,
Proteobacteria and 5 rare divisions
Coevolution
-
mammalian associated CFB members are most derived
CFB subgroups are divided among different mammalian
species, suggests subgroups coevolved with their hosts
The 55 bacterial divisions
Red: common in intestine
Green: rare
Black: not detected
Note: evolutionary distance of divisions marked in red
Phylogenetic tree of CFB division based on 16S rRNA gene sequences
graphical symbols represent the source of the sequences
Ratio: number of sequences derived from human gut relative to total number in the subgroup
red: majority of sequences derived from human gut
yellow: minority
black: absence
Who makes up our intestinal microbiota?
-
Few divisions, but high strain and species diversity
Who makes up our intestinal microbiota?
-
Few divisions, but high strain and species diversity
although “genus” and “species” not precisely defined
for microbes
Few divisions, but many strains...
a result of host-selection?
-
Natural selection at two levels (at least)
-
-
competition among individual microbes
integrated microbiota do not harm the host
So...is there a mechanism to promote cooperation
and functional stability?
-
bacteria must break down nutrients and provide the host
with energy
-
cooperation...group selection (ambiguous)
-
functional stability...redundancy of key processes distributed
among many strains
How stable is our gut microbiota?
i.e. can functional stability be maintained among strains
-
stability was shown for ~6 months with TGGE
What is responsible for maintaining stability?
-
Physical factors
-
-
Our immune system
-
-
*
pH, oxygen tension, temperature, peristalsis, bile acids*
IgA in mice **
Also shown that gut microflora are unable to induce
antibodies, especially when present in GI tract *
These microbes often share antigens with the mucosa of
the gut (recognized as self) *
**
What is responsible for maintaining stability? (cont.)
-
-
Phage attack
-
is there enough strain diversity to withstand phage attack and
maintain functional stability?
-
could we recruit phage to help shape our microbiota?
Influence of host genotype vs. type of food consumed
-
adult monozygotic twins living apart have flora more similar
than unrelated individuals
-
marital partners, consuming the same food, do not
What is responsible for maintaining stability? (cont.)
What is responsible for maintaining stability? (cont.)
But...
- were the twins fed the same way as infants?
- do they have similar eating habits?
How are we colonized?
-
GI tract sterile in normal fetus
-
Colonization occurs during suckling
-
Lactobacillus sp. predominate in formula-fed infants
(Firmicutes division)
-
Bifidobacterium sp. predominate in breast-fed infants
(Actinobacteria division)
A model organism: Bacteroides thetaiotaomicron
-
Habitat is distal intestine
-
Genome reflects towering ability to digest
otherwise indigestible polysaccharides
-
163 paralogs of outermembrane proteins involved
in starch binding and uptake
-
15 polysaccharide lyases
-
226 predicted glycoside hydrolases (we have 98)
-
64 predicted enzymes involved in the degradation
of dietary fiber (we have one)
How is the carbohydrate foraged?
-
Gnotobiotic mice colonized exclusively with B. thetaiotaomicron
-
Communities of bacteria assemble on:
-
undigested food particles, shed mucosa, exfoliated epithelial cells
actively degrade food particle, and release SCFA, CO2 and H2
-
Methanogenic archaea improve transformation
efficiencies by converting CO2 and H2to CH4
-
B. thetaiotaomicron lacks adhesive organelles
-
relies on outer membrane glycan binding proteins
binding protein expression is diet dependent
What to do when there are no food particles?
-
B. thetaiotaomicron is able to turn to host glycosides
when diet is scarce
-
glycans on host mucosa and epithelial cells
- depend on host genotype and microbial regulation of host
glycosyltransferase gene expression
-
maintain gut ecosystem stability during starvation
-
may avoid immune response by
-
ability to change carbohydrates on surface (recognized epitopes)
in response to glycans in the gut
-
ability to alter its genome content (63 transposases, 43
integrases, 4 homologs of a conjugative transposon) but growth
rate?
1) no adhesive organelles
3) methanogens drive
carbohydrate utilization
2) glycan specific binding
on food platform
4) bind to host glycans
in absence of food
1) no adhesive organelles
3) methanogens drive
carbohydrate utilization
2) glycan specific binding
on food platform
4) bind to host glycans
in absence of food
1) no adhesive organelles
3) methanogens drive
carbohydrate utilization
2) glycan specific binding
on food platform
4) bind to host glycans
in absence of food
1) no adhesive organelles
3) methanogens drive
carbohydrate utilization
2) glycan specific binding
on food platform
4) bind to host glycans
in absence of food
What is the difference between
germ-free and conventionally raised mice?
from Table S-2
GF mice have 40% less body fat than CONV-R animals fed same polysaccharide rich diet
- CONV-R eat less food
- - innoculating GF adults with CONV-R cecal contents increases body fat
Why does gut microflora result in body fat?
-
Colonization increases glucose uptake and elevates
serum glucose, SCFA, and insulin levels
-
-
induces lipogenesis (fat production) from liver
Triglycerides from liver taken up by adipocytes (fat
storage cells) via lipoprotein lipase (LPL)
-
microbiota suppress expression of LPL inhibitor
Why does gut microflora result in body fat?
-
Colonization increases glucose uptake and elevates
serum glucose, SCFA, and insulin levels
-
-
induces lipogenesis (fat production) from liver
Triglycerides from liver taken up by adipocytes (fat
storage cells) via lipoprotein lipase (LPL)
-
microbiota suppress expression of LPL inhibitor
White Adipocyte
Brown Adipocyte
http://www.bioeng.auckland.ac.nz
How does this impact nutrition fact labeling?
-
Our intestinal microbiota dictate (in part) how
efficiently we produce and store fat
-
Could individual gut microflora efficiency really
make a difference?
-
microflora dependent on host genotype
-
small but chronic difference between energy produced:
consumed can make a significant difference (ambiguous)
-
microbes themselves consume a lot of energy
-
obese mice study
image credit: Ralph House
-
ob/+ mothers produce obese (ob/ob), lean (ob/+) and wild type
(+/+) offspring
-
all mice fed the same diet since birth
-
Analyzed 5,088 cecal-micobiota 16S rDNA sequences
-
Obese mice have a 50% reduction in the abundance of
Bacteroides and a proportional increase in Firmicutes
-
Mouse and human gut microconsortia are similar at the division
level, but not at the species level
-
Could this be why domestic animals gain weight more efficiently
when fed antibiotics?
Future Work
-
Focus on contribution from archaea
-
Metagenome sequencing
-
identify gene content (extension of HGP)
-
characterize difference between healthy and sick ethnically
diverse groups
-
characterize difference between lean and obese individuals
-
-
monitor changes in microflora with weight loss
How do metabolites from the microbial consortia
influence host physiology
in the end....
in the end....
You are what you eat!