Unit 9: Human Microbiome LECTURE LEARNING GOALS 1. Describe the human microbiome: how many microbes there are, how you get your microbiome, who’s there, and how it changes over time and by region. 2. Describe the domain eukarya. List the five superkingdoms and a few notable species. 3. Explain how the human microbiome is related to health and disease.

1. DIVERSITY OF THE HUMAN
MICROBIOME
Unit 09, 3.4.2021
Reading for today: Brown Ch. 16, Walter & Ley
Reading for next class: Brown Ch. 15
Dr. Kristen DeAngelis
Office Hours by appointment
deangelis@microbio.umass.edu

2. Unit 9: Human Microbiome
LECTURE LEARNING GOALS
1. Describe the human microbiome: how
many microbes there are, how you get
your microbiome, who’s there, and how
it changes over time and by region.
2. Describe the domain eukarya. List the
five superkingdoms and a few notable
species.
3. Explain how the human microbiome is
related to health and disease.
2

3. Unit 9: Human Microbiome
LECTURE LEARNING GOALS
1. Describe the human microbiome: how
many microbes there are, how you get
your microbiome, who’s there, and how
it changes over time and by region.
2. Describe the domain eukarya. List the
five superkingdoms and a few notable
species.
3. Explain how the human microbiome is
related to health and disease.
3

4. Human
microbiome
• All microbes in
and out of the
body
4

5. Human microbiome
• Collection of microbes in and on your body
• Wherever the human body is exposed to the
outside world, there is a microbial community.
– Even your GI tract is “outside” technically
– Communities are shaped by their environment…
– Communities also shape their environment
• Our microbiome helps us extract energy and
nutrients from our food, and helps to outcompete or
inhibit pathogens.
• Your microbiome is an essential organ, like the skin
– You cannot live without it
– You take it for granted until it’s broken
https://commons.wikimedia.org/wiki/File:Staphylococcus_on_catheter.png (cover slide)
https://commons.wikimedia.org/wiki/File:Animalcules_observed_by_anton_van_leeuwenhoek_c1795_1228575.jpg
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6. Estimates for the concentration and
number of bacterial cells in the body
Sender et al. 2016
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7. How many microbes are there?
• 1:1 bacteria vs human cells
– Ratio of bacteria to human cells used to be 10:1 BUT new
paper on Revised estimates for the number of human and
bacteria cells in the body suggests 1:1
– does not count your blood cells: they are anucleate
– Your microbiome is 1-3% of your body mass
• The bulk of your microbiome is in the colon, which
can fluctuate from 1013 – 1014 bacteria
• The highest concentrations of cells is a tie between
colon & teeth
Cho, Ilseung, and Martin J. Blaser. "The human microbiome: at the interface of health and
disease." Nature Reviews Genetics 13.4 (2012): 260. 7

8. Gut microbiome origins
http://bit.ly/HumanMicrobiome; https://www.youtube.com/watch?v=Pb272zsixSQ
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9. Development of the Gut
microbiome
• Baby microbiomes are variable until they
are about 2 years old
– https://www.youtube.com/watch?v=Pb272zsixSQ
• Colonization history impacts microbial
community composition & diversity
• Environmental & stochastic factors affect
community composition & diversity
• Twins may have different microbiomes!
Walter & Ley, 2011
9

10. HMP Consortium, 2012
10

11. How is the microbial community
of the GI tract so different?
• There are several ways by which the human
host restricts bacterial biomass in the
stomach and SI
– Bile salts are strongly bacteriocidal
– pH as low as 2 inhibits most microbial growth
– Immunoglobulin (Ig), specifically IgA recognizes
the dominant microbes present
– Epithelial cells produce antimicrobial
compounds (e.g., defensins, cathelicidins, and C-
type lectins), some constitutively and some
activated by the presence of bacteria
11

12. Gut microbiome
Walter & Ley, 2011
12

13. Why is the microbial community
of the GI tract so different?
• The human digestive tract is partitioned to
segregate the host digestive processes from most of
the microbial biomass, so that the host has the first
shot at dietary substrates.
• The human gut microbiota in their metagenome
encodes 150 times more genes than are present in
the human host genome.
• The gut microbiome has the biosynthetic capacity
to break down a greater range of plant
polysaccharides; microbial fermentation provides
roughly 10% of daily energy from a Western diet
13

14. Human Microbiome Project
HMP Consortium, 2012
• Despite variation in community structure (phyla, top),
metagenomic carriage of metabolic pathways was stable
among individuals (metabolic pathways, bottom).
14

15. Human Microbiome Project
• To characterize the ecology of human-
associated microbial communities, the Human
Microbiome Project has analyzed the largest
cohort and set of distinct, clinically relevant
body habitats so far
• Healthy individuals differ in the taxonomy
microbes that occupy habitats such as the gut,
skin and vagina
• Based on metagenomics, metabolic pathways
are consistent among individuals despite
variation in community structure
HMP Consortium, 2012
15

16. Who’s
there?
• Human
microbiome is
mostly bacteria
but also archaea,
fungi and other
eukaryotes
Spor et al., Nat Rev Micro 2011
16

17. Human microbiome
• Bacteria
– Bacteroidetes dominate gut communities
– Firmicutes dominate esophagus and
vagina
– Actinobacteria live in the mouth, where
they make biofilms (plaque)
– Cyanobacteria live in the hair
– Fusobacteria (phylum with very few
cultivated members, all symbionts)
– Proteobacteria
17

18. Human microbiome
– Microbes from all three domains are
represented in the human microbiome
– Most of the cultured diversity is contained in
five phyla (Bacteroidetes, Firmicutes,
Actinobacteria, Cyanobacteria,
Proteobacteria)
– Only Fusobacteria (phylum with very few
cultivated members, all symbionts; found in
mouth & GI tract) is a common microbiome
organisms with few cultured
representatives… is this a coincidence?
HMP Consortium, 2012
18

19. Human microbiome
• Archaea
– dominant group are the methanogens,
particularly Methanobrevibacter smithii
and Methanosphaera stadtmanae
– No archaeal pathogens are known
19

20. Human microbiome
• Eukaryotes
– Mostly fungi, e.g., yeasts like Candida spp.
– Malassezia spp.
– Yeasts are also present on the skin, where
they consume oils secreted from the
sebaceous glands
20

21. Activity for Review of
Unit 09.1 Human microbiome
• How do we get our microbiomes?
• How does the human microbiome
functional diversity compare to the
phylogenetic diversity.
21

22. Unit 9: Human Microbiome
LECTURE LEARNING GOALS
1. Describe the human microbiome: how
many microbes there are, how you get
your microbiome, who’s there, and how
it changes over time and by region.
2. Describe the domain eukarya. List the
five superkingdoms and a few notable
species.
3. Explain how the human microbiome is
related to health and disease.
22

23. 5 Eukaryotic
supergroups:
• Excavates
• Chromalveolates
• Plantae
• Rhizaria
• Unikonts
Bacteria
Eukarya
Euryarchaea
Crenarchaea
Domain Eukarya
Bacteria
Eukarya
Archaea
Archaea
Bacteria
Eukarya

24. Eukaryotes
*
Excavates
Chromalveolates
Plantae
Unikonts
Rhizaria
24

25. Eukaryotes
• * You are here. (SK Unikonts, kingdom
Opisthokonts)
• Five major superkingdoms
– The superkingdoms derived from a single
radiation (common ancestor)
– How the superkingdoms are related is not clear
and subject to intense debate
• Within the superkingdoms are sometimes
called kingdoms, but there is little
consistency among the taxonomy
25

26. Eukaryotes
Five major superkingdoms
1. Excavates – flagellated single-celled eukaryotes,
pathogens
2. Chromalveolates – mostly phototrophic algae,
diatoms
3. Plantae –plants, including land plants, green and
red algae; all have plastids (chloroplasts) derived
from cyannobacteria
4. Rhizaria – all unicellular eukaryotes, very diverse
5. Unikonts*- include Amoebozoa and Opisthokonts,
which have two main groups, fungi & animals
* You are here.
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27. Metabolism of the Eukaryotes
• Generally heterotrophic or phototrophic
• in most cases metabolism is supported by
organelles derived from endosymbionts
– Mitochondria derived from the
Alphaproteobacteria Rickettsia
– Chloroplasts derived from the Cyannobacteria
– Plastids derived from other eukaryotic
phototrophs
27

28. Eukaryotic microbiome:
Malassezia spp
M. furfur in skin scale from
a patient with tinea
versicolor. Notice the
budding and slightly
filamentous growth,
characteristic of yeasts.
28

29. Eukaryotic microbiome:
Malassezia spp
• Most fungi identified on healthy skin resemble
Malassezia spp.
• Malassezia is a yeast, which is a non-
filamentous fungus
• In one study, Malassezia spp. were calculated
to constitute 53–80% of the total skin fungal
population, depending on the skin site
• retroauricular crease harbors the highest
proportion of these microbes, where they
consume oils secreted from the sebaceous
glands
Grice and Segre, Nat Rev Microbiol. 2011 April ; 9(4):
244–253. doi:10.1038/nrmicro2537.
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30. Eukaryotes
Ernst Haeckel’s drawings of
radiolarians (rhizaria)
A fellow unikont, the slime mold
dictyostelium (amoebozoa)
A fellow unikont, Sacchromyces
cerevisiae (opisthokont)
30

31. Activity for Review of
Unit 09.2 Eukarya
Match the eukaryotic superkingdom to its major
characteristics
1. Excavates
2. Chromalveolates
3. Plantae
4. Rhizaria
5. Unikonts
a) mostly phototrophic algae, diatoms
b) flagellated single-celled
eukaryotes, pathogens
c) all unicellular eukaryotes, very
diverse
d) include Amoebozoa and
Opisthokonts, which have two main
groups, fungi & animals
e) plants, including land plants, green
and red algae; all have plastids
(chloroplasts) derived from
cyannobacteria
31

32. Unit 9: Human Microbiome
LECTURE LEARNING GOALS
1. Describe the human microbiome: how
many microbes there are, how you get
your microbiome, who’s there, and how
it changes over time and by region.
2. Describe the domain eukarya. List the
five superkingdoms and a few notable
species.
3. Explain how the human microbiome is
related to health and disease.
32

33. How does your microbiome
affect health and disease?
• We have co-evolved with
our microbiomes
• Antibiotics, probiotics and
prebiotics
– change the microbiome
– but the system is dynamic
• Some diseases can be
treated by targeting the
microbime
– Obesity
– C. dif. or CDI
– Severe acute malnutrition
33

34. Gut microbiome
Brussow & Parkinson, 2014
• Gut morphology reflects co-evolution
with the microbiome
34

35. Gut microbiome
• Gut morphology reflects co-evolution with the
microbiome
– Host digests simple nutrients
– Host relies on abilities of microbes to digest complex
components & generate short-chain fatty acids (SCFAs)
• Most gut metabolites are beneficial
– Butyrate – energy source for gut wall epithelial cells
– Acetate – quells overactive immune response; may protect
host from E. coli infections
– Proprionate – interacts with T cells, influences immune
response
– Polyphenols are metabolized by bacteria to antioxidants &
anti-cancer compounds, e.g., ellagic acid (in berries &
nuts)
Walter & Ley, 2011
35

36. Gut microbiota can make metabolites
that are detrimental to the host
• Damaging to host DNA
– Heterocyclic amines (HCAs)
in char are converted by
gut microbes to
electrophilic derivatives
– Hydrogen Sulfide (H2S) is
produced from sulfur
reducers in high-protein
diets
Rooks & Garrett, F1000ReportsBiology, 2011
36

37. • Probiotics are live microbes that are eaten
• The U.S. Food and Drug Administration (FDA)
has not approved any probiotics for
preventing or treating any health problem.
• If you want to change your microbiome…
feed it the good stuff!
https://nccih.nih.gov/health/probiotics/introduction.htm
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38. The original prebiotic: mother’s milk
• Humans cannot digest many human milk
oligosaccharides!
• Selective for Bifidobacteria (phylum Actinobacteria)
– Activity of this group lowers gut pH
– Low pH restricts Gram-negative bacteria growth
Smilowitz et al., Annu. Rev. Nutr. 2014
38

39. The original prebiotic: breast milk
• Human milk contains
– higher amounts and more complex structures
of soluble oligosaccharides than any other
mammalian milk
– Antibodies for immune protection
• Human Milk Oligosaccharides are
prebiotics for beneficial Bifidobacteria
• associated with numerous benefits
– improved vaccine effectiveness
– enhanced gut barrier function
– protection from enteropathogen infection
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40. Host lifestyle affects human
microbiota on daily timescales
40

41. Host lifestyle affects human
microbiota on daily timescales
• The human microbiome is generally stable, but
can be quickly and profoundly altered
• Over 10,000 measurements of human wellness
and action were linked to the daily gut and
salivary microbiota dynamics of two individuals
over one year.
• Rare events in each subjects’ life rapidly and
broadly impacted microbiota dynamics.
– Travel
– Enteric infection
• Changes in host fiber intake positively correlated
with next-day abundance changes among 15%
of gut microbiota members.
41

42. A core gut microbiome in obese
and lean twins
Turnbaugh et al., Nature 2009 42

43. A core gut microbiome in obese
and lean twins
Turnbaugh et al., Nature 2009 43

44. Human microbiome and obesity
• Community sequencing of total gut
microbiota taken from obese and lean twins
show substantial differences in their
compositions.
• Obesity is associated with phylum-level
differences in the microbiota, a significantly
reduced bacterial diversity, and an increase
in the population expression of enzymes
which result in an increased efficiency of
calorie harvest in the diets of the obese
twins.
44

45. Bacteriotherapy
• Fecal microbiome
transplants (FMT)
• Successful in
treating
Clostridium
difficile infections
45
A pathological specimen showing
pseudomembranous colitis, Wikipedia

46. Bacteriotherapy
• Aka fecal microbiome transplantation, or
fecal transplant
• Transfer of stool from a healthy donor into
the gastrointestinal tract to treat Clostridium
difficile infections
• Successful in treating a range of
gastrointestinal diseases, including colitis,
constipation, irritable bowel syndrome, and
neurological conditions such as multiple
sclerosis and Parkinson's
46

47. Human microbiome and
malnutrition
A malnourished
child with
kwashiorkor
Trehan et al. NEJM 2013. 47

48. Human microbiome and malnutrition
• Kwashiorkor, an enigmatic form of severe acute
malnutrition (SAM), is the consequence of
inadequate nutrients plus additional environmental
stress.
• 1 million children die annually due to SAM.
• In this randomized, double-blind, placebo-
controlled trial, we randomly assigned Malawian
children, 6 to 59 months of age, with severe acute
malnutrition to receive amoxicillin, cefdinir, or
placebo for 7 days in ready-to-use therapeutic food
(RUTF) for the outpatient treatment of
uncomplicated severe acute malnutrition.
48

49. Gut microbiome is a causal
factor in kwashiorkor
Smith et al. Science. 2013.
Mouse model
Kwashiorkor
Gut
communities
Healthy
Gut
communities
49

50. Gut microbiomes of Malawian twin
pairs discordant for kwashiorkor
• Fecal communities from several discordant pairs
were each transplanted into gnotobiotic mice
• Mice were then given a representative (nutrient-
deficient) Malawian diet followed by RUTF (ready-
to-use therapeutic food) and then the Malawian
diet.
• Malawian diet fed to mice with a kwashiorkor
microbiome produced marked weight loss in the
gnotobiotic mice.
• These findings implicate the gut microbiome as a
causal factor in kwashiorkor and suggest that
additional nutritional support may be required to
correct persistent metabolic defects arising from
microbiome dysfunction in malnourished children.
50

51. How is the human microbiome
related to health and disease?
• Health
– Barrier to disease
– Gut microbiota production of short-chain
fatty acids for nutrition
• Disease
– Gut microbiota also produces Heterocyclic
amines (HCAs) and hydrogen sulfide (H2S)
– Obesity has a distinct microbiome
– Severe acute malnutrition can sometimes be
helped using antibiotics
51

52. Activity for Review of
Unit 09.3
• Compare the mechanism of action for
probiotics and prebiotics. Which is proven
to be effective in changing the
microbiome?
52

53. Unit 9: Human Microbiome
LECTURE LEARNING GOALS
1. Describe the human microbiome: how many
microbes there are, how you get your
microbiome, who’s there, and how it
changes over time and by region.
2. Describe the domain eukarya. List the five
superkingdoms and a few notable species.
3. Explain how the human microbiome is
related to health and disease.
Next class is Unit 10: Diversity of Permafrost
Reading for next class: Brown Ch. 15
53