Humans and their symbiotic

relationships with microorganisms

some parasitic but by far with commencel on us/inws Or
(dont harmus)
Each adult has more than 1013 human cells. mutualisti
not I

Bacterial cells outnumber these human cells. help u)

Sender et al. 2016. Revised estimates for the number of human and bacteria cells in the body. PLoS Biology, 14: p.e1002533.
 Bacterial cells outnumber human
cells, but their biomass is lower
red blood

,
cells

muscie
Distribution of cell number and mass for different cell types in a
70 kg adult. The contribution of bacteria to body mass amounts to
about 0.2 kg, which is about 0.3% of body weight.

Sender et al. 2016. Revised estimates for the number of human and bacteria cells in the body. PLoS Biology, 14: p.e1002533.
The Human Microbiota is Diverse
Many thousands of species have been described from the
human microbiota in the mainly gut

Morgan et al. 2013 Trends in Genetics 29: 51-58; Cho & Blaser 2012 Nature Reviews Genetics, 13: 260-270.
 Genes in the Microbiota
The microbiota encodes enormous functional diversity, and their genes
outnumber our human genes 100 to 1. These genes are collectively
called the microbiome.

↳ of

* -

agree
Ackerman 2012 Scientific American: 306: 36-43; Gilbert et al. 2018 Nature Medicine 24: 392-400
i
 Different bacteria inhabit specialised
for
different body ‘ecosystems’ different
ecosystems

Ackerman 2012 The ultimate social network. Scientific American, 306, 36-43.
 Recognized as long ago as 1969
long before molecular/DNA revolution

‘For creatures your size I offer

a free choice of habitat,
So settle yourselves in the zone
that suits you best,
In the pools of my pores, or the
tropical forests of arm-pit and
crotch,
In the deserts of my fore-arms,
or the cool woods of my scalp.’

A New Year Greeting

W.H. Auden read t
Wrote poem
Hear Auden’s ghost read this poem: differentparts of human
http://media.nybooks.com/auden-new-year-greeting.mp3 body= different
ecosystems
Marples 1969. Life on the human skin. Scientific American, 220: 108-115.
 Human – Bacterial mutualism
The skin, mouth, digestive and urogenital systems all have different, complex
microbial communities, dominated by different types of microbes.
Land populations
&

from
colonising.
establish
a

↑
cant space,ur
becauseup
taken endy
These associations are~largely
baclerke
mutualistic, with bacteria gaining nutrients, a stable
environment (pH, water, temperature) and transport. Benefits to the human host
include nutrition, immune function, development and exclusion of pathogens.
↳Particularly Immune syst. gut +

Mitreva 2012 Nature, 486: 207-214; Appanna 2018 In Human Microbes-The Power Within pp. 1-36, Springer, Singapore.
 Different body sites have
different species How
many type/
The size of each pie chart represents the abundance of bacterial cells. The relative
proportion of the four most common bacterial phyla differs between body sites.

I most
4

common

phyla
each IS

adapted
large -
to live
intestine in each
location

Dethlefsen et al 2007. An ecological and evolutionary perspective on human–microbe mutualism and disease. Nature, 449: 811-818.
Distribution of bacteria on skin
essential for
health ofSkin

Depending on whether skin

sites are generally oily, moist
or dry, they harbor different
microbial populations.

↓
feet diff from others, not
because has
too
offungi

W
Grice and Segre 2011. The skin microbiome. Nature Reviews Microbiology, 9: 244-253.
 Specialization in the digestive system
The dominant species change in various regions of the
gastrointestinal tract.
not
sch
I argeinzelne
assoc.
With -
has more diversity
Stomach M
is
unders
24 overgrows 3)%-

fecal
small - matter
intestine
-

Sartor 2008. Microbial influences in inflammatory bowel diseases. Gastroenterology, 134: pp.577-594.
 The large intestine has the greatest
numbers of bacteria

of
number
max
rege
we
cells
↑ run
be there

⑪
②
⑱
⑤

⑧
Sender et al. 2016. Revised estimates for the number of human and bacteria cells in the body. PLoS Biology, 14: p.e1002533.
 integration
ofbacteral
3) microbial cells
with human
body
long
indeaten period
co-evolution
of
Evolution of the Human Microbiota
Are we
degrading our

ecosystem?
internal

Because the microbiota is

so well integrated with
human anatomy,
physiology and
biochemistry, the
microbiota has clearly co-
evolved with humans.

Can we reconstruct this evolution?

Gillings et al. 2015. Ecology and evolution of the human microbiota: fire, farming and antibiotics. Genes, 6: 841-857.
 What was the ‘ancestral’
microbiota like?
There are three ways to address this question:
① • Compare humans with other great apes -
ChMP
-

gorzku
② • Examine fossil microbiota -orang
③• Examine microbiota of hunter-gatherers human
I still ancestral
living "festyle
① Bacteria cospeciate with humans
a) faming tree
b)everleben interlane

gutbaue,dehumanse
Family tree
↑
Family trees of
bacterial species from
the gut are the same
as family trees of the
great apes.
all stres
back common
to
go et
ancestor
aper
great

Moeller et al. 2016. Cospeciation of gut microbiota with hominids. Science, 353: 380-382.
Human microbiota has lost
ancestral diversity
much
notas
diversity

ge
M
Humans carry significantly fewer
bacterial genera than gorillas, chimps
and bonobos urbanised
subsistance formers ->
tread: human
-

C
Moeller 2017. The shrinking human gut microbiome. Current Opinion in Microbiology, 38: 30-35.
Humans in↳urban societies have the
for
least diversity.... consequence
human
health?
yes

Moeller 2017. The shrinking human gut microbiome. Current Opinion in Microbiology, 38: 30-35.
 What caused loss of diversity
in the microbiota?
There appear to be multiple stages (and multiple causes) for
the loss of diversity from the human microbiota.

↑ I
These stages occurred during:
• the Palaeolithic (2.6 mya – 10,000 BC)
• the Holocene (10,000 BC +) agricultive
-

to be
skcorked
mickly
• the Industrial Revolution (1760 +) practices
• the Anthropocene (1950 +)
-

casorts
of
prackers
E
antibiotics
feeding
- bottle
-
a sections
-
overcleanliness
Gillings et al. 2015. Ecology and evolution of the human microbiota: fire, farming and antibiotics. Genes, 6: 841-857.
 eariene The Palaeolithic
from food
- more colones
The use of fire for food preparation, and a shift in diet away from
plant-based food, towards animal fat and protein, led to a
reorganized gut morphology. This reduced the volume of the gut
and altered its resident microbiota. we have a much
smaller d.
System
for our

Size
the would
be
expectac

Ferraro et al. 2013. Earliest archaeological evidence of persistent hominin carnivory. PloS One, 8(4); Milton 1987. Primate diets and gut
morphology: implications for hominid evolution. Food and evolution: toward a theory of human food habits, 93-115.
Reconstructing ancient microbiota
Ancient DNA analysis can help reconstruct the
ancestral microbiota
fossil faeces
t

Pre-Columbian Andean
mummy with paleofeces
& fossilized
looking
hremar

Santiago-Rodriguez et al. 2015. Gut microbiome of an 11th century AD pre-Columbian Andean mummy. PloS one, 10(9);
Tito et al. 2012. Insights from characterizing extinct human gut microbiomes. PloS one, 7(12).
Coprolites can tell us about the
ancient gut microbiota poop
~
Microbial DNA recovered from coprolites has similarities with
gut microbiota from modern rural populations, rather than
urban populations. tells we're run as

shifted from
o
agrarca-
urbanised
society out
gutdiversity
has
declined

The Lloyds Bank coprolite: A human coprolite from a Viking site at

Coppergate, York, England.
Cano et al. 2014. Paleomicrobiology: revealing fecal microbiomes of ancient indigenous cultures. PloS one, 9(9); Tito et
al. 2012. Insights from characterizing extinct human gut microbiomes. PloS one, 7(12).
 Examining hunter-gatherer
evolution
Across human
microbiota
attainment
multiple
have been
cultural changes
have inquenced
diversity
and
microbial
↑

and becoming
lower... ditional
bropped ↓ ive
hunter gatherer
↓ Curban life style

I
↓

Yanomami (hunter-gatherers) have the highest diversity of microbiota (microbial

species) and microbiome (microbial genes) ever documented; higher than
subsistence farmers and urban populations.
Clemente et al. 2015 Science Advances 1:e1500183
How do we get our microbiota?
We acquire microbiota from our mothers, our
families, and from our environment.

from
directly
Transmission and Therehe
~

colonization are dynamic

and ongoing processes. ↑ quee
initially
Acquisition can be vertical
or horizontal, and is subject

Samig,
to change due to
environment, diet and age.
kin,
environment

Koskella et al. 2017 Nature Ecology & Evolution, 1: 1606-1615.

 Unborn babies are sterile before
amniot
membrane break

Despite some papers that suggest elements of the microbiota b

could be present in amniotic fluid and the placenta, these delivered
claims have now been largely dismissed.
b
fristexpose
40

microcrys
depend
on how

zue
at

born

Willyard 2018. Could baby's first bacteria take root before birth?. Nature, 553: 264-266.
de Goffau et al. 2019. Human placenta has no microbiome but can contain potential pathogens. Nature, 572: 329-334.
 Newborns acquire maternal
microbiota

⑧
dugebt
8 -
helps
Lactobe
sugar
E mik
7
braasfered

composed
maining of

lactobacillus
↑
Vaginal
microbiota

The microbiota of neonates largely reflects the vaginal and

skin microbiota of the mother
Chu et al. 2017. Maturation of the infant microbiome community structure and function across multiple body sites and in relation
to mode of delivery. Nature medicine, 23: 314.
Colonization depends on delivery mode
Vaginal births generate newborn microbiota similar to vaginal microbiota,
while in caesarean births they are more similar to the mother’s skin microbiota.
↳- miss out
or vertical
first transmission

~you
so start owl
with diff
rukrebiote
↳ Stabilisez

↑
around briths.
-> inhom
mute sterit butin those our
Because of the concerns around microbiota changes in caesarean babies, vaginal
swabs have been used to inoculate newborns and restore their ‘natural’ microbiota
~ swale the baby doneofmother has viral
de
reppes,
can't be
Dominguez-Bello et al. 2010 PNAS 107: 11971-11975; Dominguez-Bello et al. 2016 Partial restoration of the microbiota of cesarean-
born infants via vaginal microbial transfer. Nature Medicine 22: 250-253 caesarian requred
 The microbiota changes with
development
As children grow, their gut microbiota changes with changing diet

, ow diversity
2 sol food
L changes
-
moe
complex

Derrien et al. 2019. The gut microbiota in the first decade of life. Trends in Microbiology.
 Eventually stabilizing in adultsintroduce
we
as
Sold
saval
M Anriver on dail
The infant gut is dominated by Bifidobacterium and Escherichia. In adults,
these are replaced by Bacteroides, Clostridium, Eubacterium and
Fecalibacterium. There are crucial windows for colonization that could
influence immune, metabolic and nervous systems.
& If youre
not
serious consequences

Rook et al. 2017. Evolution, human-microbe interactions, and life history plasticity. The Lancet, 390: 521-530.
 What do the microbiota do?
Significant
Microbiota have a role in the development and education of
the immune system

Gut microbiota have a role in the

production of blood cells. They stimulate
production of lymphocytes and
WBL
macrophages.
compounds secreted
Microbial compounds promote activity of
the innate and adaptive immune system
against bacterial and viral infections.

HSC = hematopoietic stem cells

HPC = hematopoietic progenitor cells

Theilgaard-Mönch 2017. Gut microbiota sustains hematopoiesis. Blood, The Journal of the American
Society of Hematology, 129: 662-663.
If
gel
we
Changes in colonization can
balanced loud diversity
microbial
immune
change immune responses
appropriately tuned responds approprially to en condillun
-

system is
8 Changes to microbial populations in the respiratory system or the gut can lead to
If chronic and inappropriate inflammatory responses, such as asthma and allergy.
~makes - to
lead
sys-15
Immune
blused
towards
inflammatog
responses

Marsland and Salami 2015. Microbiome influences on allergy in mice and humans. Current Opinion in Immunology, 36: 94-100.
 The microbiota prevent colonization
by pathogens
↳
Commensal bacteria actively exclude pathogens by occupying niches,
rapidly using up nutrients, and by secreting antimicrobials and toxins
-

lactuely
fills up all prevent
colonisation
available WIL

space for foreign

microbia organisms
colonisablem natural
-

actively free immune

exclude system
pattrogen
ski mouth
nose gentals gut
Sassone-Corsi and Raffatellu 2015. No vacancy: how beneficial microbes cooperate with immunity to provide colonization resistance
to pathogens. The Journal of Immunology, 194: 4081-4087. urat
The microbiota has multiple functions
that are advantageous
Taste
rasp.
Sprg
long surate, dretary fibre
-
Highlan fight junctions

↓ developmental
functions
These functions are protective, structural and metabolic
Grenham et al. 2011. Brain–gut–microbe communication in health and disease. Frontiers in Physiology, 2: 94
 The human-microbiota
interaction is an ecosystem

....and ecosystems everywhere are changing under human influence....

 Are elements of the human gut
microbiota becoming extinct?
Evidence suggests a significant loss of diversity in the microbiota
of urbanized populations ancient

microblota
/
more dresse
P

ones
why

for
A

Peoplehar
set up
microbiota
banks
(por) microbiota
presence
euse-reinbroduation
fur futu to
Blaser 2017. The theory of disappearing microbiota and the epidemics of chronic diseases. Nature Reviews Immunology, 17: 461.
Gillings and Paulsen 2014. Microbiology of the Anthropocene. Anthropocene, 5: 1-8. memans
 Significant numbers of taxa are
missing in urbanized populations

I
-
&

-
taxa commute in us POR.
missing
in PNG

pathogens -

disorder
The gut microbiota of New Guinea highlanders contains many
species that are never found in urbanized populations.

Martinez et al. 2015 Cell Reports 4:527-538

 What aspects of modern life
might affect our microbiota?
Change
ar
M
Caesarean birth
cause geneinten
Bottle feeding
anxiblotagasinlessant
Antimicrobials
processedDiet highen
foods

sugars.

Host genetics
/
thus
genes
encode
on
recelors
our cells -
with
Interact reicrobluta

Dominguez-Bello et al. 2016 Nature Medicine 22: 250-253; Gillings et al. 2015 Genes, 6: 841-857;
Ardeshir et al. 2014 Science Translational Medicine 6: 252ra120; Dethlefsen & Relman 2011 PNAS, 108: 4554-4561
 Caesarean delivery alters early
colonization
Birth by C-section alters early microbiota. By 4-12 months old, these
differences largely disappear, but developmental and physiological changes
may have already occurred because of key -

role microbiola has

in
early development
immune
sys
physiology

Shao et al. 2019. Stunted microbiota and opportunistic pathogen colonization in caesarean-section birth. Nature, 574: 117-121.
 Formula feeding in humans
Formula Breast milk

Preterm infants fed breast milk had higher initial diversity of microbiota,
and accumulated additional diversity in a predictable succession. This
acquisition and succession was perturbed in formula fed infants.
breastm ilk is
better
Gregory et al. 2016. Influence of maternal breast milk ingestion on acquisition of the intestinal microbiome in preterm infants.
Microbiome, 4: 68.
 Antibiotic treatment a we
turelbe
Ch
kills of lots bacteric

Antibiotics have an immediate and profound effect on the microbiota,

lowering the diversity and abundance of microbial species.
It can take up to 2 years to recover diversity in the microbiota
r
stande-treatment I often
the
regulate original diver

people
most go through
~ I antibio treatmentper year
prevents recoveracy
all
as
Jernberg et al. 2010. Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiology, 156: 3216-3223;
Gillings et al. 2015. Ecology and evolution of the human microbiota: fire, farming and antibiotics. Genes, 6: 841-857.
 Other pharmaceuticals also affect
gut microbiota
Significant proportions of all classes of pharmaceuticals affect the gut
microbiota. Are their effects mediated through influencing the microbiota, rather
-than human cells? SSRI effect
ceraxity this wing eg mostserotonin.
IS ->
trey
gux produce
brain.
than
saxe 2-3
woks xuv anterim

Maier et al. 2018. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature, 555: 623-628.
 What can go wrong?
Multiple factors can adversely impact the gut microbiota, altering microbial
diversity and the balance of microbiota communities. These imbalances
(dysbiosis) are increasingly being associated with disease.
ray/ sea-

I
processed for d
saL
sweet cicnes
fatay
activity of certain
small Increases
xypes of cytes
=

provalnee
of &normally
involved
in Inflamm
response

Round and Mazmanian 2009. The gut microbiota shapes intestinal immune responses during health and disease. Nature
Reviews Immunology, 9: 313-323.
 Diseases associated with dysbiosis
are surprisingly diverse
common assuncter all have
featches in
microo
identify single *
- cant
human
in
freq
came identify With

s
-

assoc.
variation
genetic wer
↑

- tend to run
in families
onset
internity,
but

y ruptors
-extinction
variable of microrgs
In herman
microbiota
increasing
A
disbiosis.

populations of
comp lecated of
microorys interactingwith all sorts
human differentcellularsystems, harder to Magnose, treat, find cause
 obesity sympany
Microbiota and obesity ↑ Since 1950s
Humans were trying
figure genes lured in obesity, bradlines ofmulc
to out

Obese mice differ from lean mice in the ratio of Bacteroidetes to Firmicutes in their
gut microbiota. Transplanting the ‘obese’ microbiota into germ-free mice makes
them fat. Similar differences are found in lean and obese humans.Ibabies
gut
large proporkunighx
druen by shifts in microbial communities of
in

suggests:Microbiota might be behind age cares obesling

modern human populables
in because same defes in microbial

pops
our
obese
en change
set
point
in
for girzuie
humans
↳ insulinsensi

-
*
nflamm
response

↓
candes
plantpolymers,more
completed colones from same
food
and

Turnbaugh et al. 2006. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature, 444: 1027;
Schwiertz et al. 2010. Microbiota and SCFA in lean and overweight healthy subjects. Obesity, 18: 190-195.
 Metabolic syndrome
A chronic inflammatory disease manifested by symptoms including
cardiovascular disease, insulin resistance and type 2 diabetes. Dysbiosis is
increasingly being investigated as a driving factor.

Pedersen et al. 2016. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature, 535: 376-381; Tremaroli
and Bäckhed 2012. Functional interactions between the gut microbiota and host metabolism. Nature, 489: 242-249.
 Immune system disorders
Exposure to microbiota in the early postnatal period affects immune
homeostasis and disease susceptibility. Caesarean and pre-term babies may
have increased susceptibility to dysfunction of the immune system,
manifesting as eczema, asthma and allergies.
Immune
Inmaproplate
activity inflammation

BUT – the evidence is still being

accumulated, and there is a strong
publication bias towards studies
that show effects

Torow and Hornef 2017. The neonatal window of opportunity: setting the stage for life-long host-
microbial interaction and immune homeostasis. The Journal of Immunology, 198: 557-563; Sevelsted
et al. 2015. Cesarean section and chronic immune disorders. Pediatrics, 135: e92-e98.
 Irritable bowel syndrome
Complex feedback loops between environment, diet, host immune function and
microbial communities alter the functioning of the human gut

other
&

functional
gastro
intestree
disorders

Collins 2014. A role for the gut microbiota in IBS. Nature Reviews Gastroenterology & hepatology, 11: 497-505.
 via
vagus nerve

The gut-brain axis- via nellrobransmitter

The gut microbiota influences brain development in mammals, and gut

microbes have effects on brain activity. There is good evidence for an
association between dysbiosis and anxiety/depression.

Bravo et al. 2011. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the
vagus nerve. Proceedings of the National Academy of Sciences, 108: 16050-16055;
Heijtz et al. 2011. Normal gut microbiota modulates brain development and behavior. Proceedings of the National Academy of Sciences,
108: 3047-3052..
 A change in diet can be mood
↑
better than therapy..... wellbeing
In randomised clinical trails, dietary intervention can reduce
depression more effectively than therapy
Montgomery–Åsberg Depression Rating Scale

Francis et al. 2019. A brief diet intervention can reduce symptoms of depression in young adults–A randomised controlled trial. PloS One,
14: 10; Jacka et al. 2017. A randomised controlled trial of dietary improvement for adults with major depression (the ‘SMILES’trial).
BMC Medicine, 15: 23.
 Microbiota in the Anthropocene
1 test
(the Age of Humans) geological age
1930s
Changes in human microbiota Caesarean birth
Bottle feeding
correspond with phases of the Sanitation
Anthropocene of
onset
industrial Antibiotics / Disinfectants
r ew-

Processed food Transport / Dispersal

Shift to agricultural diet Mercury / Arsenic
⑯
Diet
Anelwoblal
agents

100,000 10,000 1,000 100 10 1

Gillings and Paulsen 2014. Microbiology of the Anthropocene. Anthropocene, 5: 1-8

 The Challenges
Understanding how the microbiota affects health and disease is
complicated by the fact that individuals can carry unique
microbiota ecosystem
picated

Gilbert et al. 2018. Current understanding of the human microbiome. Nature medicine, 24: 392-400
 The Challenges
Understanding the complex microbial ecosystems that inhabit every organism,
and managing these ecosystems when they become degraded is a major
challenge.

transplan
facal
diorheadinflamm
/
causes

An example: Clostridium difficile invades the human gut, like a weed invades degraded
land. The cure is similar to bush regeneration – ‘Poo transplants’ from healthy volunteers.
↓replace needs with natural
regelation wo days
~ 6mtr mrboxorginal
Van Nood et al. 2013. Duodenal infusion of donor feces for recurrent Clostridium difficile. New England Journal of Medicine, 368: 407-415.
But we need to avoid over-
enthusiasm and hype.....
 And we need to avoid microbial
extinctions
Generation by generation loss of microbial diversity leads to
depauperate microbiomes, with serious consequences for health
-

e
-
less resilimb, and well-being
less spaces,
to lead to disease states decline need to reverse
more likely

⑧ collect
sample
7 preserve
por banks
- fecal
famhunter
gatherers
microbial hig
W
diversity with
levels of
microbial
does it

so in future
Whenwe
have

better idea of
hour to indrange
easystems
Blaser 2018. The past and future biology of the human microbiome in an age of extinctions. Cell 172: 1173-1177;
Bello et al. 2018. Preserving microbial diversity. Science, 362: 33-34. reinoculate
 Microbial conservation? conservati
Will groups such as the Yanomami become the last
custodians of microbial species that are otherwise
extinct in the developed world?