School of Medicine @UoLmedicine

bjcampbl@liv.ac.uk

http://pcwww.liv.ac.uk/~bjcampbl/Microbiota.htm

Dept of Infection Biology & Microbiomes, IVES

Prof. Barry Campbell

Introduction to the gut microbiota

Year 1 MBChB –

Gastrointestinal system

➢ LO1 - Define the gut microbiota and microbiome, and its role in

development and health

➢ LO2 - Explain how diet impacts on the microbiota and microbial

activity

➢ LO3 - Describe the role of the microbiota in the production and

absorption of short chain fatty acids from dietary fibre in the large

intestine

➢ LO4 - Introduce the concept of dysbiosis (microbial imbalance),

reduced diversity and gut disease

Learning outcomes

The ‘microbiome’

Joshua Lederberg - argued that microorganisms

inhabiting the human body should be included as part of

the human genome, because of their influence on human

physiology.

The importance of microbiota

Lederberg & McCray 2001 Scientist 15: 8

. ~100 trillion bugsNIH Human Microbiome Project Genome Res 2009; 19, 2317-23

Human microbiome

LO1

Estimated numbers of bacteria

on/within the human body

Original dogma: We are only 10% human (more or less)

10 trillion cells vs. ~100 trillion bugs

Sender et al. Plos Biol 2016;

doi:10.1371/journal.pbio 10002533

Revised estimates:

3 x 1013 Human cells

3.9 x 1013 Bacteria

Approx. 76% Human now !!

LO1

• Established in the first few years of life

Co-evolves with the immune system

• Highly variable between individuals

Gene set ~150 times the human genome

• The range of bacteria appears to be fairly stable with time

But influenced by environment, diet, host genotype, age and disease

What do we know about our gut

microbial community (microbiota)?

LO1

Early development of the human faecal microbiota during first 10 days of life

➢ The meconium is sterile. ➢ On the second day of life, coliform bacteria, Lactobacilli and Enterococci could be isolated➢ On third day strains of Bacteroides➢ On fifth day Bifidobacteria

Hoogkamp-Korstanje et al. 1979. Antonie van Leeuwenhoek 45; 35-40

LO1

Healthy individuals have:

➢ Higher taxonomic diversity

➢ Higher gene diversity

➢ Microbial communities are

important for development

and stability of immunity

➢ Host-microbiota mutualismi.e. the way two organisms ofdifferent species exist in arelationship in which each individualbenefits from the activity of the other

➢ Bacteria are controlled by the

intestinal barrier & underlying

mucosal immune

compartment

Gut microbiota shapes intestinal immune system

Cerf-Bensussan & Gaboriau-Routhiau 2010;

Nat. Rev. Immunol. 10(10):735-44

LO1

% of bacteria

Six major phyla

Firmicutes

Bacteroidetes

Actinobacteria

Proteobacteria

Fusobacteria

Verrucomicrobia

Bacteria in the normal distal gut

Petersen et al. 2008 Cell Host & Microbe 3, 417-27

13,000 16S rRNA sequences

analysed from healthy young

adults and non-IBD controls.

>90%

LO1

MUC2 bacteria

• Colonic mucus is continuous with two

layers

– inner layer is normally free from bacteria

• Small intestinal mucus is discontinuous

The importance of the mucus barrier

Johansson et al. PNAS 2011; 108, 4659-65

LO1

“90% of the diseases ofcivilization are due to improperfunctioning of the colon…”

“…poor diet favors harmfulbacteria that can then infectother tissues in the body; thatthe intestinal flora is changedby the diet of the individual,and is changed for the better…”

Diet, microbiota and colonic health

– a long history

1852-1943Dr John Harvey Kellogg

LO2

Habitual diet shapes the gut microbiota

16S rRNA gene surveys reveal a clear separation of two child

populations from Burkina Faso and EU

De Filippo et al. 2010 PNAS 107, 14691-6

High fruit/legume fibre diet

High milk fat/Animal protein diet

More Gram +vesaccharolytic spp.High SCFA levels

Low SCFA levelsMore Gram -veProteobacteria

LO2

LO3

Microbiota fermentation of dietary fibre

generates short-chain fatty acids (SCFAs)

Firmicutes

Bacteroidetes>90%

Dietary SCFAs

– All dairy

SCFAs from Dietary

fibre fermentation –

soluble and insoluble

High numbers of anaerobic, sacchrolytic species

SCFAs.. a subset of fatty acids that contain 6 or less carbon molecules

Acetate Propionate Butyrate

LO3

➢ Microbial diversity (the

difference between each

subject’s baseline and diet-

associated gut microbiota)

changed within 1 day on

animal-based diet reaching

the colon.

➢ Beneficial SCFA’s on plant

based diet

➢ harmful branched (iso)

SCFAs on animal based diet

Even short-term dietary intervention alters

the human gut microbiota and microbial activity.

David et al. 2014 Nature 505:559-63

LO2

LO3

Human short-term dietary intervention study

▪ Plant based diet – High dietary fibre, low animal protein, low animal fat

▪ Animal based diet – Low fibre, high protein, high fat

Absorption of SCFAs in the large intestine

▪ Butyrate (BT) is the major source of

energy for the bowel and a potent

inhibitor of histone deacetylases

(HDAC), BT enhances tumour

suppressor gene expression.

▪ MCT transporter/receptor uptake of

SCFAs

▪ Also diffusion through apical

membrane and tight junctions

Gill & Dudeja 2011. Am. J. Physiol. 301: C977-C979

Kimura et al. 2013 Nat. Commun. 4, # 1829

▪ SCFA receptors link the metabolic

activity of the gut microbiota with

host body energy homeostasis

▪ Also immunomodulatory

Also GPR41 (SCFAs) and GPR109a (butyrate)G-protein coupled receptors

LO3

Systemic metabolism of SCFA

▪ SCFA entering into the portal vein undergoes first-pass metabolism by

the liver

▪ within the liver the may enter a number of metabolic pathways

depending on the metabolic state

➢ Acetate and butyrate may be

converted to acetyl-CoA and utilized

to form lipids and ketone bodies.

➢ SCFA may also enter the citric acid

cycle and is utilized for glucose

production via gluconeogenesis.

➢ Acetate may also pass through into

the peripheral circulation and can be

detected in peripheral blood.

LO2

Summary of how diet shapes the gut microbiota

Simpson & Campbell 2015. Aliment Pharmacol Ther. 42:158-79

LO1

LO2

LO3

Dysbiosis

An alteration in the microbiome caused by a change in microbiota

composition, a change in microbial metabolic activity, and/or a

shift in local distribution of communities of microbes

symbionts commensals pathobionts

Homeostasis

Loss of beneficial microbes

Reduced diversity

Pathobiontexpansion

LO4

Factors shaping intestinal microbial composition

and effects of dysbiosis on host health

Sommer & Bäckhed. 2013. Nature Reviews Microbiology 11, 227–238

LO4