Introduction to the gut microbiota - Liverpoolpcbjcampbl/Lecture 15 - Y1 MBChB Gut Microbiota.pdf · The ‘microbiome’ Joshua Lederberg - argued that microorganisms inhabiting

School of Medicine @UoLmedicine

[email protected]

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

Cellular & Molecular Physiology, Institute of Translational Medicine

Prof. Barry Campbell

Introduction to the gut microbiota

Year 1 MBChB –

Gastrointestinal system

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

development and health

➢ Explain how diet impacts on the microbiota and microbial activity

➢ Describe the role of the microbiota in the production and absorption

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

➢ 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

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 !!

• Established in the 1st year of life

Co-evolves with the immune system

• Highly variable between individuals

In 154 individuals no single shared abundant species

About 160 bacterial species in each faecal sample

gene set ~150 times human genome

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

But influenced by diet Turnbaugh & Gordon 2009 J Physiol 587:4153-8

Turnbaugh et al. 2009. Nature 457:480-4

Qin et al. 2010. Nature 464, 59-65

What do we know about our gut

microbial community (microbiota)?

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

➢ The meconium was 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

Host-Microbiota mutualism

i.e. the way two organisms of different species exist in a relationship in which each individual benefits from the activity of the other

In blood only 1000 bacteria are required to induce

an inflammatory response.

Yet, 1014 bacteria in the gut induce no such response!!

WHY? Bacteria are confined to the mucosal immune compartment

by the intestinal barrier & the innate immune system where

they are not recognised as foreign

Healthy individuals have:

➢ Higher taxonomic

diversity

➢ Higher gene diversity

➢ Microbial communities

are important for

development and stability

of immunity

Gut microbiota shapes intestinal immune system

Cerf-Bensussan & Gaboriau-Routhiau 2010; Nat. Rev. Immunol. 10(10):735-44

% 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%

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

includes bacteria that are asaccharolytic (eg some Firmicutes)

or aerobic/ microaerophilic bacteria typically absent from the

faeces (eg E. coli)

Mucosa-associated bacteria differ from faecal bacteria!

Aldenburg et al. Gastroenterology 2014; 147, 1055-63

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

Microbiota fermentation of dietary fibre

generates short chain fatty acids

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

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

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 the central metabolite,

acetyl-CoA and utilized to form lipids

and ketone bodies.

➢ SCFA may also enter the citric acid

cycle and become utilized for

glucose production via

gluconeogenesis.

➢ Acetate may also pass through into

the peripheral circulation and can be

detected in peripheral blood.

• 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 (blue marker).

Even short-term dietary intervention alters the human

gut microbiota and microbial activity.

David et al. 2014 Nature 505:559-63

Bacterial 16S ribosomal RNA gene sequencing

Summary of how diet shapes the gut microbiota

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

Dysbiosis

An alteration in the microbiome caused by a change in microbiotacomposition, a change in microbial metabolic activity, and/or a shiftin local distribution of communities of microbes

symbionts commensals pathobionts

Homeostasis

Loss of beneficial microbes

Reduced diversity

Pathobiontexpansion

Factors shaping intestinal microbial composition and

effects of dysbiosis on host health

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

% of bacteria % of bacteria

Inflammation re-shapes the gut microbiome

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

5,405 16S rRNA

sequences from

patients with

Inflammatory

bowel diseases

[IBD], i.e.

Crohn’s disease

& ulcerative

colitis.

“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

Diet, microbiota and colonic health

– a long history

“ A full colon is the rootof all suffering”

?

1856-1943Sir William Arbuthnot Lane

An early advocate of dietaryprevention of cancer.

Promoted whole foods, fruitsand vegetables, sunshine andexercise: his plan to fosterhealth and longevity via 3bowel movements daily.

By Photogravure after Elliott & Fry. - [1], CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=33387516

High intake of fruit fibre (but not cereal or legumes)

protects against Crohn’s disease

Ananthakrishnan et al. 2013 Gastroenterology 145:970-77

Prospective Nurses health study – 170,776 women followed up for 3,317,425 person years

1.4g/d vs. 6.4 g/d fruit fibre