School of Medicine @UoLmedicine [email protected] 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
School of Medicine @UoLmedicine
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