View
9
Download
0
Category
Preview:
Citation preview
School of Medicine @UoLmedicine
bjcampbl@liv.ac.uk
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
Recommended