February 2014

The Human Gut Microbiota

and Type 2 Diabetes

Matt Collison

February 2014

Outline

• Introduction to the central concepts

• Proposed mechanisms of microbiota

contributing to the disease

• Population level studies in humans

• Chinese

• European

• Potential therapeutic interventions

involving the microbiota

February 2014

What is the microbiome?

Collison et al, Brief. Bioinf. (2012)

February 2014

What is the microbiome?

Collison et al, Brief. Bioinf. (2012)

GUT

Microbiome

1014 prokaryotic cells

4,500,000 genes

(Taxonomic composition

and LGT)

1013 human cells

30,000 unique genes

(CNVs, SNPs)

Human

Genome Genetic & cellular features

Human host Microbiota

February 2014

Type 2 Diabetes

Plasma glucose

Alpha cells

Beta cells

insulinglucagon

GlycogenolyisisGluconeogenesis

Ketones

GlycolysisGlyogenesisLipogenesis

High glucoseLow glucose

February 2014

Causes of Insulin Resistance

Bad

diet

Increased

adiposity

Increased

inflammation

Insulin

resistance

Genetic

predisposition

February 2014

Causes of Insulin Resistance

Bad

diet

Increased

adiposity

Increased

inflammation

Insulin

resistance

Genetic

predisposition

Microbiota

dysbiosis

[1,2,3]

1. Qin et al, Nature (2010)

2. Turnbaugh et al, Nature (2009)

3. Turnbaugh et al, Nature (2006)

February 2014

Causes of Insulin Resistance

Bad

diet

Increased

adiposity

Increased

inflammation

Insulin

resistance

Genetic

predisposition

Microbiota

dysbiosis

[1,2,3]

Pro-

inflammatory

microbiota [2]

1. Qin et al, Nature (2010)

2. Turnbaugh et al, Nature (2009)

3. Turnbaugh et al, Nature (2006)

February 2014

Causes of Insulin Resistance

Bad

diet

Increased

adiposity

Increased

inflammation

Insulin

resistance

Genetic

predisposition

Microbiota

dysbiosis

[1,2,3]

Endotoxaemia

[4]

Gut barrier

permeability [4]

Pro-

inflammatory

microbiota [2]

1. Qin et al, Nature (2010)

2. Turnbaugh et al, Nature (2009)

3. Turnbaugh et al, Nature (2006)

4. Cani et al, Gut (2009)

February 2014

Mechanisms of Insulin Resistance

Bad

diet

Increased

adiposity

Increased

inflammation

Insulin

resistance

Genetic

predisposition

Microbiota

dysbiosis

[1,2,3]

Endotoxaemia

[4]

Gut barrier

permeability [4]

Pro-

inflammatory

microbiota [2]

To what extent does

microbiota dysbiosis

contribute through each

mechanism in humans?

February 2014

Diabetes in Chinese population

• 345 (170 vs 174) Chinese metagenomes.

• Identified 60,000 differentially abundant genes.

• Degrees of dysbiosis:

• Taxonomic

• Decrease butyrate producers

• Increase in opportunistic pathogens

• Functional

• Increase in sulphur reduction

• Increase in oxidative stress resistance

Qin et al, Nature (2012)

February 2014

Diabetes in Chinese population

Qin et al, Nature (2012)

February 2014

Functional inference

Qin et al, Nature (2012)

February 2014

Diabetes in European Women

• 145 metagenomes from European women

• Degree of dysbiosis:

• Taxonomic

• Decrease butyrate producers

• Increase in opportunistic pathogens

• Inconsistent contributors:

• Akkermansia not discriminate in European T2DM

• Lactobaccilus not discriminate in Chinese T2DM

Karlsson et al, Nature (2013)

February 2014

Can microbiome modulation

have any therapeutic value in

T2DM treatment?

February 2014

Microbiome Modulation

Approaches

• Microbiota transplantations – Vrieze et al,

Gastroenterology (2012)

• Probiotics – Everald et al, PNAS (2013)

• Prebiotics – Cani et al, Gut (2009)

• Antibiotics – Murphy et al, Gut (2013)

February 2014

References

Cani, P.D., Possemiers, S., Wiele, T.V. de, Guiot, Y., Everard, A., Rottier, O., Geurts, L.,

Naslain, D., Neyrinck, A.M., Lambert, D.M., et al. (2009). Changes in gut microbiota

control inflammation in obese mice through a mechanism involving GLP-2-driven

improvement of gut permeability. Gut.

Collison, M., Hirt, R.P., Wipat, A., Nakjang, S., Sanseau, P., and Brown, J.R. (2012).

Data mining the human gut microbiota for therapeutic targets. Briefings in

Bioinformatics.

Everard, A., Belzer, C., Geurts, L., Ouwerkerk, J.P., Druart, C., Bindels, L.B., Guiot, Y.,

Derrien, M., Muccioli, G.G., Delzenne, N.M., et al. (2013). Cross-talk between

Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity.

PNAS.

Karlsson, F.H., Tremaroli, V., Nookaew, I., Bergström, G., Behre, C.J., Fagerberg, B.,

Nielsen, J., and Bäckhed, F. (2013). Gut metagenome in European women with

normal, impaired and diabetic glucose control. Nature 498, 99–103.

Murphy, E.F., Cotter, P.D., Hogan, A., O’Sullivan, O., Joyce, A., Fouhy, F., Clarke, S.F.,

Marques, T.M., O’Toole, P.W., Stanton, C., et al. (2013). Divergent metabolic

outcomes arising from targeted manipulation of the gut microbiota in diet-induced

obesity. Gut 62, 220–226.

February 2014

References (continued)

Qin, J., Li, R., Raes, J., Arumugam, M., Burgdorf, K.S., Manichanh, C., Nielsen, T., Pons,

N., Levenez, F., Yamada, T., et al. (2010). A human gut microbial gene catalogue

established by metagenomic sequencing. Nature 464, 59–65.

Qin, J., Li, Y., Cai, Z., Li, S., Zhu, J., Zhang, F., Liang, S., Zhang, W., Guan, Y., Shen, D.,

et al. (2012). A metagenome-wide association study of gut microbiota in type 2

diabetes. Nature 490, 55–60.

Turnbaugh, P.J., Ley, R.E., Mahowald, M.A., Magrini, V., Mardis, E.R., and Gordon, J.I.

(2006). An obesity-associated gut microbiome with increased capacity for energy

harvest. Nature 444, 1027–1031.

Turnbaugh, P.J., Hamady, M., Yatsunenko, T., Cantarel, B.L., Duncan, A., Ley, R.E.,

Sogin, M.L., Jones, W.J., Roe, B.A., Affourtit, J.P., et al. (2009). A core gut

microbiome in obese and lean twins. Nature 457, 480–484.

Vrieze, A., Van Nood, E., Holleman, F., Salojärvi, J., Kootte, R.S., Bartelsman, J.F.W.M.,

Dallinga–Thie, G.M., Ackermans, M.T., Serlie, M.J., Oozeer, R., et al. (2012).

Transfer of Intestinal Microbiota From Lean Donors Increases Insulin Sensitivity in

Individuals With Metabolic Syndrome. Gastroenterology 143, 913–916.e7.