Diabetes and microbiota: the evidence of a gut signature

1. Microbiota, small intestine
inflammation and type 2 diabetes
Li Wen, MD, PhD
Yale University School of Medicine

2. ? Viruses
? Toxins
??
ENVIRONMENT
GENETIC PREDISPOSITION
PATHOGENESIS OF TYPE 2 DIABETES
DIABETES
Diet and life
style
Gut
bacteria

3. CDC 2014
White Adults Black Adults
Hispanic Adults
Genetic influences on human T2D

4. Genetic influences on Mouse Models
Leptin deficiency TLR5 deficiency

5. Outline
• What are gut microbiota?
• How is the composition determined?
• What have animal models taught us?
• Is the gut microbiome influenced by DIET
and linked to human type 2 diabetes?
• Is there a gut signature that promotes
intestinal inflammation and subsequently
low grade systemic inflammation in human
type 2 diabetes?

6. Gut Microbiota (Gut Flora)

7. Which bacteria make up the gut microbiota?
There are 4 large groups (phyla)
Actino-bacteria
Bacteroidetes
Firmicutes
Proteobacteria
The genes of the bacteria in our gut are 150 times larger than that in the human
genome (Qin et al, 2010). The mass of the bacteria may reach up to 1.5 Kg.

8. What factors determine our gut
bacterial composition?
Birth –
Mode of
delivery
Infant
feeding
methods
Infections Antibiotics
Diet
“Hygiene”
During the development

9. Environmental influences on human T2D
Diet
High fat
High calorie
“Junk food”
Drugs: Wide usage of antibiotics
Life style: physical inactivity

10. Effect of Diet on Obesity
10% fat 35% fat 60% fat

11. Enterotype of Human Gut Microbiota
Wu, et al, Science 2011
Animal protein
enriched diet
Carbohydrate
enriched diet

12. Effect of Diet on Human Gut Microbiota
David, et al; Nature, 2014

13. Major findings from metagenome-wide association
studies (MGWAS) in patients with T2D
Butyrate-producing Roseburia intestinalis and Faeclibacterium prausnitzii
concentrations are lower in T2D
Lactobacillus gasseri and Streptococcus mutans and certain Clostridiales are higher
in T2D
Genes involved in vitamin synthesis is lower in T2D
Proteobacteria are higher in T2D
Increased expression of microbiotal genes involved in oxidative stress, that is,
overall a pro-inflammatory signature in the intestinal microbiota
Shortcomings of the studies: heterogenous populations, data on diabetes
medication incomplete and its role unclear, studies lack gender balance; mucosa-
associated microbiota not studied Qin, et al. Nature, 2012
Karlsson, et al. Nature, 2013
Tilg, Gut, 2014

14. Evidence for a beneficial effect of Akkermansia
muciniphila on metabolic functions
A Mucin-degrading Gram-negative bacterium constituting 3-5% of the intestinal microbiota
Concentrations inversely correlated with obesity and T2D in many experimental and human
studies
Prebiotic consumption such as oligofructose is metabolically beneficial and increases A
muciniphila concentrations
Administration of A muciniphila to mice improves weight loss, metabolic control and
adipose tissue inflammation
Metformin (T2D drug) increases A muciniphila concentrations
Controversies: some animal/human studies show conflicting results
H Tilg et al, Gut 2014

15. Gut Microbiota and Metabolism in Yogurt
Consumers vs non Yogurt Consumers
Group N
(n=21)
Group Y
(n=30)
P value
b-galactosidase 68.9+/-2.43 85.43+/-5.1 0.048
Bacterial enzyme activities
Group N
(n=21)
Group Y
(n=30)
P value
Lactobacillus
bulgaricus
28% 68% 0.003
Bacterial Composition
Alvaro et al. BJN, 2007

16. “You Are What You Eat”

17. Gastric bypass – the most effective
intervention of obesity and T2D

18. Alpha diversity
Diversity of Fecal Microbiota Is Significantly
Increased After Gastric Bypass
Am J Clin Nutr. 2013 Jul;98(1):16-24

20. Summary
• What are gut microbiota?
a complex community of bacteria in the intestine (endogenous non-self)
• How is the composition determined initially?
Birth route, feeding, medication, sanitation
• What have animal models taught us?
Genetic, diet and environmental factors can alter gut microbiota
• Is the gut microbiome influenced by DIET and linked to human type 2
diabetes?
YES
• Is there a gut signature that promotes intestinal inflammation and
subsequently low grade systemic inflammation in human type 2 diabetes?
Most likely (mouse models, human studies, gastric bypass study)
• Can surgery treat T2D and by what mechanism?
Gastric bypass can effectively treat obesity and T2D. Change diet and
gut microbiota.

21. Acknowledgements
Funded by NIH and ADA
Collaborators
Andrew Duffy (Yale)
Robert Sherwin (Yale)
Susan Wong
(Cardiff, UK)