View
4.319
Download
1
Category
Preview:
Citation preview
Microbiota, small intestine inflammation and type 2 diabetes
Li Wen, MD, PhDYale University School of Medicine
? Viruses? Toxins
??
ENVIRONMENT
GENETIC PREDISPOSITION
PATHOGENESIS OF TYPE 2 DIABETES
DIABETES
Diet and life style
Gut bacteria
CDC 2014
White Adults Black Adults
Hispanic Adults
Genetic influences on human T2D
Genetic influences on Mouse Models
Leptin deficiency TLR5 deficiency
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?
Gut Microbiota (Gut Flora)
Which bacteria make up the gut microbiota?
There are 4 large groups (phyla)
Actino-bacteria
Bacteroidetes
Firmicutes
ProteobacteriaThe 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.
What factors determine our gut bacterial composition?
Birth –Mode of delivery
Infant feeding methods
Infections
Antibiotics
Diet
“Hygiene”
During the development
Environmental influences on human T2D
Diet High fatHigh calorie“Junk food”
Drugs: Wide usage of antibiotics
Life style: physical inactivity
Effect of Diet on Obesity
10% fat 35% fat 60% fat
Enterotype of Human Gut Microbiota
Wu, et al, Science 2011
Animal protein enriched diet
Carbohydrate enriched diet
Effect of Diet on Human Gut Microbiota
David, et al; Nature, 2014
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, 2013Tilg, Gut, 2014
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
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
“You Are What You Eat”
Gastric bypass – the most effective intervention of obesity and T2D
Alpha diversity
Diversity of Fecal Microbiota Is Significantly Increased After Gastric Bypass
Am J Clin Nutr. 2013 Jul;98(1):16-24
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.
Acknowledgements
Funded by NIH and ADA
Collaborators
Andrew Duffy (Yale)Robert Sherwin (Yale)Susan Wong(Cardiff, UK)
Recommended