microbiota in health and disease · overview ! obesity ! multiple sclerosis ! colorectal cancer !...

Microbiota in health and disease

Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”

Overview

q  Obesity

q  Multiple Sclerosis

q  Colorectal cancer

q  Antibiotic resistant infections


Microbiota and obesity


Increase trend in child obesity around the world


Obesity in America


Reduced diversity of the gut microbiota in obese individuals


Taxonomic and functional variations in the human gut microbiome

Le, lean; Ov, overweight; Ob, obese;


Pathways enriched or depleted in the distal gut microbiome of obese twin

Enriched Fatty acid biosynthesis Nicotinate and nicotinamide metabolism Other ion-coupled transporters Other transporters Pentose and glucuronate interconversions Phosphotransferase system (PTS) Protein folding and associated processing Signal transduction mechanisms Transcription factors

Depleted Bacterial chemotaxis Bacterial motility proteins Benzoate degradation via CoA ligation Butanoate metabolism Citrate cycle (TCA cycle) Glycosaminoglycan degradation Other enzymes Oxidative phosphorylation Pyruvate/Oxoglutarate oxidoreductases Starch and sucrose metabolism Tryptophan metabolism

75% of the obesity-enriched genes were from Actinobacteria 25% of the obesity-enriched genes were from Firmicutes


TLR5 knock out (KO) mice develop obesity


Mice subjected to food restriction show a similar body and fatpad mass but with an increased glucose level

Insulin suppresses food intake. Increase of insulin in TLR5 KO might cause disturbed insulin signaling that prevent the insulin-mediated suppression of food intake.


TLR5 KO’s gut microbiota can transfer metabolic syndrome phenotype to germ-free

mice

fecal transplant fecal transplant


Microbiota and multiple sclerosis (MS)

q  Multiple Sclerosis (MS) is an chronic inflammatory demyelinating disease of the brain and spinal cord.

q  Areas affected by MS •  Brain •  Spinal cord •  Optic nerves


Risk of developing MS and region of origin


What causes MS? Genetics versus environmental factors

"   Monozygotic (identical) twins

"   Dizygotic (non-identical) twins

"   Child of parent with MS

"   Sibling of person with MS

25 – 30%

3 – 4.5% 1.9%

0.9%

Up to 19% of patients have an affected relative


Incidence of spontaneous EAE in mice housed in germ-free or SPF facility

Autoantigen: myelin oligodendrocyte glycoprotein (MOG)

Ant

i-MO

G a

ntib

ody


Impaired Th17 differentiation in germ-free mice


B-cell recruitment is impaired in germ-free mice

(inguinal lymph node) (cervical lymph nodes)


Microbiota and colitis-associated colorectal carcinoma (CAC)


Analysis of tumor induction and inflammation

azoxymethane (AOM) carcinogen


Il10−/− mice exhibit accelerated tumor progression


Il10−/− normal colon and adenomas exhibit increased cell proliferation


Modulation of microbiota-dependent colitis directly affects tumor development

Bacteroides vulgatus


MyD88 signaling is required for bacterial-induced CAC


Microbiota and antibiotic resistant infections

q  Antibiotic-resistant bacteria are an increasing problem in hospitalized patients

•  Already, 1.7 million people in the U.S. acquire infections in

the hospital each year, resulting in 99,000 deaths, according to the Centers for Disease Control and Prevention

•  But while 16 new antibiotics were approved between 1983 and 1987, only two have been approved since 2008.

q  Vancomycin-resistant Enterococcus faecium (VRE)

infection


Antibiotic treatment: the returning bacteria profile is not the same!


Antibiotic treatment promotes intestinal colonization by Clostridium, Enterococcus, and Enterobacteriaceae


Ampicillin treatment promotes VRE intestinal colonization in mice


VRE dominates the intestinal microbiota in humans prior to invading the bloodstream


Microbiota dysbiosis-associated diseases

IBD

Multiple Sclerosis

Microbiota-independent autoimmune disease Human autoimmune polyendocrinopathy- candidiasis-ectodermal dystrophy (APECED) MRL/lpr mouse model of human systemic lupus erythematosus


Conclusions

q  Twin study indicate obesity-associated microbiome harbors a increase in genes encoding enzymes in fatty acid synthesis and polysaccharide breakdown.

q  Dysfunctional interaction of the microbiota and innate immune player such as TLR5 may promote the inflammatory-related obesity

q  The gut microbiota can trigger of a spontaneous CNS-specific autoimmune disease.

q  Gut microbiota-induced inflammation drives progression of invasive carcinoma

q  Antibiotics perturb the normal commensal microbiota and set the stage for intestinal domination by bacteria associated with hospital-acquired infections

"   .


Future questions

q high-throughput DNA sequencing of the intestinal microbiota could identify patients at high risk of developing bacterial sepsis

q Understanding the interaction of gut microbes with the host immune system is a crucial health topic as the rate of many diseases are rising at an alarmingly high speed and may result from dysbiosis

q The link of gut microbiota to a non-gut associated disease?


Thank You and More Questions?


microbiota in health and disease · overview ! obesity ! multiple sclerosis ! colorectal cancer !...

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