microbiota in health and disease · overview ! obesity ! multiple sclerosis ! colorectal cancer !...
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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
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
Microbiota and obesity
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
Increase trend in child obesity around the world
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
Obesity in America
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
Reduced diversity of the gut microbiota in obese individuals
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
Taxonomic and functional variations in the human gut microbiome
Le, lean; Ov, overweight; Ob, obese;
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
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
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
TLR5 knock out (KO) mice develop obesity
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
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.
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
TLR5 KO’s gut microbiota can transfer metabolic syndrome phenotype to germ-free
mice
fecal transplant fecal transplant
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
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
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
Risk of developing MS and region of origin
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
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
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
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
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
Impaired Th17 differentiation in germ-free mice
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
B-cell recruitment is impaired in germ-free mice
(inguinal lymph node) (cervical lymph nodes)
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
Microbiota and colitis-associated colorectal carcinoma (CAC)
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
Analysis of tumor induction and inflammation
azoxymethane (AOM) carcinogen
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
Il10−/− mice exhibit accelerated tumor progression
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
Il10−/− normal colon and adenomas exhibit increased cell proliferation
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
Modulation of microbiota-dependent colitis directly affects tumor development
Bacteroides vulgatus
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
MyD88 signaling is required for bacterial-induced CAC
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
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
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
Antibiotic treatment: the returning bacteria profile is not the same!
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
Antibiotic treatment promotes intestinal colonization by Clostridium, Enterococcus, and Enterobacteriaceae
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
Ampicillin treatment promotes VRE intestinal colonization in mice
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
VRE dominates the intestinal microbiota in humans prior to invading the bloodstream
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
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
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
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
" .
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
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?
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
Thank You and More Questions?
Hsin-Jung Joyce Wu "Microbiota and man: the story about “us”
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