Mimm 465 Lecture 6 Moual

Front 1

Dysbiosis

Back 1

Concept introduced by Ellie Metchnikoff to describe a stete of microbial imbalance in the gut that produces a disruption in the homeostasis btw host and microbes.

Front 2

Causes of dysbiosis

Back 2

1. Host genetics: mutations in NOD2, IL23R, ATG16L and IGRM

2. Lifestyle: Diet and stress

3. Early colonization: birth in hospitals

4. Medical practices: vaccination, antibiotic, hygiene

Result in

1. Disease: Th1, Th2, Th17

2. Health: Treg

Front 3

Dysbiosis associated disease

Back 3

1. Obesity

2. Inflammatory bowel disease (Crohn's disease, ulcerative colitis, pouchitis)

3. Irritable bowel disease

4. type 1 diabetes

5. autism

6. allergy

7. asthma

8. Celiac disease

Front 4

Obesity and gut flora

Back 4

1. genetically obese mice (ob/ob, prevent production of leptin) have 50% less Bacteroidetes and 50% more firmicutes.

In humans too.(hypothesis: possibly bacteria extraction of energy different)

2. in mice, obese phenotype is transmissible through microbiota transplantation from ob/ob to germ-free.

3. When obese lose weight over a year, bacteroidetes increase

Front 5

Richness of human gut microbiome

Back 5

1. Super-organism: we are composed of our own genome plus the genomes of the commensal bacteria

2. Genetic richness of the microbiome is estimated to 500 000 different genes(21 000 human genes)

3.non-obse --> 350 000 genes, obese --> 550 000 genes

4. individual with low bacterial richness had

more adiposity, insulin resistance, more pronounced inflammation.

Front 6

Probiotic treatment for obesity

Back 6

1. Akkermansia muciniphila (Verrucomicrobia phylum) is a mucus-colonizing member constituting up to 3% of gut microbiota

2. Mucin-degradation activity leads to production of acetate and propionate

3. its abundance inversely correlates with body weight

Front 7

Antibiotics and adiposity

Back 7

Low doses of antibiotics are used to promote growth of farm animals

1. in young mice, low doses of antibiotics icnreased adiposity without changing total bacteria numbers

2. Composition altered, firmicutes increased. Increased level of SCFAs in large intestine too

3. Antibiotic use during infancy before age of 6 months significantly associated with obesity development

Front 8

Effects of SCFAs

Back 8

1. large amount of SCFAs (acetate and propionate) delivered to liver through portal vein resulting in enhanced lipogenesis and gluco.

2. inhibit HDAC, signaling through GPR42 resulting in promotion of Treg

Front 9

Obesity cancer

Back 9

1.Obesity increases firmicutes proportion including Cluster IX clostridium spp. Some can transform primary bile acids into secondary bile acids (deoxycholic acid, DCA), a known carcinogen.

2. Treatment of mice w/ vancomicin(target firmicutes) results in reduction of liver cancer.

Front 10

Inflammatory bowel disease

Back 10

1. Crohn's disease(ileum), ulcerative colitis(colong)

2. IBD: inflammation caused by intestinal microbiota is not down-regulated to state of tolerance

3. changes in microbiota composition

Front 11

Genetic predispositions to IBD

Back 11

1. 100 distinct susceptibility loci

2. Point mutation in NOD2 gene lead to defect in secretion of alpha-defensins by paneth cells --> predispose to Crohn's disease.

3. Mutations in autophagy gene ATG16L1 also results in Paneth cell abnormalities

Front 12

Nod2 role in colon

Back 12

1. prevents inflammation caused by Bacteroides vulgatus

2. Nod2 -/- mice develop inflammatory gene expression, goblet cell defects, excessive immune response.

3. Nos2 -/- susceptible to colonization by B. vulgatus --> mediates inflammation.

Front 13

Change in microbiota composition IBD

Back 13

Overall, decrease in nb of symbionts and increase in pathobionts.

-Bacteroides(vulgatus), adherent-invasive E.coli, Helicobacter hepaticus.

-stool and tissue sample are different --> Fusobacteria not detected in stool.

Front 14

Role of microbiota in IBDs

Back 14

1. Germ-free mice do not develop chemically induced IBDs

2. susceptible IL-10 -/- in GF environment do not develop IBDs

3. susceptible IL-10 -/- lacking TLRs or Myd88 do not develop IBDs. Indicating that recognition of commensal bacteria by innate immune system is important for IBD,

Front 15

Influence of diet on IBD

Back 15

1. Dietary fat can alter bile acid composition synthesized by liver --> increase in taurocholic acid.

2. This promotes an increase in number of Bilophila wadsworthia. part of proteobacteria (gram -, rod), usually less than 0.01%

3. Bilophila wadsworthis increases onset and incidence of colitis in susceptible IL-10 -/- mice

4. B. wadsworthia is good example of pathobiont

Front 16

Faecalibaterium prausnitzii

Back 16

1. gram +, part of firmicutes phylum

2. most abundant in human gut microbiota(5%)

3. Anti-inflammatory properties, it secretes compound able to block Nf-kB and IL-8 production. Promotes IL-10 secretion

4. Oral administration of F. prausnitzii or culture supernatant reduces the severity of trinitrobenzenesulfonic acid-induced colitis

5. together with Bacteroides fragilis, clostridium spp. clusters IV and XIVa can be used as a probiotic to prevent IBD

Front 17

Fusobacterium nucleatum

Back 17

1. Fn most abundant in oral cavity, associated with periodontis

2. non-spore forming, anaerobic gram negative part of fusobacteria phylum, pathogenesis due to adherance and invasive properties.

3. Fn is rarely detected in the luminal flora, easily detected in mucosa

Front 18

Colorectal cancer

Back 18

1. second most occuring cancer worldwide

2. most common mutation in colon cancer is in APCgene. (APC is part of beta-catenin signaling pathway)

3. gut microbiota linked to CRC(3)

-Enterotoxigenic Bacteroides fragilis

-Adherent-invasive E. coli

- Fusobacterium nucleatum

Front 19

Fusobacterium nucleatum and cancer

Back 19

1. Enrichment of fusobacterium species in colorectal tumor

2. adheres and invades intestinal cells through FadA surface adhesin

3. FadA binds to EC5 domain of E-cadherin and activates beta-catenin signaling, promote tumor growth and inflammation

4. fadA gene levels from patients 10-100 fold higher than normal individuals

Front 20

Clostridia in food allergies

Back 20

1. GF mice or mice treated w/ antibiotics have increased allergic responses to dietary Ag like peanuts.

2. Colonization with clostridia prevents sensitization to these allergens

-Clostridia modulate a subset of ILC in GALT to produce IL-22(regulates(close) intestinal epithelial permeability to allergens)