helicobacter pylori not just for ulcers. pre-lecture discussion questions what is the germ theory of...

Helicobacter pylori

Not just for ulcers

Pre-lecture discussion questions

• What is the germ theory of disease?• What are some of the initial ways in which it

was demonstrated?• What is a germ-free animal and how are they

produced?• What are the effects of being germ-free?

H. pylori

Stomach Microbiota

• at rest: pH 4 – 5.• At full function: pH 1- 2.

• Once thought to be sterile.• Not very diverse.

H. pylori

• Gram negative, spiral, flagella.• Adapted to high acid.• High urease activity.– C-14 test.

H. Pylori Infection Rates

• Historically: 70 – 80% (or higher?).• <10% of U.S. children.• Much higher for those over 60.• Much higher for those in under-developed

countries.

• Association pre-dates our species.

Gastric antral biopsies from an H. pylori–positive patient (left) and an H. pylori–negative patient (right; photomicrographs courtesy of Zhiheng Pei, M.D., Ph.D.). The H. pylori–positive biopsy shows deeper staining of the epithelial cells, indicating tissue reactivity.

http://www.med.nyu.edu/medicine/labs/blaserlab/v1-sld_H-pylori.html

Peptic Ulcers

• Inflammation and bleeding.• Lining of distal stomach or duodenum.

• Often a precursor to gastric cancers.

HP-NAP = H. pylori Neutrophil-activating protein

Clin. Microbiol. Rev. October 2010 vol. 23 no. 4 713-739

Dysregulation of the apical-junctional complex by H. pylori. H. pylori preferentially adheres to the apical-junctional complex of epithelial cells and alters localization of apical-junctional component proteins, disrupts epithelial barrier function, cell adhesion, and cell polarity, and induces an invasive phenotype. Translocated CagA interacts with PAR1, preventing phosphorylation of PAR1 by blocking PAR1 kinase activity, which culminates in disruption of the tight junction. In addition, functional urease activity can disrupt the tight junction via a mechanism involving MLC phosphorylation, which can be regulated by MLCK and Rho kinase. VacA can also increase tight junction permeability to low-molecular-weight molecules and ions.

Barry Marshall

• (1984-5) Fulfills Koch’s postulates with H. pylori.– But only for gastritis (not peptic ulcers).

• Nobel Prize in 2005.

Electron photomicrograph of Helicobacter pylori colonizing the stomach of a human volunteer who ingested the organism as part of an experimental inoculation. The spiral microaerophilic bacteria live in the mucus layer that overlays the gastric epithelium. Photo copyright, Martin J. Blaser, 1989.

Cag Island

• Horizontally acquired.• 40 kb, 31 genes.• Type IV secretion system.• CagA is translocated to host cells.– Alters host cell morphology.

• cagA+ strains – highest risk of ulcers & gastric cancer.

Type IV Secretion System

Helicobacter exploits integrin for type IV secretion and kinase activationTerry Kwok, Dana Zabler, Sylwia Urman, Manfred Rohde, Roland Hartig, Silja Wessler, Rolf Misselwitz, Jürgen Berger, Norbert Sewald, Wolfgang König & Steffen BackertNature 449, 862-866(18 October 2007)

Lack of H. pylori

• Gastro-esophageal reflux disease (GERD).• Esophageal adenocarcinoma.– Inc. in last 40 years.

• Disregulated leptin & ghrelin.– Obesity, type 2 diabetes, metabolic disease.

• Asthma!

Asthma Study in Mice

• Neonatal H. pylori (cag+) infection protected.– Stimulated Regulatory T (Treg) cells.

Arnold et al. (2011). J. Clinical Investigation.

• But H. pylori cag genes stimulates IL-8 (pro-inflammatory) release.

• Timing of H. pylori colonization matters.– Early (infancy) is probably better.

• Balance of cagA+ to cagA-??

Lessons from H. pylori

• Koch’s postulates.• Horizontal gene transfer.• Toxin delivery and action.• Adaptation to acidic environment.• Role of normal microbiota.– Effects of antibiotics & sanitation.– Bacteria can affect cancers.– Bacteria impact the immune system.– Bacteria effect overall metabolism.

Hygiene Hypothesis

• Martin Blaser prefers “Disappearing Microbiota.”

• Others refer to “Missing Old Friends.”

Germ Theory of Disease

• Not so straightforward.

Other Missing “Old Friends?”

• Epstein-Barr Virus.– Herpes Viruses.

• Mycobacterium tuberculosis.• Trichuris trichuria.• Ancylostoma duodenale/Necator americanus.• More?

Trichuriasis

• Whipworm (nematode).

• Trichuris trichiura. • 4 cm adults.• 3,000 – 20,000 eggs

per day.• Feed on undigested food.

604M

Trichuriasis

Hookworm

• Can lead to longstanding anemia.– Affects physical & cognitive development.– Low birth weight & reduced maternal health.

Ancylostoma duodenale576M

Summer Reading

• An Epidemic of Absence by Moises Velasquez-Manoff.