the normal microbiota
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The Normal Microbiota
Natural Human Flora
• What organisms are part of normal flora
• Where do they colonize- microbial ecosystems
• How are they able to cause disease?- exposure- virulence factors
NATURE REVIEWS | MICROBIOLOGY VOLUME 9 | APRIL 2011 | 279
MICROBIAL COMMUNITY COMPOSITION IN A HEALTHY HUMANS
Colon
Distribution of bacterial species along the gutDistribution of bacterial species along the gut
Stomach• Streptococcus
Small bowel (ileum)• Lactobacillus• Streptococcus• E. coli• Clostridium• Bacteroides• Eubacterium• Vellonella
• Bacteroides• Eubacterium• Clostridium• Ruminoccus• Bifidobacteriu
m• Streptococcus• Lactobacillus• E. coli
BacteroidesEubacteriumClostridiumRuminococcusBifidobacteriumStreptococcusLactobacillusE. coli
non -E. coli coliformes
Colon
Eckburg et al., 2005 Science
>13 500 sequences 16S rRNA
Metabolism- supplies enzymatic activities not encoded by host- modifies bioavailability and bioactivity- can induce/reduce obesity & T2DProtection- develops local and systemic
immunity- regulates tolerance, allergies &
homeostasis
A healthy microflora regulates diverse biological roles
Behavior - alters host behavior through its
effects on the central nervous system
Adult microbiota: acquired by 2 yrsStable?
In utero = sterile “germ free”
Birth: colonization begins
Environment & host influence species
dominance
Maternal vaginal, colonic & skin
microflora
Vaginal vs C-section
Antibiotics
Initial feedings
Developing immune system
Stability could impart resilience to disturbance to ensure continued gut function, but in a disease context, this could be detrimental if the gut community is pathogenic.
Gut microbes are “inherited” maternallyGut microbes are “inherited” maternally
Species diversity profiling of fecal adult microbiota
Zoetendahl et al. 1998Seksik et al. 2003Vanhoutte et al. 2004
The faecal microbiota is specific of individuals
14 healthy adults
Microbiota is variable between individuals but each individual microbiota is stable
Once colonized your microflora is stable throughout life.
Denaturing/thermal gradient gel electrophoresis separates DNA by differing thermal stability; patterns reflect bacterial diversity
Factors can change the microbiota composition: dysbiosis
• Stress: (O'Mahony, 2009)Stress: (O'Mahony, 2009)• Exercise: (Matsumoto, 2008)Exercise: (Matsumoto, 2008)• Inflammation: Inflammation: (Lupp, 2007)• Old Age: (Biagi, 2010)Old Age: (Biagi, 2010)• Diet:Diet:
• carbohydrate reduced(Walker, 2011); high fiber diets (De Filippo carbohydrate reduced(Walker, 2011); high fiber diets (De Filippo 2011); high-fat, high-sugar "Western" diet (Turnbaugh 2010); 2011); high-fat, high-sugar "Western" diet (Turnbaugh 2010); calorie-restricted diets (Santacruz 2009); vegetarianism (Liszt K, calorie-restricted diets (Santacruz 2009); vegetarianism (Liszt K, 2009); alcohol consumption (Mutlu, 2009); high fat (Mozes, 2009); alcohol consumption (Mutlu, 2009); high fat (Mozes, 2008)2008)
Diseases associated with gut microbial dysbiosis
Inflammatory Bowel Disease
Type I and II Diabetes
Irritable Bowel Syndrome
Celiac’s Disease
Autism?
Does dysbiosis cause disease?
Obesity-Associated Gut Microbiota Induces Adiposity
Mice + lean microflora = resistant to the fattening effects of high fat diets, despite eating the same amount of food.
Microflora from an obese mouse
Microflora from a lean mouse
(Turnbaugh et al, 2006 Nature).
Reduced Microbiota Diversity with Obesity
Turnbaugh et al. 2009, Nature 457:480-485.
The microbiota diversity is reduced in obese subjects.
A healthy microflora balances immunological A healthy microflora balances immunological responsesresponses
Probiotics
Can probiotics treat or prevent disease? Assumed to be a safe benign treatment All yogurts have at least two probiotics
• Lactobacillus bulgaricus• Streptococcus thermophilus
Bifidobacteria isolated from the intestinewww.livingfoodsusa.com/library/probiotic.html
Probiotics: Live microorganisms when administered in adequate amounts confer a beneficial health effect on the hostPrebiotics: compounds that promote the growth of probiotics
– Some microbes that are non-pathogenic in normal host can produce severe life-threatening disease in immunodeficient – may be normal flora components (endogenous)
• Ex. Fungal pathogens;
• Infection with organisms of known pathogenicity– Reactivation
• Ex. TB in AIDS patients
– Exogenous• Pathogens which normally cause mild conditions can cause
life-threatening illness in immunodeficient
• Opportunist infections
Causes of Immunodeficiency• Disease or trauma
– Ex. HIV; neoplasia; burns; compromised clearance (ex. cystic fibrosis, obstructed urine flow)
• Therapy– Ex. steroids, chemotherapeutic cytotoxic agents,
radiotherapy, splenectomy; prosthetic devices; catheters• Age
– Neonates (immature immune system)– Elderly (decrease in immunity, malnutrition
Some Common Causes of Infection in Immunocompromised Patients
Infectious Agent Disease
E. Coli Urinary infections, septicemia
Pseudomonas aeruginosa Pneumonia, septicemia
M. Tuberculosis Pulmonary, miliary TB
C. Difficile Diarrhea, pseudomembranous colitis
Candida Thrush, systemic candidiasis
Cryptococcus neoformans Meningoencephalitis
Clostridium difficile• Present in less than 5% of people in their normal flora at very low numbers• Can be “acquired” through community or hospital• Antibiotic use (particularly broad spectrum) causes disruption of normal flora →
overgrowth of C. difficile → C. difficile produces exotoxins → – Diarrhea– Characteristic fibrinous pseudomembrane covers colonic mucosa (hence the
name “pseudomembranous colitis”)• Treatment: metronidazole or oral vancomycin (resistance has emerged)• Oral fecal bacterial therapy has been successful
C. difficile is acquired the hospital: patients are exposed through contact with the hospital environment or health care workers. After antibiotic-treatment they can develop infection but only if the strain is toxigenic and they fail to produce IgG responses.
• Bioterrorism = intentional or threatened use of viruses, bacteria, fungi, or toxins from living organisms to produce death or disease in humans, animals, and plants– Agent chosen for mass casualties
• Biocrime: agent chosen as a means for a localized attack• Characteristics that favour use of particular agent:
– Invisible, odourless, tasteless– Difficult to detect– Take hours or days before awareness that they have been used
Examples of Intentional Uses of Biological Agents for Criminal or Terror Intent
• 1984 in Dalles, Oregon– Salmonella typhimurium in 10 restaurant salad bars
• 1996 in Texas– Intentional release of Shigella dysentariae in a
hospital lab break room
• 2001 in seven eastern U.S. states– Use of weaponized Bacillus anthracis spores delivered
through U.S. postal systems– 22 infected persons– Five deaths
Agents Considered a High Priority Threat
• Yersinia pestis• Francisella tularensis• Small pox• Bacillus anthracis• Botulinum toxin• Exotic viruses (ex. Ebola, Marburg)• Genetically modified organisms
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