Human Microbiome Flashcards
Infection def
presence of microbes
infection does not equal disease
microbiome def
minimal “core” of persistent species
1) residents = always there
2) transients = come and go
opportunists def
microbes of low pathogenic potential
able to cause disease only in hosts with compromised defenses
often members of normal microbiome!
pathogenicity def
VIRULENCE.
the potential to cause disease
some microbes are inherently virulent
PRESENCE IS A MEDICAL ISSUE.
dysbiosis def
disrupted microbiome, frequently associated with a diseased state
probiotics def
microbes believed to provide health benefits
fecal microbial transplants
restore beneficial microbiome
prebiotics def
substances that induce the growth or activity of beneficial microbes
what type of relationship do we have with our gut biome?
COMMENSALISM! bacteria are happy and were neutral - usually
symbiotic (mutalistic) def
microbe happy, host happy
ex. rumen bacteria of cattle digest cellulose
pathogenic (parasitic) microbial relationships - def
good for microbe, bad for host
the microbial metabolic capacity of our body is greater than our liver..
…
superorganism def
our body plus our microbiome
Diff body sites serve as ecosystems. Diversity is high at every body site. The same anatomical site in diff people tend to have similar organisms.
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Mouth bac?
streptococci
Throat bac?
streptococci
neisseria ssp.
staphloccocci
hemophilus
conjuctiva bac?
staph epidermidis
prprionibacteria
teeth bac?
streptococcus mutans(decay) bacteroides fusobacterium streptococcus actinomycetes
nose bac?
staphlococci (S. aureus and S. epidermidis)
corynebacteria
streptococci
Skin bac?
S. epidermidis (staphylococci)
proprionibacteria
corynebacteria
Staphlococcus aureus
MRSA = methicillin resistant
Colonize where..?
Nares!! (not the skin)
Nose has the staphylococci (s. aureus and s. epidermidis)
Vagina bac?
lactobacillus
Colon has extreme diversity of microbes!!
…
Normal bac at one site can be disease at another anatomical site. Opportunistic infections can happen when barriers are breached.
Exs: -Carier (Strep Mutans in mouth) Sepsis/endocarditis pneumonia gastroenteritis peritonitis urogenital infectiosn abscesses in the brain, tissue, GI (often anaerobes - wall themselves off from outside/o2)
Conditions for opportunistic infections?
malnutrition diabetes immunodeficiency (AIDs, transplants, leukemia) radiation trauma/surgery/burns
Sterile sites?
Inside dermis from trachea to upper GI
trachea, lungs, heart/blood, organs, bladder, stomach, upper intestinal tract, fetus!
Anatomical /Mechanical Defenses in the Lungs
10 micrometers?
5-10?
5 or less?
- 90 degree angle in throat where bac get splattered on back of palate (swallow them and get destroyed in stomach)
- > 10 micrometers - deposited on baffle plates and swallowed - killed by stomach acid
5-10 micrometers - carried down to trachea BUT THE MUCILLIARY ESCALATOR - causes them to be swept upward and swallowed and killed
<5 micrometers - they enter the lungs and are phaogcytosed by alveolar macrophages
small intestine - bile - antimicrobials maintain sterility
bladder - sheer stress of urine flow
urine is also antimicrobial!!!!
skin is a physical barrier/ has secretions!
…
The extreme diversity of the colon/microbial competition keeps away pathogens.
Vagina produces lactobacillus. Host what promotes its colonization?
glycogen!!!
Vagina also produces antimicrobials (lactic acid - pH=4.6) and hydrogen peroxide (h2o2)
Antimicrobial aspects of gut?
fatty acids, acid, peroxide, BACTERIOCINS (produced by normal gut
Damaged mucosa in gut can come from..
chem/phys damage
irradiation
immune suprresion
antibiotic tx
Commensal microbes in gut produce antibmicrobial products. They also educate the immune system to avoid producing antibodies that are too strong but help them make cross-reactive Ab.
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The Normal Microbiome produce…
Vitamins (B12 and K)
degrade polysaccharides
generate nutrients (short chain FA)
detoxify coumpounds
normal microbiome stimulates…
gut vasculatrue nervous and immuen system promotes development of intestinal lymphatic system produces cross-reactive AB
normal microbiome modifies behavior…
synpatic connectivity
anxiety
pain
perception
we know that oral drugs/pill can influence neurologic responses…it is not a stretch to thin that metabolites from gut microbes can also do this!
…
Significance of the normal micro biome - Harmful effects
1) nutrient competition (farm animals given antibiotics grow larger)
2) synergistic protection of each other- antibiotic destruction [resistant bacteria degrade antibiotics, protects sensitive bacteria]
3) toxic metabolites - produced by gut bacteria and CAN CAUSE CANCER!
4) low grade toxemia/inflammation - CAN CAUSE CANCER
…
For who is the microbe essential?
Cattle - Ruminates - digest cellulose and are essential for life
Microbiome is NOT essential for mice and man
microbial colonization begins at birth!
Maternal factors that influence the microbiome?
mother’s gut micro biome
vaginal microbiome
oral microbiome
**Maternal vaginal infections or PERIODONITIS (gum infection) can result in bacteria invading the uterine environment
Does the mode of delivery effect the micro biome of the child?
YES
C- section babies are at an elevated risk for developing inflammatory bowel disease, celiac disease, allergy, and obesity (sometimes decades later!)
vaginal delivery prominent bac?
lactobacillus
c section bac?
staphylococcus
propionibacterium (mothers skin)
If you breast feed, the infant has a…
increased resistance to infection
lower risk of obesity
lower allergies
Milk acts as “prebiotic” - sugars/glycans in it feed the biome (non digestible)
If you breast feed the mom…
decreased risk of... hypertension hyperlipidemia cardiovascular disease type 2 diabetes
Antibiotics in a child do what?
Increase risk of obesity, inflame bowel disease
At about 1 yr, the child has a typical adult diet and adult-like microbiota..
..
Adult gut microbiota is influenced by….
1) environmental factors (antibiotics, lifestyle, diet, hygiene)
2) host genetics:
- hyperimmunity (expression of pro-inflamm mediators - IL-1, IL-6, and TNF)
- immunodeficiency (NOD10/IL-10)
* *These two affect the biome/biome causes these things!
3) dysbiosis - induces both chronic inflamm and metabolic dysfunction
Recently - Incidence of chronic diseases affecting different body systems has markedly increased… Those are?
Obesity asthma hay fever food allergies inflamm bowel disease juvenile type 1 diabetes autism etc
**FIRST SEEN IN DEVELOPED COUTNRIES, SPREADS TO TOHER AREAS AS THEY DEVELOP!
Theory behind increase in chronic diseases?
Theory is that loss of human microbiota alters immunological, metabolic, and cognitive development in early life, resulting in disease
Historically, we used innate immunity to combat infections and we had a mature adaptive immune response.
Now, we have decreased vertical transmission (mom to baby) with C-section and formula milk and less horizontal exposure (hygiene -were “too clean”).
This had made us currently rely on ADAPTIVE IMMUNITY, then secondly on innate. (adaptive is informing innate - opposite of how it should be!)
This altered maturation of adaptive immunity has done what..?
decreased tolerance and increased reactivity to things.
This has led to increased incidence of autoimmune and inflame diseases!
Clostridium difficile…
- anaroebic or aerobic?
- There has been an emergence of a hyper virulent strain! It overproduces toxins.
- Spread how?
- Spores can persist on environmental surfaces for months!
Anaroebic!
Spread through fecal-oral route.
Clostridium difficile causes what?
symptoms?
where is it normally acquired?
Pseudomembranous colitis!
- recurrent diarrhea, toxic megacolon, sepsis, and then death
- acquired in healthcare settings!
After antibiotic use, you have a compromised epithelium and little to no mucus layer and loss of microbial diversity… This allows the growth of Clostridium difficult! Subsequently, toxin is produced!
** In the inactive state, C.difficile is not producing toxins! It is in the spore form.
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What is the poster child for dysbiosis?
Clostridium dificile!
What is the single most important risk factor for clostridium difficile?
Antibiotic exposure! (previous 28 days)
What is the Tx for Clostridium difficile?
Fecal microbial transplantation !
For severe recurrent diarrhea from antibiotic resistant C. difficile
Efficacious in 90% of patients!
What microbial product leads to elevated risk for atheroschlerosis?
What lowered levels of this product and therefore prevented atheroschlerosis?
TMAO (trimethylamine - TMA from bacteria converted to TMAO by liver)
choline analogue
Reduction of bacterial TMA prevents atherosclerosis!
…
Which foods metabolized by gut microbes produce trimethylamine (TMA)?
Foods rich in cholesterol and fat!
TMA is converted to TMAO by the liver and then it enters circulation! TMAO enhances what?
What is TMAO associated with?
macrophage cholesterol accumulation/atheroschlerosis.
Associated with cardiovascular disease/stroke/death
** we now have a drug that can prevent production of TMA
Bacteroides fragilis…loss leads to what IN MICE?
ANXIETY!
Autistic like behavior, dysbiosis, increased gut permeability, and altered serum metabolome.
Feeding bacteroides fragilis to the mice restored mucosal barrier and diminished behavioral abnormalities!
How do parasites affect host behavior.... Fungal parasite on ants? Toxoplasma gondii in mice? Rabies virus in dogs? Salmonella enterica in mice?
1) induces ants to climb to canopy and emerge from head
2) reduces aversion to cat urine
3) increases aggression and biting, promoting transmission
4) increases appetite to it can be fed in gut
Microbiome in cancer… Which two immune checkpoint blockade therapies rely on gut micro biome for efficacy in immune activation?
anti-CTLA4
anti-PD-L1
(can’t generate T-cells?)
***gut colonization with specific bacteria is needed to generate anti-tumor responses!!!
Blocking of PD-1 binding on T cell with the PD-L1 on the tumor allows for the tumor cell to be killed! - normal gut microbiota is necessary so we can create anti-PD-L1 so that these tumor cells can be killed by T cells
Some intratumor bacteria are important in the fact that they can create tumor resistance to chemotherapies!!! Ex. Certain bacteria can inactivate the cancer drug gemcitabine. Human pancreatic ductal adenocarcinoma (Very lethal) often have bacteria. Therapeutic efficacy of gemcitabine might be improved by what?
co treatment with antibiotics!
Microbiomes in obese people are….
less diverse and different from non-obese!
Mice with microbes from obese gained more weight than mice with microbes from lean mice.
Mice could not be colonized with the lean microbes if they were fed unhealthful western diet that was…
high in unsaturated fats and low in fiber!
E.coli strains engineered to secrete precursors of anorexigenic agents reduced food intake, adiposity, and obesity in mice fed a high-fat diet!
Tx = ENGINEERED E.COLI!
Early-life probiotic supplementation is important for pancreatic islet autoimmunity!!!
Genotype importnat?
HLA-DR3/4 increases susceptibility
americans rate physicians higher when they get antibiotics.
people prescribe because easier to do that than explain why you won’t.
proposal?
exclude reviews from respiratory tract infection appts from ratings
Up to what percentage of antimicrobial use is inappropriate?
50%!
Antibiotics is the only drug where use in one patient can impact the effectiveness in another!!!
….
Antibioitcs are a SHARED resource and becoming a SCARCE one and perhaps NONRENEWABLE!
..
Examples of antibiotic misuse….
given when not needed (viral infec) continued when not needed given at wrong dose broad spectrum agents used to treat highly susceptible bacteria wrong antibiotic for patient's infection
What is the real job of the appendix?
Safe house to store and protect good microbes for your gut
If micro biome is purged by diarrhea or antibiotics, the appendix repopulates the digestive track with protective microbes.
important in less hygienic societies, less so in industrialized ones.
Individuals without an appendix were 4x more likely to have a recurrence of C.difficile.
