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Flashcards in Section 1- The Human Microbiome Deck (34)
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The totality of microbes, including their genetic content (genomes), in a given environment
Live in close association with plants and animals
Usually only consider disease states of microbiome, but it is so much more
Organisms do not live in isolation; have evolved in context of complex communities



Bacteria, yeast, fungi, virus, etc.
Estimated to outnumber human cells by 3-10 to 1 in human body
Their total genes may exceed human genes by 100-300 to 1 (extreme functional content)
Many have not been cultured in a lab and their role in human physiology and disease is largely unknown
Community dynamic very important



Disrupted relationship between living organisms
Opposite of symbiosis


Human Microbiome Project (HMP)

Major initiative from NIH to catalog human microbiota and initiate the investigation of its role in human health and disease
Shows substantial intra-individual variation at different anatomical sites
Substantial inter-individual variation at the same anatomical site
Temporal stability in individuals at specific sites (stable through different conditions and times
Disruptions can have long-lasting effects


Distribution of human microbiota

30% GI tract (most dense microbiome on earth)
Then oral, skin, airway, urogenital, blood, eye
GI tract contains 1000 or more phenotypes
Each individual has a unique diversity of flora (fingerprint), but functions are stable across individuals
Deeper in body, higher ratio of anaerobic microbes


Main force in bacterial evolution over past 200 years

Unnatural (anthropogenic) selection


How is information about microbial niche populations generated if most have never been cultured in the lab?

rRNA phylotyping
rRNA is the common denominator in all microbial genomes- is the ideal substrate for phylotyping
DNA sequence analysis of individual organisms or populations
Use 16S r RNA- every microbe has and sequence is evolutionarily conserved
Can analyze an entire population at once
A 1% change represents a new species


How does one begin to study the microbiome?

Next generation DNA sequencers capable of generating 2-20 gigabases (billion bases) of sequence per run (=1 human)
1000's of bacteria per run



Analysis of DNA sequences within a particular environment (gut, nasopharynx, UG tract, environment)
Bacterial speciation within environment based on conserved DNA sequences (rRNA, conserved housekeeping genes)


Gut microbiome

Know the most about the gut
Where the immune system begins to develop
Microbes break down foods we can't
Most bacteria are Firmicutes and Bacteroidetes (>90%)
Substantial diversity between healthy individuals, esp. between infants; converges to more similar later in life
A few Proteobacteria and Actinobacteria



95% are Clostridial species (Botulism, C. diff)
Also Lactobacillus, Mycoplasma, Bacillus, and many butyrate-producers
Function in maintenance and protection of normal intestinal epithelium (produce short chain fatty acids)



Added to gut microbiome with solid food introduction
Highly variable species
Bacteroides thetaiotaomicron is most abundant species (opportunistic pathogen)
Function to help digest food


Skin microbiome

Exogenous and endogenous factors contribute to variation between individuals over lifetime of the individual
Highly dependent on microenvironment of sampled site (Ex: dry vs moist)


Vaginal microbiome

Lactobacillus characteristic of normal healthy reproductive aged women
Growth of non-indigenous organisms like pathogens is restricted
Protection due to low pH (<4.5), lactic acid, antimicrobial compounds, and other things
Human vagina has no single core microbiome; there are multiple that are defined by 5 community groups
Genetic component exists (by race)


Ancient vs Modern mother to child microbiome transmission

Ancient: Oral (chewing food), Mammary (breastfeeding), Cutaneous (skin), Vaginal (birth canal)
Modern: Oral, Mammary, Cutaneous, Vaginal + Maternal exposures (Antiseptics, Antibiotics, Diet, Epigenetics), Bottle feeding (formula), Early-life antibiotics, C-section, Early/extensive bathing


Changes in human behavior that can alter the microbiome composition

Clean water, C-sections, Preterm antibiotics, Reduced breast feeding, Smaller family size, Widespread antibiotic use, Increased bathing/showering and use of antibacterial soaps, Use of mercury amalgam dental fillings
"Cleaner" not always better


Main vaginal bacteria



Main C-section delivery bacterium



Main breast milk bacterium



Main bacteria in solid food



Main contributions of microbiota to host

Digestion and fermentation of carbohydrates
Production of vitamins
Development of the gut-associated lymphoid tissues (start of immune system)
Polarization of gut-specific immune responses (ex: inflammation)
Prevention of colonization by pathogens
Gut immune responses induced by commensal populations regulate the composition of the microbiota as well.
The immune system has evolved adaptations that work to contain the microbiota and preserve the symbiotic relationship


Microbiota-Induced Maturation of the GI Tract

Changes in gut microbiota promotes substantial changes in gut morphology
Villus architecture (healthy=long)
Crypt depth (healthy=deeper)
Stem cell proliferation
Blood vessel density
Mucus layer properties
MALT maturation


Microbiome and Gut Immune System Interactions

Lymphoid structures develop prenatally before bacterial colonization
M cells at apical surfaces sample luminal antigens and bacteria
Dendritic cells present antigens to induce immune cell maturation
Secretion of IgA and AMPs to control bacterial penetration of gut defenses
Dysbiosis can trigger pro-inflammatory responses


Differences in gut microbial composition between obese and lean individuals

2 experiments performed
Preliminary human studies indicated that proportion of genetic material from Firmicutes was higher in obese individuals
When placed on carb-restricting diets, bacteroidetes increased over Firmicutes, correlated with decrease in body fat
In mice, microbiota from obese mice was rich in genes encoding enzymes that break down otherwise indigestible polysaccharides; assists host in extracting extra calories from ingested food



Hormone that signals levels of body fat
Low levels send message to brain to increase caloric intake


Glycan Microhabitats and Food Chains in Gut

Food from plants or meat are rich in source-specific glycans
Attacked in distal gut by primary glycan degraders
More soluble glycan fragments digested by secondary glycan degraders, liberating pools of short chain fatty acids (SCFAs) as fermentation products
Similar food chain occurs in mucus layer


Short chain fatty acids (SCFAs)

Important for intestinal epithelial homeostasis


Effect of antibiotics on gut flora

Direct and Indirect effects
Indigenous microbes form an ecological barrier that prevents ingress of many pathogenic microorganisms
Antibiotic use sometimes leads to development of C. diff-associated colitis, due to loss of intrinsic "colonization resistance" offered by commensal species
Usually followed by decrease in microbiota diversity
Community is resilient and resembles pretreatment state in matter of days or weeks
Different antibiotics have different recovery periods (up to 6 months)
Gut microflora will never return COMPLETELY to normal-some bacteria lost indefinitely



Have high levels of antibiotic resistance genes


Diseases associated with antibiotic overuse

Clostridium difficile-associated diarrhea
Experimental autoimmune encephalopathy
Type 1 diabetes
Type 2 diabetes
Vancomycin-resistant Enterococcus