Lecture 28 & 29 PMB

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The Human Microbiome
Candice Young
Flashcards by Candice Young, updated more than 1 year ago
Candice Young
Created by Candice Young over 6 years ago
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sterile sites of human body bloodstream, CSF, heart, liver, kidneys
Human Microbiome Project goal was to acquire a “reference” microbiome of healthy adult humans samples from 250 people, analyzed by 16S rRNA sequencing --> community metagenomes obtained, genes and biological pathways can be guessed
conclusions of human microbiome project 1) NO reference microbiome exists for healthy adult humans 2) One body site is more likely to be similar to an identical body site on another person than a different body site on same person 3) No virulent pathogens just waiting around, just opportunistic pathogens 4) At a given site there are different phylogenies for each individual BUT same metabolic pathways still represented
How might different microbial communities perform the same functions at a given site? --> distinct groups of microbes can provide roughly the same set of metabolites as each other
How to compare two colonies from two different individuals do metagenomics, then BLAST, then predict all the different functional genes for each community
What areas of the skin can microbes occupy? can occupy sweat glands, sebaceous glands, hair follicles, epidermal surface --> NOT a uniform environment depending where on the body the skin is!
different skin environments surface = cool, dry, salty, acidic (gram positive S. epidermis love this) axilla, scalp, ear, genital = more humid face, chest, back = more sebaceous glands
P. acnes lives in sebaceous glands, digests triglycerides in sebum --> stimulates immune system --> produce inflammatory fatty free acids --> clog pores, create ACNE! lots of diversity at the strain level = metagenome sequencing shows diversity, not 16S
oral cavity microenvironments: below the gum line anoxic, microbes digest proteins secreted by host & catabolize amino acids healthy state: streptococci, actinomyces, veillonella diseased state: P. gingivalis dominates! --> gum detachment + tooth loss
oral cavity microenvironments: above the gum line bacteria must be able to withstand antibacterial factors in saliva (lysozymes) streptococci are most abundant, ferment carbohydrates to acids (lactate, formate, acetate) --> sugars abundant, pH drops --> enamel dissolution when carbohydrates are exhausted, pH rises and enamel dissolution stops
What happens with poor oral hygiene? acid-loving S. mutans and lactobacilli dominate and produce more acids through fermentation --> destroy enamel, more grow with increase in acids is a positive feedback loop
Stages of enamel decay 1) Healthy, only a few commensals 2) Healthy, more commensals pack in 3) Damaging, acid-tolerant fermenters enter and alter environment 4) Damaging, acid-tolerant fermenters completely outcompeting commensals and taking over biofilm
Microbiome of vaginally born babies vs Cesarean section vaginally born babies have higher species diversity 3 days after birth babies of CS in prospective studies found to have greater instances of asthma and allergies --> early exposure to microbes can influence immune system?
microbiome pH going down the human gut stomach pH = 2 small intestine pH = 4-5 large intestine pH = 7
alpha diversity the average human's diversity in the GI (about 1000 species)
beta diversity ALL GI microbiota sampled to date (about 10,000)
in general, what AFFECTS the GI microbiome? host genes; birth procedure (C section vs vaginal); early diet; early microbial exposure; antibiotic perturbation
in general, what is the EFFECT of the GI microbiome? --> digestion --> nutrient processing --> immune system --> nervous system
How do we tolerate billions of commensals? we NEED these microbes for the development of an immune system
Experimental evidence of gut microbiome's important role in the immune system Germ free mice: accumulate a lot of iNKT T-cells in GI mucosa --> more susceptible to CHEMICALS that cause IBD + asthma IF production of iNKT cells blocked --> germ free mice get less sick! Non-sterile mice: imbalance of T-cells balanced by transfusion of microbes NEONATALLY (as babies), not not as adults
TH17 cells vs Treg cells in segmented filamentous bacteria (SFB) TH17 helper cells ramp up infection, while Treg dampen inflammation If balanced: healthy microbiome If imbalanced: disease (IBD, asthma, eczema OR lack of protection from pathogens)
Gut microbiome link to obesity/metabolic disease: antibiotics and weight gain feed constant low level antibiotics to healthy mice with no change in diet --> gain weight faster GI microbiome changes how the body stores/metabolizes food?
Gut microbiome link to metabolic disease: H. pylori and hormones test humans with or without H. pylori in stomachs after eating --> those WITH had much lower hormone ghrelin (hormone which stimulates us to eat) --> alters our behavior *H. pylori can help us to stop eating*
CHO diet effect on microbiome (diet --> GI) germ free mice fed (plant carbohydrates) CHO diet --> after twelve weeks were colonized with non-sterile mice fed same diet --> half stay on CHO diet, half fatty western diet --> 16S sequencing shows GI microbiomes between diets are diff! --> more species diversity for CHO + gain less body fat
Microbiome effect on fat accumulation (GI --> body) donor mice NOT sterile, half raised on CHO diet and half on Western --> both donors GI microbes transplanted to GF mice raised on CHO diet --> no change in diet for recipients!! --> GF mice who got microbes from Western donor had a larger body fat increase than from CHO diet (donors genetically obese --> same result)
disbiosis sweeping changes in population of microbes that produce an imbalance in your GI microbes
gnotobiotic mice germ free mice, easier to study than humans
Bacteriodes fragillis and Clostridiae in Human Microbiome SFBs that grow in GI, you need a balance of these to end up with a balance of TH17 and Tregs or else disbiosis will cause disease!
effect of human fecal transplant on GF mice take obese human twins, and lean human twins --> inoculate fecal samples into GF mice --> feed mice same LF-HPP diet --> measure fat mass after 35 days *microbes from obese twins led to greater fat gain than from lean twins*
results of cohousing mice with "lean" microbiota and "obese" microbiota (fed on same diet) Lean + obese = obese mice gain some fat mass but not much, lean don't change Obese + obese = obese mice gain the most fat mass Lean + Lean = no change GF + Lean + Obese = GF LOSE fat mass
results of cohousing mice with "lean" microbiota and "obese" microbiota (fed on different diets) "lean" microbes protect mice with "obese" microbes IF diet is low in saturated fats + high in fruits and veggies (LoSF-HiFV) NOT protected if fed opposite: HiSF-LoFV --> change in microbiome must be accompanied by change in diet to be healthy!
signaling pathways that most affect metabolic outcomes --> fermenting bacteria production of short-chain fatty acids --> small intestine microbes modification of bile salts
What happens when you disturb the GI ecosystem? antibiotics --> reduction in species diversity "weed" species C. difficile can survive and become dominant --> painful antibiotic-resistant diarrhea (AWFUL) occurs NOT from exposure but from killing off its competition
treatments for recalcitrant C. difficile Fecal microbial transplant: harvest stool from healthy patient --> transplant to patient through colonoscopy
probiotics effect on health provided in food or capsules can help people but negative side effects occur from adding dominant species to gut in high numbers
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