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34 Cards in this Set
- Front
- Back
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Microbe |
- A living thing that is too small to be seen with the naked eye. Bacteria, archaea, fungi, protists, viruses, microscopic animals |
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Microbiome |
- The totality of microbes, their genetic information and the milieu in which they interact - Typically consist of environmental or biological niches containing complex communities of microbes. Eg: gut microbiome, tongue microbiome |
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Microbiota |
- The microbial organisms that make up a specified microbiome - Composition of the microbiota in a community can vary substantially between environmental sites, among host niches and between health and disease - Not just bacteria but often focused on bacteria - Found in humans: skin and hair, conjunctiva, nares, airways, oral cavity, GI tract, urogenital tract |
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Metagenome |
- Genetic information of a complex population - typically from microbes in an environmental or host niche sample - that is made up of the genomes of many individual organisms - The human microbial metagenome (all of our microbes' genes) can be considered a counterpart to the human genome (all of our human genes) |
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Commensal bacteria |
- "commensalism": type of symbiotic relationship between two different organisms in which one specifics benefits and the other is unaffected - Commensal bacteria: used to indicate normal/expected microbiota in different environments in the ody - Relationship between humans and microbiota is often interdependent and mutualistic (both species benefit, but "friendly" bacteria can become pathogenic when its growth becomes uncontrolled or occurs in the wrong anatomical place |
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How many bacteria make up our microbiome? |
- Idea has been 100 trillion for a long time - More recent studies have placed the number between 37 and 40 trillion, ratio bacterial to human cells 1:1 |
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Phylotype |
- Microbial group defined by 12S rRNA sequence similarity - 16S rRNA is a component of the 30S small subunit of prokaryotic ribosomes - Portions of the sequence from distantly related organisms are remarkably similar and stable over time - Sequences from distantly related organisms can be precisely aligned and compared, making the true differences easy to measure |
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Dysbiosis |
- Disturbed homeostasis of the microbiota composition - Antibiotics (and other drugs) are a major cause - Relationship is bi-directional: meds and other factors, including disease, can cause dysbiosis, but dysbiosis can cause disease - Cause and effect is not always clear (ie observed differences in microbiota in disease states may or may not be causing the disease) |
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Factors associated with the development of gut microbiome |
- health: nutrition of the mother, vaginal delivery, breast feeding, family size/pets - Risk of disease: non-optimal nutrition of the mother, formula feeding, antibiotics, urban environment |
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Gut microbiome changes dramatically in early life |
- Due in part to diet changes - Keep in mind that the child undergoes many and complex environmental exposures |
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Hygiene hypothesis |
- The idea that being exposed to animals, microbes, etc early in life "trains" the immune system to respond better - and more appropriately - to pathogens and allergens later - Implicated in autoimmune disease? - Possible connection to allergy |
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Prebiotic |
- Food ingredients resistant to digestion (think: fiber) fermented by gut microbiota, with a selective effect on the microbiota and consequent beneficial effect on the host's health - Stimulate growth or activity of certain types of bacteria |
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Probiotic |
- Live micro-organisms which, when consumed in adequate amounts, confer a health benefit on the host - Must meet ID criteria, safety assessment, and efficacy assessment to qualify |
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Culture-independent methods |
- Sequencing target genes (including 16S rRNA analysis) - Metabolomics: characterizing small molecule metabolites that result from biological and biochemical processes in which microbiota are involved - "shotgun metagenomic sequencing": all DNA is sequenced, yielding data on taxonomic properties, as well as data on function(s) or bacteria - Proteomics: characterizing structure/function of proteins produced by bacterial genes |
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Gut microbiota |
- Usually referring to gut bacteria, but includes other types of microbes as well - Concentration: increases distally down the gut, from 10^1 to 10^12 per gram of content - Composition of bacteria: primarily gram-positive (upper gut) to primarily gram-negative and anaerobes (lower gut). Also differs between the lumen and outer mucin layer - 700 genera; many more species. Estimated 14 core genera common to all humans - Phyla are dominated by firmicutes and bacteroidetes. Relative % can change in disease states, inflammatory states, etc. - Strict (obligate) anaerobes outnumber facultative anaerobes by about 100:1 - Considerable diversity from one individual to another - Adult diet influences types of bacterial species in the gut |
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Gut microbiota's influence on health and disease |
- Carbohydrate fermentation includes carbs that are otherwise indigestible by the human GI system: produce important by-products such as SCFAs - Digest proteins that reach the gut, including host-derived proteins such as epithelial cells - Metabolism of bile acids that escape enterohepatic circulation; removal of amino acid side chain - Conversion of bilirubin to products excreted in feces and urine - Role in cholesterol metabolism - Role in vitamin synthesis: vitamin K, B12 and other B vitamins - Prevent colonization by pathogens by competing for nutrients and sites of attachment - Produce bacteriocins which kill or antagonize non-endogenous species - Play a role in the development and maintenance of the protective mucous layer in the gut - Important role in "training" the immune system: distinguishing self from non-self; friendly from pathogenic bacteria. Promoting anti-inflammatory activity of T regulatory cells. Promotes production of anti-inflammatory products such as defensins or IgA, which prevent pathogen bacteria entry into tissue - 2-way communication with immune system - Role in controlling inflammation or promoting it (dysbiosis) |
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Gut bacteria implicated in: |
- Depression, anxiety, autism, obesity, response to cancer chemo, atopy/allergy, autoimmune diseases, type 2 diabetes, IBS, IBD - Constantly finding new connections! - More study has led to associations, not so much direct causation |
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Example of dysbiosis: C. diff |
- Antibiotic therapy --> disruption of colonic microbiota --> C. diff exposure and colonization --> release of toxin A ("enterotoxin") and toxin B ("cytotoxin") --> mucosal injury and inflammation - C. diff: gram positive, spore-forming, anaerobic bacillus that infects the colon. May be present in small numbers in the colon, but spores usually ingested via fecal-oral route. - Once ingested, spores germinate to their vegetative state in the small intestine, which then travels to colon, attaches to colonic epithelium, reproduces! - Can severely injure the colonic mucosal layer. Injury to the colon caused by release of exotoxins by the bacteria, attach to the colonic mucosa - Toxin A: causes inflammation leading to intestinal fluid secretion and mucosal injury - Toxin B: 10x more potent than toxin A, causes much more damage to the colonic mucosa - Toxins cause colonic epithelial cell necroses, apoptosis and disruption of cellular tight junctions - Hypervirulent stain discovered in early 2000s: produces a third toxin: CDT, which modifies the cell cytoskeleton which causes cell collapse and death. Produces larger quantities of toxins A and B than other strains, lower cure rates, more severe disease and death |
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Risk factors for C diff infection |
- Recent antibiotic use - Hospitalization or nursing home residency - Age over 65 - GI surgery - Immunocompromised - Serious illnesses - Use of gastric acid-reducing medications - Hospital bed previously occupied with someone who had C. diff: the spores remain viable in the environment for weeks to months and are resistant to killing by heat, acid, sanitizers, antibiotics |
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Does everyone who ingests C. diff get an infection? |
- No - People with undisturbed gut microbiota are far more likely to not become infected - Resident microbiota may compete with C diff and/or outright kill it - It may also continue to live in the colon but kept in check, though these people can be carriers |
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S/Sx of C. diff |
- At least 3 watery, unformed BMs a day - Diarrhea is the cardinal symptom - Abdominal pain, cramping (colon is inflamed and painful = colitis) - Nausea, though rarely vomiting - Fever - Leukocytosis - Confusion in older adults - Severe infection: toxic megacolon (colon severely dilated, inflamed), pseudomembranous colitis, perforation of the colon, death - Pseudomembranes: occur following C. diff-toxin induced ulcer formation on mucosal surface of the intestine, which leads to release of serum proteins, mucus, and inflammatory cells. They replace normal, healthy, pink mucosa and do not act like normal mucosa. Yellow, raised tissue. |
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Prevention of C. diff transmission |
- Handwashing! - Contact precautions - Private rooms or cohorting - Dedicated equipment - BLEACH equipment |
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C. diff tx |
- Stop antibiotic if possible, and start another one to kill C. diff - Can be difficult to eradicate, and can recur - Fecal microbiota transplant may be necessary - Drugs that slow bowel motility, including drugs like loperamide (Immodium) should not be administered if C. diff is confirmed or suspected. Can lead to increased toxicity |
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Therapeutics |
- Prebiotics: complex cards/polysaccharides. Present in food or extracted and added to foods - Probiotics: naturally present in food or added to food - FMT |
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Prebiotics |
- Food ingredient that is resistant to digestion, is fermented by the intestinal microbiota, and resists gastric acidity, hydrolysis by mammalian enzymes, and absorption in the upper GI tract- - Has selective effect on microbiota composition, growth, and acitvity - All prebiotics are "fibers" but not all dietary fibers meet definition of a prebiotic - Most commonly used additives: inulin (chicory root) and fructooligosaccharides (fibers present in plants as storage carbs): wheat, chicory, bananas, onions, leeks, etc. - About long-term dietary patterns! Fruits, veggies, grains will lead to increased richness/diversity of both bacteria and their genes which is associated with health - Agrarian diet (vs Western): greater microbial richness, increased SCFA production, and appears to protect integrity of gut mucus layer and epithelial tight junctions - Fiber-free diet encourages growth of microbiota that erode gut mucus layer, which leads to disruption of tight junctions - Prebiotics may mediate high-fat diet obesity and its metabolic consequences |
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Fermentation of prebiotics in gut microbiota |
- Saccharolytic bacteria: - In proximal colon: produce SCFAs, lactate - SCFAs: butyrate are used by colonic epithelium as main energy source, acetate, propionate - SCFAs play important roles in colonic epithelium and in immune system - Colonic epithelium: main energy source, less oxidative DNA damage, regulation of proliferation, maintenance of barrier function, tumor suppression, cytokine production - Immune system: enhanced ROS burst, more phagocytosis, induction of apoptosis, modulation of recruitment, cytokine production - SCFAs also play important roles in metabolism and inflammation. Obesity can shift the balance of microbiota species in the gut, leading to an imbalance of the SCFAs that play metabolic roles |
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Summary of major SCFA benefits |
- Main energy source of colonic epithelium - Maintains barrier function of colonic epithelium - Regulates cytokine production - Protects DNA from damage; tumor suppression - Anti-inflammatory effects, but also promotes robust immune response when needed - Promotes glucose control, improved insulin sensitivity - Other roles in metabolism, including inhibition of inappropriate lipogenesis - Role in signaling pathway that generates gut hormones such as GLP-1 |
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Probiotics |
- Most common strains are bifidobacterium, lactobacillus - INSERT IMAGE |
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Major mechanisms of action: probiotics |
- Enhancement and repair of the epithelial barrier - Increased adhesion to intestinal mucosa, leading to inhibition of pathogen mucosa - Competitive exclusion of pathogenic microorganisms - Production of anti-microbial substances - Promote digestion and uptake of dietary systems - Modulation of the immune system: interact with epithelial cells and dendritic cells and with monocytes/macrophages and lymphocytes. Helps DCs and naive helper T-cells mature, influence development of anti-inflammatory Tregulatory cells |
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Brain-gut communication |
- 2 way communication system between the ENS (enteric nervous system) and CNS - Disturbances in the microbiome can lead to disturbances in the CNS and vice-versa - Brain has the ability to influence the intestinal microbiota, and the microbiota can influence brain, behavior, and mood |
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Functional GI disorders |
- Comprises symptoms arising in the mid or lower GI tract that are not attributable to anatomic or biochemical defects - Sx include abdominal pain, early satiety, nausea, bloating, distention, and various sx of disordered defecation - Three most common are IBS, constipation, functional dyspepsia |
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IBS (NOT same as IBD!) |
- Most common functional GI disorder (10% prevalence) - Chronic or recurrent sx of lower abdominal pain related to BMs, change in bowel habit, a sense of incomplete rectal evacuation, passage of mucus with stool, abdominal bloating and distention - Known to sometimes occur as a post-infectious problem - Emotional stress is one trigger - "Good evidence" that microbiota perturbance (ie dysbiosis) is implicated in etiology of IBS - Some probiotics help some patients with some symptoms of IBS. Degree of help varies |
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Limitations to probiotics |
- Product regulation: food additive, dietary supplement, drug or biologic. Claims may be vague and unsupported. Little incentive for the industry to maintain standards of quality, or even to test for specific advertised strains - Product information: practical (strains, dose, route, frequency, duration). Clinical (trial methodology, endpoints, outcomes, safety) - Product efficacy: survival in GI transit, pH of stomach. Present in sufficient numbers? Refrigerated? - rare complications: bacteremia, endocarditis, sepsis: requires probiotic to translocate from the gut to the systemic circulation |
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Fecal microbiota transplantation |
- The administration of a solution of fecal matter from a donor into the intestinal tract of a recipient in order to directly change the recipient's microbial composition and confer a health benefit - Mixture administered through NG/NJ tube, colonoscopy or retention enema, capsules - Both drug and biological without approval yet - Proof of concept established via effective tx of refractory C diff infection: cure rates around 85-90% |
