Flashcards in L12. Benefits and Mischiefs of Normal Microbiota Deck (29)
What is the human microbiome?
Humans live with a whole range of COMMENSAL organisms in and on their body. This CO-EVOLUTION of species has led to collaboration and genetic sources to enable PHYSIOLOGICAL DIVERSITY.
= Mutualist relationship
What is dysbiosis? What is the consequence of this?
Dysbiosis is the disruption of the mutualistic relationship between host and bacterium.
Leads to disease. Eg. malnutrition, infection, inflammation, autoimmune disease, obesity and metabolic syndrome, allergy
What is the general profile and distribution of bacteria along the gut?
It is highly diverse and variable: between people.
There is both a site specific and a individual specific distribution of bacteria.
The gut is generally colonised with gram negative, anaerobic bacteria. And the area of highest concentration is distally along the tube.
What four bacterial phyla make up the majority of commensal species in humans?
How does the composition of bacteria vary within a host?
It is generally stable in the host unless dysbiosis or major impacts occur
The microbiota are able to function in favour of and influence the host. What are some major ways it does this? 
3. Immune System development and regulation
4. Protection against enteropathogens (competition)
What factors influence the gut microbiota? 
1. Mode of delivery (eg. vaginal or ingestion)
2. Age of the individual
4. Genes and Environment
5. Antibiotic usage
6. Chronic Inflammatory states
What is the effect of age on the gut microbiota?
The diversity of the gut microbiota increases with age especially as diet and environmental factors change.
Infants have very volatile profiles and change dramatically with major changes in diet.
What is the effect of diet on the gut microbiota?
Fat and fibre content affects microbiota profile (available of nutrients for bacteria to consume)
Animal based or plant based diets alter composition
How does antibiotic use affect the gut microbiota?
Kills some microflora and allows some others to thrive. Thus the whole environment is changed.
Different antibiotics cause different changes.
Often takes a very long period of time for the gut to recover the baseline (pre-antibiotic) profile.
What role do microbiota have in nutrition?
Microbiota is very important to nutrition in 2 ways:
1. Direct supply of nutrients (eg. Vitamin B2, K, folate, CHO) = metabolic pathways
2. Altering the metabolic machinery of the host celld by inducing gene changes or by maintaining differentiation and functions
How does colonic fermentation of dietary fibres affect the gut?
Microbiota in the colon ferment complex carbs (digested into oligosaccharides and monosaccharides) that can't be broken down further or absorbed yet.
Bacteria FERMENT these into short chain fatty acids (acetate, proprionate, butyrate).
- These are absorbed in the colon and provide energy for colonic epithelial cells.
- They also move to the liver and peripheral organs and acts as substrates for gluconeogenesis and lipogenesis.
- Short Chain fatty acids also control colonic gene expression
What is important about how the immune system works in the gut?
The immune system needs to be able to differentiate between the host's microbiome and the pathogenic and dangerous organisms.
Thus there needs to be a highly regulated system to maintain HOMEOSTASIS between microbiome and immune activity.
The mucosa-associated lymphoid tissue (MALT) is the largest collection of lymphoid tissue in the body. Why is this so?
Because the gut is exposed to large amounts of antigenic challenge.
- requires protection from pathogens
- requires tolerance to normal microbiota
There are three major sites of lymphocyte COLLECTIONS in the gut. Where and what are these?
1. Isolated Lymphoid Follicles (ILFs) in the large and small intestines in the lamina propria
2. Payer's Patches are patches in the small intestine immediately beneath the the enterocytes (especially under M cells) that are the sites for induction of T and B cell activation
3. Mesenteric Lymph Nodes along the GIT
What are some innate defences of the gut?
Peristalsis and flushing action
Acidity and presence of many digestive enzymes and bile
Paneth Cells located in the base of the crypts that secrete antimicrobials
Innate leukocytes: NK cells and specialised immune cells (IELs)
M cells and dendritic cells
There are several specialised T cell populations in the gut. What are some examples of these?
1. Innate Lymphoid Cells (ILCs)
2. Lymphoid Tissue Inducer Cells (LTi)
3. Intraepithelial lymphocytes (IELs)
4. NK22 cells
5. Mucosal associated invariant T cells (MAIT)
6. Invariant NKT cells
What are the innate lymphoid cells?
They act like Th cells by secreting multiple cytokines like IFN-y, IL-17, IL-22, IL-5 and IL-13
What are the lymphoid tissue inducer cells?
They stimulate the recruitment of DC, T and B cells to the peyer's patches and isolated lymphoid follicles
What are the intraepithelial lymphocytes?
Lymphocytes of CD8 T cell subsets that are scattered in between the intestinal epithelia.
These CD8 cells have LIMITED DIVERSITY - innate cells
They are associated with protection, epithelial repair, promotion of tolerogenic DCs, and produce IL-22.
What is the role of the NK-22 cells?
They act like Th17 cells and have a regulatory role. They secrete cytokines like IL-22, which enhances antimicrobial defences and others like epithelial repair.
What are the mucosal associated invariant T cells?
These respond very rapidly to bacterial antigens and secrete IL-12 and IL-18. Their function as a whole is still unknown.
What is the role of the Invariant NK T cells?
They secrete pro-inflammatory cytokines
How do the Microfold (M) cells control antigenic access?
M cells are located interspersed between epithelial cells; they don't have microvilli nor do they secrete mucous hence antigens are more readily accessing to these cells.
They allow transcytosis of antigens or they are a target for bacterial killing allowing antigens to pass into the mucosa and interact with the lymphoid tissues.
M cells do not express MHC II and so cannot act as antigen presenting cells.
What is underneath the M cells?
Dendritic cells and Peyer's Patches
Dendritic cells in the mucosa are specialised. Describe what is meant by this.
DC cells induce Treg (TGFb) and the Th2 response. The Th2 switches isotype to IgA. These ultimately lead to DEREGULATION OF INFLAMMATION
They instead induce Th1 and Th17 to bias the isotype switch to secretory IgA and PROMOTE INFLAMMATION.
What is an important function of the specialised dendritic cell in the gut?
Induces mucosal HOMING RECEPTORS called ADRESSIN a4b7 on the presented to and activated T and B cells such that they express this receptor whose ligand is ONLY on gut epithelia (gut endothelial cells selectively express integrin MAdCAM1).
Hence activated T and B cells will leave the patches and follicles and drain into the lymph nodes before eventually entering the circulation and home to the gut and bind and act in the gut.
What additional receptor will T and B cells activated in the gut mucosa express?
CCR9 which is a receptor for CDL25, a ligand expressed only by small intestinal epithelium.