Microbial cross talk with the immune system Flashcards
how does the microbiota develop
- you are born sterile and colonized by microbes from the moment you are born
- vaginal microbes and skin microbes (C-section)
- community develops with facultative microbes, then transitions to anaerobes
characteristics of the microbiota in the adult colon
- dense colonization
- varies in composition between people but same function
- varies between body sites
- anaerobic
- dominated by Firmicutes and Bacteroidetes
what are beneficial functions of the microbiota
- digestion complex carbs to produce SCFA’s in anaerobic fermentation
- produce diverse metabolites that influence locally and systemically
- provide colonization resistance
- processes host compounds, mucus and bile acids
what is homeostatic immunity
when a response occurs without inducing overt inflammation
relative abundance of different types of bacteria during microbiota development
- initial surge in proteobacteria expansion
- after 1 week, actinobacteria expansion increases
- firmicutes and bacteroidetes have a more constant growth pattern
what is the window of opportunity in the microbiota
- a privileged period of development where the influences of the microbiota on the immune system are durable
- restoring microbial interactions after the window does not rescue the impact on the immune system
- adult-like stability in the gut microbiota takes place by 2-3 years of age
key factors which affect development of the microbiota
- route of delivery
- antibiotics
- environmental exposure to different microbes and antigens
- feeding (breast milk or formula)
early development of the microbiota - mouse example
- a mothers microbiota influences their offsprings immune system before birth
- SCFA’s reach the fetus
- experiments using transient colonization of germ-free mice show alterations of innate lymphoid cell populations in pups (all germ-free but have different immune populations)
development of the microbiota - LPS and Type I diabetes example
- showed difference inHMO utilizing bacteria of microbiome composition between people living in Finland, Russia and Estonia
- regions with more bacteroides (Finland) have higher susceptibility to T1D
what happens when there is failure to induce endotoxin tolerance
increased autoimmune activity
what are the interactions between the gut microbiota and the immune system that help to promote health as we mature
- antibodies and B cells
- T cell differentiation
- innate immune signalling
interactions between the microbiota and B cells
- microbiota members coated by IgA and some by IgG
- lost in germ-free mice
- follow T-dependent and independent pathways
what is IgA-Seq
how we study which bacteria are coated by IgA under different conditions
interactions between the microbiota and T cells
- SFB in the microbiota controls differentiation of T-cells
- germ free mice have low TH17 cells
- mono-colonizing mice rescues TH17
- can protect mice from pathogen
- close attachment delivers Ag that drive TH17
how do interactions between the microbiota and bile acids effect T cell function here
- the microbiota converts bile acid to secondary bile acids (DCA, LCA)
- these are then further modified and they o on to alter T cell differetntiation
- colonize mice with mix of bacteria that produce isoDCA - more Tregs
interactions between the microbiota and the innate immune system
- NOD1 and NOD2 detect peptidoglycan (activate NFkB) from microbiota
- PG ends up In serum
- altered immune system development on NOD1/2 knockouts
- mutation of NOD2 is the strongest risk factor for Crohn’s disease
what happens to the microbiota during disease
changes in microbiota cause dysbiosis in interactions with T cells, B cells and the innate immune system
cancer and the immune system
- cancerous cells are supposed to get eliminated by our immune system
- T-cells recognize cancer Neo-antigens
- NK cells kill by altered expression of cell surface markers
- in cancer immunotherapy, we try to harness and accelerate this function - focused on T cells
How do T-cells kill cancer infected cells
- TCR recognizes antigen by MHC
- need co-stimulation (2 signals)
- after T cell activation inhibitory receptors (CTLA4 and PD1) are indeed as a checkpoint
- these checkpoints prevent hyperactivation - lack of T cell response allows proliferation of cancerous cells
true or false: Dysbiosis during disease or antibiotic use is associated with lack of PD-1 blockade response?
true
what is a fecal microbiota transplant
- transfer fees from a healthy donor because they contain an incompletely defined community of microorganisms
- goal is rapid re-establishment of community
- 90% effective
- concert with FMT include transferring harmful bacteria
classes of microbiome-bases therapeutics and what they treat
- FMT: used to treat recurrent C. difficile infections
- diets and prebiotics: supplementation of dietary fibres to promote desired compositional change in the microbiota
- symbiotic microbial consortia: transfer a group of isolates to promote function
- engineered symbiotic bacteria: transfer engineered bacteria at the target site that have a desired function
- microbiota-derived proteins and metabolites: direct supplementation with proteins of metabolites (SCFA)
cancer immunotherapy associated with the microbiota
- microbiota influences response to caner treatments
- antibiotic use can reduce immunotherapy response
- specific microbes in the microbiota (Akk muciniphila) are associated with better treatment outcomes
- effictiveness of CLTA4 and PD1 inhibition linked to microbiota
most potent T cell immune checkpoints - how they are relevant in cancer
- CTLA4 and PD1 inhibitory receptors
- put the breaks on T cell hyper activation
- in cancer T cell exhaustion is high - lack of this immune response allows proliferation of cancer cells
- anti-CD28, anti-CTLA4 and control antibiotics cause tumour size to shrink (b/c more immune cells present)
PD-1 based immunotherapy against tumours
- influenced by gut microbiome - disrupting it with antibiotics = less response
- survival and response to cancer immunotherapy
what are some beneficial functions of the Microbiome in Immune Development and Regulation
- IgA production
- Treg induction
- pathogen competition
- barrier protection
- immune system maturation through innate immunity
what are some consequences of Dysbiosis (Microbial Imbalance)
- increased inflammation
- autoimmune diseases
- allergic disorders
- infection
- metabolic disorders
- specific diseases = cancer, Crohn’s, extra-intestinal conditions
how can the Mother’s Microbiota Shape the Offspring’s Microbiome
- During pregnancy: Maternal microbiota transfers microbial metabolites SCFAs
- During birth: Vaginal birth exposes the infant to the mother’s vaginal and gut microbiota, C-sections may limit microbial diversity and lead to a microbiome dominated by skin-associated bacteria.
- Breastfeeding: Breast milk contains carbs and beneficial bacteria
