Gut microbe function
○ Regulates immune system
○ Extracts energy from food
○ Controls potential pathogens
○ Makes essential metabolites (vitamins etc.)
○ Improves intestinal function
○Removes toxins
How do we acquire and lose microbes
Acquire: through vaginal delivery, breast feeding (contains microbes and food for gut microbiome), interaction with environment
Lose: C-section, maternal antibiotics, formula feeding, indoor living, excessive sanitation, chemical preservation of food
Importance of gut microbial diversity, what happens with high and low diversity?
High Diversity of species
§ Healthy ecosystem
§ Balance
§ Functional redundancy (high gene
count)
§ Resistance to damage
Low diversity of species
§ Sick ecosystem
§ Imbalance
§ Functional disability (low gene count)
§Susceptibility to damage
The compromised host
- Normally kept in check by physical barriers and/or immune system
- Accidental penetration of barrier/damage can lead to microbiota misfunctioning
- Host is compromised
- Opportunistic pathogens or pathobionts: microbes that breach the barriers
Patient can be repeatedly infected
how is the microbiota protective
- Competitive exclusion
○ Colonization is niche - Environment modification
○ Can create hostile environment for pathogens - Host simulation
- Direct pacification
Can make molecules to make microbes act as
○defense
The microbiome-gut-brain-axis
- Brain affects microbiome, vice versa
Type of microbes in guts can affect mod and behaviour
What happens when microbial balance is compromised?
- Containment breaches
○ Ex: cancerous lesion in colon allows bacteria to penetrate and cause infection- Niche disturbance
○ Ex: ecosystem structure temporarily changed from lifestyle changes, infections - Extinction events
Ex. Ecosystem permanently changed through loss of taxon or taxa
- Niche disturbance
Example: Obesity (compromised microbial balance)
- Gut microbiota influences nutrient acquisition and regulation of energy metabolism and fat storage
- In obesity: microbiome balance is less diverse
- Obesity associated with low-grade intestinal inflammation
○ Potential loos of microbes which increases tight junctions between epithelial cells in the gut
Potential increase of microbes which make pro-inflammatory
Gnotobiotic animals
- Animal where associated microbiota is know and defined
○ Includes germ-free animals
§ Abnormal physiology
§ Lower cardiac output (weak)
§ Require more calories
§ Thin/poorly developed intestinal walls
§ Misshapen mitochondria
§ Odd behaviour
Expensive to manage, but valuable for research
Microbes In Immune System, how do we protect and manage
- Not all microbes are pathogens
- We have physical and chemical barriers to manage microbes
- Immune system: highly complex system of organs, tissues, cells, and cell products that work together to recognize and neutralize potentially pathogenic threats
○ Innate
Adaptive
Innate immune system
- Aka non-adaptive or non-specific
- “rapid” response system
- Composed of physical barriers and chemical and cellular responses that act if barriers are breached
- Hardwired into the body, present at birth
Infection vs disease
- Contact with an infectious agent does not guarantee that person will get sick
- If number of infecting organism is small/immune system is effective, disease will not follow infection
- To cause disease: pathogen needs to
○ Breach host defenses
○ Survive inante defesne mechanisms
Begin to multiple
Physical barriers to infection
Skin
○ Difficult to penetrate by microbes when intact
Mucous membranes
○ Epithelial cells tightly connected to support strong barrier function
○ Are selectively permeable to absorb nutrients
Lungs
○ “mucociliary escalator”: removes small particles
* All physical barriers tightly connected to lymphoid tissue in the body
* Specialized cells monitor these sites to present antigens to immune cells in lymph nodes
Primary lymphoid organs: factory for lymphoid cells
Secondary lymphoid organs: stations for antigen encounters
The complement system (body’s surveillance system)
- “complement”=set of proteins made by the liver
○ “complement” antibodies in killing bacteria- C3 splits into two smaller proteins (C3a and C3b)
- These proteins circulate blood and enter tissues over the body
- Circulate as inactive forms, proteolytically cleaved to activate them
- Complement components/complexes named from C1 to C9
3 complement activation pathways, and describe
Classical
Lectin
Alternative
§ The three pathways all converge on the lytic pathway
§ C3b acts as an opsonin
§ C3a and C5a-act as anaphylatoxins, directing immune cell traffic to where it is most needed
§ membrane attack complex punches holes in target bacterial cells, killing them
cytokines
- Cytokines: molecules secreted by cells that have effect on other cells
- Helpful for complement system
- Ex: interferon: intruder alert cytokine
- When cell is infected by a virus, it secretes interferons that help other cells nearby to fend off the virus
Neighbouring cells step up their defense systems
Natural antimicrobial peptides: for closer proximity attack encounters
Small molecules able to lyse mot microbial cells and some enveloped viruses
○ Ex: defensins, has concentration gradient of this in the gut
§ Higher in close proximity to the crypts of the epithelium
§ Secretion is from the crypts
§Keeps out even the normal microbiota
Cells found within blood
- Red blood cells
- Platelets
- White blood cells (part of immune system)
○ Includes polymorphonuclear leukocytes (PMNs, granulocytes or polys)
○ Monocytes and macrophages
○ Dendritic cells
○ Mast cells
Lymphocytes
Myeloid bone marrow stem cells differentiate into phagocyte cells
- Phagocyte-cell that eats
- Bacterium binds to surface of phagocytic cell
- Phagocyte pseudopods engulf organism
- Invagination of phagocyte membrane traps the organism within phagosome
- Lysosome fuses and deposits enzymes into phagosome, enzymes cleave macromolecules and generate reactive oxygen species, destroying organism
Neutrophils capture pathogens with NETs
- Neutrophil extracellular trap
- Form of cell death by neutrophil called NETosis
- Neutrophil senses invader, spews a latticework of chromatin and antimicrobial compounds into vicinity
○ Prevents spread of the pathogen
Allows rapid phagocytosis
