Session 3 Lecture 1 Dynamics of the GIT

Session 3 Lecture 1 Dynamics of the GIT

Session 3 Lecture 1 Dynamics of the GIT Microbiome: Microbial Darwinism 10 14 bacteria representing ~1000 species and many phyla live in a crowded ecological space: The GIT Four major phyla dominate: By comparison, all animals with backbone comprise only one phyla! Survival and proliferation within the microbiome depends on: Availability of oxygen, an optimal external pH, which differs regionally as does the makeup of the microbiome Competition for space and attachment sites on enterocyctes Susceptibility/resistance to anti-microbial from other members of the microbiome, e.g. bacitracin Susceptibility to therapeutic antibiotics Ability to metabolize complex carbohydrates to SCFA Ability to survive the host immune system Stomach Duodenum Ileum Colon Survival also depends on the ability of bacteria to undergo rapid genetic change

A small genome and rapid replication allows generation of mutants 1000-fold faster than their host (see later). Genomic variants resulting from spontaneous mutation may no longer be susceptible to therapeutic antibiotics, antibiotic produced by other members of the microbiome, or by the host immune system In addition, bacteria can horizontally transfer genetic survival traits to other bacteria by using plasmids [see later] Bacteria Avoid Death from Antibiotics and Host Lymphocytes by Rapid Genetic Change Bacteria disguise themselves by becoming moving genetic targets Bacteria undergo reproduction in hours while their vertebrates hosts require years Reproduction requires DNA replication when the genome is most susceptible to spontaneous mutation The probability that a mutation will have a phenotypic effect depends on genome size The rate of genome change depends on the time required for reproduction ( 1hr or 20yr) Thus, the rate of genetic change= genome size X replication time Human 8.6 x 10-12 Bacteria 1.2 x 10-9 Influenza 2.6 x 10-5 Thus, bacteria can alter their genome 1000 faster than humans Viruses can do it at least a million

times faster! Here comes the Smut: Bacterial Porn Bacteria divide and replicate themselves and their DNA like all life forms on earth Bacteria can also transfer genetic traits horizontally Transformation Transduction Conjugation [Plasmid Transfer] Plasmids are replicating circular DNA that carry genes not found in chromosomal (genomic) DNA Plasmid cannot transfer life, but can hand-off virulent/resistance genes to other bacteria A pathobiont can hand off virulent traits to good members of the microbiome that are not recognized by the immune system or are not the target of antibiotics Many antibiotic resistance traits are carried by plasmids hidden in eubiotic i.e. good bacteria Enter the Jedi Lymphocyte: How higher Vertebrates compete with the rapid genetic changes of bacteria (and viruses) Mutualism requires Peaceful Co-existence : Dont kill the microbiome, control it! Lymphocytes somatically alter their genes to compete with bacterial genome changes Earliest versions of lymphocytes appeared in jawless fishes

The current human lymphoid system appeared first in jawed fishes The lymphoid system is most sophisticated in warm-blood birds and mammals Jawless fish Fishes Amphibians Birds Reptiles Mammals Lymphocyte-like True Lymphoid Systems How do lymphocytes accomplish this somatic genetic modification? Extensive gene duplication followed by mutation of the duplicated genes, a process called somatic gene conversion which involves: 1. Somatic recombination of the many duplicated and slightly different genes (see next diagram) 2. Subsequent somatic mutation of the somatic recombinants Combinatorial Diversity: The First Weapon in the Arsenal of the Jedi Lymphocyte Number of Variable Gene Segments in Humans Antibody structure and genetics

Composed of two different sized polypeptide chains: heavy and light The N-terminal portion of each is encoded by gene segments that encode the antibody binding site [red, yellow and green in diagram] These regions and the genes that encode them are called variable light (VL) and variable heavy (VH) Light and heavy chains combine to form the complete antibody Antibodies are made by terminal B- lymphocytes called plasma cells 40 5 91 30 6

How does Somatic Recombination and Mutation by Jedi Lymphocytes Compare to the Rate of Genetic Change of Bacteria and Viruses? Recombination Math Human heavy chain variable genes: 91 VH x 30DH x 6JH yields > 9,000 possibilities Only 30-50% are productive so that means 3.6 x 103 Human light chain variable genes: 40 VL x 5JL yields 200 possibilities Only 30-50% are productive so that mean 80 In forming the entire antibody it means 2.8 x 10 5 Somatic hypermutation (Second weapon of the lymphocyte) After each productive variable heavy and variable light chain rearrangement occurs, they are subjected to a hypermutation process that generates 100-1000 more variants How does this lymphocyte process compare to the genomic capability of microbes? Antibody variants = 2.8 x 106 Genomic variants in bacteria= 1 x 103 Genomic variants among viruses ~1 x 106 Fortunately for higher vertebrates, the Jedi lymphocytes win the battle against bacteria and save humanity! The Mucosal Antibody System of the GIT Antigen is sampled by M-cells and dendritic cells (DC) and delivered to germinal centers

B cells specific for the antigen are selected from a million possibilities in the germinal center Selected B cells leave the follicle to become mature plasma cells (antibody factories) Secreted IgA is transported through the enterocyte barrier into the lumen Antibodies bind and clump the luminal bacteria that goes to the feces SIgA antibodies also bind non-specifically via carbohydrate moieties Gut lumen SIgA transported by enterocytes Migratory pathways 60% of feces is made of bacteria from the microbiome Many are coated with SIgA antibodies (the rotor-rooter antibody) Plasma cell

Feces Removal of especially pathobionts helps to prevent translocation and bacteremia Oral Tolerance The GIT is exposed daily to pounds of foreign proteins and 10 14 bacteria However, antibodies to food proteins and non-pathogenic GIT bacteria in healthy individuals are subclinical in serum and stool Mucosal antibodies are limited to SIgA in healthy individuals, and the majority are specific for pathobionts but SIgA also attaches non-specifically to many bacteria through carbohydrate moieties Intravenous injection of even a small amount of food antigen e.g. ovalbumin, results in a vigorous serum antibody response and increase in TH2, CD4 T cells However, prior feeding of the same antigen will suppress or eliminate the serum response and lower the number of CD4-T cells This is call oral tolerance and is antigen-specific Oral tolerance depends on T-cells called regulatory T-cells or Tregs A special type of CD-4 T cells specific for dietary and the healthy microbiome Tregs secrete immunosuppressive cytokines like IL-10 Other CD-4 cells called helper or TH2 cells, are very low in healthy individuals but not in those with forms of IBD

Tregs Patrol the Gut mucosa The T cell system is complex We will consider three variants Tc are cytotoxic and kill virus-infected cells TH1 cells are inflammatory and TH2 cells are helper cells Tregs especially regulate the activity of TH1 and TH2 T cells Blocked pathway Cell Cross-talk Three different scenarios are illustrated Cell Cross-talk The Healthy GIT Tregs block antibody responses to food proteins Tregs block inflammation by neutrophils and Tc activity The virus-infected Mucosa Blockage of antibody production to the virus is removed Tc are activated to kill virus-infected cells Inflammation is blocked Bacterial Invasion, i.e. Translocation Antibody responses are allowed

Blockage of TH1-induced inflammation is removed to allow local inflammation in which neutrophils remove the bacteria Blocked pathway Cell Cross-talk Blocked pathway A Faulty Treg On-Off-Switch can Result in an Unhealthy GIT Cytotoxic cells do not stop with the killing of virus-infected cells and do collateral damage to adjacent enterocytes, i. e. friendly fire Antibodies attack both pathobionts and good eubiotic bacteria The inflammatory response is not controlled when the threat of the infection ends which leads to damage of the mucosal barrier Oral tolerance to food antigens and members of the healthy microbiome is lost

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