L5: Gut Microbiome and Cancer and Cancer Immunotherapy (D. Philpott) Flashcards
microbiome
theatre of activity + community of microorganisms
microbiota
assemblage of microorganisms present
largest diversity and number of bacetria
colon
2 main phyla: Firmicutes and Bacteroidetes
development of microbiota
fetus sterile until birth
vaginal delivery vs cesarean delivery dictate which type of organisms first colonize the infant
infant: milk consumption and solid food introduction
toddler: full adult diet –> adult-like microbiota
dysbiosis
altered microbiota - associated with disease
compositional and functional changes
IBS, GI cancers, T1Diabetes, infectious disease, T2Diabetes, obesity, atherosclerosis
factors that might impact microbiota composition
diet, lifestyle, antibiotics, hygiene
how do we assess composition of microbiota
through 16s rRNA amplicon sequencing
16s rRNA is the RNA portion of the ribosome - highly conserved in all bacteria (specific to bacteria) V4 region, PCR
this can help us understand which gene is associated with which bacteria
metagenomic shotgun sequencing
more expensive but more info about functionality of microbiome
take fecal matter - sequence everything
using germ-free mice to study contribution of microbiota to host health and disease
born and raised in sterile conditions, HEPA filter
have a tendency to consume more calories, weigh less (bacteria important for breaking down food), live longer
very little IgA, no development of GALT, very few T cells
role of microbiota in allogeneic hematopoietic stem cell transplantation
simpson index high diversity correlated with survival for patients with blood cancers
simpson index, alpha diversity
a measure of how well represented each taxon is relative to others
high diversity = healthy microbiota
role of microbiota in allogeneic hematopoietic stem cell transplantation: use of antibiotics
decreased diversity = greater mortality
ICI (Immune checkpoint inhibitors) efficacy correlates with…
mutation burden
high levels of PD-L1 expression
profile of gut microbiota
cancer patients treared with ICI got antibiotics
led to decreased OS
role of the microbiota in anti-PDL1 cancer therapy
JAX microbiome has a specific abundance –> associated with greater CD8 T cell infiltration of tumors
role of microbiota in anti-CTLA4 cancer therapy
Didn’t work in germ-free mice= microbes are crucial for efficacy of therapy
Antibiotics similarly reduced efficacy of anti-CTLA4
role of microbiota in humans treated with ICIs
Transfer of responder microbiota compared to nonresponder microbiota into germ-free mice correlates with response to anti-PD1
Greater CD4/ fewer Tregs in tumors
Prove causation of these microbes of promoting efficacy of cancer therapy
how do microbes impact ICI outcomes - caveats with microbial studies
Increase levels of CD8 + T cells
Alterations of tumor microenvironment (bacterial translocation and infiltration of tumor)
Cross reactive antigens (anticancer or antimicrobial T cell response boosts ICIs)
ways to modulate gut microbiota to improve ICI outcomes
Fecal microbial transplants
Probiotics/ bacteria consortia
Pre-biotics -metabolites for bacteria to break down complex carbohydrates
Postbiotics
knowing that microbiome affects tumor progression, describe the strategy to mitigate any microbial effects on your animal experiments. How would you ensure your strategies worked
- Co-house animals
- Give antibiotic treatment then FMT for desired microbiome
- Do 16S rRNA sequencing/shotgun sequencing to ensure microbiomes are the
same from each mouse strains
