FP - Gut Microbiome IBD Flashcards
What is Inflammatory Bowel Disease (IBD)? (2)
- Chronic, relapsing, immune-mediated disorders of the GI tract
- Multifactorial nature with gene-environment interactions and microbiome involvement
What are the 2 main forms of IBD?
- Crohn’s disease (CD)
- Ulcerative colitis (UC)
How can you distinguish Ulcerative Colitis (UC) from Crohn’s Disease (CD)? (8)
Ulcerative Colitis (UC):
- Distribution: Continuous, symmetric, diffuse
- Depth of Inflammation: Mucosal/submucosal
- Site: Colon only
- Rectal Involvement: Almost always involves rectum
Crohn’s Disease (CD):
- Distribution: Discontinuous, asymmetric, skipped segments
- Depth of Inflammation: Mucosal, submucosal, and/or transmural
- Site: May affect any part of the GI tract
- Rectal Involvement: Relative rectal sparing may occur
What trends are associated with the incidence of Inflammatory Bowel Disease (IBD)? (4)
- Increased in the Western world since the Industrial Revolution
- Accelerated further during the 1950s “Great Acceleration”
- Rising in newly industrialized countries with globalization
- Western lifestyle linked to higher IBD risk via immune modulation and microbiota changes
How does antigen exposure affect the microbiota in IBD? (2)
- Leads to dysbiosis or selection of pathobionts
- Microbiota changes drive IBD pathogenesis
What roles do immune cells play in IBD pathogenesis? (2)
IECs and SCs: Critical for immune surveillance
Tregs and Th17 cells: Regulate immune tolerance and activation
What genetic mechanisms underlie IBD? (4)
- Barrier integrity loss: CDH1, MUC19
- Paneth and goblet cell dysfunction: XBP1, ORMDL3
- Innate immune activation loss: NOD2, ATG16L1, IRGM
- Immune regulation loss: TNFSF15, IL-10RB, IL-23R
How does barrier integrity disruption contribute to IBD pathogenesis? (2)
Barrier integrity is disrupted at all levels, leading to chronic inflammation.
- Microbiota changes: Dysbiosis or pathobiont selection drive inflammation.
- Genetic susceptibility: Alters intestinal tissue and immune responses, promoting chronic inflammation.
What is dysbiosis and its role in disease? (3)
- An alteration in microbiota community structure and/or function
- Capable of causing/driving a detrimental distortion of microbe-host homeostasis
- Specifically, it initiates or propagates disease
What microbiota changes are observed in twin cohorts with IBD? (5)
Crohn’s Disease (CD):
- Lower levels of Faecalibacterium and Roseburia
- Higher levels of Enterobacteriaceae and Ruminococcus
- Presence of adherent-invasive Escherichia coli (AIEC) in ileal lesions
Ulcerative Colitis (UC):
- Reduced species richness and alpha diversity
- Enrichment of Actinobacteria (Rhodococcus) and Proteobacteria (Shigella/Escherichia)
How do microbial effectors contribute to IBD pathogenesis? (6)
Nod2-deficient mice:
- Elevated commensal bacterial load
- Dysbiosis and reduced pathogen defense
Microbial effectors:
- Single or combined bacterial effectors can elicit pathogenesis
- Maintain barrier function for intestinal homeostasis
IL10-/- model:
- Colitis depends on enteric bacteria (e.g., Enterococcus faecalis)
- Attenuated with ΔepaB (antigen) or Δlgt lipoprotein mutants
How does diet influence microbiota and immune response during inflammation? (5)
High saturated fat diet:
- Alters microbial assemblage conditions
- Expands sulphite-reducing pathobiont Bilophila wadsworthia
Milk-derived saturated fat:
- Promotes taurine conjugation of bile acids, increasing organic sulphur for B. wadsworthia
Th1 immune response:
- High-fat diet increases colitis incidence in genetically susceptible IL10-/- mice
How can microbial effectors exert anti-inflammatory effects? (2)
- Certain bacterial gene products drive protective inflammation in the intestine
- Crucial for rebalancing homeostasis in inflammatory diseases and malignancies
How does Lactobacillus paracasei prtP-encoded lactocepin affect inflammation? (2)
- Lactocepin degrades IP-10, reducing lymphocyte recruitment
- Significantly attenuates inflammation in an ileitis model after intraperitoneal injection
What is the genetic aspect of colorectal cancer (CRC)? (2)
- CRC is primarily a genetic disease
- Most cases occur sporadically without a known genetic predisposition
How does microbial disturbance contribute to colorectal cancer (CRC)? (5)
- Impairment of epithelial barrier function
- Imbalance in epithelial self-renewal
- DNA damage
- Altered immune responses
- Fosters colorectal tumour initiation and progression
How does Escherichia coli contribute to colorectal cancer (CRC) via microbial-induced DNA damage? (3)
- E. coli (group B2) produces colibactin, a genotoxin found in 30-50% of human faecal isolates
- Precolibactin is cleaved inside host cells, causing DNA damage through cell-cycle arrest, alkylation, and double-strand breaks
- Precancerous lesions promote colonization and expansion of pks+ E. coli strains
How does Helicobacter hepaticus contribute to colorectal cancer (CRC)? (3)
- H. hepaticus produces CDT (cytolethal distending toxin), with CdtB as the active domain
- Induces hepatocyte proliferation, overproduction of antiapoptotic proteins, and genomic instability
- Upregulates NF-kB pathway and downregulates IL-10, leading to colitis and colon carcinoma development
How do microbial-induced ROS and proliferation contribute to colorectal cancer (CRC)? (4)
Enterotoxigenic Bacteroides fragilis:
- Increases reactive oxygen species (ROS) and DNA damage
- Weakens tight junctions
Fusobacterium nucleatum:
- Elevated in colon biopsies compared to normal mucosa
- Adhesin FadA promotes attachment, cancer cell invasion, and proliferation
How do chemokine networks link the gut microbiome to colorectal cancer (CRC)? (4)
Fusobacterium nucleatum:
- Inhibits T cells and NK cells by binding T cell immunoreceptor (TLX/PPRR ligands)
Gut microbiota:
- Trigger chemokine production by crossing a dysfunctional epithelial barrier
- Recruit immune cells to the lamina propria, promoting pro-inflammatory cytokine secretion
- Increase T-cell infiltration into tumors, improving outcomes
How does microbiota composition link T-cell-recruiting chemokines to colorectal cancer (CRC)?
- T-cell-infiltrated tumors are enriched in Lachnospiraceae, Ruminococcaceae, and Bacteroidaceae, associated with T-cell-attracting factors
- Bacteroides, Proteobacteria, and Desulfovibrio correlate with most T-cell-recruiting chemokines and higher intratumoral T-cell densities
