Theme 3: Intestinal homeostasis Flashcards
What is intestinal homeostasis and why is it important?
Intestinal homeostasis refers to the balance between digestion, absorption, and immune regulation in the GI tract. It prevents excessive inflammatory responses to commensal bacteria while maintaining the ability to defend against pathogens.
What are the main functions of the intestinal microbiota?
The microbiota aids in:
- Digestion
- Vitamin production
- Energy extraction from indigestible carbohydrates
- Competitive exclusion of pathogens
- Immune system modulation.
What changes occur in intestinal E. coli of IBD patients during active disease?
Studies in IBD patients have identified an increased presence of E. coli strains that do not contain virulence genes, but have a capacity to adhere to and invade epithelial cells in vitro.
What are the virulence mechanisms of pathobiont E. coli that harm the host?
These strains (generally referred to as pathobionts) have been shown to disrupt the epithelium in vitro which would enable them to penetrate into and beyond the epithelial monolayer, replicate in cells, disseminate within the host, and induce a chronic immune response in vivo.
How do host mutations in the NOD2 gene affect gut barrier defence?
NOD2 loss of function mutations may lead to uncontrolled bacterial growth, which eventually triggers extensive local inflammation, granuloma formation and transmural abscesses. This would be a typical example of the effect of a ‘breakdown’ in the finely tuned network of physiological inflammation in the intestinal tissue.
What is the role of the epithelial barrier in intestinal defence?
The intestinal epithelium forms a physical barrier preventing pathogen entry. It includes tight junction proteins (occludins, claudins, ZO-1) and antimicrobial peptides from Paneth cells.
How does the mucus layer protect the intestine?
The mucus layer, produced by goblet cells, consists of:
- An outer layer containing bacteria
- An inner, sterile layer that prevents direct contact between microbes and epithelium
- It is essential for preventing infections and maintaining homeostasis
What are the main antimicrobial peptides in the gut?
The primary antimicrobial peptides include:
- α-Defensins (produced by Paneth cells, activated by trypsin)
- β-Defensins (expressed in enterocytes, inducible by microbial products)
- Reg3γ (kills Gram-positive bacteria)
Name two innate receptors involved in microbial recognition and their ligands.
- TLR (located in the cytoplasmic membrane) binds to lipopolysaccharides (LPS) from Gram-negative bacteria.
- NOD (intracellular receptor) detects muramyl dipeptide from bacterial peptidoglycan.
Name the key transcription factor involved in Toll-like receptor (TLR) signalling and its role.
NF-κB is the key transcription factor. Upon activation by TLRs, it translocates to the nucleus, inducing expression of inflammatory cytokines and antimicrobial peptides.
Describe the TLR signalling pathway leading to NF-κB activation.
- TLRs recognise microbial ligands.
- Adaptor proteins (e.g., MyD88, TRIF) are recruited.
- This activates kinases (IKK complex) that phosphorylate IκB.
- IκB is degraded, releasing NF-κB.
- NF-κB enters the nucleus, initiating gene transcription.
What types of genes are expressed due to NF-κB activation?
Pro-inflammatory cytokines (IL-8, TNF-α), chemokines, and antimicrobial peptides.
How is TLR signalling regulated to prevent chronic inflammation?
Regulation occurs through:
- Low expression of TLRs on the intestinal surface
- Negative regulators like PPARγ, TOLLIP, and A20
- Commensal bacteria inducing anti-inflammatory pathways
How do commensal bacteria modulate immune responses?
- Bacteroidetes upregulate PPARγ, inhibiting NF-κB activation
- Lactobacillus casei prevents IκB degradation, reducing inflammation
How does gut microbiota composition differ in IBD patients?
- Reduced Faecalibacterium prausnitzii (anti-inflammatory)
- Increased E. coli and Ruminococcus gnavus (pro-inflammatory)
- Reduced Akkermansia muciniphila, which strengthens the mucus barrier
What is the role of Akkermansia muciniphila in gut health?
It degrades mucin, providing nutrients for beneficial bacteria and supporting gut barrier integrity. Its reduction is linked to IBD.
What is the role of secretory IgA (sIgA) in gut immunity?
sIgA binds to luminal antigens, preventing bacterial adhesion and invasion, and helps maintain microbial balance.
How do M cells contribute to gut immunity?
M cells transport antigens from the lumen to underlying immune cells, facilitating antigen presentation and adaptive immune responses.
