Challenges to the GI System Physiology

Flashcards covering fundamental GI biological pathways, Inflammatory Bowel Disease (UC and Crohn's), and the pathophysiology of Coeliac disease.

What are the three fundamental cell biological pathways in the regulation of GI function discussed in the lecture?

1. Autophagy, 2. Intracellular bacterial sensing, and 3. Unfolded protein response ($\text{UPR}$).

What is macroautophagy and what are its primary physiological responses?

A conserved biological process that serves as a selective response to remove damaged organelles and microorganisms, and a non-selective response to cellular starvation.

According to the notes, what are the six main steps of autophagy?

1. Induction, 2. Cargo recognition, 3. Vesicle formation, 4. Autophagosome-lysosome fusion, 5. Breakdown of autophagic content, and 6. Release of degradation products into cytosol.

How is Atg8 ($\text{LC3-I}$) recruited to the autophagosomal membrane?

Via membrane anchoring and phosphatidylethanolamine modification of Atg8 to become $\text{LC3-II}$.

What is Nucleotide-binding Oligomerization Domain 2 ($\text{NOD2}$)?

A cytosolic pattern recognition receptor that acts as an intracellular bacterial sensor and is activated upon binding to muramyl dipeptide ($\text{MDP}$).

From what substance is muramyl dipeptide ($\text{MDP}$) derived?

Peptidoglycan ($\text{PGN}$) present in gram-positive and gram-negative bacteria.

What was the first susceptibility gene identified for Inflammatory Bowel Disease ($\text{IBD}$)?

The gene encoding $\text{NOD2}$.Check

Name the three major ER stress sensors of the unfolded protein response ($\text{UPR}$).

Activating transcription factor 6 ($\text{ATF6}$), protein kinase $\text{RNA}$-like ER kinase ($\text{PERK}$), and inositol-requiring kinase ($\text{IRE1}$).

What is the role of glucose-regulated protein $\text{grp78}$ in the unfolded protein response?

It regulates the sensors; when sensors are bound to $\text{grp78}$, the $\text{UPR}$ is inactive.

Mutations of which two proteins result in the apoptotic death of Paneth cells and Goblet cells in IBD?

$\text{IRE1}$ and X Box Protein1 ($\text{XBP1}$).

How do Ulcerative Colitis and Crohn’s disease differ in their location and extent of inflammation?

Ulcerative Colitis involves diffused mucosal inflammation restricted to the colon and rectum, while Crohn’s disease involves patchy, segmental, transmural inflammation that may affect any part of the $\text{GI}$ tract.

Which protein associated with $\text{IBD}$ risk is expressed in the intestinal epithelium and various immune cells like $\text{CD4/8 T}$-cells and B cells?

$\text{ATG16L1}$.

What abnormality is observed in Paneth cells that are deficient in $\text{ATG16L1}$ and $\text{ATG5}$?

They exhibit abnormalities in the granule exocytosis pathway.

According to the pathophysiology of Ulcerative Colitis, what cytokines do infiltrated macrophages produce to activate T helper type 1 ($\text{TH1}$) cells?

$\text{TNF}$, $\text{IL-12}$, $\text{IL-23}$, and $\text{IL-6}$.

What is Coeliac disease and what triggers its clinical symptoms?

An immune-mediated inflammatory disease of the small intestine caused by sensitivity to dietary gluten and related proteins in genetically predisposed individuals.

Which $\text{HLA}$ molecules are responsible for presenting deamidated gluten peptides to $\text{CD4+ T}$ cells in Coeliac disease?

$\text{HLA-DQ2}$ (found in $95\%$ of patients) or $\text{HLA-DQ8}$ (found in $5\%$).

What characterizes a duodenal biopsy in a patient with Coeliac disease?

Flattened villi, crypt hyperplasia, infiltration with lymphocytes and plasma cells, and reduced cell differentiation.

What is Zonulin and where is it released?

A $47\,\text{kDa}$ paracrine protein released by the epithelial cells of the small intestine that regulates intestinal permeability.

What is the role of tissue transglutaminase ($\text{TTG}$) in the pathogenesis of Coeliac disease?

It modifies gluten peptides in the lamina propria (deamidation), which then trigger an adaptive immune response.

What are some long-term consequences of villous atrophy in Coeliac disease?

Malabsorption, secondary disaccharide deficiency (e.g., lactose intolerance), deficient $\text{GI}$ hormone production, and anaemia due to iron deficiency.