Diseases of the Small Intestine Flashcards
Describe the anatomy and purpose of the functional unit of the small intestine: the villus
- The villi are finger like projections of the small intestinal mucosa that greatly enhance the functinoal surface area of the GIT
- They are covered by epithelial cells (enterocytes) and goblet cells
- Crypt cells are located at the base of the villi and are responsible for intestinal secretions and continually produce undifferentiated epithelial cells
- The epithelial cells differentiate as they migrate up the villus and are shed in ~3 days
- Differentiated enterocytes are responsible for both digestive and absorptive processes
Describe the normal process of digestion within the small intestinal lumen
- The SI lumen essentially provides an optimal environment for hydrolysis and emulsification of major dietary constiuents
- The lumen provides an optimal pH and temperature and movements aid in mixing of the contents
- Bile salts are mixed to emulsify fats
- Pancreatic enzymes are released into the lumen to hydrolyse proteins and carbohydrates
- Only terminal hydrolysis of proteins and carbohydrates are performed by enzymes on the microvillar membrane.
By which process are the following absorbed from the small intestine?
- Simple sugars
- Amino acids
- Oligopeptides
- Products of fat digestion
- Fat soluble vitamins (A, D, E, K)
- Folate
- Cobalamin
- sugars: active or facilitated carrier-mediated transport
- amino acids: active or facilitated carrier-mediated transport
- Oligopeptides: active or facilitated carrier-mediated transport
- Passive diffusion
- Passive diffusion
- Via carrier mediated diffusion in the proximal small intestine
- Bound to intrinsic factor, via receptor mediated endocytosis in the ileum
The default response of the SI immune system is one of tolerance.
Describe the role of the various cells in maintaining mucosal immune system tolerance
Lymphocytes
- Lymphocytes are present within the Peyer’s patches and mesenteric lymph nodes
- Plasma cells are abundant in the lamina propria
- Most plasma cells produce locally acting IgA
- T cells are either located within the LP or intra-epithelial spaces
- T cells are differentiated by expression of CD4+ and CD8+ molecules
- CD4 (T helper cells) recognise antigen presented with MHC II molecules on antigen presenting cells
- CD8 (cytotoxic T cells) recognise MHC I presented antigen
- CD4 cells predominate in the canine LP, whereas CD8 cells predominate in the feline LP
- Continuous recognition and interaction with antigen leads to the LP lymphocytes being highly differentiated and specific.
The default response of the SI immune system is one of tolerance.
Describe the role of the various cells in maintaining mucosal immune system tolerance
Dendritic Cells
- Dendritic cells capture, store and present antigen to the lymphocytes
- The can extend processed between the enterocytes to sample the luminal contents
- They essentially provide surveillance of the local microbiome
- The DCs are responsible for either upregulation of an immune response or tolerogenesis by activation of regulator T cells (Treg)
The default response of the SI immune system is one of tolerance
Describe the role of the various cells in maintaining mucosal immune system tolerance:
Macrophages, neutrophils, mast cells and eosinophils
- Macrophages in the Peyer’s patches and LP phagocytose and present antigen in conjunction with MCH II
- antigen thus presented can stimulate T cells (regulator or effector cells) and B cells
- Macrophages also secrete cytokines, chemokines and inflammatory mediators
- Neutrophils are only present in small numbers unless there is significant inflammation
- Eosinophils and mast cells have primarily pro-inflammatory roles (less involved in self-tolerance)
The default response of the SI immune system is one of tolerance
Describe the role of the various cells and note their role in maintaining mucosal immune system tolerance:
Enterocytes
- The enterocytes provide a functional barrier to entry or both the microbiome and potential pathogens
- Enterocyte express TLRs and interact with the microbiome
- MHC II is constituitively produced by dog enterocytes,and upregulated during inflammation in cats
- Enterocytes can produce cytokines, chemokines and pro-inflammatory mediators in disease states
The default response of the SI immune system is one of tolerance
Describe the roll of the various cells noting their involvement in maintainance of mucosal immune system tolerance:
Enteric neurons
- Bidirectional communication exists between the neurons and the gut and vice versa
- Immune cell release of mediators can generate axon reflexes
- Enteric neurons release immunoactive neuropeptides including substance P
- The enteric neurons can alter and effect intestinal motility, secretion and absorption.
List the innate immune defenses of the small intestine
- Peristaltic movement - antigen clearance
- Mucus layer
- Enterocyte barrier
- Presence of the microbiome
- Presence and function of the innate immune cells
- Possibly the production of defensins by enterocytes
- This is poorly defined in the dog and cat
List the major mechanisms by which normal SI homeostasis can be disrupted
- Genetic factors
- Barrier dysfunction
- Dysbiosis
All lead to inappropriate exposure to luminal antigen. This can lead to inflammation and alteration of the balance between effector and regulatory mucosal T cells.
Describe the two main outcomes following an inappropriate antigenic challenge in the small intestine.
- Challenge contained:
- mucosa repairs and the normal tolerogenic environment returns
- Challenge continues unabated / mucosa cannot repair / abnormal immune response:
- Chronic inflammation ensues
- Increased antigen - increased MHC II expression
- Increased expression of vascular addressins leads to enhanced recruitment of lymphocytes (via MAdCAM-1) and other inflammatory cells
- Increased expression of matrix metalloproteinases leads to architectural changes
List the various mechanisms that can contribute to signs of small intestinal disease.
Provide an example of a disease causing each mechanism
- Luminal disturbance
- exocrine pancreatic insufficiency
- Brush border membrane disease
- Poorly defined diseases in dogs
- Various breed specific abnormalities that lead to cobalamin deficiency
- Microvillar membrane damage
- Enteropathic E coli.
- Enterocyte dysfunction
- Bacterial exotoxins
- Malnutrition and ischaemia also inpair enterocyte function
- Epithelial barrier dysfunction
- NSAID use
- Villus atrophy
- Viral infections
- Chemotherapy drugs incl. vincristine
- Disordered motility
- secondary to intestinal obstruction
- Mucosal inflammation
- numerous triggers
- Hypersensitivity
- dietary responsive bowel disease
- Neoplasia
- focal (adenocarcinoma) or diffuse (lymphoma)
- Nutrient delivery failure
- Lymphangiectasia
- Congenital abnormalities
- atresia, stenosis, duplications, diverticulae
List the broad mechanisms that can trigger ileus
Provide 2 examples of each mechanism.
- Functional
- Post-surgery
- Irritable bowel syndrome
- Inflammatory
- Parvovirus / other infectious disease
- Peritonitis
- Metabolic
- Diabetes mellitus
- hypokalaemia
- Endotoxaemia
- Neuromuscular
- Dysautonomia
- Visceral myopathy
- Physical
- Foreign body
- Mass / Tumour
- Intussusception
List the major clinical features of small intestinal disease
- Diarrhoea
- Malabsorption
- Melena
- Protein losing enteropathy
- Borborygmi / flatulence
- Weight loss / failure to thrive
List and describe the pathophysiological mechanisms the contribute to the formation of diarrhoea
Note: While the various mechanisms can be describe separately, it is most often a combination of mechanisms that ultimately cause diarrhoea
- Osmotic
- Most SI diseases have a component of osmotic
- Water is passively drawn into the lumen due to changes in the luminal environment
- Malabsorption
- reduced absorption leads to osmotic diarrhoea
- increased bacterial fermentation of unabsorbed solutes can lead to the production of volatile fatty acids and products that cause an increase in colonic secretions
- Permeability
- Inflammatory or neoplastic disease that causes exudation
- Secretory
- Chemical or bacterial toxins trigger increased secretions