Diseases of the Large Intestine Flashcards
Describe the nervous supply and function of the large intestine
- The vagus nerve supplies parasympathetic innervation to the upper colon.
- Pre-ganglionic neurons in the lumbosacral spinal cord (pelvic nerves) provide parasympathetic supply to the distal colon
- Both stimulatory and inhibitory
- Sympathetic nerves arise from the paravertebral ganglia
- Primarily inhibitory to smooth muscle contractility within the wall
- Stimulatory to the muscle of the sphincters, especially the anal spincter
- Large sympathetic supply to the GIT vascular bed - modulation of GIT blood flow is an important regulatory of systemic blood pressure.
- Myenteric plexus - Intramural nerve supply
- Most of the nervous supply responds via reflex pathways to control colonic wall movement, water and electolye secretion / absorption and local blood flow.
- Central nervous system centres exerts an influnce over contractility, primarily in preventing and assisting defecation.
Describe the epithelial layer of the colon.
What are the important functions of the colonic epithelial cells?
- Numerous straight tubular crypts make up the epithelial layer.
- Within the crypts there are
- epithelial cells
- goblet cells
- endocrine cells
- As for the SI, crypt cells continuously replicate and migrate to the tips of the epithelial layer with turnover each 4-7 days.
- GH can upregulate colonic epithelial differentiation for repair purposes
- Epithelial cells provide a functional barrier
- Goblet cells produce mucus which aids faecal evacuation via lubrication and inhibits bacterial invasion.
- The endocrine cells produce somatostatin, polypeptide P, insulin like growth factor and glucagon-like peptides
Describe the process by which the colon regulates water and electrolyte resorption
- In health, the colon resorbs ~ 90% of the water that enters from the small intestine
- With profuse SI diarrhoea, the resorptive capacity is overwhelmed
- With colonic disease, these functional capabilities are reduced
- Water is resorbed via passive osmosis in conjunction with sodium
- Aldosterone modulates the expression of the colonic Na+/K+ ATPase pump
- Corticosteroids also modulate expression of the Na+/K+ pump
- Potassium is absorbed by the K+/H+ exchange transporter in the proximal colon, and can be actively excreted in the distal colon.
- Chloride passively follows sodium driven by the electrochemical gradient
- Chloride can also be actively absorbed with bicarbonate exchange
Colonic mucus
Describe the production, regulation and role of colonic mucus
- Colonic mucus is a high molecular weight glycoprotein or mucin produced by the colonic goblet cells
- Exfoliated epithelial cells are incorporated within the mucus
- The mucus serves to protect the colonic wall from damage and pathogenic invasion while lubricating the colon for faecal passage
- Mucin secretion is dependent on
- the cystic fibrosis transmembrane regulator which secretes chloride
- Exocytosis for the mucin to leave the goblet cell
- Mucus secretion is increased with colonic inflammation and after parasympathetic stimulation
Describe the mechanisms that control colonic motility including neural involvement and the relevant neurotransmitters
- The colonic wall receives neural inputs from the:
- parasympathetic nervous system via the vagus nerve and pre-ganglionic spinal nerves from the lumbosacral spinal cord
- Sympathetic nervous system from the paravertebral ganglia - inhibitory to the myenteric plexus, ontracts sphincter muscles and supresses secretion of water and electrolytes while constricting the blood vessels (diverting blood elsewhere)
- Myentric plexus - coordinates control of smooth muscle contraction
- Numerous neutrotransmitters are involved in the co-ordinated control of the colon in mixing of faeces within the proximal colon to resorb water, through to storage and defecation.
- Cholecystokinin, neurotensin, somatostatin, serotonin and substance P
- Acetycholine, adrenaline and noradrenalin from the sympathetic nervous system
- Rhythmic Phase Contractions (RPCs) occur in the proximal colon, allowing mixing of contents and water resorption
- Retrograde Giant Contractions (RGCs) initiate in the transverse colon and propogate towards the caecum - for mixing
- Giant Migrating Contractions (GMCs) in the distal colon propel faeces towards the rectum
Briefly describe the process of defecation
- Triggered by ingestion of a meal (gastrocolic reflex) or by distension of the distal colon/rectum
- GMCs are stimulated within the distal colon and rectum
- Anal sphincter is relaxed ~ simultaneously
- Afferent fibres from the rectal wall ascend into the brainstem for UMN control and cerebral cortex for conscious perception
- The rectum can relax to accomodate a large volume of stool under conscious control
- Intrapelvic pressures are increased by abdominal muscle and diaphragmatic contraction
Describe the major roles of the colonic microflora
How is the microflora altered in disease and by antibiotic use?
- Interaction with the mucosal immune system
- Includes maintenance of self tolerance
- Protection agains pathogenic bacteria via competition for nutrients and mucin binding sites
- Provision of energy for utilization by the colonocytes
- SCFAs - acetate, butyrate and proprionate
- Butyrate can induce production of IL-10, an anti-inflammatory cytokine
- SCFAs also promote proliferation and differentiation of the colonic epithelial cells, stimulate water and electrolyte absorption and modify colonic motility
- Synthesis of amino acids and vitamins
Antibiotic use, chronic inflammation and a lack of dietary fibre can all result in alterations to the normal colonic microbiome. Generally with a reduction in the diversity of the bacterial species
Describe the processes of immune surveillance in the large intestine.
Include the roles of the various cell types - macrophages, dendritic cells, enterocytes and lymphoid elements
- Microfold cells are abundant in the epithelium overlying the mucosa associated lymphoid tissues (MALT)
- M cells sample antigen for presentation to the underling B cells in the MALT
- Dendritic cells also sample antigen for presentation to lymphocytes
- The colonocytes can also sample antigen and present via MHC II to B cells, T cells and macrophages
- Antigen is presented to the lymphocytes (B and T) for both innate and adaptive immune responses
- The innate immune system appears most responsible for maintaining the balance of the immune response to each stimuli - self-tolerance is the normal default
Define chronic colitis.
What histopathological classifications of chronic colitis can be seen in dogs?
- Chronic colitis is an inflammatory condition involving the colon that has shown clinical signs for at least 3 weeks.
- Lymphocytic / plasmacytic
- Eosinophilic
- Neutrophilic / suppurative
- Granulomatous (macrophages predominate)
How does inflammation affect the normal functions of the colon?
- Loss of normal immune tolerance
- Cause or effect?
- Loss of normal absorptive capacity of the mucoa
- Water
- Electrolytes
- Increased secretion of water
- Altered sodium and chloride transport
- Altered motility
- Decreased retrograde giant contractions and rhythmic phase contractions - decreased mixing of contents and reduced transit time
- Increased giant migrating contractions
- Leads to increased defectation frequency
- Increased NF-kB expression leading to increase inflammatory cytokine production
- Altered microbiome due to altered luminal contents
Discuss the interpretation of the following:
IBD can improve clinically if not resolve with dietary manipulation (hydrolysed, novel protein and highly digestible diet). However, histopathological resolution often does not occur.
- Dietary manipulation or change to a more digestible can improve absoprtion and reduce faecal output, thus improving the clinical signs associated with IBD
- The improvement may suggest the disease or clinical signs are not due to idiopathic IBD, but rather to a food responsive disease. In human IBD, food antigens do not play a direct role in the pathogenesis of IBD
- Highly digestible diets may improve the delivery of nutrients to the microbiome and improve diversity
- It is currently unknown if the dietary change is merely masking the clinical signs of IBD or longer time is needed to see changes to the degree of histopathological change. It is also possible that dietary manipulation slows progression of the inflammatory disease, rather than reversing the damage already done.
Comment on the intent of the WSAVA scoring system for evaluation of endoscopic intestinal biopsies
- The endoscopic biopsy guidelines were developed such that pathologists were reporting changes in a consistent and reproducible way.
- These guidelines were not intended to formulate a score to assess or correlate to clinical severity
- It is not known which component of histological change is most relevant to clinical disease. Similarly, it is not known which change/s are relevant to document a response to treatment
- The guidelines can be used to allow easy comparison between prospective studies. This may help determine the most relevant histopathological changes and also the changes most correlated to clinical disease.
Discuss the mechanism of action of the various diet components and supplements that may provide benefit for dogs and cats with colitis.
Include: soluble, insoluble and fermatable fibre,
The major dietary recommendations for dogs and cats with chronic colitis include provision of either:
- Highly digestible / low residue diet
- Single / novel protein or hydrolysed diet
Insoluble fibre: (grains/vegetables/beans
- Reduced nutrient availability but may improve colonic motility
- Absorbs water and blocks absorption of some byproducts of digestion
Soluble fibre: (psyllium)
- Dissolves in water to form a gel
- The gel blocks absorption of some fats and cholesterol
- Slows carbohydrate digestion, thus stabilising glucose absorption
- Provide nutrition to the microbiome
Fermentable fibre: (A form of soluble fibre - includes psyllium, beet pulp, FOS and MOS
- Metabolised to SCFAs which provide energy to the colonocytes
- Increased colonic blood flow
- Increase colonocyte proliferation
- May act as a prebiotic and alter the colonic microbiome - decreased E. coli and C. perfringens in cats.
Briefly describe the major clinical, endoscopic and histopathological changes in granulomatous colitis
How is the disease definitively diagnosed?
What is the treatment of choice for GC?
- Primarily diagnosed in young bower dogs (signalment)
- Signs of large bowel diarrhoea/disease - tenesmus, increased urgency, hematochezia, mucoid diarrhoea
- Weight loss and inappetance are seen with chronicity and in severe cases
The general investigation for GC is similar as for all other forms of chronic colitis. Parasites must be excluded with faecal testing or fenbendazole trials. Blood and urine testing should help to exclude extra-GIT disease. Food trials could be considered with early and mild disease.
The disease is definitively diagnosed by obtaining endoscopic biopsies of the colon and documenting granulomatous inflammation in the presence of intracellular E.coli in PAS positive macrophages. The presence of PAS positive macrophages is highly suggestive and the organism can be identified using FISH techniques.
Treatment involves the use of enrofloxacin at 5 mg/kg PO q 24 hours for 4-8 weeks. Culture and sensitivity of biopsy tissue is advised prior to treatment as resistance to enrofloxacin has been identified.
Note the various mechanisms by which E. Coli can cause colitis in dogs and cats.
- Various E. coli species are present as a part of the normal microbiome is most dogs/cats.
- Pathogenic E. coli carry various plasmids that encode for:
- Enterotoxins (enterotoxigenic)
- Produce heat labile and heat stable toxins that primarily stimulte excessive secretion in the small intestine.
- LI diarrhoea can be seen with chronic SI diarrhoea and secondary to changes in the luminal environment
- Enteropathogenic (adherent and invasive)
- Cause attaching and effacing damage to the microvilli primarily in the ileum and colon
- GC is caused by an EPEC
- Enterohaemorrhagic
- EHEC have a trophism for the LI and cause colonocyte death through production of a shiga-like toxin - inhibit protein synthesis leading to cell death, oedema, submucosal haemorrhage, arteritis and arteriolar thrombosis
- A cause of haemorrhagic diarrhoea
- Enterotoxins (enterotoxigenic)
- ~ 15% of healthy dogs and ~5% healthy cats can have EHEC as part of their microbiome.
