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Colonic Fluid and Electrolyte Transport in Health and Disease
PROGRESS IN GASTROENTEROLOGY
0195-5616/99 $8.00 + .00
COLONIC FLUID AND ELECTROLYTE TRANSPORT IN HEALTH AND DISEASE Vivien Rolfe, BSc, PhD
Do not judge the stools by their quantity but by their quality and the manner of them, what is needful and comfortable for the patient. HIPPOCRATES, 450
BC31
A major function of the mammalian colon is the absorption of water and electrolytes from the luminal contents that enter through the ileocecal valve. The absorptive capacity of the colon is influenced by the rate of passage of the luminal contents. To maximize the efficiency of these processes, there is close coordination between motility and absorptive functions. A balance between the benefits of prolonged time of contact between the colonic mucosa and the luminal contents and the adverse effects of accumulated toxic and carcinogenic metabolites is essential. Diseases of the colon often result in diarrhea, but the underlying pathophysiological mechanisms are largely obscure. This article provides an overview of water and electrolyte transport in health and highlights some putative changes in colonic structure and function that occur during diarrheal disease. COLON STRUCTURE
The large intestine of the dog comprises the cecum, colon, rectum, and anus; morphologically, it consists of several tissue layers. The innerFrom the Waltham Centre for Pet Nutrition, Waltham-on-the-Wolds, Melton Mowbray, Leicestershire, United Kingdom VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 29 • NUMBER 2 • MARCH 1999
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most epithelial layer provides an interface with the luminal contents and a barrier to the passage of macromolecules into the host. The epithelium is continuous along the length and circumference of the colon and houses mucus-secreting goblet cells, enteroendocrine cells, Paneth cells, and differentiating stern cells. Tubular structures called "crypts" increase the surface area of the colon by extending into the lamina propria some 450 to 500 f.Llll in depth. There are 70 to 80 crypts per square micrometer in the colon of the dog. Each crypt produces roughly 300 new cells per day, and these cells migrate along the crypt axis, where they enter a death program or are exfoliated. 19 In health, the continuity of the colonic surface epithelium is well maintained. The colonocytes are joined at their apical border by the zona occludens of the tight jw1ction that is central in the maintenance of epithelial integrity and mucosal barrier function. A microscopic view of the canine colon surface in health is shown in Figure 1. Subjacent to the epithelium is the lamina propria, which is enriched with blood capillaries and lymphatic vessels. The outermost layer of the colon is muscular and consists of circurnferentially aligned circular smooth muscle fibers and longitudinal muscle with fibers aligned parallel to the direction of the lumen. The colon is extensively innervated by the intrinsic nerves of the enteric nervous system and extrinsic fibers of the central nervous system, which coordinate healthy gut function.
Figure 1. Surface structure of canine distal colon labeled for F-actin with BODIPY phallacidin (Molecular Probes, Leiden, The Netherlands). Image obtained by digital confocal microscopy (lmprovision Inc., Boston, MA, original magnification x 100). In health, the epithelial integrity is well maintained (unpublished observation).
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COLONIC TRANSPORT IN HEALTH
Colonic transport is regulated by neurohumoral signaling processes in response to changes in the physical and chemical nature of the luminal contents. These signals are mediated by intracellular messengers that alter apical and basolateral cell transport processes. Much of the current understanding of colonic transport function has been derived from in vivo fluid perfusion studies and in vitro measurements of electrogenic ion transport using intestinal sheets isolated in Ussing chambers. 15 More recently, patch-clamp techniques have characterized the electrical activities of individual ion channels and significantly advanced the understanding of intestinal ion transport and its regulation. Much of the following experimental evidence has been obtained from rodent and human clinical studies, as research in the dog is sparse. lon Transport Across the Epithelium
Due to the low permeability or high resistance of the colonic epithelium, ion transport is largely energy dependent. Energy is obtained from the hydrolysis of adenosine triphosphate facilitated by sodiumpotassium adenosine triphosphatase (Na+-K+ ATPase) pumps located on the basolateral membrane of the cell. The spatial localization of these Na+-K+ ATPase pumps on the basolateral border is critical for the generation of a steep cation gradient across the mucosa, the driving force for water transport? In health, Na+ and chloride (Cl-) ions are absorbed from the luminal contents, and K+ and bicarbonate (HC03 -) ions are secreted. Na-t is absorbed into the cell against a steep electrochemical gradient through highly selective apical ion channels. 59 In addition, the absorption of Na + may occur by electroneutral Na +/hydrogen (H +) and Cl- /HC03 exchange processes. The Na+ is extruded via the basolateral Na+-K+ ATPase pump, and Cl+ exits through membrane channels. The accumulating intracellular K + is secreted into the lumen down a favorable gradient through apical channels. 15, 18 Many in vitro studies demonstrate regional and species differences in Na + absorption along the length of the colon. The rabbit colon displays greater Na + fluxes in proximal regions due to a higher passive permeability than the distal colonY In distal regions, Na+ absorption is predominantly electrogenic. 51 This is a consequence of the distal colonic epithelium being generally "tighter" or of higher resistance. 49 In the rat, however, the Na + absorption in the proximal and distal colon is entirely electroneutral,4 and in the human distal colon, the Na + absorption is electrogenic. 23 The ion transport mechanisms in the canine colon are poorly elucidated. In a series of unpublished studies (V. E. Rolfe, unpublished observations, 1998), colonic transport was assessed in vivo by placing
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Table 1. CHANGES 1N COLONIC TRANSPORT OF WATER AND ELECTROLYTES*
Transport
Fluid transport (mL/h) Na + (mEq/L/h) K+ (mEq/L/h) o- (mEq/L/h) Hco- 3 (mEq/L/h) pH (U/h)
Health (mean± SEM)
-2.35 - 62.04 3.22 -57.48 0.14 0.35
± ± ± ± ± ±
0.53 23.57 3.28 23.71 0.07 0.05
Dietary Sensitivity (mean± SEM)
-0.94 -25.18 1.48 -27.45 -0.35 0.36
± 0.33t ± 10.84t ± 0.65
± 10.87t ± 0.03 ± 0.10
*Measured by inserting dialysis bags into the lumen of six healthy dogs and six dogs with dietary sensitivity. A negative value represents absorption from the lumen of the colon. Comparisons were made between healthy dogs and dietary-sensitive dogs. tP <0.05, Student's t test (V.E. Rolfe, unpublished data, 1998).
dialysis bags into the lumen of the colon containing the following concentrations of ions (mEq/L): 147 Na +, 5 K +, 25 HC03 -, 135 CI-, 2.4 SOl-, 1.2 Mg2 +, 1.2 Ca2 +, 1.2 H 2 POl-. Changes in ion transport were assessed by an electrolyte analyzer after the bags had remained in the colon for 1 hour. In healthy dogs, Na + and CI- were absorbed from the luminal contents, although K + and HC03 - were secreted (Table 1). In terms of electroneutral or electrogenic ion transport processes, the mechanisms are not clear. Other electrolytes present in the colon at high levels also have an influence on colonic ion transport. Short chain fatty acids (SCFAs) are products of bacterial fermentation that are absorbed by the colon and often utilized by the epithelial cells as an energy source. The human colon preferentially absorbs butyrate above propionate and acetate. 10 In the canine colon, the rates of acetate, propionate, and butyrate absorption are similar. 24 It is not clear whether SCFAs are absorbed by electrogenic or electroneutral processes; again, there are likely to be dramatic species and regional differences. Research has shown that SCFAs enter the cell by nonionic diffusion, being transported across the apical membrane in a protonated form (SCFAH) before dissociating into SCFA- and H + inside the cell. The H + recycles back into the lumen in exchange for Na+. In dogs, the absorption of SCFAs are Na+ dependent/4 but in humans, there may be a relationship between SCFA and HC03 - uptakeY In a recent study, a carrier protein was identified on the intestinal epithelium which was involved in the transport of butyrate. 40 Colonic Water Transport
Approximately 90% of fluid entering the colon is reabsorbed across the mucosa; thus, the colon plays an important role in fluid and electrolyte homeostasis. The uptake of Na+ from the lumen creates a hypertonic environment in the interstitial fluid surrounding the crypts. This generates a steep electrochemical gradient across the colonic mucosa, which
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drives the uptake of water from the luminal contents by osmosis. 38 In rats and sheep, which form solid feces, the Na + gradient is steep across the crypt as indicated by the high-intensity accumulation of Na+-sensitive fluorescent dyes in the interstitial fluid. In the cow, where feces is less solid, Na + gradients are reduced in magnitude. 38 The production of a near isotonic absorbate surrounding the bovine crypts is due to a high rate of transepithelial salt leakage. 34 This explains why the bovine colon is incapable of producing hard feces, and these data suggest that the dissipation of electrochemical gradients across the mucosa may be an important feature of diarrheal disease. The pathway for water uptake across the colonic mucosa is likely to be transcellular, with a water channel protein CHIP28 located on colonic epithelial cells in the rat,ZZ which is composed of an integral protein of 28 kDa. 57 Whether dysfunction of the water channel protein results in diarrheal disease is not known. Regulation of Colonic Transport Function
The opening and closing of cell membrane channels and the activation of cell transport components are controlled by intracellular messengers. These include cyclic adenosine monophosphate, cyclic guanosine monophosphate, calcium (Ca 2 +), calmodulin, phosphatidylinositol metabolites, and G-proteins. These intracellular mediators are triggered by neurohumoral signals in order to regulate colonic transport function in health and disease. A multitude of hormones and neurotransmitters influence colonic ion transport as outlined in a review by HubeP7 Table 2 summarizes
Table 2. SUMMARY OF INTESTINAL HORMONES AND NEUROTRANSMITTERS THAT STIMULATE ABSORPTION AND SECRETION Substance
Proabsorptive substances Aldosterone Glucocorticoids Noradrenaline Adrenaline Enkephalins Somatostatin Prosecretory substances Acetyl choline Vasoactive intestinal polypeptide 5-Hydroxytryptamine Prostanoids Guanylin Nitric oxide
Action
Sodium and water absorption30 Sodium absorption56 Sodium chloride absorption14 Water absorption26 Sodium chloride absorption 12 Reduces chloride secretion11 Chloride secretion54 Water secretion55 Chloride secretion58 Chloride secretion60 Chloride secretion29 Sodium secretion9 Chloride secretion33
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some of the hormones and neurotransmitters that influence colonic absorption and secretion, but the list is by no means exhaustive. A host of inflammatory mediators, including cytokines, prostanoids, nucleotides, reactive oxygen metabolites, biogenic amines, and immunoglobulins, influence intestinal transport as part of gut immunity. 37 These mediators are released in response to luminal antigen or in defense against noxious substances, and they stimulate water secretion to flush the irritant from the host.
Organization of Enteric Reflexes
Local neural reflexes control transport function by monitoring the physical and chemical nature of the luminal contents. Mucosal sensory fibers respond to mechanical stimuli8 and chemical stimuli43 by altering fluid and electrolyte transport. It was initially thought that intestinal electrolyte transport was regulated by enteric nerves that were routed through the submucosal plexus (situated adjacent to the circular smooth muscle layer). Many experiments were carried out on intestinal sheets that had the longitudinal muscle and myenteric plexus removed. Recent evidence, however, has shown that the myenteric plexus is also involved in the integration of mucosal transport function, mediating secretory responses induced by luminal glucose in the rat jejunum50 as well as Escherichia coli heat-stable enterotoxin43 and 5-hydroxytryptamine44 in the rat ileum. These sophisticated neural networks convey signals from local sensory fibers via intrinsic and extrinsic nerves to control both local and systemic physiological responses. 3' 42 Ashton et aF found that the gastrointestinal tract communicates with the central nervous system to coordinate digestive functions in dogs, with colonic fluid and electrolyte absorption in perfused colonic loops increasing after the ingestion of food.
COLONIC TRANSPORT IN DISEASE: DIETARY SENSITIVITY Frothiness of the stools in certain cases of diarrhoea is due to substances flowing down from the head. HIPPOCRATES, 450
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Dietary sensitivity is an adverse reaction to food that may be either immune-mediated (food hypersensitivity) or not (food intolerance). Many dogs are referred to veterinary clinics with diarrhea that may be caused by adverse food reactions. 47 Furthermore, some studies suggest
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that dietary sensitivity may exacerbate other diseases of the gastrointestinal tract, including lymphocytic-plasmacytic colitis in German Shepherd dogs/5 canine eosinophilic gastroenteritis/ 6 and some cases of colitis. 36 There are numerous causes of dietary sensitivity, including allergens such as meat, dairy, and cereal proteins as well as toxic compounds that are often ingested as a result of indiscriminate feeding by the dog. Despite the wide array of potential trigger substances, the repertoire of pathophysiological responses in the colon is limited and largely involves the infiltration of immune cells into the colonic mucosa, causing a local inflammatory response. Because the pathophysiological mechanisms underlying diarrhea in dietary sensitivity are unknown, a study was carried out to assess the structural and functional features of the colon in dogs with dietary sensitivity in comparison to healthy age- and weight-matched controls. Dietary sensitivity was diagnosed in dogs if they had diarrhea after being fed a range of diets but showed no signs of clinical disease. The diarrhea disappeared after changing the diet but resumed when the original diet was reintroduced. It is not clear what in the diet the dogs were sensitive to, but the trigger may include dietary allergens from meat, dairy, or cereal components or irritants such as some gelling agents. Colonic transport function was assessed in vivo using dialysis bags. The colonic absorption of water, Na + and Cl- was significantly reduced in dogs with dietary sensitivity compared to healthy controls (see Table 1 and V. E. Rolfe, unpublished data, 1998). An in vitro study in humans also demonstrated that inflammatory diarrhea was associated with impaired NaCl absorption and active Cl- secretion. 28 These data demonstrate that loss of absorptive function is an important factor underlying diarrhea in the dietary-sensitive dog. The mechanisms underlying the failure of colonic absorption were investigated further by obtaining colon samples at endoscopy. Colon samples were fixed in formalin, stained for F-actin with BODIPY phallacidin (Molecular Probes Europe BV, Leiden, The Netherlands), and visualized using a digital confocal microscope system (Improvision Inc., Boston, MA). In healthy dogs, the epithelial barrier was well maintained (see Fig. 1), although in dogs with dietary sensitivity, the continuity of the epithelium was disrupted with an increase in cell sloughing (Fig. 2). The resultant increase in permeability may reduce the absorptive capacity of the colon or facilitate the translocation of luminal allergen into the lamina propria, triggering the immune system inappropriately. Another important feature of the colonic mucosa in dogs with dietary sensitivity was an increase in the numbers of lymphocytes and plasmacytes in the lamina propria as identified in longitudinal sections stained with hematoxylin and eosin. The infiltrating immune cells may release inflammatory mediators into the mucosa, resulting in tissue damage and impaired transport function. 32• 53 Studies have shown that infiltrating inflammatory cells such as neutrophils migrate through the
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Figure 2. Surface structure of colon from a dog with dietary sensitivity. The colon is stained for F-actin with BODIPY phallacidin (Molecular Probes, Leiden, The Netherlands). Image obtained by digital confocal microscopy (lmprovision Inc., Boston, MA, original magnification x 100). The continuity of the epithelium is disrupted (unpublished obseNation, 1998}.
epithelial tight junctions, disrupting barrier function and increasing mucosal permeability. 13• 35 This would lead to the dissipation of electrolyte concentration gradients and the failure of colonic absorption. In dogs with dietary sensitivity, there were increased levels of nitrite in the colonic mucosa, indicating that nitric oxide (NO) was involved in the pathogenesis of diarrheal disease (healthy colon, 0.014 ± 0.001 vs inflamed colon, 0.038 ± 0.001 [micro] Eq/L/pg of protein; n = 6; P < 0.05 Student's t test; unpublished data, 1998). The NO may reduce colonic absorption by two mechanisms, First, by stimulating cyclic guanosine monophosphate-dependent electrogenic c- secretion/6 and second, by increasing tight junction permeability. 48 The overproduction of NO is involved in epithelial barrier dysfunction/ and NO has been implicated in the pathogenesis of inflammatory bowel disease with levels of inducible NO synthase gene expression increased in human patients.39 More recently, Gunawardana et aF0 demonstrated that nitrite levels in colonic lavage fluid were significantly increased in d ogs with inflammatory bowel disease compared to healthy controls, indicating that NO may play a role in inflammatory bowel disease and provide a novel approach to treat the condition in dogs. Inflammation of the colon also disrupts motility in dogs, with deranged segmenting and propulsive contractile activity. 52 Because the transit time of the luminal contents through the colon greatly influences the absorptive capacity of the mucosa,21 diarrheal disease may also be a
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consequence of impaired motility, but it is not yet clear whether this is the case in dogs with dietary sensitivity. CONCLUSIONS A north wind brings constipation. HIPPOCRATES, 450
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The mechanisms underlying colonic transport function in health and disease involve cellular transport components that are regulated by a multitude of neurohumoral signals. In the canine colon, Na and Cl are absorbed, and K and HC03 are secreted. Information extrapolated from other species must be interpreted cautiously due to interspecies variation and regional differences in transport along the length of the colon. The colon actively absorbs Na against a steep electrochemical gradient, causing water uptake by osmosis and fecal dehydration. In some diseases of the colon, the absorptive function may be impaired by disruption to the epithelial barrier integrity and defects in mucosal immunoregulation. Novel nutrient and therapeutical interventions aimed to restore barrier function, reduce inflammatory cell infiltration, and suppress the release of inflammatory mediators may be beneficial in the management of diarrhea in dogs with nonspecific dietary hypersensitivity and inflammation of the colon. For example, supplementation of the diet with fish oil improved epithelial integrity in murine inflammatory bowel disease. 45 Diets enriched with fiber may also be beneficial in the treatment of inflammatory diarrhea by increasing fecal bulk and improving contractility. 6 Fiber also releases fermentation products such as butyrate, which provide an energy source for the epithelium and have been demonstrated to be beneficial in the treatment of colitis in humans. 5 References 1. Alican I, Kubes P: A critical role for nitric oxide in intestinal barrier function and
dysfunction. Am J Physiol 270(suppl):G225-G237, 1996 2. Ashton KA, Chang LK, Anthone GJ, et al: Basal and meal-stimulated colonic absorption. Dis Colon Rectum 39:865-870, 1996 3. Aziz Q, Thompson DG: Brain-gut axis in health and disease. Gastroenterology 114:559578, 1998 4. Binder HJ, Foster ES, Budinger MF, et al: Mechanism of electroneutral sodium and chloride absorption in distal colon of the rat. Gastroenterology 93:449-455, 1987 5. Breuer Rl, Buto SK, Christ ML, et al: Rectal irrigation with short chain fatty acids for distal ulcerative colitis. Dig Dis Sci 36:185-187, 1991 6. Burrows CF, Merrit AM: Influence of cellulose on myoelectric activity of proximal canine colon. Am J Physiol 245(suppl):G301-G306, 1983 7. Caplan MJ: Ion pumps in epithelial cells: Sorting, stabilisation and polarity. Am J Physiol 272(suppl):G1304-G1313, 1997
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8. Cooke H, Sidhu M, Fox P, et al: Substance P as a mediator of colonic secretory reflexes. Am J Physiol 272(suppl):G238-G245, 1997 9. Cuthbert AW, Hickman ME, MacVinish LJ, et al: Chloride secretion in response to guanylin in colonic epithelia from normal and transgenic cystic fibrosis mice. Br J Pharmacol112:31-36, 1994 10. Dawson AM, Holdsworth CD, Webb J: Absorption of short chain fatty acids in man. Proc Soc Exp Bioi Med 117:97-100, 1964 11. Dharmsathaphom K, Racusen L, Dobbins JW: Effect of somatostatin on ion transport in rat colon. J Clin Invest 66:813-820, 1980 12. Dobbins J, Racusen L, Binder HJ: Effect of D-alanine methionine enkephalin amide on ion transport in rabbit ileum. J Clin Invest 66:19-28, 1980 13. Evans CW, Taylor JE, Walker JD, et al: Transepithelial chemotaxis of rat peritoneal exudate cells. British Journal of Experimental Pathology 64:644-654, 1983 14. Field M, McColl I: Ion transport in rabbit ileal mucosa. III. Effects of catecholamines. Am J Physiol 225:852-857, 1973 15. Field M, Rao RC, Chang EB: Intestinal electrolyte transport and diarrhoeal disease. N Engl J Med 321:80Q-806, 1989 16. Franklin RT, Jones BD, Feldman BF: Medical diseases of the small intestine. In Jones BW (ed): Canine and Feline Gastroenterology. Philadelphia, WB Saunders, 1986, pp 161-203 17. Frizzell RA, Koch MJ, Schultz SG: Ion transport by rabbit colon. I. Active and passive components. J Membr Biol27:297-316, 1977 18. Giebisch G, Stanton B: Potassium transport in the nephron. Annu Rev Physiol41:241256, 1979 19. Gordon JI, Hooper LV, McNevin MS, et al: Epithelial cell growth and differentiation. III. Promoting diversity in the intestine: Conversations between the microflora, epithelium and diffuse GALT. Am J Physiol 273(suppl):G565-G570, 1997 20. Gunawardana SC, Jergens AE, Ahrens F, et al: Colonic nitrite and immunoglobulin G concentrations in dogs with inflammatory bowel disease. JAVMA 211:318-321, 1997 21. Hammer J, Pruckmayer M, Bergmann H, et al: The distal colon provides reserve storage capacity during colonic fluid overload. Gut 41:658-663, 1997 22. Hasegawa H, Zhang R, Dohrman Z, et al: Tissue-specific expression of mRNA encoding th~· rat kidney water channel CHIP28k by in situ hybridisation. Am J Physiol 264(suppl):C237-C245, 1993 23. Hawker PC, Mashiter KE, Tumberg LA: Mechanisms of transport of Na, Cl and K in the human colon. Gastroenterology 74:1241-1247, 1978 24. Herschel DA, Argenzio RA, Southworth M, et al: Absorption of volatile fatty acid, Na and H 20 by the colon of the dog. Am J Vet Res 42:1118-1124, 1981 25. Hayden DW, Van Kruinigen HJ: Lymphocytic-plasmacytic enteritis in German Shepherd dogs. J Am Anim Hosp Assoc 18:89-96, 1982 26. Hubel KA: Intestinal ion transport: Effect of norepinephrine, piloca;pine and atropine. Am J Physiol 231:252-257, 1976 27. Hubel KA: Intestinal nerves and ion transport: Stimuli, reflexes and responses. Am J Physiol 248(suppl):G261-G271, 1985 · 28. Jenkins HR, Milia PJ: The effect of colitis on large intestinal electrolyte transport in early childhood. J Pediatr Gastroenterol Nutr 16:402-405, 1993 29. Keenan CM, Rangachari PK: Contrasting effects of PGE2 and PGD2: Ion transport in the canine proximal colon. Am J Physiol 256(suppl):G673-G679, 1989 30. Levitan R, Ingelfinger FJ: Effect of D-aldosterone on salt and water absorption from the intact human colon. J Clin Invest 44:801-808, 1965 31. Lloyd GER (ed): Hippocratic Writings. London, Penguin Books, 1978 32. Macdermott PR, Stenson WF: Alterations in the immune system in ulcerative colitis and Crohn's disease. Adv Immunol42:285-328, 1988 33. MacNaughton WK: Nitric oxide-donating compounds stimulate electrolyte transport in the guinea pig intestine in vitro. Life Sci 53:585-593, 1993 34. McKie AT, Goecke AI, Naftalin RJ: Comparison of fluid and electrolyte absorption from isolated bovine and ovine descending colon. Am J Physiol261(suppl):G433-G442, 1991 35. Nash SJ, Stafford J, Madara JL: The selective and superoxide independent disruption
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of intestinal epithelial tight junctions during leukocyte transmigration. Lab Invest 59:531-537, 1985 Nelson RW, Stookey LJ, Kazacos E: Nutritional management of idiopathic chronic colitis in the dog. J Vet Intern Med 2:133-137, 1988 Perdu MH, McKay DM: Integrative immunophysiology of the intestinal mucosa. Am J Physiol 267(suppl):G151-G165, 1994 Pedley KC, Naftalin RJ: Evidence from fluorescence microscopy and comparative studies that rat, ovine and bovine colonic crypts are absorptive. J Physiol (Lond) 460:525-547, 1993 Rachmilewitz D, Stamler JS, Bachwich D, eta!: Enhanced colonic nitric oxide generation and nitric oxide synthase activity in ulcerative colitis and Crohn's disease. Gut 36:718-723, 1995 Ritzhaupt A, Ellis Z, Hosie KB, et a!: The characterisation of butyrate transport across pig and human colonic luminal membrane. J Physiol (Lond) 507:819-830, 1998 Roediger WEW, Moore A: Effect of short-chain fatty acid on sodium absorption in isolated human colon perfused through the vascular bed. Dig Dis Sci 26:100-106, 1981 Rogers RC, McTigue DM, Hermann GE: Vagovagal reflex control of digestion: Afferent modulation by neural and "endoneurocrine" factors. Am J Physiol 268(suppl):G1G10, 1995 Rolfe VE, Levin RJ: Enterotoxin Escherichia culi STa activates a nitric oxide-dependent myenteric plexus secretory reflex in the rat ileum. J Physiol (Lond) 475:531-537, 1994 Rolfe VE, Levin RJ: Neural and non-neural activation of electrogenic secretion by 5hydroxytryptamine in rat ileum in vitro. Acta Physiol Scand 162:469-474, 1998 Rolfe VE, Menon RA, Lindley KJ, et a!: Dietary fish oils inhibit epithelial disruption and reduce colonic secretion in murine inflammatory bowel disease. J Pediatr Gastroenterol Nutr 24:454, 1997 Rolfe VE, Brand MP, Heales SJR, et a!: Tetrahydrobiopterin regulates cyclic GMPdependent electrogenic CI- secretion in mouse ileum in vitro. J Physiol (Lond) 503:347352, 1997 Rosser EJ: Diagnosis of food allergy in dogs. JAVMA 203:259-262, 1993 Salzman AL, Menconi MJ, Unno N, et a!: Nitric oxide dilates tight junctions and depletes ATP in cultured Caco-2BBe intestinal epithelial monolayers. Am J Physiol 268(suppl):G361-G373, 1995 Sandie GI, McGlone F: Segmental variability of membrane conductances in rat and human colonic epithelia. Implications for Na, K and Cl transport. Pflugers Arch 410:173-180, 1987 See NA, Bass P: Glucose-induced ion secretion in rat jejunum: A mucosal reflex that requires integration by the myenteric plexus. J Auton Nerv Sys 42:33-40, 1993 Sellin JH, DeSoigne R: Rabbit proximal colon: A distinct transport epithelium. Am J Physiol 246(suppl):G603-G610, 1984 Sethi AK, Sarna SK: Colonic motor activity in acute colitis in conscious dogs. Gastroenterology 100:954-963, 1991 Sharon P, Ligumsky M, Rachmilewitz D, et a!: Role of prostaglandins in ulcerative colitis: Enhanced production during active disease and inhibition by sulfasalazine. Gastroenterology 75:638-640, 1978 Tapper EJ: Local modulation of intestinal ion transport by enteric neurones. Am J Physiol 244(suppl):G457-G468, 1983 Tidball CS: Active chloride transport during intestinal secretion. Am J Physiol 200:309312, 1961 Turmanian SG, Binder HJ: Regulation of active sodium and potassium transport in the distal colon of the rat: The role of aldosterone and glucocorticoid receptors. J Clin Invest 84:1924-1929, 1989 Verkman AS, Van Hoek AN, Ma T, et a!: Water transport across mammalian cell membranes. Am J Physiol 270(suppl):C12-C30, 1996 Wu SC, O'Dorisio TM, Cataland S, et a!: Effects of pancreatic polypeptide and vasoactive intestinal polypeptide on rat ileal and colonic water and electrolyte transport in vivo. Dig Dis Sci 24:625-630, 1979
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59. Zeiske W, Wills NK, Van Driessche WV: Sodium channels and amiloride-induced noise in the mammalian colon epithelium. Biochim Biophys Acta 688:201-210, 1982 60. Zimmerman TW, Binder HJ: Serotonin-induced alteration of colonic electrolyte transport in the rat. Gastroenterology 86:310-317, 1984
Address reprint requests to Vivien Rolfe, BSc, PhD Waltham Centre for Pet Nutrition Waltham-on-the-Wolds Melton Mowbray Leicestershire LE14 4RT
UK
0195-5616/99 $8.00 + .00
COLONIC FLUID AND ELECTROLYTE TRANSPORT IN HEALTH AND DISEASE Vivien Rolfe, BSc, PhD
Do not judge the stools by their quantity but by their quality and the manner of them, what is needful and comfortable for the patient. HIPPOCRATES, 450
BC31
A major function of the mammalian colon is the absorption of water and electrolytes from the luminal contents that enter through the ileocecal valve. The absorptive capacity of the colon is influenced by the rate of passage of the luminal contents. To maximize the efficiency of these processes, there is close coordination between motility and absorptive functions. A balance between the benefits of prolonged time of contact between the colonic mucosa and the luminal contents and the adverse effects of accumulated toxic and carcinogenic metabolites is essential. Diseases of the colon often result in diarrhea, but the underlying pathophysiological mechanisms are largely obscure. This article provides an overview of water and electrolyte transport in health and highlights some putative changes in colonic structure and function that occur during diarrheal disease. COLON STRUCTURE
The large intestine of the dog comprises the cecum, colon, rectum, and anus; morphologically, it consists of several tissue layers. The innerFrom the Waltham Centre for Pet Nutrition, Waltham-on-the-Wolds, Melton Mowbray, Leicestershire, United Kingdom VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 29 • NUMBER 2 • MARCH 1999
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most epithelial layer provides an interface with the luminal contents and a barrier to the passage of macromolecules into the host. The epithelium is continuous along the length and circumference of the colon and houses mucus-secreting goblet cells, enteroendocrine cells, Paneth cells, and differentiating stern cells. Tubular structures called "crypts" increase the surface area of the colon by extending into the lamina propria some 450 to 500 f.Llll in depth. There are 70 to 80 crypts per square micrometer in the colon of the dog. Each crypt produces roughly 300 new cells per day, and these cells migrate along the crypt axis, where they enter a death program or are exfoliated. 19 In health, the continuity of the colonic surface epithelium is well maintained. The colonocytes are joined at their apical border by the zona occludens of the tight jw1ction that is central in the maintenance of epithelial integrity and mucosal barrier function. A microscopic view of the canine colon surface in health is shown in Figure 1. Subjacent to the epithelium is the lamina propria, which is enriched with blood capillaries and lymphatic vessels. The outermost layer of the colon is muscular and consists of circurnferentially aligned circular smooth muscle fibers and longitudinal muscle with fibers aligned parallel to the direction of the lumen. The colon is extensively innervated by the intrinsic nerves of the enteric nervous system and extrinsic fibers of the central nervous system, which coordinate healthy gut function.
Figure 1. Surface structure of canine distal colon labeled for F-actin with BODIPY phallacidin (Molecular Probes, Leiden, The Netherlands). Image obtained by digital confocal microscopy (lmprovision Inc., Boston, MA, original magnification x 100). In health, the epithelial integrity is well maintained (unpublished observation).
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COLONIC TRANSPORT IN HEALTH
Colonic transport is regulated by neurohumoral signaling processes in response to changes in the physical and chemical nature of the luminal contents. These signals are mediated by intracellular messengers that alter apical and basolateral cell transport processes. Much of the current understanding of colonic transport function has been derived from in vivo fluid perfusion studies and in vitro measurements of electrogenic ion transport using intestinal sheets isolated in Ussing chambers. 15 More recently, patch-clamp techniques have characterized the electrical activities of individual ion channels and significantly advanced the understanding of intestinal ion transport and its regulation. Much of the following experimental evidence has been obtained from rodent and human clinical studies, as research in the dog is sparse. lon Transport Across the Epithelium
Due to the low permeability or high resistance of the colonic epithelium, ion transport is largely energy dependent. Energy is obtained from the hydrolysis of adenosine triphosphate facilitated by sodiumpotassium adenosine triphosphatase (Na+-K+ ATPase) pumps located on the basolateral membrane of the cell. The spatial localization of these Na+-K+ ATPase pumps on the basolateral border is critical for the generation of a steep cation gradient across the mucosa, the driving force for water transport? In health, Na+ and chloride (Cl-) ions are absorbed from the luminal contents, and K+ and bicarbonate (HC03 -) ions are secreted. Na-t is absorbed into the cell against a steep electrochemical gradient through highly selective apical ion channels. 59 In addition, the absorption of Na + may occur by electroneutral Na +/hydrogen (H +) and Cl- /HC03 exchange processes. The Na+ is extruded via the basolateral Na+-K+ ATPase pump, and Cl+ exits through membrane channels. The accumulating intracellular K + is secreted into the lumen down a favorable gradient through apical channels. 15, 18 Many in vitro studies demonstrate regional and species differences in Na + absorption along the length of the colon. The rabbit colon displays greater Na + fluxes in proximal regions due to a higher passive permeability than the distal colonY In distal regions, Na+ absorption is predominantly electrogenic. 51 This is a consequence of the distal colonic epithelium being generally "tighter" or of higher resistance. 49 In the rat, however, the Na + absorption in the proximal and distal colon is entirely electroneutral,4 and in the human distal colon, the Na + absorption is electrogenic. 23 The ion transport mechanisms in the canine colon are poorly elucidated. In a series of unpublished studies (V. E. Rolfe, unpublished observations, 1998), colonic transport was assessed in vivo by placing
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Table 1. CHANGES 1N COLONIC TRANSPORT OF WATER AND ELECTROLYTES*
Transport
Fluid transport (mL/h) Na + (mEq/L/h) K+ (mEq/L/h) o- (mEq/L/h) Hco- 3 (mEq/L/h) pH (U/h)
Health (mean± SEM)
-2.35 - 62.04 3.22 -57.48 0.14 0.35
± ± ± ± ± ±
0.53 23.57 3.28 23.71 0.07 0.05
Dietary Sensitivity (mean± SEM)
-0.94 -25.18 1.48 -27.45 -0.35 0.36
± 0.33t ± 10.84t ± 0.65
± 10.87t ± 0.03 ± 0.10
*Measured by inserting dialysis bags into the lumen of six healthy dogs and six dogs with dietary sensitivity. A negative value represents absorption from the lumen of the colon. Comparisons were made between healthy dogs and dietary-sensitive dogs. tP <0.05, Student's t test (V.E. Rolfe, unpublished data, 1998).
dialysis bags into the lumen of the colon containing the following concentrations of ions (mEq/L): 147 Na +, 5 K +, 25 HC03 -, 135 CI-, 2.4 SOl-, 1.2 Mg2 +, 1.2 Ca2 +, 1.2 H 2 POl-. Changes in ion transport were assessed by an electrolyte analyzer after the bags had remained in the colon for 1 hour. In healthy dogs, Na + and CI- were absorbed from the luminal contents, although K + and HC03 - were secreted (Table 1). In terms of electroneutral or electrogenic ion transport processes, the mechanisms are not clear. Other electrolytes present in the colon at high levels also have an influence on colonic ion transport. Short chain fatty acids (SCFAs) are products of bacterial fermentation that are absorbed by the colon and often utilized by the epithelial cells as an energy source. The human colon preferentially absorbs butyrate above propionate and acetate. 10 In the canine colon, the rates of acetate, propionate, and butyrate absorption are similar. 24 It is not clear whether SCFAs are absorbed by electrogenic or electroneutral processes; again, there are likely to be dramatic species and regional differences. Research has shown that SCFAs enter the cell by nonionic diffusion, being transported across the apical membrane in a protonated form (SCFAH) before dissociating into SCFA- and H + inside the cell. The H + recycles back into the lumen in exchange for Na+. In dogs, the absorption of SCFAs are Na+ dependent/4 but in humans, there may be a relationship between SCFA and HC03 - uptakeY In a recent study, a carrier protein was identified on the intestinal epithelium which was involved in the transport of butyrate. 40 Colonic Water Transport
Approximately 90% of fluid entering the colon is reabsorbed across the mucosa; thus, the colon plays an important role in fluid and electrolyte homeostasis. The uptake of Na+ from the lumen creates a hypertonic environment in the interstitial fluid surrounding the crypts. This generates a steep electrochemical gradient across the colonic mucosa, which
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drives the uptake of water from the luminal contents by osmosis. 38 In rats and sheep, which form solid feces, the Na + gradient is steep across the crypt as indicated by the high-intensity accumulation of Na+-sensitive fluorescent dyes in the interstitial fluid. In the cow, where feces is less solid, Na + gradients are reduced in magnitude. 38 The production of a near isotonic absorbate surrounding the bovine crypts is due to a high rate of transepithelial salt leakage. 34 This explains why the bovine colon is incapable of producing hard feces, and these data suggest that the dissipation of electrochemical gradients across the mucosa may be an important feature of diarrheal disease. The pathway for water uptake across the colonic mucosa is likely to be transcellular, with a water channel protein CHIP28 located on colonic epithelial cells in the rat,ZZ which is composed of an integral protein of 28 kDa. 57 Whether dysfunction of the water channel protein results in diarrheal disease is not known. Regulation of Colonic Transport Function
The opening and closing of cell membrane channels and the activation of cell transport components are controlled by intracellular messengers. These include cyclic adenosine monophosphate, cyclic guanosine monophosphate, calcium (Ca 2 +), calmodulin, phosphatidylinositol metabolites, and G-proteins. These intracellular mediators are triggered by neurohumoral signals in order to regulate colonic transport function in health and disease. A multitude of hormones and neurotransmitters influence colonic ion transport as outlined in a review by HubeP7 Table 2 summarizes
Table 2. SUMMARY OF INTESTINAL HORMONES AND NEUROTRANSMITTERS THAT STIMULATE ABSORPTION AND SECRETION Substance
Proabsorptive substances Aldosterone Glucocorticoids Noradrenaline Adrenaline Enkephalins Somatostatin Prosecretory substances Acetyl choline Vasoactive intestinal polypeptide 5-Hydroxytryptamine Prostanoids Guanylin Nitric oxide
Action
Sodium and water absorption30 Sodium absorption56 Sodium chloride absorption14 Water absorption26 Sodium chloride absorption 12 Reduces chloride secretion11 Chloride secretion54 Water secretion55 Chloride secretion58 Chloride secretion60 Chloride secretion29 Sodium secretion9 Chloride secretion33
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some of the hormones and neurotransmitters that influence colonic absorption and secretion, but the list is by no means exhaustive. A host of inflammatory mediators, including cytokines, prostanoids, nucleotides, reactive oxygen metabolites, biogenic amines, and immunoglobulins, influence intestinal transport as part of gut immunity. 37 These mediators are released in response to luminal antigen or in defense against noxious substances, and they stimulate water secretion to flush the irritant from the host.
Organization of Enteric Reflexes
Local neural reflexes control transport function by monitoring the physical and chemical nature of the luminal contents. Mucosal sensory fibers respond to mechanical stimuli8 and chemical stimuli43 by altering fluid and electrolyte transport. It was initially thought that intestinal electrolyte transport was regulated by enteric nerves that were routed through the submucosal plexus (situated adjacent to the circular smooth muscle layer). Many experiments were carried out on intestinal sheets that had the longitudinal muscle and myenteric plexus removed. Recent evidence, however, has shown that the myenteric plexus is also involved in the integration of mucosal transport function, mediating secretory responses induced by luminal glucose in the rat jejunum50 as well as Escherichia coli heat-stable enterotoxin43 and 5-hydroxytryptamine44 in the rat ileum. These sophisticated neural networks convey signals from local sensory fibers via intrinsic and extrinsic nerves to control both local and systemic physiological responses. 3' 42 Ashton et aF found that the gastrointestinal tract communicates with the central nervous system to coordinate digestive functions in dogs, with colonic fluid and electrolyte absorption in perfused colonic loops increasing after the ingestion of food.
COLONIC TRANSPORT IN DISEASE: DIETARY SENSITIVITY Frothiness of the stools in certain cases of diarrhoea is due to substances flowing down from the head. HIPPOCRATES, 450
BC31
Dietary sensitivity is an adverse reaction to food that may be either immune-mediated (food hypersensitivity) or not (food intolerance). Many dogs are referred to veterinary clinics with diarrhea that may be caused by adverse food reactions. 47 Furthermore, some studies suggest
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that dietary sensitivity may exacerbate other diseases of the gastrointestinal tract, including lymphocytic-plasmacytic colitis in German Shepherd dogs/5 canine eosinophilic gastroenteritis/ 6 and some cases of colitis. 36 There are numerous causes of dietary sensitivity, including allergens such as meat, dairy, and cereal proteins as well as toxic compounds that are often ingested as a result of indiscriminate feeding by the dog. Despite the wide array of potential trigger substances, the repertoire of pathophysiological responses in the colon is limited and largely involves the infiltration of immune cells into the colonic mucosa, causing a local inflammatory response. Because the pathophysiological mechanisms underlying diarrhea in dietary sensitivity are unknown, a study was carried out to assess the structural and functional features of the colon in dogs with dietary sensitivity in comparison to healthy age- and weight-matched controls. Dietary sensitivity was diagnosed in dogs if they had diarrhea after being fed a range of diets but showed no signs of clinical disease. The diarrhea disappeared after changing the diet but resumed when the original diet was reintroduced. It is not clear what in the diet the dogs were sensitive to, but the trigger may include dietary allergens from meat, dairy, or cereal components or irritants such as some gelling agents. Colonic transport function was assessed in vivo using dialysis bags. The colonic absorption of water, Na + and Cl- was significantly reduced in dogs with dietary sensitivity compared to healthy controls (see Table 1 and V. E. Rolfe, unpublished data, 1998). An in vitro study in humans also demonstrated that inflammatory diarrhea was associated with impaired NaCl absorption and active Cl- secretion. 28 These data demonstrate that loss of absorptive function is an important factor underlying diarrhea in the dietary-sensitive dog. The mechanisms underlying the failure of colonic absorption were investigated further by obtaining colon samples at endoscopy. Colon samples were fixed in formalin, stained for F-actin with BODIPY phallacidin (Molecular Probes Europe BV, Leiden, The Netherlands), and visualized using a digital confocal microscope system (Improvision Inc., Boston, MA). In healthy dogs, the epithelial barrier was well maintained (see Fig. 1), although in dogs with dietary sensitivity, the continuity of the epithelium was disrupted with an increase in cell sloughing (Fig. 2). The resultant increase in permeability may reduce the absorptive capacity of the colon or facilitate the translocation of luminal allergen into the lamina propria, triggering the immune system inappropriately. Another important feature of the colonic mucosa in dogs with dietary sensitivity was an increase in the numbers of lymphocytes and plasmacytes in the lamina propria as identified in longitudinal sections stained with hematoxylin and eosin. The infiltrating immune cells may release inflammatory mediators into the mucosa, resulting in tissue damage and impaired transport function. 32• 53 Studies have shown that infiltrating inflammatory cells such as neutrophils migrate through the
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Figure 2. Surface structure of colon from a dog with dietary sensitivity. The colon is stained for F-actin with BODIPY phallacidin (Molecular Probes, Leiden, The Netherlands). Image obtained by digital confocal microscopy (lmprovision Inc., Boston, MA, original magnification x 100). The continuity of the epithelium is disrupted (unpublished obseNation, 1998}.
epithelial tight junctions, disrupting barrier function and increasing mucosal permeability. 13• 35 This would lead to the dissipation of electrolyte concentration gradients and the failure of colonic absorption. In dogs with dietary sensitivity, there were increased levels of nitrite in the colonic mucosa, indicating that nitric oxide (NO) was involved in the pathogenesis of diarrheal disease (healthy colon, 0.014 ± 0.001 vs inflamed colon, 0.038 ± 0.001 [micro] Eq/L/pg of protein; n = 6; P < 0.05 Student's t test; unpublished data, 1998). The NO may reduce colonic absorption by two mechanisms, First, by stimulating cyclic guanosine monophosphate-dependent electrogenic c- secretion/6 and second, by increasing tight junction permeability. 48 The overproduction of NO is involved in epithelial barrier dysfunction/ and NO has been implicated in the pathogenesis of inflammatory bowel disease with levels of inducible NO synthase gene expression increased in human patients.39 More recently, Gunawardana et aF0 demonstrated that nitrite levels in colonic lavage fluid were significantly increased in d ogs with inflammatory bowel disease compared to healthy controls, indicating that NO may play a role in inflammatory bowel disease and provide a novel approach to treat the condition in dogs. Inflammation of the colon also disrupts motility in dogs, with deranged segmenting and propulsive contractile activity. 52 Because the transit time of the luminal contents through the colon greatly influences the absorptive capacity of the mucosa,21 diarrheal disease may also be a
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consequence of impaired motility, but it is not yet clear whether this is the case in dogs with dietary sensitivity. CONCLUSIONS A north wind brings constipation. HIPPOCRATES, 450
BC31
The mechanisms underlying colonic transport function in health and disease involve cellular transport components that are regulated by a multitude of neurohumoral signals. In the canine colon, Na and Cl are absorbed, and K and HC03 are secreted. Information extrapolated from other species must be interpreted cautiously due to interspecies variation and regional differences in transport along the length of the colon. The colon actively absorbs Na against a steep electrochemical gradient, causing water uptake by osmosis and fecal dehydration. In some diseases of the colon, the absorptive function may be impaired by disruption to the epithelial barrier integrity and defects in mucosal immunoregulation. Novel nutrient and therapeutical interventions aimed to restore barrier function, reduce inflammatory cell infiltration, and suppress the release of inflammatory mediators may be beneficial in the management of diarrhea in dogs with nonspecific dietary hypersensitivity and inflammation of the colon. For example, supplementation of the diet with fish oil improved epithelial integrity in murine inflammatory bowel disease. 45 Diets enriched with fiber may also be beneficial in the treatment of inflammatory diarrhea by increasing fecal bulk and improving contractility. 6 Fiber also releases fermentation products such as butyrate, which provide an energy source for the epithelium and have been demonstrated to be beneficial in the treatment of colitis in humans. 5 References 1. Alican I, Kubes P: A critical role for nitric oxide in intestinal barrier function and
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