Introduction
Perhaps no other organ system is so directly and immediately affected by nutrition than the gastrointestinal tract. Timing and frequency of feeding, route of feeding, macronutrient and micronutrient compositions of the diet have profound influences on oral and intestinal health. In addition to the direct effect of diet on the body, there is a considerable indirect effect through dietary influences on the intestinal microflora. However, there are few controlled clinical trials that have evaluated specific dietary manipulation in either prevention or management of canine and feline gastroenteric diseases. Acute gastroenteritis is a common reason for presentation of cats and dogs to veterinarians. Common causes include bacterial toxin ingestion (e.g., staphylococcal enteritis), bacterial endotoxin production (e.g., Clostridium perfringens enteritis), viral enteritis (e.g., rotavirus, coronavirus, parvovirus), self-limiting infections (e.g., Cryptosporidium felis and parvum, Coccidia spp), and adverse reactions to food. Because of the transient and non-life threatening nature of many cases, the cause of the majority remains undetermined. Despite ignorance of the exact cause, standard therapy is instigated, of which, dietary management remains the cornerstone. Standard dietary recommendations for dogs and cats with acute gastroenteritis have been to withhold food for 24-48 hours, followed by the introduction of small quantities of a "bland" diet fed 4-6 times per day for 3-7 days. These dietary recommendations have stood the test of time but are based on common assumptions rather than any specific research. Arguments offered in support are that withholding food provides bowel rest, reduces the risk of vomiting, increases bacterial proliferation and fermentation, and produces osmotic diarrhoea. However, such arguments can be rebutted, or satisfied by optimal feeding. Thus, the long-held belief in the value of bowel rest for the treatment of diarrhoea has been challenged by the benefits of "feeding-through" diarrhoea. Recent studies of acute diarrhoea in several species have shown that feeding through diarrhoea maintains greater mucosal barrier integrity.
Benefits of Luminal Nutrition in Acute Enteritis
Even in the absence of enteritis, fasting for even as short a period as one day in rats causes a significant decrease in villous height and/or crypt depth in jejunum, ileum, and, to a lesser extent, colon.1,2 In addition, fasting is associated with gut mucosal cell impairment marked by decreased levels of reduced glutathione (GSH), the major intracellular antioxidant, enhanced permeability to macromolecules, increased bacterial translocation from the lumen, and increased rates of enterocyte apoptosis.3 Even with total parenteral nutrition, after 14 days of oral fasting in cats, small intestinal villous atrophy, fusion, and infiltration of the lamina propria with lymphocytes, plasma cells, and neutrophils occurs.4 Thus, oral fasting alone, and in the absence of nutritional deficiency, induces an intestinal insult.
Fasting also significantly reduces the specific activity and expression of certain digestive enzymes in the small bowel mucosa such as disaccharidases, which can lead to impaired digestion following the re-introduction of food.5 Transient lactase deficiency is common, particularly after rotavirus gastroenteritis.6 Occasionally it persists, and lactose intolerance may be a cause of post-gastroenteritis diarrhoea. Gastric and pancreatic secretions are markedly reduced following a period of under-nutrition.7 Generalized malnutrition, protein depletion, or deficiencies of specific nutrients, including essential fatty acids, folate, zinc, vitamin A, and vitamin B12 inhibit the growth and turnover of the intestinal mucosa. It has long been recognized that small intestinal enterocytes utilize luminally-derived glutamine as their main oxidative fuel (see above). In addition, glutamine provides the carbon skeleton and amino nitrogen required for purine synthesis and hence is critical for normal DNA synthesis involved in enterocyte turnover. Oral supplementation with zinc improves histological recovery, normalizes absorption, decreases permeability, and decreases NF-κB nuclear binding in experimental models of diarrhoea.8,9 Additional mechanisms for the effect of zinc treatment on the duration of diarrhoea include improved absorption of water and electrolytes, increased levels of brush border enzymes, and faster regeneration of the intestinal epithelium. Multiple factors, including luminal nutrients, pancreaticobiliary secretions, and humoral agents have been implicated in controlling the intestinal adaptive response after an intestinal insult. Despite the multifactorial regulation of intestinal adaptation, luminal nutrients are fundamental to the adaptive response such that recovery is minimized or prevented in the absence of luminal nutrients. This conclusion is largely based on studies that show significant adaptive intestinal re-growth in rats and dogs fed orally compared with those fed parenterally following an intestinal resection. Indeed even in the absence of an intestinal insult, total parenteral nutrition (TPN) causes dramatic intestinal atrophy in dogs, cats, rats and humans.4,10,11 This fasting-induced atrophy is accompanied by inflammatory cell infiltrates in the lamina propria, increased intestinal permeability, and increased bacterial translocation.
It has long been known that the immunological derangements that accompany malnutrition cannot all be prevented when nutrients are delivered parenterally.12 A lack of luminal nutrients results in an increased expression of proinflammatory adhesion molecules, especially ICAM-1.13 This results in an increased number of primed neutrophils adhered to the microvasculature throughout the intestinal tract where they are able to contribute to oxidative and enzymatic tissue damage following activation. Fasting or TPN results in decreases in IL-4 and IL-10 that correlate with decreases in IgA and increases in ICAM-1.14 Lack of enteral feeding impairs the coordinated system of sensitization, distribution, and interaction of T and B cells important in the production of IgA, in the maintenance of normal gut cytokines, and in the regulation of endothelial inflammation.2,10,15,16 Thus the lack of luminal nutrients has been described as a "first hit", and increases the inflammatory response to a secondary insult in the GIT, but also the lungs, liver, and potentially other organs as well.
The amino acid glutamine reverses many of these defects and favourably influences the proinflammatory effects of gut starvation.17 The source of supplemental glutamine can influence gut mucosal glutamine concentrations, suggesting differences in its availability or utilization. Glutamine-rich intact proteins appear to be more effective in increasing mucosal glutamine content than glutamine-enriched solutions.18 Arginine is an essential amino acid for cats because of their inability to synthesize sufficient quantities in the fasting state. However, beyond its role as an essential intermediate in the ornithine cycle, dietary arginine has long been known to enhance certain aspects of immunity.
Even short periods of enteral fasting result in an increase in intestinal permeability in humans.19 Early refeeding of dogs and cats with acute gastroenteritis has been shown to reduce the increase in intestinal permeability that occurs in response to the inflammation and apoptosis.18,20 Some of the effect of luminal feeding may come from the luminal provision of glutamine alone, which can restore enterocyte glutathione concentrations, proteins synthesis, and normalise intestinal permeability. Even in single layer cell cultures of enterocytes, the application of glutamine to the apical (luminal) membrane normalises permeability to a large molecular weight molecule, whereas applying glutamine to the basal membrane (simulating parenteral nutrition) does not.21
Veterinary Evidence and Recommendations
The effect of early enteral nutrition has been evaluated in dogs with severe parvoviral enteritis and in cats with severe mucosal damage from methotrexate toxicity. Early enteral nutrition in canine parvovirus reduced the time for normalization of demeanour, appetite, vomiting, and diarrhoea, increased bodyweight, and may have improved mucosal permeability compared with the traditional approach of fasting until resolution of vomiting.20 In methotrexate-induced enteritis, feeding a complex diet abrogated the proximal small intestinal atrophy and bacterial translocation associated with feeding an amino acid-based purified diet, and was associated with a marked attenuation of the clinical signs associated with the toxicity.18 In contrast, when dogs that presented with severe haemorrhagic gastroenteritis were fed a commercial dry hydrolyzed protein diet soon after presentation, there was an initial increase in the frequency of vomiting, despite being fed at below maintenance rates.22 Thus, early reintroduction of feeding does not seem to exacerbate disease even in severely affected animals, and complex diets appear to be superior to purified diets in some models. Clinicians must make individual decisions about the risks and benefits of feeding in patients with persistent vomiting.
It can be seen then that not only can the traditional concerns of feeding in acute gastroenteritis be allayed, but there are considerable arguments for not delaying feeding at all. However, it is unlikely that attempting to feed the daily maintenance energy requirements (MER) is a sensible approach in the short-term management of dogs and cats suffering from acute diarrhoea, and certainly not in cases of frequent vomiting. Therefore, if only 25% of the animals resting energy requirements (RER) is fed as a highly digestible, low fat diet, mucosal recovery may be optimized, and exacerbation of diarrhoea or vomiting minimized. This has led to the concept of "minimal luminal nutrition". At the current point of understanding, the ideal dietary characteristics would be:
High digestibility. This is easier to recommend than it is to specifically practice. Most commercial premium dry diets would qualify, as would many home-prepared ingredients. For protein sources, cooked fresh chicken or fish, cottage cheese, or egg would qualify. Cooked white rice or potato are suitable carbohydrate sources, although rice may be superior (see below). Commercially canned diets generally have a lower digestibility than dry diets, often have a high fat or viscous fibre content, and thus cannot be recommended over a similar dry product. However, there is no evidence that the difference in digestibility has any clinically measurable consequences.
Low fat. No fat-titration studies have been performed to guide firm recommendations. However, a pragmatic recommendation would be to choose the lowest fat content available. An almost arbitrary cut off of 20% of ME could be made.
Novel antigen content. For acute gastroenteritis, strict adherence to protein novelty is not prioritized over other considerations, and simple avoidance of the staple dietary protein sources of the particular patient is prudent, without being excessive. Some hydrolyzed protein diets are also excellent choices.23
Dietary fibre content. Some fermentable fibre is almost always beneficial, whilst excessive contents can exacerbate delayed gastric emptying, diarrhoea, flatulence, and abdominal pain. An empirical recommendation is to select diets that contain less than 8% dietary fibre, or less than 5% crude fibre.
Initial feeding should not exceed 25% of the calculated RER, divided into 3 feeds per day. This amount can be rapidly increased with clinical improvement.
Few commercial diets are currently available that could be considered ideal in all respects for acute non-specific gastroenteritis and commercial formulations change such that firm recommendations cannot be made. Most commercial diets both provide significantly more fat (> 25% of ME), but are complete and balanced. In addition, when feeding as little as 25% of RER, it is unlikely that the fat content will be sufficient to exacerbate vomiting or diarrhoea, if less than 30% of ME is composed of fat. The evaluation of diets formulated around protein hydrolysates such as Hill's z/d, Nestle-Purina HA, and Royal Canin Hypoallergenic, warrants further study. Despite the greater than ideal fat content, the combination of high digestibility and reduced antigenicity make them attractive options for the management of acute gastroenteritis.
References
1. Ziegler TR, Evans ME, Fernandez-Estivariz C, et al. Trophic and cytoprotective nutrition for intestinal adaptation, mucosal repair, and barrier function. Annu Rev Nutr 2003;23:229-261.
2. Kudsk KA. Effect of route and type of nutrition on intestine-derived inflammatory responses. Am J Surg 2003;185:16-21.
3. Jonas CR, Estivariz CF, Jones DP, et al. Keratinocyte growth factor enhances glutathione redox state in rat intestinal mucosa during nutritional repletion. J Nutr 1999;129:1278-1284.
4. Lippert AC, Faulkner JE, Evans AT, et al. Total parenteral nutrition in clinically normal cats. J Am Vet Med Assoc 1989;194:669-676.
5. Holt PR, Yeh KY. Effects of starvation and refeeding on jejunal disaccharidase activity. Dig Dis Sci 1992;37:827-832.
6. Zijlstra RT, Donovan SM, Odle J, et al. Protein-energy malnutrition delays small-intestinal recovery in neonatal pigs infected with rotavirus. J Nutr 1997;127:1118-1127.
7. Winter TA. The effects of undernutrition and refeeding on metabolism and digestive function. Curr Opin Clin Nutr Metab Care 2006;9:596-602.
8. Altaf W, Perveen S, Rehman KU, et al. Zinc supplementation in oral rehydration solutions: experimental assessment and mechanisms of action. J Am Coll Nutr 2002;21:26-32.
9. Sturniolo GC, Di LV, Ferronato A, et al. Zinc supplementation tightens "leaky gut" in Crohn's disease. Inflamm Bowel Dis 2001;7:94-98.
10. Renegar KB, Johnson CD, Dewitt RC, et al. Impairment of mucosal immunity by total parenteral nutrition: requirement for IgA in murine nasotracheal anti-influenza immunity. J Immunol 2001;166:819-825.
11. Thor PJ, Copeland EM, Dudrick SJ, et al. Effect of long-term parenteral feeding on gastric secretion in dogs. Am J Physiol 1977;232:E39-43.
12. Dionigi R, Ariszonta, Dominioni L, et al. The effects of total parenteral nutrition on immunodepression due to malnutrition. Ann Surg 1977;185:467-474.
13. Fukatsu K, Lundberg AH, Hanna MK, et al. Route of nutrition influences intercellular adhesion molecule-1 expression and neutrophil accumulation in intestine. Arch Surg 1999;134:1055-1060.
14. Fukatsu K, Kudsk KA, Zarzaur BL, et al. TPN decreases IL-4 and IL-10 mRNA expression in lipopolysaccharide stimulated intestinal lamina propria cells but glutamine supplementation preserves the expression. Shock 2001;15:318-322.
15. Ikeda S, Kudsk KA, Fukatsu K, et al. Enteral feeding preserves mucosal immunity despite in vivo MAdCAM-1 blockade of lymphocyte homing. Ann Surg 2003;237:677-685; discussion 685.
16. Johnson CD, Kudsk KA, Fukatsu K, et al. Route of nutrition influences generation of antibody-forming cells and initial defence to an active viral infection in the upper respiratory tract. Ann Surg 2003;237:565-573.
17. Kudsk KA, Wu Y, Fukatsu K, et al. Glutamine-enriched total parenteral nutrition maintains intestinal interleukin-4 and mucosal immunoglobulin A levels. JPEN J Parenter Enteral Nutr 2000;24:270-274; discussion 274-275.
18. Marks SL, Cook AK, Reader R, et al. Effects of glutamine supplementation of an amino acid-based purified diet on intestinal mucosal integrity in cats with methotrexate-induced enteritis. Am J Vet Res 1999;60:755-763.
19. Hernandez G, Velasco N, Wainstein C, et al. Gut mucosal atrophy after a short enteral fasting period in critically ill patients. J Crit Care 1999;14:73-77.
20. Mohr AJ, Leisewitz AL, Jacobson LS, et al. Effect of early enteral nutrition on intestinal permeability, intestinal protein loss, and outcome in dogs with severe parvoviral enteritis. J Vet Intern Med 2003;17:791-798.
21. Le Bacquer O, Laboisse C, Darmaun D. Glutamine preserves protein synthesis and paracellular permeability in Caco-2 cells submitted to "luminal fasting". Am J Physiol Gastrointest Liver Physiol 2003;285:G128-136.
22. Will K, Nolte I, Zentek J. Early enteral nutrition in young dogs suffering from haemorrhagic gastroenteritis. J Vet Med A Physiol Pathol Clin Med 2005;52:371-376.
23. Cave NJ. Hydrolyzed protein diets for dogs and cats. Vet Clin North Am Small Anim Pract 2006;36:1251-1268, vi.