Equine gastric ulcer syndrome is a disease of the equine stomach and is found worldwide. It is indicated by the presence of lesions in the stomach lining, that can range from hyperkeratosis or hyperaemia and erosions to ulcers depending on the part of the organ affected and on the severity of the condition. The term was first used in 1999 by the Equine Gastric Ulcer Council and since then, two different diseases have been identified and described: one affecting the squamous mucosa (equine squamous gastric disease) and one affecting the glandular mucosa (equine glandular gastric disease). Equine squamous and gastric disease are now considered two different diseases, with separate pathophysiological causes, prevalence and treatment options (Sykes et al, 2015a; Rendle et al, 2018). This review provides an update on the current knowledge about treatment and management of squamous gastric disease in adult horses.
Anatomy and physiology of the stomach
The horse is a monogastric species, with a small stomach compared to its size. The gastric lining has two different portions: one dorsal, with a stratified squamous epithelium, without any absorptive or secretive capacity, and one ventral, with a glandular mucosa that secretes mucus and hydrochloric acid continuously, without the influence of food. This means that there is acidic pH in the lower part of the stomach, near the glandular mucosa, while the upper part, the one lined by the squamous part, has a higher pH, with more variations during the day. Food has a huge influence on the pH of the stomach content in the upper part, where the presence of fibre can increase the pH for several hours after feeding. The pH of the glandular mucosa is more stable throughout the day, with minimal or no influence of the food (Hewetson and Tallon, 2021).
Equine squamous gastric disease
Equine squamous gastric disease is indicated by the presence of lesions in the squamous gastric mucosa (Sykes et al, 2015a). The prevalence, pathophysiology and risk factors are well established for this disease. Lesions are caused by an exposure of the squamous mucosa to the acidic environment of the stomach: protective factors in this area are lacking, because of the reduced blood supply and the absence of the mucus–bicarbonate layer, and are limited to the physical barrier provided by thick keratinised epithelium, high electrical resistance, tight epithelial junctions and osmophilic surfactant layer. Exposure to an acidic environment can rapidly overcome this physical barrier, causing lesions. These can range from hyperkeratosis (ie a thickening of the keratinised layer, with yellowing of the mucosa) to erosions (if the injury does not reach the lamina propria) to ulcers, when the injury goes beyond the lamina propria (Hewetson and Tallon, 2021). Risk factors commonly associated with squamous gastric disease are usually related to the management, such as trainers, high amount of starch in the diet and lower number of feedings per day, performing high-intensity exercise and longer periods in training (Sykes 2019; Busechian et al, 2021; van den Boom, 2022). Prevalence has been described in various kinds of horses, with the highest prevalence found in racehorses in training and endurance horses during competition season; asymptomatic pleasure horses and breeding mares at pasture can also be affected (le Jeune et al, 2009; Niedźwiedź et al, 2013; van den Boom, 2022). Clinical signs are vague and nonspecific: recurrent colic, poor performance, low body condition score and ill thrift are usually associated with this condition, but correlation between clinical signs and gastroscopic findings is not always possible, and many horses with squamous gastric disease do not show symptoms (Busechian et al, 2021; van den Boom, 2022; Vokes et al, 2023).
Diagnosis is based on gastroscopic examination, and severity of the disease can be described using a recognised scoring system (Table 1). The correlation between grading scores and clinical signs is not completely understood, especially for lower grades (1–2). Some studies consider hyperkeratosis as the first response of the mucosa to the acid environment, and a return to grade 1 has been considered healing when evaluating the effectiveness of omeprazole treatment (Sykes et al, 2015b). However, other anecdotal reports showed the disappearance of clinical signs in horses with grade 1 squamous gastric disease when treated with omeprazole (Sykes et al, 2015a; Hewetson and Tallon, 2021).
| Grade | Description |
|---|---|
| 0 | Intact epithelium, without hyperkeratosis |
| 1 | Intact mucosa, but hyperkeratosis present |
| 2 | Small, single or multifocal lesions |
| 3 | Large, single or extensive superficial lesions |
| 4 | Extensive lesions with deep ulceration |
Other tests have been proposed, but their low specificity and sensitivity leaves them as only screening tests. Haematological and biochemical results are not indicative of gastric disease, but a cross-sectional study on Thoroughbred racehorses found an increase in serum alkaline phosphatase and creatinine concentrations in horses with squamous ulcers (Vatistas et al, 1999). Blood and urine sucrose levels have also been found to be related to the presence of gastric lesions, but the diagnostic accuracy of these tests is low (O'Conner et al, 2004; Hewetson et al, 2006; 2017). Detection of faecal occult blood with a commercially available test is considered unreliable for the diagnosis of equine gastric ulcer syndrome because of a lack of association between the presence of gastric lesions and faecal albumin or haemoglobin (Sykes et al, 2015a).
Management of equine squamous gastric disease
Pharmacological treatment
Proton pump inhibitors are the mainstay of therapy for equine squamous gastric disease (Table 2). They are delivered as prodrug and, after being activated by acid, they bind irreversibly to the hydrogen/potassium adenosine triphosphatase pump of the gastric parietal cells, blocking the last step in acid production and thus increasing the pH of the stomach content and creating a good environment for ulcer healing (Shin and Kim, 2013; Ahmed and Clarke, 2023). Oral omeprazole is currently the only registered medication for the treatment and prevention of gastric ulcers in horses in various countries.
| Pharmacological treatment |
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| Dietary changes |
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| Exercise and management strategies |
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Omeprazole is acid labile, so it should be protected from the acid environment of the stomach and reach the small intestine to be absorbed in amounts sufficient to be effective. It has been demonstrated that plain formulations (those without gastroprotection) have low bioavailability and effectiveness compared to those with gastroprotection (Sykes et al, 2015c; Wise et al, 2021). All other ‘protected’ formulations have similar pharmacokinetics, pharmacodynamic profiles and healing rates. Different oral formulations are currently marketed; some use a buffered medium for delivering the prodrug to the small intestine, while in others, omeprazole is encapsulated in a gastroresistant medium (Andrews et al, 1999; Birkmann et al, 2014; Raidal et al, 2017; Wise et al, 2021; Busechian et al, 2023).
The recommended dose, irrespective of the formulation, is 4 mg/kg once daily for at least 3 weeks (Sykes et al, 2015a). A number of studies have investigated different doses for the treatment of gastric ulcers: they demonstrated that both lower (1 mg/kg or 2 mg/kg) and higher doses (the recommended 4 mg/kg) could be effective for the treatment of squamous gastric disease, but higher doses were generally associated with more consistent response and better healing rates depending on the formulation used. Gastroresistant formulations, especially, being more protected from the acid environment of the stomach, could be used at lower dosages (1 mg/kg) (Sykes et al, 2015b; Sykes, 2019). A gastroscopy should be repeated before the end of the treatment, to evaluate the healing of the mucosa (van den Boom, 2022; Vokes et al, 2023).
Healing rates for equine squamous gastric disease range from 67–92%, depending on the formulation used, the population of animals investigated and the conditions in which the omeprazole is given (fed or fasted, distance from exercise, etc) (Sykes et al, 2015a; Hewtson and Tallon, 2021). Even among racehorses, the population most commonly investigated, the response to treatment is variable, and it seems that the type of formulation, in particular the use of gastroprotected omeprazole, is the most important determinant of the response to treatment (MacAllister et al, 1999; Doucet et al, 2003; Lester et al, 2005; Gough et al, 2020; Wise et al, 2021; Busechian et al, 2023b). In one paper where the response to treatment was the lowest reported in the literature (Gough et al, 2020), both plain and buffered paste were used and combined in the analysis. It is not possible to determine if the type of formulation or the type of population (mixed horses from an equine hospital) was the reason for this low response.
The diet and feeding status of the horse has an effect on the pharmacokinetics and pharmacodynamic variables of omeprazole. Studies have evaluated the effect of feeding ad libitum hay on the bioavailability of the drug; gastroresistant formulations seem to be less influenced by the feeding status of the horses. For buffered formulations, a higher area under the curve and consequently higher duration and magnitude of acid suppression (that seems to be determined primarily by the area under the curve), were found when the drug was administered after a period of withholding food (Daurio et al, 1999; Sykes et al, 2015c). Current recommendations indicate that, irrespective of the formulation, omeprazole should be administered in the morning, at least 30 minutes before feeding and after an overnight fasting period (Vokes et al, 2023).
Few studies have evaluated the effect of exercise on omeprazole administration in Thoroughbreds: one paper showed that a gastroresistant formulation at a dose of 1 mg/kg increases the gastric pH similarly to higher doses if it is administered before exercise (Sykes et al, 2015b). A second study failed to demonstrate a difference in the response to treatment when the omeprazole was administered before or after training (Sykes et al, 2014).
Studies have also considered the use of oral omeprazole for the prevention of gastric ulcers, especially in populations considered at risk for the disease, such as racehorses in active training. It was found that 1 mg/kg and 2 mg/kg for 4 weeks were effective at preventing the development of gastric lesions compared to placebo preparations (Andrews et al, 1999; McClure et al, 2005a; 2005b; White et al, 2007; Endo et al, 2012; Mason et al, 2019). Omeprazole is regulated in racehorses and its administration on racing days is forbidden. According to one study, detection time was 48 hours after oral administration of 4 mg/kg of a buffered formulation, and the authors suggested a withdrawal time of 72 hours in racehorses (Viljanto et al, 2018). However, a 2-day withholding period for omeprazole was associated with a recurrence of squamous gastric disease in Thoroughbreds in a racing setting; in the same study, a protective effect was demonstrated for a nutraceutical supplement (Shan et al, 2023).
Similar findings were described in a study on Thoroughbreds, where healing rate of omeprazole-treated horses was lower than previously reported; in this population, withdrawal period for omeprazole before racing was 5 days (Kerbyson et al, 2016). A prolonged effect of omeprazole on gastrin and chromogranin A (an indirect measurement of the density of enterochromaffin-like cells that release histamine and, consequently, gastric acid) could not be found, so a tapering protocol is not needed at the end of the therapy (Clark et al, 2023). However, a change in management or the use of nutraceutical supplements is warranted, especially in the 24–48 hours after discontinuation of treatment, to prevent recurrence secondary to transient rebound gastric hyperacidity (Clark et al, 2023). Oral omeprazole is considered safe, but studies in human and equine medicine indicate possible side effects that should be considered, especially in horses that are treated for prolonged periods of time (more than 60–90 days) (Sykes, 2021). Despite having no detectable effect on gastric and faecal micro-biota (Tyma et al, 2019; Cerri et al, 2020), the concurrent administration of omeprazole and phenylbutazone was associated with an increased risk of intestinal complications, from small and large colon impaction to severe inflammatory conditions of the large intestine (Ricord et al, 2021).
In human medicine, prolonged administration of omeprazole has been associated with increased risk of fractures in various age groups (Sykes, 2021). The same has not been yet described in horses, but one study detected a decrease in the calcium digestibility in Thoroughbreds, advising that calcium levels should be increased in the diet of animals treated with omeprazole (Pagan et al, 2020).
Rand et al (2011) investigated the rectal route for the registered oral omeprazole (4 mg/kg every 24 hours for 5 days), especially for horses who were not able to receive oral medications (because of nasogastric reflux, dysphagia etc). They found that the drug has poor availability and the effect on gastric pH was variable, with different values in different animals.
A new formulation of long-acting injectable omeprazole has been marketed in some countries. Studies on this medication are quite promising: the drug can be administered intramuscularly once a week at 4 mg/kg, with healing rates of up to 97% after four injections (Sykes et al, 2017b; Sykes, 2019; Gough et al, 2020; Lehman et al, 2022; Sundra et al, 2024). A recent study compared the efficacy of administering the medication every 5 or 7 days on the healing of gastric ulcers; no difference was found for squamous gastric disease, while glandular gastric disease responded better with a 5-day interval of administration (Sundra et al, 2024). Diet has no influence on the pharmacological parameters, and it can also be administered to horses that cannot receive oral medications. Side effects may include oedema, pain and swelling at the site of injection; the incidence of adverse reactions increased with subsequent administrations, even when given on alternating sides of the neck (Rendle et al, 2018; Gough et al, 2020; Lehman et al, 2022).
Esomeprazole, an s-isomer of omeprazole, has also been investigated for either oral or intravenous administration. It is the most common proton pump inhibitor prescribed in human medicine, where its administration results in a more prolonged suppression of gastric acid production, with a more rapid onset of action, slower metabolism in the liver and higher area under the curve (which is considered an indication of efficacy) compared to omeprazole (Sundra et al, 2023). A dose of 0.5 mg/kg intravenously increased gastric pH, but the values were variable in the horses enrolled in the study (Videla et al, 2011). Additionally, 0.5 mg/kg and 2 mg/kg orally were effective in increasing gastric pH, but an effect of diet (especially of ad libitum hay administration) was also found (Huxford et al, 2017; Sykes et al, 2017a). In a more recent study, a higher proportion of horses with squamous gastric disease improved after 28 days of treatment with 4 mg/kg once daily of oral esomeprazole compared to the same dose of omeprazole. Of the 74 horses treated with esomeprazole, 85% healed and 10% improved, while in the omeprazole group of 73 animals, 59% healed and 15% improved. Non-responders were 5% and 26% in the esomeprazole and omeprazole group respectively (Sundra et al, 2023).
H2-receptor antagonists, such as ranitidine, suppress acid production by binding to histamine receptors in gastric parietal cells. Ranitidine (6.6 mg/kg orally every 8 hours or 8 mg/kg orally every 12 hours) and cimetidine (20 mg/kg orally every 12 hours) have been investigated for the treatment of gastric ulcers, and were found to be inferior to omeprazole (Lester et al, 2005; Knych et al, 2017). To the authors' knowledge, neither drug is currently registered for use in horses.
Sucralfate is a polyaluminium hydroxide salt that binds to the glandular mucosa, acting as a barrier for gastric lesions. Because of its mode of action (it adheres to the negatively charged ulcer bed, stimulates bicarbonate and mucus secretion and prostaglandin production and inactivates pepsin and bile salts – all mechanisms considered to be involved in the pathophysiology of glandular gastric disease but not squamous gastric disease) it has been investigated for the treatment of equine glandular gastric disease (van den Boom, 2022). Bishop et al (2021) evaluated the effect of this drug on the prevention of squamous lesions in an experimental model. Sucralfate administered at a dose of 20 mg/kg orally 3 times a day was considered inferior to 1 mg/kg once daily of omeprazole (Bishop et al, 2021).
The use of antibiotics has been advocated because in other species, bacteria, especially Helicobacter spp., have been associated with the development of gastric ulcers. This has not been confirmed in lesions of the squamous mucosa of horses and studies on the effectiveness of antibiotic treatment for squamous gastric disease are lacking (Sykes et al, 2015a; Hewetson and Tallon, 2021; Vokes et al, 2023).
Feed supplements
Because of the regulation around the administration of omeprazole in certain categories of horses, more and more supplements are being developed and studied for the management of gastric ulcers. Single ingredients and complex food supplements have been demonstrated to reduce the prevalence of squamous gastric disease and to prevent its development in various clinical and experimental settings. Aloe vera, corn oil, long chain polyunsaturated fatty acids, pectin-lecithin complexes and various herbal extracts have been studies, with variable results for both the treatment and the prevention of squamous gastric disease (Cargile et al, 2004; Hellings and Larsen, 2014; Sanz et al, 2014; Woodward et al, 2014; Bonelli et al, 2016; Luca et al, 2017; Bush et al, 2018; Conner et al, 2018; Lo Fuedo et al, 2021; Pagan et al, 2022). Generally, these products are effective in reducing the severity of squamous gastric disease but have lower efficacy than omeprazole. They tend to perform better if used for longer periods of time and for the prevention of the condition, especially when administered at the end of the omeprazole treatment (Shan et al, 2023).
Pectin-lecithin complexes, alone or combined with other ingredients with buffering capabilities, showed conflicting effects on squamous gastric disease, with some studies demonstrating a positive effect after at least 30 days of supplementation, and others showing no changes in the squamous mucosa (Venner et al, 1999; Murray and Grady, 2002; Ferrucci et al, 2003; Woodward et al, 2014; Sanz et al, 2014). In Norway, ImproWin, a mixture of sodium, calcium and iron fumarate, folic acid, cobalamin and pyridoxine, was found to be effective in reducing squamous gastric disease in Standardbred horses, especially with longer periods of supplementation (7 weeks) (Hellings and Larsen, 2014). Bush et al (2018) tested aloe vera against omeprazole in a mixed group of horses presented at an Australian University Hospital. The found that improvement and healing rates were significantly lower (57% and 17% respectively) in the supplement group, compared to the drug group. Pagan et al (2022) demonstrated that 3 months of supplementation of long-chain fatty acids, but not short-chain fatty acids decreased the prevalence of severe squamous gastric disease in Thoroughbreds in training.
Prebiotic and probiotic products have rarely been evaluated on their own, instead as a component of feed supplements: an in vitro study demonstrated the negative effect of butyric acid produced by fructo-oligosaccharides on the integrity of squamous mucosa, raising concerns about the effect of these supplements on the development of squamous gastric disease (Cehak et al, 2019).
Dietary and management recommendations
Various studies have highlighted the importance of management in the prevention of equine squamous gastric disease. As previously stated, an intermittent feeding regimen, especially with low fibres and high concentrate, is a known risk factor for squamous gastric disease. Feeding ad libitum hay and low starch compound complementary feed resulted in a significant decrease in disease score after 4 weeks (Kranenburg et al, 2023). Alfalfa hay as main ingredient had a positive impact on the development of squamous gastric disease, but pasture turnout should be considered a first-line intervention whenever possible. Using slow feeders and hay nets could also be implemented to increase the chewing time and the production of saliva; the saliva's basic pH helps to counteract the acidic gastric environment. Oil or fat should be the main source of energy in concentrate feed in order to reduce the amount of sugar in the diet (Vokes et al, 2023).
Exercise is also a risk factor for squamous gastric disease. In sport horses, feeding a small amount of roughage before exercise has a protective effect on squamous mucosa; additionally, reducing the time trotting or cantering to below 40 minutes per day helps to reduce the incidence of squamous gastric disease (Husted et al, 2009; Banse et al, 2018; Sykes et al, 2019). Electrolyte supplements should be administered mixed with food to decrease their irritant effects on the gastric mucosa (Vokes et al, 2023). Long-distance transportation increases the prevalence of squamous gastric disease, but no information is available on the effect of feeding during travel on its prevention (Padalino et al, 2020; Gharehaghajlou et al, 2023).
Conclusions
Equine squamous gastric disease is a disease of the equine stomach which is quite common in various populations, with prevalences that change based on the breed and the activity of the animals. Pathophysiology and risk factors have been investigated in various groups. The mainstay of the treatment is oral omeprazole administered at a dose of 4 mg/kg once daily for at least 3–4 weeks and a gastroscopy to confirm healing before the end of the therapy. In non-responders or when the oral route cannot be used, injectable omeprazole (4 mg/kg intramuscularly every 5–7 days) or oral esomeprazole (4 mg/kg once daily) have been investigated. Oral omeprazole at 1 mg/kg once daily has also been found to prevent the development of gastric ulcers in animals at risk of developing the disease. Changes in management (ad libitum hay, pasture turnout, low starch/high fat concentrate) and exercise levels (reduce heavy training to less than 40 minutes per day) can be implemented to reduce the incidence of squamous gastric ulcers. In at-risk populations, or after the end of omeprazole treatment, some dietary and herbal supplements aimed at improving gastric health have been found to prevent the development or the recurrence of the disease, and to reduce the severity of the disease in some groups.