The Current Status of Equine Gastric Ulcer Syndrome in Horses - Focusing on Diagnosis, Treatment and Prevention

1. Introduction

Equine Gastric Ulcer Syndrome (EGUS) is the umbrella term used for diseases of both mucosal layers of the stomach. The dorsal part of the stomach is covered by squamous epithelium and the ventral part by glandular epithelium, which secrete hydrochloric acid, pepsinogen, histamine, mucus and sodium bicarbonate [1]. Currently, there is no clear relationship between the presence of ESGD and EGGD [2].

Primary ESGD is a result of acid exposure and secondary a direct result of delayed gastric emptying [2,3]. The equine gastric squamous epithelium is susceptible to acid injury, as it is poorly perfused and lacks a mucus-bicarbonate layer to protect it [4]. Some protection is provided by the thick keratinized epithelium together with the presence of high electrical resistance, tight epithelial junctions and an osmophilic phospholipid surfactant-like layer [2,5]. However, endogenous hydrochloric acid (HCl) and also other synergistic gastric components such as short chain fatty acids (SCFAs), lactic acid and bile salts can erode the outer keratinized layers and lead to disruption of the electrical properties of the transport cells [6]. Hyperkeratosis (thickening of the stratum corneum) also appears to be a response to excessive acid exposure [7]. Risk factors for ESGD are summarized in Table 1. Although stress is often cited as a risk factor for EGUS, there is little scientific evidence to support this. ESGD has also been found in wild horses that are not exposed to recognized risk factors and many horses show no clinical signs and mild lesions can heal spontaneously, raising the question of whether some degree of ESGD is “normal” [2,8].

The pathophysiology of EGGD is only partially understood. It is thought that a breakdown in the glandular mucosal barrier, which has protective factors (mucus, bicarbonate, prostaglandins, mucosal blood flow and epithelial restitution [9]), stress or inflammation may be responsible [3,10]. Prostaglandin E plays a crucial role in protecting the stomach by stimulating bicarbonate secretion, inhibiting hydrochloric acid secretion, maintaining microvascular flow and increasing mucus production. The severity of EGGD is associated with increased adrenal cortical sensitivity to ACTH, suggesting that stress inducing management factors should be investigated in horses with EGGD [11]. Risk factors for EGGD are shown in Table 2.

Prevalence rates for ESGD ranged from 11% to 100% and for EGGD from 6% to 70% in different studies, depending on the study population [12,13,14,15]. The prevalence of EGUS is highest in performance horses and reflects changes in management and intensity of exercise [2,10].

In recent years, there have been a number of notable publications, particularly on diagnostic markers and new therapeutic and preventive approaches. These developments underline the need for this review to provide a comprehensive overview of the current state of knowledge and to critically discuss the practical clinical applicability of these findings.

2. Diagnosis

ESGD can be associated with a variety of very non-specific clinical signs, such as inappetence, poor body condition or weight loss, behavioral changes, acute or recurrent colic, bruxism, poor performance and stereotypic behavior [3]. In addition, the signs do not necessarily correlate with the severity of the lesions [30]. It is difficult to distinguish which signs are associated with ESGD or EGGD [31].

To date, gastroscopy remains the gold standard for antemortem diagnosis of equine gastric ulcers [2]. Various scoring systems are available, such as the commonly used 0-4 scoring system of the Equine Gastric Ulcer Council (EGUC) of 1999 [2] (Table 3). The EGUC system has demonstrated acceptable intraobserver and interobserver reliability in a study and was found to be reliable regardless of clinician experience [32].

The ECEIM Consensus Statement [3] recommends a descriptive rather than a grading system for EGGD, as the clinical relevance of the various manifestations of glandular disease has not yet been adequately investigated. However, EGGD scores have been used in many studies [28,33,34] to better assess treatment success.

In addition to a purely visual diagnosis of the gastric mucosa, it is also possible to perform a biopsy in combination with gastroscopy. This can be useful in the area of the glandular mucosa, as the appearance of the lesion is a poor indicator of the underlying severity [35]. Mucosal biopsies can determine the type and severity of the underlying disease. Biopsy can be particularly helpful in cases of EGGD that do not respond to management adjustments and medical therapies [36]. The biopsies can be examined histopathologically and/or culturally.

The clinical relevance of gastroscopically identified lesions should be assessed in the context of the severity of the clinical signs observed. It is also necessary to consider alternative differential diagnoses as previously described [37].

Other diagnostic methods for EGUS such as biomarkers or owner questionnaires have been investigated with variable results [2]. In the following section, biomarkers that have been recently identified as a result of research into alternative diagnostic methods are examined in more detail, with the corresponding abbreviations explained in Table 4 and in the abbreviations section.

Serum protein markers for a normal horse stomach were B4GALNT2 and XDH, for mild/moderate ESGD it was KRT10, while the marker for severe ESGD was KLK13 [38]. Other markers for both types of ESGD were SLC4A7, PPARG, FCGBP, PKP1, ASPRV1 and KRT5-like proteins. A total of 10 serum proteins were found to be potential markers for ESGD.

Using gel electrophoresis and mass spectrometry, 14 proteins were identified as potential markers of NSAID-induced EGGD. Many of them are mitochondrial proteins (MIA40, ACSM3, HSCB, DNAJA3, ECI1, AGXT2, AK2, AK4 and MRPL2) released from apoptotic gastric cells, while some proteins interact directly with phenylbutazone (PTGR2, UGT1A1 and PTBP1). These proteins may enter the blood circulation during NSAID-induced inflammation.

Horses with moderate or severe EGGD had a larger and quicker increase in cortisol concentration after ACTH stimulation with the best diagnostic accuracy 60 minutes after injection (sport horse population: 100% sensitivity and 75% specificity; general population: 75% sensitivity and 52% specificity)[39]. There were no significant associations with ESGD.

Hair cortisol concentration (HCC) was lower in horses with ESGD and was a negatively correlated with lesion severity [40]. HCC was inversely related to the severity of ESGD, as high plasma cortisol concentrations associated with stress lead to lower levels in the hair via a negative feedback mechanism [31]. Mares had lower HCC than geldings and a higher prevalence of ESGD. Age did not show a significant effect [40].

Blood sucrose was neither a sensitive (51-79%) nor specific (43-72%) test for the detection of EGUS in adult horses with naturally occurring gastric ulcers [41].

Serum levels of gastrin and pepsinogen showed no significant changes in horses with EGUS compared to healthy horses [42]. TNF-α and IL-6 showed a significant increase in serum levels in horses with EGUS. Due to oxidative stress, higher levels of malondialdehyde (MDA; product of lipid peroxidation) and decreased serum levels of total antioxidant capacity (TAC), superoxide dismutase (SOD), glutathione (GSH) and nitric oxide (NO) are present in EGUS patients compared to healthy horses. MDA and TNF-α showed better sensitivity and specificity than IL-6 in differentiating horses with EGUS from control horses. In conclusion, higher levels of TNF-α and IL-6 indicate the development of EGUS. For preliminary screening of EGUS, MDA, TNF-α and IL-6 could be used as non-specific biological markers.

Twenty-three salivary biomarkers were tested for non-invasive EGUS diagnosis in 147 horses [43]. Samples were collected just prior to gastroscopy. The biomarkers tested included enzymes (ADA1, ADA2, ALP, AST, BChE, CK, gGT, LIP, LDH and sAA), metabolites and proteins (Creat, Ferr, TChol, TP, Trig and urea), redox biomarkers (AOPP, FRAS and UA) and minerals (Ca and P). Analytes that showed significantly higher concentrations in the animals with EGUS included ADA (both isoenzymes), ALP, AST, BChE, CK, gGT, LDH, sAA, Ferr, TP, Trig, urea, FRAS, UA, Ca and P (AOPP showed a trend with P = 0.055). The analytes that showed differences between the group of animals with EGUS and the group of animals with similar clinical signs but with other diseases were Ca, Trig and UA, which were higher in the EGUS group, and Ferr, which was higher in the group with other diseases. In general, no differences were found between animals with ESGD, EGGD or ESGD and EGGD, with the exception of ADA2, which was higher in the ESGD and EGGD group compared to ESGD alone, and Trig and Ca, which were higher in the ESGD and EGGD group compared to the EGGD alone.

Measurement of salivary calprotectin (CALP) and aldolase was evaluated as potential biomarkers for EGUS [44]. CALP is a calcium-binding S100 leukocyte protein associated with the innate immune response and inflammation. Aldolase belongs to a family of proteins involved in gluconeogenesis and glycolysis. Commercial assays are available for the measurement of CALP and aldolase. CALP was significantly higher in horses with EGUS than in healthy horses. Salivary CALP was able to detect EGUS patients from healthy horses with >84% sensitivity and 100% specificity. However, no significant differences were found between horses with EGGD and ESGD and between horses with EGUS and horses with other diseases. Aldolase activity was significantly higher in patients with EGUS than in healthy horses (67% sensitivity and 86.7% specificity). No significant difference was found between horses with EGGD and ESGD and between horses with EGUS and horses with other diseases. The increase in CALP in horses with ESGD may be influenced by the hyperkeratosis of the squamous epithelial cells. Aldolase is involved in the impairment of cell growth and proliferation of gastric epithelial cells. In conclusion, CALP and aldolase can be considered as potential biomarkers to differentiate horses with EGUS from healthy horses.

Horses with EGUS showed an increase in salivary proteins such as adenosine deaminase (ADA), triosephosphate isomerase, keratins and immunoglobulin heavy constant mu and a decrease in carbonate anhydrase (CA), albumin and prolactin induced protein [45]. These changes indicate that several pathophysiological mechanisms are involved in this disease, such as activation of the immune system, reduction of gastric defences mechanisms and inflammation. The omeprazole-treated horses showed lower levels of thioredoxin (TRX) expression after successful treatment, as measured by proteomic analysis and commercially available ELISA kit. These proteins could be potential biomarkers for the detection and monitoring of treatment success in EGUS.

Another study [46] showed that horses with EGUS had changes in the trace elements of saliva. In particular, zinc and magnesium concentrations were significantly lower in horses diagnosed with EGGD, while horses with both ESGD and EGGD had reduced salivary iron concentrations. These results are promising in two aspects: on the one hand, the altered concentrations could serve as potential biomarkers; on the other hand, they open up interesting perspectives for therapy, especially with regard to the possible effectiveness of systematic supplementation.

Table 4 provides an overview of the potential diagnostic markers for EGUS and an outlook on the clinical potential.

3. Treatment and Prevention

The successful treatment of gastric ulcers in horses requires not only the use of medications, but also a change in management to minimize the risk factors mentioned above, such as stress [48]. In the older literature, general recommendations were often given for EGUS, which now leads to misunderstandings in practice regarding the specific recommendations for the subtypes ESGD and EGGD. For example, it is now recognized that stress management plays a greater role in the management of EGGD, whereas dietary management is crucial for ESGD. For this reason, the recommendations for ESGD and EGGD are presented separately below.

3.1. Equine Squamous Gastric Disease

3.1.1. Oral Omeprazole

The drug of choice is omeprazole, a prodrug, which is absorbed in an alkaline environment, such as the small intestine, due to its enteric coating, which protects it from degradation in the stomach, and is converted into its active form, a sulfonamide, in the acidic secretory parietal cells. This in turn irreversibly binds to the gastric H+/K+-ATPase, and thus inhibits the acid production of the stomach [49]. The half-life of the oral formulations was longer (approximately 100 minutes) than that of the intravenous formulation (approximately 35 minutes) [50]. The oral formulations are approved for use in horses in many countries and are available in buffered and enteric-coated forms. Enteric-coated formulations have been shown to have higher bioavailability and that lower doses can be as effective as higher doses [50]. The bioavailability was with a mean of 21.5% higher in the orally enteric-coated omeprazole (4 mg/kg once daily) and fast (no feed for 16 h) group than with orally unprotected plain omeprazole under the same conditions with a mean of 10.1%. Similar differences were also observed in the area under the concentration-time curve (AUC), while there was no difference in the maximum plasma concentration (Cmax) between the both formulations. In addition, the data show that bioavailability is comparable in fed and non-fed horses receiving enteric-coated omeprazole. This indicates that the influence of feeding is less than previously assumed. In a further contrast to the recommendation to give omeprazole before feeding, it has been shown that for the most effective bioavailability, buffered omeprazole (Gastrogard™) should be administered during feeding to achieve a rapid increase in intragastric pH above 4 and to reduce the degradation of omeprazole by excessively acidic gastric contents [51]. On the other hand, the effects of diet (16 hours fasting or free choice alfalfa hay) or formulation (enteric-coated (Gastrozol™) or buffered (Omoguard™) omeprazole) on bioavailability was not statistically significant [52]. But examination of the raw data indicated a feeding effect that could reduce the bioavailability of omeprazole in the fed animal.

In Thoroughbreds in race training clinical signs often improved within 48 hours of starting omeprazole treatment [53]. Cure rates with oral omeprazole (ORLO) range from 67-94% and improvement rates from 89-100% depending on the study [54,55]. For the buffered formulation, a standard dosage of 4 mg/kg once daily for 28 days was used, while for the enteric-coated formulation, the dosage ranged from 1 to 4 mg/kg once daily for the same period. Both oral omeprazole formulations, powder paste and gastro-enteric resistant granules, in a dosage of 4 mg/kg bwt for 28 days showed resolution of lesions in 78.6% of ESGD [56]. In the gastro-resistant omeprazole granules group, 100% of ESGD lesions were improved or healed, compared with 71% in the omeprazole powder-paste group.

Without initial omeprazole treatment, the dietary change had no additional effect [57]. Horses with grade ≥ 3/4 ESGD showed a significant effect of omeprazole. In the group initially treated with omeprazole and maintained on their original diet, there was a significant improvement in ESGD, but this did not reflect any apparent long-term benefit of the medication. It was also shown that an appropriate feed conversion may be a beneficial management strategy for ESGD.

At a dosage of 1 mg/kg, omeprazole paste significantly prevented the occurrence of ESGD in training horses, with similar efficacy observed at a dosage of 2 mg/kg. Omeprazole prophylaxis was shown to be superior to placebo treatment, with only 23.4% of horses in the omeprazole group developing gastric ulcers compared to 77.2% in the placebo group. In addition, the severity of ulcers was significantly lower in the omeprazole groups [58]. It was shown that the ‘ultra-low’ dosage of 0.5 mg/kg omeprazole is equivalent to the 1 mg/kg dosage for the prevention of EGUS [59].

It was investigated whether the rebound gastric hyperacidity (RGH) known in human medicine, which leads to increased gastrin production and hypergastrinemia due to the loss of negative feedback to gastrin by the use of proton pump inhibitors, also exists in horses [60]. An additional effect of gastrin, which has a positive trophic effect on enterochromaffin-like cell (ECL) density, was used by measuring this increased cell density by serum chromogranin A. The aim was to investigate, whether this effect also occurs in horses, leading to a rapid recurrence of ESGD after omeprazole withdrawal. The mean serum gastrin concentrations increased 2.5-fold from the initial value up to the 7th day, but did not increase with further treatment. Mean serum gastrin concentrations returned to baseline within 2 to 4 days after administration of the last dose of omeprazole. No clear increases in serum chromogranin A concentrations were observed as an effect of treatment or discontinuation. In conclusion, these results do not support the use of tapering protocols in horses.

3.1.2. Long-Acting/Extended Release Injectable Omeprazole

The long-acting injectable omeprazole treatment (LAIO), administered intramuscularly at 4 mg/kg once weekly for two or four weeks, showed success rates of 86% and 97% in ESGD and had an improvement rate of 100% [54]. A minor complication rate of 5.1% was observed with the injectable treatment, which did not require further medical intervention. This study [54] showed that in contrast to a previous study in thoroughbred racehorses [61] which reported 100% healing after 2 doses of LAIO, it took 4 weeks for almost 100% of lesions to heal with LAIO therapy. In horses receiving four intramuscular injections of 2 g of a 100 mg/ml extended-release injectable omeprazole (ERIO) the cure rates (grade 0) for ESGD were 97% when administered every 5 days and 82% when administered every 7 days, with no significant difference. [62]. Injection-site reactions occurred in only 1% of cases. A measurement with the same dosage showed that the pH value was above 4 in 66% of all horses on days 1 to 4 and in 4 out of 6 horses on days 1 to 7 [61].

3.1.3. Esomeprazole

A comparison between oral esomeprazole and oral omeprazole concluded that treatment with esomeprazole, an S-enantiomer, was more effective when given once daily for 28 days at a dosage of 4 mg/kg for ESGD [63]. Esomeprazole achieved a cure rate (grade 0/4) of 85% compared with 59% for omeprazole. Currently, there are no registered esomeprazole formulations for horses.

3.1.4. H2-Receptor Antagonists

H2-receptor antagonists (such as ranitidine, famotidine and cimetidine) reduce acid secretion, but have been shown to be inferior to omeprazole for the treatment of ESGD [64]. H2-receptor antagonists bind to histamine receptors and thus reduce proton pump stimulation (without affecting gastrin and acetylcholine, which stimulate acid secretion) [10]. The duration of acid supression is short, which is why oral administration of 6.6 mg/kg ranitidine, for example, should ideally take place every 8 hours [64], which represents a significant additional expense compared to omeprazole.

3.1.5. Non-Pharmacological Treatment Options

Alternative, non-pharmacological treatments have been studied, as omeprazole is very expensive, horses should not be unnecessarily treated with medication and there are restrictions on the use of omeprazole in some equestrian competitions [31].

It could be shown that severe ESGD could be improved or even cured within 4 weeks without drug therapy by providing horses with roughage ad libitum and a small amount of a low-starch supplement [65]. Also a predictable daily routine with a limited number of good caretakers may help to reduce stress levels and therefore improve gastric health. However, spontaneous healing of ulcers is rare and refusal of treatment may be considered unethical [66].

The protective management factors are set against the risk factors and include, for example, open stabling, the use of hay nets and recommend omeprazole in stressful situations [22].

Fibre is important in the horse’s diet, and failure to meet the 1.5% of bodyweight fibre requirement, as well as inadequate access to forage for at least eight hours a day, can have consequences [67]. Providing hay can reduce behavioral abnormalities such as crib biting and wood chewing, as well as stress. To provide horses with a source of energy, rations often contain starch rather than fibre, which can lead to gastrointestinal health problems. Choosing a high fibre alternative to starch significantly reduces the risk of EGUS and acidosis and improves digestion, gastrointestinal pH, body condition, behavior and performance. The increased energy provided by starch-rich diets can also be provided in fibrous form, such as sugar beet pulp. Fibre can form a barrier between gastric acid and the cutaneous gastric mucosa when fed 30 minutes before exercise, which increases intra-abdominal pressure during exercise and pushes gastric acid to the cutaneous mucosa. Starch increases the production of short chain fatty acids and reduces the buffering capacity in the stomach by reducing saliva production due to low chewing activity, which in turn increases the risk of ESGD. Fibre type is crucial, which is why lucerne hay is said to be a better solution for gastric ulcers than grass hay. A high-fibre, low-starch diet has been shown to have a positive effect on the microbiota in the stomach and faeces and to promote the healing of gastric ulcers [68]. In horses with gastric ulcers, a lower diversity of the microbiota was observed (ulcer improvement with an increase in specific carbohydrate-utilizing and a decrease in lactate-fermenting species).

Water is also important because water deprivation causes stress, which increases serum cortisol concentrations, which is reflected in serum gastrin concentrations, which stimulates HCl secretion [67,69].

There are many supplements, such as antacids that work by buffering stomach acid. A combination of aluminium (30g) and magnesium (15g) hydroxide can increase gastric pH ≥ 4 for up to 2 hours [70]. A 30-day supplementation with a mixture of magnesium oxide (MgO) (20 g ionized Mg2+ per horse per day) given to 2-year-old French trotters in training significantly reduced ESGD severity, while the mean/median grade in the control group was unchanged [71]. This may be related to the buffering capacity of the Mg supplementation. There was no significant correlation between the plasma concentration of lipid peroxides (markers of oxidative stress) and the ESGD value.

Feeding the nutraceutical supplement Trophogast Pellet for 30 days (200 g once daily) significantly decreased the ESGD score in the treatment group (supplements + management changes), while in the control group (management changes only) the score remained the same [72]. The management changes carried out in both groups included an increase in pasture time, constant access to good quality hay and a reduction in the intake of non-structural carbohydrates. There was a significant reduction in the ESGD score in the treatment group, but no change in the control group. In conclusion, Trophogast pellet may be effective in promoting the healing of mild ESGD lesions in endurance horses. Trophogast pellet is designed to protect the gastric mucosa and contains pectin, soy lecithin, zinc oxide and sweet chestnut extract. Pectins turn into gel in an acidic environment and can therefore protect the mucous membrane from acid. They can also stimulate an increase in the pH value in the stomach. Lecithin is an exogenous phospholipid that can form a highly hydrophobic protective layer, thereby enhancing the acid-repellent properties of the phospholipids of the squamous mucosa. Zinc oxide and sweet chestnut extract may provide additional benefits due to their antioxidant properties by protecting the mucosa from the formation of harmful free oxygen radicals. Sugar beet pulp also contains pectin and lecithin [73]. Beet pulp feeding decreased the odds of ESGD grade ≥ 1/4 in a study of show jumping Warmbloods [14]. The beneficial effect of pectin-lecithin complex was also demonstrated in another study [74], but in still another study, lesions caused by intermittent feed deprivation could not be prevented [75].

Feeding oil has shown variable results in studies, but may be useful as a caloric replacement when switching to a low starch diet [2]. Feeding 118 ml of soybean oil, wild-caught fish oil and d-alpha-tocoperol before morning feed for 28 days did not prevent gastric ulcers [76], although omega-3 fatty acids found in fish oil have been used with some success in humans with gastric ulcers associated with Helicobacter pylori [77]. Omega-6 fatty acids found in soybean oil reduce gastric acid secretion in ponies [78]. Alpha-tocopherol supplementation in rats reduces the frequency and increases the healing rate of gastric ulcers [79].

Furthermore aloe vera (17.6 mg/kg bwt BID) appeared to have a positive effect on ESGD improvement [66].

An overview of ESGD prevention is summarised in Table 5. For the effective implementation of preventive measures, it is essential to consider the table of risk factors (Table 1) in combination with this table (Table 5), as the avoidance of risk factors is also a preventive approach.

3.2. Equine Glandular Gastric Disease

3.2.1. Oral Omeprazole

Horses given an oral omeprazole paste (4 mg/kg po q 24 h for around 28 days), 50% of EGGD were cured, 75% improved and 25% were unchanged or worse [80]. In this study the cure rate with ORLO was greater than previously reported in other studies [81,82]. The comparison of both oral omeprazole formulations, powder paste and gastro-enteric resistant granules, showed resolution of lesions in 35.7% of EGGD [56]. The equal efficacy of enteric-coated (2 mg/kg) and buffered (4 mg/kg) omeprazole was also confirmed in another study [33].

When phenylbutazone (4.4 mg/kg po q 12 h) is given, the gastric pH increased more over time with omeprazole (4 mg/kg po q 24 h) than with phenylbutazone alone and the EGGD score increased with phenylbutazone alone compared to the combination with omeprazole [83]. Omeprazole reduced the formation of EGGD, but had no effect on the development of ESGD. In conclusion, the use of omeprazole improved phenylbutazone-induced EGGD, but was associated with an increase in intestinal complications (such as colic, impaction, diarrhoea, enterocolitis or typhlocolitis), whereas the use of omeprazole alone was shown not to alter the faecal microbiome [84].

3.2.2. Long-Acting/Extended Release Injectable Omeprazole

After 14 days of LAIO therapy (4 mg/kg once weekly), 52% of EGGD lesions were healed, 88% were improved, 6% were unchanged and a further 6% had worsened [80]. At the end of treatment (14 or 28 days), 82% were healed, 91% improved and 9% were unchanged or worse. The number of horses cured was greater with LAIO therapy than with ORLO therapy. There is no correlation between the cure or improvement rate and the resolution of clinical signs. 6.7% of the injection sites had self-limiting reactions.

Horses given four intramuscular injections of 2 g of a 100 mg/ml extended release injectable omeprazole (ERIO) with an 1% injection reacting, had a cure rate of EGGD (grade 0 or 1) of 93% with a 5-day treatment interval and 69% with a 7-day interval [62].

It is important to note that in many studies [54,62,80], owners were given dietary and management recommendations, which allowed several factors to influence the success of the therapy.

3.2.3. Esomeprazole

In horses with EGGD, esomeprazole (4 mg/kg once daily for 28 days) resulted in 55% success (grade 0 or 1) compared to 25% for omeprazole and for complete healing (grade 0), esomeprazole had a success rate of 47% compared to 17% for omeprazole [63].

3.2.4. Sucralfate

Omeprazole is less effective in treating EGGD, so a minimum of 8 weeks of therapy is recommended before considering complementary therapies [3]. Omeprazole is often combined with sucralfate, a hydroxyl aluminium salt of sucrose octasulfate, which binds to the negatively charged ulcer bed and forms a protective barrier [31]. The combination resulted in better healing of EGGD than omeprazole alone [85]. Sucralfate acts as a physical barrier that protects the mucosa from acid and prevents mucus breakdown, as well as increasing the viscosity of the mucus layer and enhancing hydrophobicity, resulting in reduced back diffusion of hydrogen ions [86]. It also stimulates mucus and bicarbonate secretion and may stimulate prostaglandin E (PGE) synthesis.

Omeprazole was more effective than sucralfate in reducing the development of EGUS [26]. In addition, horses treated with sucralfate developed a thickening of the colon.

When sucralfate (Sucrabest™, 12 mg/kg twice daily per os) was added to the omeprazole preparations GastroGard™ (buffered, 4 mg/kg once daily) or Equizol™ (enteric coated, 2 mg/kg once daily), 6/23 horses showed complete healing of EGGD (grade 0) and 13/23 horses showed only grade 1 findings [33]. No significant difference was shown in the effect of the combination of GastroGard™ and Sucrabest™ or the administration of high dose Equizol™ (3.5-4 mg/kg omeprazole) [87].

3.2.5. Misoprostol

Misoprostol, a synthetic prostaglandin E analogue, can enhance the protective mechanisms of the glandular mucosa in humans by improving blood flow, increasing mucus and bicarbonate secretion, and reducing acid production [88]. There are no veterinary products available for horses, instead products from human medicine (e.g., Cytotec™) are used. Monotherapy with misoprostol (approximately 28 d, Cytotec™, 5 μg/kg twice daily per os), with particular caution for pregnant owners and during the lactation period, was superior to both omeprazole/sucralfate therapy and combined omeprazole/misoprostol therapy in horses with EGGD [89]. Misoprostol (standard dosage mentioned before) showed a better cure rate of 72% on average than the combination of omeprazole and sucralfate with 20% and an improvement rate of 98% to 65% on average [81].

3.2.6. Glucocorticoids and Antimicrobials

As already mentioned in the diagnosis section, in addition to the preferred treatment options, the use of glucocorticoids and antimicrobial therapy are available as alternative treatment options in the event of a non-response [36]. Although the evidence base for antimicrobial treatments is still evolving and a previous study [90] did not support its inclusion in treatment regimens for EGUS. There is evidence that the targeted use of glucocorticoids may be beneficial, as there are similarities in the histological appearance of lesions in horses with IBD and EGGD [36]. Prednisolone at 1-2 mg/kg po SID or dexamethasone at 0.05-0.1 mg/kg po SID has been described, but is not licensed for this treatment [91].

3.2.7. Non-Pharmacological

As already mentioned, the protective management factors are set against the risk factors and include, for example, open stabling, the use of hay nets and recommend omeprazole in stressful situations [22].

Sea buckthorn berry supplementation (35.6 g berries and pulp twice daily) prevented the formation of glandular lesions in horses, which may be a useful complementary prevention strategy for EGGD. The exact mechanism is unknown, but it is thought that high levels of antioxidants reduce oxidative stress in the mucosa [92].

Supplementation with essential fatty acids increases the endegenous PGE2 production of the gastric mucosa and reduces acid production [78]. Thus, corn oil supplementation (45 ml daily) can be considered or the therapeutic and prophylactic treatment of EGGD.

An overview of EGGD prevention is summarised in Table 6. For the effective implementation of preventive measures, it is essential to consider the table of risk factors (Table 2) in combination with this table (Table 6), as the avoidance of risk factors is also a preventive approach.

4. Conclusions

The gold standard for the diagnosis of EGUS is still gastroscopy. Although studies with biomarkers for diagnosis have already shown promising results, a practical implementation is still missing. ESGD is usually treated with oral omeprazole, while the long-acting intramuscular formulation of omeprazole is not approved for use and carries risks associated with the injectable route, it may be reserved as a second-line therapy in refractory cases. Treatment of EGGD is currently based on a combination of omeprazole and sucralfate or alternative approaches such as misoprostol. Another important aspect is the prevention of gastric ulcers, such as stress reduction in case of EGGD, a high-fibre, low-starch diet and limiting the intensity of exercise in case of ESGD. However, it is necessary to distinguish between ESGD and EGGD, as the pathophysiology of EGGD is not completely understood. Future research should focus on the development of practical, non-invasive and accurate diagnostic techniques and a better understanding of the pathogenesis of EGGD to further optimise treatment and prevention.