Prolonged use of NSAIDs leads to equine colic

Introduction

Equine colic is a broad term used to describe any form of abdominal pain that has a wide variety of causes. Colic is one of the leading causes of deaths in domesticated horses (1). On average 4-10% of horses will experience colic throughout their lifetime. Of those that experience colic-related problems, about 64,000 horses die each year. Death occurs due to the loss of proper function in the digestive system. Factors that can induce colic include obstructions in the digestive tract caused by sand ingestion, parasite infestation, and dehydration (2). Obstructive colic almost always requires surgery.

A horse’s gut is made up of diverse and critical bacteria that aid in food digestion. Changes in the digestive system’s microbiome, or dysbiosis, can also lead to colic. Factors that cause this change include moldy feed, high grain based diets, and bacterial infection. All of these factors can cause enteritis which is essentially inflammation in the gut, which leads to colic symptoms such as diarrhea (3). One other important cause of colic is long-term use of non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs are a very common class of medications that are used for short-term pain relief and to reduce inflammation. However, long-term use of NSAIDs can alter the microbiome which can lead to adverse effects on the gastrointestinal (GI) tract and lead to colic symptoms. Common NSAIDs prescribed by veterinarians include phenylbutazone (Bute), flunixin, and ketoprofen (Ketofen) (4).

Interestingly enough, NSAIDs have been shown to improve pain in already colicing horses (5,6). NSAIDs are often prescribed to relieve colic symptoms, but if used inappropriately they can also cause colic to worsen. Little is known about NSAID enteropathy, or the pathology of NSAID metabolism, and therefore NSAID side effects are incredibly common (7). The equine GI tract microbiome is made up of predominantly bacteroidetes and firmicutes (7). Bacteroidetes are rod-shaped bacteria that perform essential metabolic conversions of proteins and complex sugar polymers. Firmicutes are bacteria that break down carbohydrates such as starch. NSAIDs usually negatively affect the GI tract by decreasing the firmicutes population, which in turn increases the bacteroides population. This leads to decreased starch digestion, a common carbohydrate in food. Since the GI tract has no alternative way to digest the starch, it can lead to colic symptoms such as diarrhea.

NSAIDs can not only cause dysbiosis, but they also interfere with the biochemical process of inflammation by inhibiting COX enzymes. The two isozymes are COX-1 and COX-2. There has been extensive research into both isozymes and whether selective COX-2 NSAIDS, meaning that the NSAID only inhibits the COX-2 isozyme, is a safer option over non-selective COX enzymes. Studies have shown that nonselective COX enzymes may lead to ulcerations in the gut (6). Ulcerations are sores due to cell death that can be on the skin or organs. However, it is clear that more studies need to be done to find safer NSAID alternatives because even selective COX-2 enzymes have still shown to have negative effects on the GI tract microbiome (5).

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Section 1 Genetics

NSAID use in horses is much more regulated than in humans. Human NSAIDs can be sold over-the-counter whereas equine use requires a full veterinary examination before the proper NSAID can be prescribed. Equine NSAIDs such as Ketofen and Bute are used to inhibit inflammatory response enzymes including one enzyme called cyclooxygenase (COX). The COX group has two different medically relevant enzymes: COX-1 and COX-2. Recent studies have investigated the effects of selective COX-2 NSAIDs versus non-selective COX NSAIDs. They have found that COX-1 is a vital enzyme that contributes to multiple physiological pathways (7). Therefore, multiple studies have shown that selective COX-2 NSAIDs are a safer option to reduce the likelihood for ulcerations (9).

One study looked specifically at Bute, a non-selective NSAID, and found that the recommended dosage of 4.4 mg/kg led to significant degenerative effects in the GI tract (9). This is caused by increased permeability of the GI tract’s mucous membrane, or mucosa (9). A majority of the horses developed ulcerations. Ulcerations are a major and well-known limitation of all NSAIDs. These sores within the lining of the stomach can cause copious amounts of internal bleeding and can be fatal. Ulcer disease can be caused by a number of factors including NSAIDs' irritant effect on the epithelium (the causing factor of ulcerations), impair the mucosal barrier, reduction of mucosal blood flow, and more (10).

Improved technology has led to the ability to create more target-specific drugs. As shown in Figure 1, the COX-2 specific NSAID mainly targets only pain and inflammation, whereas non-selective COX NSAIDS inhibit not only pain and inflammation but also coagulation, kidney, and GI function (7,3).

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Section 2 Microbiome

NSAIDS not only manipulate the genetic inflammatory response, but they can also cause harm to the horse's microbiome in the GI tract. The GI tract is filled with healthy bacteria that contributes to metabolization and digestion in the GI tract. Firmicutes and bacteroidetes contribute to the GI tract's overall homeostasis. NSAIDs' are a heterogeneous group of compounds that are mainly metabolized in the liver by oxidation and conjugation. These chemical reactions result in metabolites that serve multiple functions including inhibition of enzymes. NSAIDs are known to decrease the firmicutes population, resulting in dysbiosis (9).

Both non-selective COX NSAIDs and selective COX-2 NSAIDs can cause GI tract dysbiosis. Numerous studies have investigated the microbiota of horses’ fecal matter from horses on both types of medications and have found no significant difference between the usage of either drug. Both drugs cause decreases in the firmicutes phylum, and more specifically the families Clostridiaceae and Lachnospiraceae (9). Both families are very important for mucosal homeostasis. Their depletion can lead to colic symptoms due to the lack of butyrate acid production. This acid is responsible for digesting starches from food the gut could not otherwise digest on its own.

Many studies have looked at the use of these medications over a number of weeks. One study looked at the effects of the administration of Bute and Firocoxib over 25 days (3). There was a significant decrease in Lachnospiraceae over the 25 day period from both medications. Another study looked at an even longer period of 68 days and found the same results for Bute (9). The exact effects and biochemical interactions between dysbiosis and how it affects the GI tract remain unknown. However there are obvious and important links between dysbiosis and colic symptoms.

Conclusion

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