View source for 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 <ref>[https://www.aphis.usda.gov/animal_health/nahms/equine/downloads/equine15/Equine15_is_Mortality.pdf. United States Department of Agriculture, Veterinary Services Center for Epidemiology and Animal Health. “Equine Mortality in the United States”. February 2017.]</ref>. 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 <ref>[https://www.myhorseuniversity.com/single-post/2017/09/25/equine-colic-causes-symptoms-treatment-and-prevention. My Horse University. “Equine Colic: Causes, Symptoms, Treatment, and Prevention”.]</ref>. 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 <ref name="three">[https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202527. Whitfield-Cargile CM, Chamoun-Emanuelli AM, Cohen ND, Richardson LM, Ajami NJ, Dockery HJ (2018) Differential effects of selective and non-selective cyclooxygenase inhibitors on fecal microbiota in adult horses. PLoS ONE 13(8): e0202527. https://doi.org/10.1371/journal.pone.0202527]</ref>. 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)<ref>[https://vet.osu.edu/vmc/sites/default/files/import/assets/pdf/hospital/equineFarmAnimals/equine/articles/2008/colic.pdf
Margaret C Mudge, VDM DACVS; Rustin M. Moore, DVM PhD DACVS. ”What Can You do to Prevent Colic?”. The Ohio State University. 3-4. 
]</ref>. 

Interestingly enough, NSAIDs have been shown to improve pain in already colicing horses <ref name= "five">[https://irishvetjournal.biomedcentral.com/articles/10.1186/2046-0481-57-8-467
Galvin, N., Dillon, H. & McGovern, F. Right dorsal colitis in the horse: minireview and reports on three cases in Ireland. Ir Vet J 57, 467 (2004). https://doi.org/10.1186/2046-0481-57-8-467]</ref><ref name= "six">[https://horsesidevetguide.com/drv/Treatment/13/bute-phenylbutazone/
Horse Side Vet Guide. “Bute, Phenylbutazone”.]</ref>. 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 <ref name="seven">[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5588883/Ziegler, Amanda et al. “Update on the use of cyclooxygenase-2-selective nonsteroidal anti-inflammatory drugs in horses.” Journal of the American Veterinary Medical Association vol. 250,11 (2017): 1271-1274. doi:10.2460/javma.250.11.1271]</ref>. The equine GI tract microbiome is made up of predominantly bacteroidetes and firmicutes <ref name="seven" />. 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 <ref name= "six" />. 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 <ref name= "five" />.

==COX inhibition==
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 <ref name="seven" />. Therefore, multiple studies have shown that selective COX-2 NSAIDs are a safer option to reduce the likelihood for ulcerations <ref name="nine">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995434/
Whitfield-Cargile, Canaan M et al. “Effects of phenylbutazone alone or in combination with a nutritional therapeutic on gastric ulcers, intestinal permeability, and fecal microbiota in horses.” Journal of veterinary internal medicine vol. 35,2 (2021): 1121-1130. doi:10.1111/jvim.16093</ref>. 

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 <ref name="nine" />. This is caused by increased permeability of the GI tract’s mucous membrane, or mucosa <ref name="nine" />. 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 <ref name="ten">Ziegler, Amanda et al. “Update on the use of cyclooxygenase-2-selective nonsteroidal anti-inflammatory drugs in horses.” Journal of the American Veterinary Medical Association vol. 250,11 (2017): 1271-1274. doi:10.2460/javma.250.11.1271</ref>.

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 <ref name="three" /><ref name="seven"/>.

[[Image:COX.jpg|thumb|420000px|right|COX isozymes physiological interaction within in the body. Inhibition of COX-1 could have negative effects on the GI tract, kidneys, and coagulation <ref name= "seven" />.]]

==Dysbiosis of the GI tract==
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 <ref name="nine" />. 

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 <ref name="nine" />. 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 <ref name="three" />. 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 <ref name="three" />. 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==
The inflammatory response can be triggered by heat, bacteria, trauma, or other causes <ref name="fifteen">https://medlineplus.gov/ency/article/000821.htm#:~:text=The%20inflammatory%20response%20(inflammation)%20occurs,into%20the%20tissues%2C%20causing%20swelling.Medline Plus. “Immune Response”. National Library of Medicine. 2021. </ref>. The COX-2 gene is triggered by inflammatory cytokines, or immune proteins used for cell signaling and this eventually leads white blood cells to the area to fight off infection. This results in increased blood flow to the wound and therefore inflammation. Gut problems such as inflammation are symptoms of colic in horses. Inflammation and pain can be reduced by NSAIDs, and therefore many veterinarians will prescribe medications like Bute and Ketofen. 

Bute has been studied recently  because it is a non-selective COX NSAID that inhibits both classes of the COX enzyme. Through these studies, it has been found that Bute can cause damage to the gut including ulcers. However, it was also found that both specific and non-specific COX NSAIDs cause dysbiosis of the gut Thus, it is impossible to say that COX-2 NSAIDs are completely safe, but they may be a better alternative. 

Colic is extremely common and can sometimes be fatal. NSAIDs are usually the first remedy for a horse to relieve pain and inflammation. However, the exact biochemical mechanisms that metabolize NSAIDs are still unclear and more research is needed in order to find a drug that reduces inflammation without causing additional harm. NSAIDs can be safe and effective as long as they are prescribed properly. Thus, a veterinary consultation is critical prior to giving a horse any form of NSAIDs.

==References==
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<br>Edited by Lauren S. Childs, student of [mailto:slonczewski@kenyon.edu Joan Slonczewski] for [http://biology.kenyon.edu/courses/biol116/biol116_Fall_2013.html BIOL 116 Information in Living Systems], 2021, [http://www.kenyon.edu/index.xml Kenyon College].

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