Effects of phenylbutazone alone or in combination with a nutritional therapeutic on gastric ulcers, intestinal permeability, and fecal microbiota in horses.
Abstract: Gastrointestinal (GI) injury and dysbiosis are adverse events associated with nonsteroidal anti-inflammatory drug (NSAID) use in horses. Phenylbutazone has been shown to alter GI barrier function both in vitro and ex vivo, but its effects on barrier function have not been assessed in vivo. In addition, the ability of nutritional therapeutics to prevent these changes is not known. Objective: Our objectives were to determine whether (a) phenylbutazone affected barrier function in vivo and (b) if phenylbutazone-induced GI injury could be ameliorated by the use of a nutritional therapeutic. Methods: Thirty healthy horses were randomly assigned to 3 groups (n = 10 per group): control, phenylbutazone, or phenylbutazone plus nutritional therapeutic. Methods: This study was conducted as a blinded, randomized block design. All horses were managed identically throughout the study period. Samples were collected throughout the study period to monitor fecal microbiota changes and gastric ulcers before and after treatment. Quantification of the bacterial 16S rRNA gene in blood was used as a marker of intestinal permeability. Results: Phenylbutazone increased amounts of bacterial 16S rDNA in circulation 3.02-fold (95% confidence interval [CI], 0.1.89-4.17), increased gastric ulceration score by a mean of 1.1 grade (P = .02), and induced specific changes in the microbiota, including loss of Pseudobutyrivibrio of family Lachnospiraceae. These changes were attenuated by nutritional treatment. Conclusions: Collectively, these findings suggest that phenylbutazone induces GI injury, including impaired barrier function, and that nutritional treatment could attenuate these changes.
© 2021 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.
Publication Date: 2021-03-03 PubMed ID: 33656183PubMed Central: PMC7995434DOI: 10.1111/jvim.16093Google Scholar: Lookup
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- Journal Article
- Randomized Controlled Trial
- Veterinary
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
The study assessed the effects of phenylbutazone, a common nonsteroidal anti-inflammatory drug (NSAID) used in horses, on the gastrointestinal system. The scientists also evaluated a nutritional therapeutic treatment that may effectively mitigate the adverse effects of the drug. They found that phenylbutazone negatively affected the horses’ digestive health, but that these impacts could be lessened through the nutritional regimen.
Objectives of the Research
- The principal intention of this study was to understand how phenylbutazone, an NSAID often administered to horses, influences gastrointestinal barrier functions in a live setting.
- Further, the investigators examined whether a nutritional therapeutic could alleviate the gastrointestinal injuries thought to be instigated by phenylbutazone.
Research Methodology
- The study involved thirty healthy horses allocated randomly into one of three groups, each group containing ten horses. One group was the control (receiving no treatment), the second was treated solely with phenylbutazone, and the third group was administered both phenylbutazone and the nutritional therapy.
- The trial was conducted as a blind study, meaning participants were unaware of which treatment was administered.
- Samples were collected throughout the study period to track changes in fecal microbiota and monitor the progression of gastric ulcers before and after treatment.
- Measurement of bacterial 16S rRNA genes in the horses’ blood served as an indicator of intestinal permeability.
Findings of the Study
- Phenylbutazone increased bacterial 16S rDNA in circulation by over three times and amplified the gastric ulceration score by an average of 1.1 grade, indicating damage to the gastrointestinal barrier.
- The drug also triggered specific changes in microbiota, including a reduction of a bacterial genus in the Lachnospiraceae family, Pseudobutyrivibrio.
- The nutritional treatment deployed in conjunction with phenylbutazone muted these adverse changes.
Conclusions of the Research
- The results of the investigation point to the conclusion that phenylbutazone can lead to gastrointestinal harm and disturb barrier function in horses.
- However, the associated changes could be softened through the nutritional treatment, suggesting possible paths towards safer application of phenylbutazone in veterinary medicine.
Cite This Article
APA
Whitfield-Cargile CM, Coleman MC, Cohen ND, Chamoun-Emanuelli AM, DeSolis CN, Tetrault T, Sowinski R, Bradbery A, Much M.
(2021).
Effects of phenylbutazone alone or in combination with a nutritional therapeutic on gastric ulcers, intestinal permeability, and fecal microbiota in horses.
J Vet Intern Med, 35(2), 1121-1130.
https://doi.org/10.1111/jvim.16093 Publication
Researcher Affiliations
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas, USA.
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas, USA.
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas, USA.
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas, USA.
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas, USA.
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas, USA.
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas, USA.
- Department of Animal Science, College of Agriculture & Life Sciences Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas, USA.
- Department of Animal Science, College of Agriculture & Life Sciences Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas, USA.
MeSH Terms
- Animals
- Anti-Inflammatory Agents, Non-Steroidal / adverse effects
- Horse Diseases / chemically induced
- Horse Diseases / drug therapy
- Horses
- Microbiota
- Permeability
- Phenylbutazone / adverse effects
- RNA, Ribosomal, 16S / genetics
- Stomach Ulcer / chemically induced
- Stomach Ulcer / drug therapy
- Stomach Ulcer / veterinary
Grant Funding
- Cohen / Link Equine Research Endowment
- Platinum Performance
- TEX09730 / United States Department of Agriculture (USDA) National Institute of Food and Agriculture (NIFA)
- National Institute of Food and Agriculture
- United States Department of Agriculture
Conflict of Interest Statement
The potential conflicts related to this study include: 1) Platinum Performance has provided financial support to our laboratory in the form of donations for gastroenterology research. 2) Dr. Whitfield‐Cargile has spoken at educational meetings that Platinum Performance has organized, and received honoraria for participation in 1 in‐person meeting and 1 webinar. 3) Platinum Performance provided gifts to members of our laboratory and routinely donates these items to our VMTH. These potential conflicts we managed in the following ways: 1) Platinum Performance has provided financial support (as a research gift) to our laboratory. They have had no control of this study or any other research conducted in our laboratory. Study design and execution were the sole responsibility of the authors of this study. In addition, Platinum Performance has had no input on what we chose to publish regardless of our laboratory\'s findings. 2) All horses and samples were blinded for all data in this manuscript. For example, the author performing gastroscopy and scoring gastric ulcers was blinded to treatment group and has no personal conflicts of interest with Platinum Performance. 3) All samples (blood and feces) were coded in a way that prevented anyone from knowing the group assignment until data were analyzed. 4) A placebo paste was used to further blind all study personnel in the study as to group assignment.
References
This article includes 52 references
- Scarpignato C, Hunt RH. Nonsteroidal antiinflammatory drug‐related injury to the gastrointestinal tract: clinical picture, pathogenesis, and prevention.. Gastroenterol Clin North Am 2010;39:433‐464.
- Duz M, Marshall J, Parkin T. Proportion of nonsteroidal anti‐inflammatory drug prescription in equine practice.. Equine Vet J 2019;51:147‐153.
- Cook VL, Meyer CT, Campbell NB, Blikslager AT. Effect of firocoxib or flunixin meglumine on recovery of ischemic‐injured equine jejunum.. Am J Vet Res 2009;70:992‐1000.
- Richardson LM, Whitfield‐Cargile CM, Cohen ND, Chamoun‐Emanuelli AM, Dockery HJ. Effect of selective versus nonselective cyclooxygenase inhibitors on gastric ulceration scores and intestinal inflammation in horses.. Vet Surg 2018;47:784‐791.
- Cohen ND, Carter GK, Mealey RH, Taylor TS. Medical management of right dorsal colitis in 5 horses: a retrospective study (1987‐1993).. J Vet Intern Med 1995;9:272‐276.
- Whitfield‐Cargile CM, Chamoun‐Emanuelli AM, Cohen ND, Richardson LM, Ajami NJ, Dockery HJ. Differential effects of selective and non‐selective cyclooxygenase inhibitors on fecal microbiota in adult horses.. PLoS One 2018;13:e0202527.
- Fukui H. Endotoxin and other microbial translocation markers in the blood: a clue to understand leaky gut syndrome.. Cell Mol Med 2019;2:1‐14.
- McConnico RS, Morgan TW, Williams CC. Pathophysiologic effects of phenylbutazone on the right dorsal colon in horses.. Am J Vet Res 2008;69:1496‐1505.
- D'Arcy‐Moskwa E, Noble GK, Weston LA. Effects of meloxicam and phenylbutazone on equine gastric mucosal permeability.. J Vet Intern Med 2012;26:1494‐1499.
- Makivuokko H, Tiihonen K, Tynkkynen S. The effect of age and non‐steroidal anti‐inflammatory drugs on human intestinal microbiota composition.. Br J Nutr 2010;103:227‐234.
- Uejima M, Kinouchi T, Kataoka K, Hiraoka I, Ohnishi Y. Role of intestinal bacteria in ileal ulcer formation in rats treated with a nonsteroidal antiinflammatory drug.. Microbiol Immunol 1996;40:553‐560.
- Hagiwara M, Kataoka K, Arimochi H, Kuwahara T, Ohnishi Y. Role of unbalanced growth of gram‐negative bacteria in ileal ulcer formation in rats treated with a nonsteroidal anti‐inflammatory drug.. J Med Investig 2004;51:43‐51.
- Whitfield‐Cargile CM, Cohen ND, Chapkin RS. The microbiota‐derived metabolite indole decreases mucosal inflammation and injury in a murine model of NSAID enteropathy.. Gut Microbes 2016;7:246‐261.
- Bjorklund M, Ouwehand AC, Forssten SD. Gut microbiota of healthy elderly NSAID users is selectively modified with the administration of Lactobacillus acidophilus NCFM and lactitol.. Age (Dordr) 2012;34:987‐999.
- Endo H, Higurashi T, Hosono K. Efficacy of Lactobacillus casei treatment on small bowel injury in chronic low‐dose aspirin users: a pilot randomized controlled study.. J Gastroenterol 2011;46:894‐905.
- Hu HH, MacAllister CG, Payton ME. Evaluation of the analgesic effects of phenylbutazone administered at a high or low dosage in horses with chronic lameness.. J Am Vet Med Assoc 2005;226:414‐417.
- Orsini JA, Ryan WG, Carithers DS, Boston RC. Evaluation of oral administration of firocoxib for the management of musculoskeletal pain and lameness associated with osteoarthritis in horses.. Am J Vet Res 2012;73:664‐671.
- Toutain PL, Autefage A, Legrand C. Plasma concentrations and therapeutic efficacy of phenylbutazone and flunixin meglumine in the horse: pharmacokinetic/pharmacodynamic modelling.. J Vet Pharmacol Ther 1994;17:459‐469.
- Murray MJ, Nout YS, Ward DL. Endoscopic findings of the gastric antrum and pylorus in horses: 162 cases (1996‐2000).. J Vet Intern Med 2001;15:401‐406.
- Sykes BW, Hewetson M, Hepburn RJ, Luthersson N, Tamzali Y. European College of Equine Internal Medicine Consensus Statement—Equine gastric ulcer syndrome in adult horses.. J Vet Intern Med 2015;29:1288‐1299.
- Vrakas S, Mountzouris KC, Michalopoulos G. Intestinal bacteria composition and translocation of bacteria in inflammatory bowel disease.. PLoS One 2017;12:e0170034.
- Kramski M, Gaeguta AJ, Lichtfuss GF. Novel sensitive real‐time PCR for quantification of bacterial 16S rRNA genes in plasma of HIV‐infected patients as a marker for microbial translocation.. J Clin Microbiol 2011;49:3691‐3693.
- Potgieter M, Bester J, Kell DB, Pretorius E. The dormant blood microbiome in chronic, inflammatory diseases.. FEMS Microbiol Rev 2015;39:567‐591.
- Šidák Z. Rectangular confidence regions for the means of multivariate normal distributions.. J Am Stat Assoc 1967;62:626‐633.
- Whitfield‐Cargile CM, Cohen ND, Suchodolski J. Composition and diversity of the fecal microbiome and inferred fecal metagenome does not predict subsequent pneumonia caused by Rhodococcus equi in foals.. PLoS One 2015;10:e0136586.
- Caporaso JG, Kuczynski J, Stombaugh J. QIIME allows analysis of high‐throughput community sequencing data.. Nat Methods 2010;7:335‐336.
- McMurdie PJ, Holmes S. Phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data.. PLoS One 2013;8:e61217.
- Callahan BJ, McMurdie PJ, Rosen MJ. DADA2: high resolution sample inference from Illumina amplicon data.. Nat Methods 2016;13:581‐583.
- McMurdie PJ, Holmes S. Waste not, want not: why rarefying microbiome data is inadmissible.. PLoS Comput Biol 2014;10:e1003531.
- Lozupone C, Knight R. UniFrac: a new phylogenetic method for comparing microbial communities.. Appl Environ Microbiol 2005;71:8228‐8235.
- Oksanen Jari, Blanchet F. Guillaume, Friendly Michael, Kindt Roeland, Legendre Pierre, McGlinn Dan, Simpson L., Solymos Peter. Vegan: Community Ecology Package.. 2019.
- Martin BD, Witten D, Willis AD. Modeling microbial abundances and dysbiosis with beta‐binomial regression.. Ann Appl Stat 2020;14:94‐115.
- Pedersen SK, Cribb AE, Read EK, French D, Banse HE. Phenylbutazone induces equine glandular gastric disease without decreasing prostaglandin E(2) concentrations.. J Vet Pharmacol Ther 2018;41:239‐245.
- Thakre‐Nighot M, Blikslager AT. Indomethacin induces increase in gastric epithelial tight junction permeability via redistribution of occludin and activation of p38 MAPK in MKN‐28 cells.. Tissue Barriers 2016;4:e1187325.
- Takeuchi K. Prostaglandin EP receptors and their roles in mucosal protection and ulcer healing in the gastrointestinal tract.. Adv Clin Chem 2010;51:121‐144.
- Chamoun‐Emanuelli AM, Bryan LK, Cohen ND. NSAIDs disrupt intestinal homeostasis by suppressing macroautophagy in intestinal epithelial cells.. Sci Rep 2019;9:14534.
- Handa O, Majima A, Onozawa Y. The role of mitochondria‐derived reactive oxygen species in the pathogenesis of non‐steroidal anti‐inflammatory drug‐induced small intestinal injury.. Free Radic Res 2014;48:1095‐1099.
- Xiao X, Nakatsu G, Jin Y. Gut microbiota mediates protection against enteropathy induced by indomethacin.. Sci Rep 2017;7:40317.
- Wallace JL, Syer S, Denou E. Proton pump inhibitors exacerbate NSAID‐induced small intestinal injury by inducing dysbiosis.. Gastroenterology 2011;141:1314‐1322.1322.e1‐5.
- Watanabe T, Tanigawa T, Shiba M. Anti‐tumour necrosis factor agents reduce non‐steroidal anti‐inflammatory drug‐induced small bowel injury in rheumatoid arthritis patients.. Gut 2014;63:409‐414.
- Tyagi A, Kumar U, Reddy S. Attenuation of colonic inflammation by partial replacement of dietary linoleic acid with α‐linolenic acid in a rat model of inflammatory bowel disease.. Br J Nutr 2012;108:1612‐1622.
- Dougal K, Harris PA, Girdwood SE. Changes in the total fecal bacterial population in individual horses maintained on a restricted diet over 6 weeks.. Front Microbiol 2017;8:1502.
- Hond ED, Peeters M, Hiele M. Effect of glutamine on the intestinal permeability changes induced by indomethacin in humans.. Aliment Pharmacol Ther 1999;13:679‐685.
- Kretzmann NA, Fillmann H, Mauriz JL. Effects of glutamine on proinflammatory gene expression and activation of nuclear factor kappa B and signal transducers and activators of transcription in TNBS‐induced colitis.. Inflamm Bowel Dis 2008;14:1504‐1513.
- Rötting AK, Freeman DE, Constable PD. Effects of phenylbutazone, indomethacin, prostaglandin E2, butyrate, and glutamine on restitution of oxidant‐injured right dorsal colon of horses in vitro.. Am J Vet Res 2004;65:1589‐1595.
- Kasiraj AC, Harmoinen J, Isaiah A. The effects of feeding and withholding food on the canine small intestinal microbiota.. FEMS Microbiol Ecol 2016;92:fiw085.
- Salem SE, Maddox TW, Berg A. Variation in faecal microbiota in a group of horses managed at pasture over a 12‐month period.. Sci Rep 2018;8:8510.
- Forbes JD, Van Domselaar G, Bernstein CN. The gut microbiota in immune‐mediated inflammatory diseases.. Front Microbiol 2016;7:1081‐1081.
- Kopečný J, Zorec M, Mrázek J, Kobayashi Y, Marinšek‐Logar R. Butyrivibrio hungatei sp. nov. and Pseudobutyrivibrio xylanivorans sp. nov., butyrate‐producing bacteria from the rumen.. Int J Syst Evol Microbiol 2003;53:201‐209.
- Zheng L, Kelly CJ, Battista KD. Microbial‐derived butyrate promotes epithelial barrier function through IL‐10 receptor‐dependent repression of Claudin‐2.. J Immunol 2017;199:2976‐2984.
- Rigottier‐Gois L. Dysbiosis in inflammatory bowel diseases: the oxygen hypothesis.. ISME J 2013;7:1256‐1261.
- Banse HE, Andrews FM. Equine glandular gastric disease: prevalence, impact and management strategies.. Vet Med (Auckl) 2019;10:69‐76.
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