Clostridial colitis can be caused by an overabundance of either Clostridium difficile or Clostridium perfringens. Each of these bacteria produces numerous toxins that combine to cause intestinal inflammation and damage. Horses of any age can be affected. Adult horses are most at risk when the intestinal microbiota has suffered a disturbance. Such disturbances include sudden alterations in the diet, stress, travel, illness or antibiotic administration. Foals are at risk simply from ingestion of clostridial spores, and tend to develop enteritis, rather than colitis.
Introduction to Clostridial Colitis in Horses
The Clostridia genus is a large group of rod-shaped, gram-positive, spore-forming anaerobic bacteria that are normal commensals of the equine GI tract, but in unbalanced dysbiotic conditions can produce a variety of toxins and cause a number of different diseases, including tetanus, botulism, gangrene and colitis.
Clostridium perfringens and Clostridium difficile are the two clostridial species most likely to cause colitis in adult horses and foals. (Weese et al. 2001) found that Clostridium difficile was detected in 22% of adult horses with colitis, and 17% of foals with colitis, while Clostridium perfringens was identified in 19% of adult colitis cases, and 29% of foal cases.
Clostridium difficile can cause primary colitis in horses, however it is also frequently involved in the development of antibiotic-induced colitis. C. difficile is an obligate anaerobe, and therefore very difficult to culture from feces, unless the feces are collected and processed under strictly anaerobic conditions. This makes diagnosis in every-day practice a challenge.
Modern PCR assays can, however, detect the genes coding for clostridial toxins in feces. Clostridium difficile produces two important toxins, named Type A and Type B. Identifying these two toxins in the feces of a horse with colitis is a useful diagnostic tool.
Although Clostridium perfringens is more ‘aerotolerant’ than C. difficile and is easier to culture in feces, this bacterium is near ubiquitous in the environment and is frequently present in the feces of normal horses. This also makes accurate diagnosis difficult.
Five types of C. perfringens have been described (A to E) based on the production of four major toxins in different combinations – alpha, beta, epsilon and iota (Table 1). Other important toxins are also produced by the five types, including the beta 2 toxin, CPE (Clostridium perfringens enterotoxin) and the netF toxin. All of these toxins can be identified in feces and assist in making a diagnosis of C. perfringens colitis. There are additional toxins, some of which are not yet fully understood or identified.
| Strain of C. perfringens | Toxins |
|---|---|
| Type A | Alpha |
| Type B | Alpha, beta, epsilon |
| Type C | Alpha, beta |
| Type D | Alpha and epsilon |
| Type E | Alpha and iota |
Epidemiology and Pathophysiology of Clostridial Colitis
Horses are at risk of developing colitis when there has been disruption to the balance of the normal microbiota in the intestinal tract. Such disruptions include a rapid change in diet, anorexia due to disease, and stressful events (that also lead to diet changes) such as travel, competition or hospitalization. Antibiotic administration can also significantly alter the intestinal microbiota of the intestinal tract. Certain bacteria can thrive and multiply in these altered conditions, the most harmful examples being Salmonella spp. and Clostridium spp.
Clostridial spores are highly resistant to environmental conditions and disinfectants, and can persist in the environment, especially in soil. When a horse ingests spores, the spores usually pass harmlessly through the intestinal tract, unaltered. However, if the microbiota has been disrupted and the conditions are right, the spores can transform into the active vegetative state, multiply and potentially produce toxins.
C. perfringens and C. difficile produce particularly harmful toxins of a variety of types. The action of many of these toxins is to bind to epithelial cell-surface receptors and gain access to the inside of the cell where they can disrupt a variety of important intracellular enzymatic processes. The consequences can include disintegration of epithelial junctions, breakdown of cell cytoskeletons and formation of pores that leak electrolytes and fluid. The toxins can also cause intestinal inflammation and increase the permeability of blood vessels. Diarrhea, epithelial necrosis, endotoxemia, septicemia and the formation of a pseudomembranous lining of the intestinal tract, composed of yellowish plaques of mucus and pus, are potential outcomes.
Antibiotics that have been associated with development of clostridial colitis include (Barr et al. 2013):
- β-lactam antibiotics – penicillin, ceftiofur
- β-lactam antibiotics in combination with gentamicin or sulfonamides
- Sulfonamides or potentiated sulfonamides
- Enrofloxacin
- Doxycycline
- Oxytetracycline
If nursing foals are being treated for Rhodococcus equi infections with macrolide antibiotic (i.e. erythromycin), the mares may be at risk of developing clostridial colitis if they inadvertently ingest the antibiotic.
Foals develop clostridial intestinal disease simply by ingestion of the bacteria.
Clinical Presentation of Clostridial Colitis
Clostridial colitis can occur in horses of any age. The disease has been reported in outbreaks, but also as individual events.
The symptoms of clostridial colitis range from mild self-limiting diarrhea, to acute fulminant hemorrhagic diarrhea and rapid deterioration to death. A rare, severe, alternative presentation of clostridial colitis involves hypomotility of the colon, with no diarrhea production, and severe abdominal pain that can resemble surgical-grade colic (Magdesian 2003). The horses are usually depressed, can be weak, and may rapidly progress to collapse in acute cases.
Rectal temperature can fluctuate from high to subnormal due to fever spikes, or the presence of hypovolemia and cardiovascular shock.
Endotoxemia may develop as a result of intestinal inflammation and altered mucosal integrity. Tachycardia, tachypnea, and congestion and/or injection of the mucous membranes can indicate endotoxemia.
Further complications from severe disease include coagulopathies (i.e. venous thrombosis), laminitis, and edema of the distal limbs and other ventrally dependent areas of anatomy. The edema can occur as a combination of hypoproteinemia and peripheral vasculature derangements from endotoxemia or sepsis.
Septicemia and intestinal perforation are rare, with serious/fatal consequences.
Foals are more prone to small intestinal clostridial disease (enteritis) and will become obtunded, have a decreased suckle, abdominal distension and colic. Afflicted foals can deteriorate rapidly and die before showing signs of diarrhea.
The presentation may be evident in a variety of ways:
- Hematology: a neutropenia with a left shift and toxic changes is common in the acute phase. As the disease progresses this may change to a mature neutrophilia with elevated fibrinogen
- Biochemistry: if the horse is dehydrated or has circulatory problems due to endotoxemia, the lactate will be elevated, as will the blood urea nitrogen (BUN) and creatinine. These derangements should resolve within 24-48 hours with appropriate fluid therapy, unless there is a secondary problem.
- Electrolyte derangements and metabolic acidosis are typical. If hypocalcemia is present, it is usually secondary to hypoproteinemia.
- Hypoproteinemia can be profound, and can progressively worsen. The severity can be masked if the horse is dehydrated.
- Liver enzymes may show mild elevations secondary to endotoxemia or ascending infections.
- Abdominocentesis results will vary from transudate to exudate depending on the severity of disease.
- Abdominal ultrasound may show some intestinal wall thickening and fluidy luminal contents but these findings are non-specific. Abdominal radiographs are recommended in foals to detect gas and fluid-filled small and large intestine (Magdesian 2003).
Diagnosing Clostridial Colitis in Horses
Accurate diagnosis of Clostridial disease is an area of ongoing research. Fresh fecal samples should be collected into airtight containers and immediately refrigerated and submitted for fecal culture and toxin analysis. The analysis available will depend upon your local laboratory, but many laboratories now have PCR panels available that include analysis of the various Clostridial toxins. A negative culture should not be considered necessarily a negative result, however a positive toxin result can, at this stage, be considered diagnostic (Weese et al. 2001).
Treatment for Clostridial Colitis in Adults and Foals
Any foal with diarrhea, or showing signs of colic and lethargy (especially neonates), should be suspected of having Clostridia, Salmonella or E. coli infections and should be monitored very closely and treated promptly, including administration of broad-spectrum antibiotics.
Antibiotic use in adult horses, on the other hand, requires very careful consideration. If the horse is already on antibiotics prior to the colitis then, if at all possible, the antibiotics should be stopped, as colitis can be more life threatening than the disease being treated. If this is not possible, then consider decreasing the dose or combination of agents used. For example, in many cases aminoglycosides and metronidazole are less likely to place the horse at greater risk, while penicillin may. Each case requires individual consideration.
Metronidazole can help treat the disease. A dose of 15 mg/kg by mouth every 8-12 hours is recommended. Neonatal foals require a lower dose at 10 mg/kg every 12 hours and also should be placed on a broad-spectrum antibiotic regime.
Treatment is otherwise supportive, depending on the severity or disease, presence of endotoxemia and other complicating factors.
Intravenous fluids. Hypertonic or isotonic solutions as required, with additional potassium if indicated.
Plasma therapy. Commercial hyperimmune plasma contains antibodies and important proteins, including albumin, that help maintain circulation, minimize edema, and minimize the effects of endotoxemia. Non-commercial fresh frozen plasma can also be appropriate, if from a reliable source, and 6-8 L of either product is recommended.
Colloid therapy. The less expensive synthetic colloids can be used to support the circulation in the face of hypoproteinemia. Hetastarch (Hydroxyethyl starch) is commonly used.
Nonsteroidal anti-inflammatories (NSAIDS) and Polymixin B administration can also minimize the effects of endotoxemia. NSAIDs may help with abdominal discomfort, as can butorphanol and alpha-2 agonists. Use all of these drugs in consideration of kidney function, gastrointestinal function and circulatory strength.
Cryotherapy for the hooves and distal limbs has been shown to reduce the incidence of laminitis in horses with colitis (Kullman et al. 2014).
Heparin may be required if a coagulopathy occurs.
Di-tri-octahedral smectite (BiospongeTM) may help absorb luminal intestinal toxins.
Nutritional support. Total or partial parenteral (TPN, PPN) nutrition should be considered in neonates. In adult horses, it may be beneficial to offer small amounts of fresh cut grass on a regular basis until the intestines have had time to heal and the horse’s appetite returns, however parenteral nutrition may be required with prolonged disease.
Prevention of Clostridial Colitis in Horses
Keep any horse with diarrhea isolated from other horses. Monitor horses undergoing antibiotic treatment closely and ensure that the owner is aware that they should call immediately if the horse develops loose stools. Ensure that mares with foals being treated for Rhodococcus equi are not inadvertently exposed to the antibiotics.
New and Alternative Treatment Options to Consider
Ongoing research in other species as well as some new research in equines shows the potential utility of some other substances for managing GI health in horses.
Glutamine
Glutamine helps to heal the mucosa and strengthen tight junctions between enterocytes. Treatment with glutamine in farmed animals has shown that it improves gut integrity and weight gain (Fasina, Y. et al. 2010) as well as mucosal healing (Kaya, E. et al. 2007).
Glutamine is a conditionally essential amino acid. During catabolic stress of the bowel, as found in infection and sepsis, glutamine is consumed at a rate exceeding its production, warranting supplementation (Rao, R. et al. 2011).
Glutamine reduces the apoptosis-signaling cascade brought on by the Clostridium toxin A. Glutamine also reduces the disruption of the ileal mucosa brought on by Clostridial infection (Carneiro, B. et al. 2006).
These studies come with a caveat: although they have been conducted on GI tracts in animals as varied as chickens, cows and pigs, there are as yet no similar studies in horses. However, these studies are consistent with reports of the utility of glutamine in right dorsal colitis (Rötting, A. et al. 2004) demonstrating a clear connection between glutamine and equine GI dysbiosis.
Mannan oligosaccharide
Mannan oligosaccharide (MOS) may be useful as a bacterial “sponge”, before, during and after a Clostridia infection. This complex sugar resembles the mannose sugars that coat enterocytes. These sugars are the main target of Clostridia, which binds to them with fimbrial lectins, bacterial projections which act as mannose receptors (Sharon, N. et al. 2015). Clostridia fimbria preferentially latch onto MOS instead of the mannose-coated enterocytes, and the unattached pathogen can then be shed in the feces. MOS can protect equines from most pathogens as effectively as antibiotics (Spring, P. et al. 2015).
MOS may also be useful as an emergency treatment for diarrhea in horses at a rate of 100-200 mg/kg, q8-24h (Orsini, J, et al, 2013).
Antibiotics save lives, but overuse or misuse can lead to resistant bacteria. MOS has not been shown to lead to bacterial resistance, which provides a good rationale for using MOS as a substitute for antibiotics wherever possible.
MOS has no known precautions or side effects (Orsini, J. et al. 2013).
References
- Barr, B.S. et al. (2013) Antimicrobial-associated diarrhea in three equine referral practices. Equine Veterinary Journal 45:154-158.
- Carneiro, B. et al. (2006) “Caspase and Bid Involvement in Clostridium Difficile Toxin A-Induced Apoptosis and Modulation of Toxin A Effects by Glutamine and Alanyl-Glutamine In Vivo and In Vitro.” Infection and Immunity 74, no. 1 (January 1, 2006): 81–87. doi:10.1128/IAI.74.1.81-87.2006.
- Feary, D. et al. (2003) “Enteritis and Colitis in Horses.” Veterinary Clinics of North America: Equine Practice 22, no. 2 (August 2006): 437–79. doi:10.1016/j.cveq.2006.03.008.
- Kaya, E. et al. (2007) “The Effect of L-Glutamine on Mucosal Healing in Experimental Colitis Is Superior to Short-Chain Fatty Acids.” The Turkish Journal of Gastroenterology: The Official Journal of Turkish Society of Gastroenterology 18, no. 2 (June 2007): 89–94.
- Kullmann, A. et al. (2014) Prophylactic digital cryotherapy is associated with decreased incidence of laminitis in horses diagnosed with colitis. Equine Veterinary Journal 46:554-559.
- Magdesian, G. (2003) Clostridium difficile. In: Current Therapy in Equine Medicine 5, chapter ed: AT Blikslager; book ed: N.E. Robinson. Saunders, St Louis Missouri pp. 56-59.
- Orsini, J. et al. (2013) Equine Emergencies: Treatment and Procedures. Elsevier Health Sciences, 2013.
- Rao, R. et al. (2011) “Role of Glutamine in Protection of Intestinal Epithelial Tight Junctions.” Journal of Epithelial Biology & Pharmacology 5, no. Suppl 1-M7 (January 2012): 47–54. doi:10.2174/1875044301205010047.
- Rötting, A. et al. (2004) “Effects of Phenylbutazone, Indomethacin, Prostaglandin E2, Butyrate, and Glutamine on Restitution of Oxidant-Injured Right Dorsal Colon of Horses in Vitro.” American Journal of Veterinary Research 65, no. 11 (November 1, 2004): 1589–95. doi:10.2460/ajvr.2004.65.1589.
- Sharon, N. et al. (2015) “Bacterial Adherence to Cell Surface Sugars.” Ciba Foundation Symposium 80 (1981): 119–41.
- Spearman, K. (2016) MOS supplements in for pregnant mares have been shown to significantly increase IgG, IgM and IgA levels in colostrum. Foals from mares fed MOS have a reduced incidence of diarrhea.
- Spring, P. et al. (2015) “A Review of 733 Published Trials on Bio-Mos®, a Mannan Oligosaccharide, and Actigen®, a Second Generation Mannose Rich Fraction, on Farm and Companion Animals.” Journal of Applied Animal Nutrition 3 (2015): e8 (11 pages). doi:10.1017/jan.2015.6.
- Weese, J.S. et al. (2001) Clostridial Colitis in Adult Horses and Foals: A Prospective Study. AAEP Proceedings 47:400-402
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