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© 2006 The American Society for Nutrition J. Nutr. 136:2103S-2107S, July 2006

Supplement: Countermeasures to Laminitis: The Role of Pasture Components in Laminitis

Gastrointestinal Derived Factors Are Potential Triggers for the Development of Acute Equine Laminitis1,2

Jonathan Elliott3 and Simon R. Bailey

Department of Veterinary Basic Sciences, The Royal Veterinary College, London, UK

3 To whom correspondence should be addressed. E-mail: jelliott{at}rvc.ac.uk.


   ABSTRACT
TOP
 ABSTRACT
LITERATURE CITED
 
Equine laminitis is the painful and debilitating condition resulting from cellular damage and inflammation of the tissues comprising the bonds supporting the pedal bone within the hoof capsule. One of the reasons why this condition is so complicated and enigmatic is its association with gastrointestinal disturbances, particularly a diet of lush grass at certain times of the year. Determining the link between disturbances to the hindgut flora and pathophysiology in the foot is one of the keys to preventing this condition. Therefore, one of the biggest challenges in equine laminitis research is to determine those events that precede the onset of the classical clinical signs of lameness, bounding digital pulses, and warm feet. A main theory for the pathogenesis of acute laminitis involves the development of vasoconstriction within the foot, which leads to ischemic and/or inflammatory tissue damage. Serotonin is an important constrictor mediator controlling digital blood flow. Certain equine hindgut bacteria produce amino acid decarboxylase enzymes that convert free amino acids into monoamines. Therefore, amines formed and released from the gastrointestinal tract are hypothesized to act as the link between the ingestion of lush grass and the digital ischemia thought to precede laminitis. Equine cecal contents contain a range of amines that are present in micromolar concentrations. Tryptamine is the most potent cecum-derived amine, causing vasoconstriction in vitro and in vivo through direct activation of serotonin receptors and displacing serotonin from platelets. Monoamines found in the cecum of the horse could potentially induce hemodynamic disturbances in the digit that result in laminar ischaemia, and so trigger laminitis.

KEY WORDS: • equine cecum • laminitis • amines • fructans

Equine laminitis remains a very common condition in the equine population. Following acute episodes, severe tissue damage may ultimately lead to detachment of the pedal bone and to chronic crippling lameness. Management of the chronic case is usually unrewarding, and intervention in the acute stage is a process of damage limitation and pain relief, focusing on efforts to stabilize the pedal bone within the hoof capsule to prevent the catastrophic complications of pedal bone rotation. Important as these factors are in the clinical syndrome, if we are to prevent laminitis from occurring in horses grazing at pasture, we need to understand the pathophysiological pathways that are activated to trigger the series of events leading to this clinical syndrome. Therefore, one of the biggest challenges facing those researching equine laminitis is to determine those events that precede the onset of the classical clinical signs of lameness, bounding digital pulses, and warm feet.

Pasture-induced laminitis, as its name suggests, is thought to be associated with excessive ingestion of pasture. Thus, the natural place to start in a search for trigger factors for laminitis is the gastrointestinal tract. Fermentable carbohydrate is thought to initiate the changes in the hindgut flora, which results in the cascade of events leading to this syndrome. Indeed, a systemic syndrome with similarities to pasture-induced laminitis can be induced in ponies and horses by oral administration of starch (1). This generally results in clinical signs of laminitis in ~24–48 h, although the severe changes that occur in the hindgut may cause diarrhea and endotoxemia, which are not generally thought to be a feature of the condition when horses are at pasture. In this model, Gram positive bacteria, notably the lactic acid–producing lactobacilli and streptococci, overgrow, and the resulting change in the environment of the hindgut may alter the growth and turnover of other bacterial populations (1).

Pasture-induced laminitis is a very difficult problem to study because of its sporadic occurrence in susceptible animals and its dependence on the climatic conditions. Studies in the U.K. indicate that the prevalence of pasture-induced laminitis is influenced by grass growth. Epidemiological studies in a closed herd in East Anglia demonstrate a distinct relation between the prevalence of laminitis and hours of sunshine (2). Clearly, the start of the disease process by which laminitis occurs begins with the ingestion of rapidly growing grass, probably of high carbohydrate content. Recent work has implicated grass storage carbohydrates, fructans, in this phenomenon (3), although direct evidence that the ingestion of fructan-rich grass causes laminitis is still lacking. Purified, commercially available fructo-oligosaccharides, such as inulin, can also be used to produce an experimental model of laminitis (4). Fructans are a readily fermentable source of carbohydrate that escapes small intestinal digestion and gains access to the cecum and large intestine, as can starch, if administered or consumed in excess of the small intestinal digestive capacity.

Thus, it seems likely that toxic compounds, produced either by carbohydrate-fermenting bacteria or from the death or adaptive metabolism of other bacteria, are released from the intestine into the circulation. These compounds then directly or indirectly trigger the changes seen in laminitis.

The experimental models mentioned above have proven to be useful in exploring possible candidates for laminitis trigger factors. However, there is currently debate among research scientists as to the pathogenic pathways leading to the clinical syndrome we recognize as laminitis. Early work in this field suggested that pathological changes in the foot were a result of reduced blood flow to the sensitive laminae, which leads to relative ischaemia and the clinical signs resulting from reperfusion of the laminar tissues (5). The histopathology occurring in the lamellar tissues in the later stages of the developmental phase, and accompanying the onset of clinical signs, is consistent with ischaemia-reperfusion injury (5), although molecular biological techniques are now also demonstrating inflammatory cytokine induction (6). Alternative hypotheses therefore suggest that trigger factors from the gastrointestinal tract activate inflammation in the prodromal stages (6). Increased activity of matrix metalloproteinases (MMPs) is an important feature of the acute phase of the disease (7), and induction of these enzymes can occur in response to inflammatory cytokines. MMP activation leads to the breakdown of the basement membrane, a structure which is key to the stability of the structures of the hoof (8). A further hypothesis is that these enzymes are directly activated by exotoxins produced by the hindgut bacteria (9). These hypotheses are not mutually exclusive, because ischaemia is also a powerful activator of MMPs in other tissues.

Following the early studies concerning carbohydrate overload, it was hypothesized that endotoxin, released from the cell walls of dying Gram negative bacteria, could be the factor triggering acute laminitis, insofar as laminitis is also a common sequel to certain forms of colic (10) and endotoxin could be detected in the plasma of horses given carbohydrate overload (11). Subsequently, studies administering endotoxin to horses have failed to induce laminitis (12) and in other models of experimental laminitis, no endotoxin was detected (13). Therefore, the role of endotoxin in laminitis is questionable (14). Some of the early inflammatory changes in the laminar tissues could, nevertheless, be consistent with the effects of mild endotoxemia.

Much research needs to be done to identify the factors produced in the gastrointestinal tract and explain why, in some susceptible horses, their production leads to clinical signs of pasture-induced laminitis. Research involving a naturally occurring disease, and which addresses the pathophysiological pathways involved, is challenging and requires interventional studies to determine the efficacy of prophylactic measures. Such studies are expensive to perform and so their design needs to be based on high quality data generated both in vitro and in vivo in experimental animals before these questions can be answered. The work summarized below presents the current evidence to support a role for amines generated in the gastrointestinal tract as trigger factors for laminitis.

The role of amines in pasture-induced laminitis

    Background. The hemodynamic theories of the pathophysiology of laminitis date back to the 1970s where models of laminitis (starch overload) (15) allowed researchers to assess hoof perfusion at different stages of the experimentally induced syndrome. The validity of these methods and their relevance to pasture-induced laminitis is still disputed. Nevertheless, there is strong evidence that blood flow to the sensitive laminae is disturbed at some stage in the disease process, and a number of researchers suggest that ischaemia reperfusion injury is the basic mechanism of laminitis (5,16,17). An important question resulting from these studies is whether there is a link between feeding carbohydrates and changes in perfusion of the hoof wall.

    Amines: The link between events in the gut and ischaemia of the foot. Studies at the Royal Veterinary College were stimulated by those of Baxter et al. (18), who demonstrated the high sensitivity of digital blood vessels to serotonin, the biogenic amine contained in both enterochromaffin cells of the gut wall and in platelets. This finding, coupled with the work of Weiss et al. (19,20), which demonstrated the importance of platelets in models of laminitis, led us to focus on serotonin as a potentially important mediator.

Our own work demonstrates the exquisite sensitivity of digital blood vessels to serotonin compared with peripheral vessels of similar size (Fig. 1; (21)). Digital arteries were found to be 30–40 times more sensitive to the constrictor effects of serotonin, and this was, in part, explained by the relatively ineffective counter-regulation of vasoconstriction provided by the vascular endothelium of the large vessels. The normal free plasma concentration of serotonin appears to be above the threshold for causing constriction in digital arteries (21) and would suggest that this mediator plays an important role in controlling blood flow in this vascular bed. Furthermore, factors increasing the release of serotonin from platelets, or preventing its clearance from the circulation, could have significant effects on digital blood flow. We also demonstrate the complexity of the serotonin receptor systems present in the digital vasculature (22).


Figure 1
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  		FIGURE 1  Contractile effects of 5-hydroxytryptamine (5-HT) on equine digital arteries ({blacksquare}), compared with facial ({circ}) and tail ({triangleup}) arteries from the same animals. Digital arteries are 30–40-fold more sensitive to the contractile effects of 5-HT compared with the other peripheral arteries. The vertical line represents the normal free plasma concentration of 5-HT, above the threshold for contraction in digital arteries. Each value represents the mean ± SEM, n = 6. Reproduced from Bailey and Elliott (21) with permission.

 
Foods produced by bacterial fermentation are high in amine content because the bacteria responsible for the fermentation of carbohydrate produce enzymes (amino acid decarboxylase enzymes) that convert free amino acids into monoamines. The human medical literature on monoamines shows that ingestion of fermented foodstuffs (cheese and wine) can lead to migraine or hypertension in some individuals (23–25). This can occur because the amines are able to mimic the effects of biogenic amines (serotonin, epinephrine, norepinephrine, and dopamine) in the circulation. Thus, in the late 1990s it seemed reasonable to hypothesize that amines formed and released from the gastrointestinal tract might act as the link between ingestion of lush grass, rich in oligosaccharides and the digital ischaemia thought to precede the onset of clinical signs of pasture-induced laminitis.

    Evidence that amines are formed in the equine gut. Support for the hypothesis that gut-derived amines are part of the link between the gut and the digital circulation in the pathophysiology of laminitis comes from in vitro and in vivo experimental studies and clinical observational studies. Cecal liquor contains a range of monoamines and diamines each present in the micromolar concentrations (26). Furthermore, cecal contents harvested from horses fed spring/summer grass had 2 to 3-fold higher concentrations of some mono and diamines compared with cecal contents harvested from animals fed winter grass or hay (26). To investigate this further, we used an in vitro model of the cecum, culturing equine cecal contents anaerobically and supplying starch or inulin to simulate excessive intake of carbohydrate. This resulted in a time-dependent decrease in cecal pH and increase in phenylethylamine and isoamylamine concentration (Fig. 2) (27). Some of the bacteria-producing amines have been identified as Lactobacillus spp. and Streptococcus bovis, which proliferated in this model. Virginiamycin inhibited the proliferation of both groups of bacteria (28) and abrogated the decrease in pH and the increase in amine production caused by excessive starch and inulin (27). Virginiamycin, the streptogrammin antibiotic, is the active ingredient in Founderguard (Vetsearch International), which has been marketed for the prevention of acute laminitis, and has been shown to prevent experimentally induced laminitis (29). Taking these studies from in vitro incubations into the in vivo situation, preliminary data show that increasing the oligosaccharide content of the diet, by adding a small amount of inulin, results in a decrease in fecal pH (30) and a rise in fecal amine concentrations (C. Crawford, S. R. Bailey, P. A. Harris, and J. Elliott, unpublished data). Monoamines present in the cecum can also be detected at much lower concentrations in the blood plasma. Furthermore, ponies sampled in the winter period had lower circulating concentrations of the monoamines tryptamine, phenylethylamine, isoamylamine, and tyramine than when they were sampled in the spring period (31).


Figure 2
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  		FIGURE 2  Effects of carbohydrate overload on phenylethylamine concentrations in equine cecal contents incubated anaerobically in vitro. Cecal contents were divided into aliquots and incubated for 24 h with the inclusion of either inulin (1 g/100 mL; {blacktriangledown}), corn starch (1 g/100 mL; {blacktriangleup}) or without added carbohydrate (control; {blacksquare}). Each value represents the mean ± SEM of estimates taken from 4 separate experiments. *Different from control values using 2-way repeated measures ANOVA with Bonferroni's post hoc test; P < 0.05. Reproduced from Bailey et al. (27) with permission.

 
    Vascular effects of amines. Monoamines formed in the cecum of the horse are structurally related to the platelet-derived amine serotonin and the sympathetic neurotransmitter norepinephrine. It is not surprising, therefore, that they are capable of mimicking and potentiating the effects of these endogenous mammalian biogenic amines. Potentiation of the action of the endogenous mammalian amines occurs through the inhibition of uptake processes into endothelial cells (32) and platelets (33) or by competition between the gut-derived and the endogenous mammalian amines for metabolism by amine oxidase enzymes. Gut-derived amines mimic the actions of the endogenous biogenic amines by displacing serotonin from platelets or norepinephrine from sympathetic nerve endings or by directly activating the receptors for these amines on the vasculature (34). Tryptamine is the most potent cecum-derived amine in many respects. It causes vasoconstriction via direct activation of serotonin receptors, with a marked selectivity for digital veins and a threshold for causing digital venous constriction of 30 nmol/L (Fig. 3) (34).


Figure 3
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  		FIGURE 3  Vasoconstrictor effects of tryptamine on digital veins ({blacktriangleup}) and digital arteries ({blacksquare}). Log of the amine concentration has been plotted against the vasoconstrictor response expressed as a percentage of the response to depolarizing Krebs solution (118 mM K+). Each point represents the mean ± SEM value obtained in vessels from 6 horses. Reproduced from Elliott et al. (34) with permission.

 
Intravenous administration of gut-derived monoamines causes rapid changes in digital perfusion (Fig. 4). These effects occur at dose rates that do not alter systemic arterial blood pressure and are associated with a rise in the free plasma concentration of serotonin (35). Similar changes in plasma serotonin concentrations are reported to occur in association with the starch overload model of laminitis (J. Moore, personal communication). These experiments provide in vivo evidence to support our observations in vitro that amines will reduce blood flow to the foot in the live animal, through direct and indirect mechanisms.


Figure 4
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  		FIGURE 4  Effects of 2 amine compounds: tryptamine (•; 1.6 µg · kg · min–1), and phenylethylamine ({blacktriangleup}; 2.13 µg · kg · min–1) or saline control ({blacksquare}; 30 min infusions, as indicated) on blood flow in the equine palmar digital artery. Blood flow was measured by Doppler ultrasound. Values represent mean ± SEM, n = 6. *Different from time 0 using 1-way ANOVA with Dunnett's post-hoc test; P < 0.05. Reproduced from Bailey et al. (35) with permission.

 
Marked changes in cecal pH have been described in vivo that were induced by rapid fermentation of carbohydrate in the starch overload laminitis model (36). The amine production by certain bacteria, possibly including these carbohydrate fermenters, may actually be part of a defense mechanism to protect the bacterium from changes in intracellular pH (37). Furthermore, changes in the permeability of the wall of the large intestine are induced by decreasing the pH of the intestinal contents (38). The marked drop in pH that accompanies carbohydrate fermentation may therefore allow ready access of amines into the circulation. The challenge is to study whether this phenomenon occurs in the natural disease (pasture-induced laminitis) and to determine why some ponies and horses are exquisitely sensitive to the effects of eating excess carbohydrate and others are not.

    Reasons for increased susceptibility to pasture-induced laminitis. Clinical observations strongly suggest there are differences in susceptibility of ponies and horses to pasture-induced laminitis. These differences may lie in the gut, resulting from the complex interrelation among different bacterial populations of the normal gut flora and from a disruption in response to sudden increases in fermentable carbohydrate. Further work is certainly warranted to determine whether ponies that are susceptible to laminitis have differences in their gut flora, perhaps making them more proficient at amine production in response to carbohydrate overload. The intestinal wall is obviously a barrier to the diffusion of amines into the circulation. Differences in susceptibility to pasture-induced laminitis could lie at the level of the gut wall and its response to changes in pH.

Alternatively, the intrinsic detoxifying abilities of the liver, the sensitivity of the vasculature or the laminar tissues to the toxic and/or vascular effects of trigger factors, may be different in certain individuals. It is clear from other species that blood vessel responses to vasoconstrictor agents are influenced by many factors, including concomitant disease and genotype. Insulin resistance is associated with endothelial cell dysfunction (39) and the endothelium is important in modulating the responses of the vasculature to vasoconstrictor agents. We have used an isolated perfused hoof model to demonstrate the influence of the vascular endothelium on responses of the digital circulation to serotonin (40). These experiments show a marked potentiation of the responses to serotonin when nitric oxide production by the endothelium was inhibited. Furthermore, homocysteine, an amino acid known to disrupt endothelial cell function in other species, also potentiated the vasoconstrictor responses to serotonin. However, we found no evidence of raised circulating plasma concentrations of homocysteine in ponies that are prone to repeated attacks of laminitis (40).

    Conclusions. Monoamines found in the cecum of the horse can potentially induce hemodynamic disturbances in the digit to result in laminar ischaemia, and so trigger laminitis. This hypothesis needs to be tested in naturally occurring pasture-induced laminitis by prospective study. Future goals of this research are to identify the precise mechanisms whereby amine-producing bacteria switch on the decarboxylase enzyme and to determine methods that will prevent them from doing so. In addition, we also need to study the factors governing individual susceptibility of ponies and horses to amine-induced vasoconstriction and determine the underlying diseases and genetic factors that are involved.


   FOOTNOTES
 
1 Published in a supplement to The Journal of Nutrition. Presented as part of The WALTHAM International Nutritional Sciences Symposium: Countermeasures to Laminitis held in Washington, DC, September 14, 2005. This conference was supported by The WALTHAM Centre for Pet Nutrition and organized in collaboration with the Virginia Polytechnic Institute and State University. This publication was supported by The WALTHAM Centre for Pet Nutrition. Guest editors for this symposium were D'Ann Finley, Francis A. Kallfelz, James G. Morris, and Quinton R. Rogers. Guest editor disclosure: expenses for the editors to travel to the symposium and honoraria were paid by The WALTHAM Centre for Pet Nutrition. Back

2 Author disclosure: J. Elliott's conference registration fee was paid by the WALTHAM Centre. Back


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C. Crawford, M. F. Sepulveda, J. Elliott, P. A. Harris, and S. R. Bailey
Dietary fructan carbohydrate increases amine production in the equine large intestine: Implications for pasture-associated laminitis
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