University of Cambridge > > Departmental Seminar Programme, Department of Veterinary Medicine > Current theories on the pathophysiology of equine laminitis – the link between the gut and foot

Current theories on the pathophysiology of equine laminitis – the link between the gut and foot

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Equine laminitis is a painful debilitating condition that seems to be a product of domestication of horses associated with the practice of feeding carbohydrate rich pasture in excess of requirements, particularly in ponies. We have been working on the hypothesis that caecal bacteria, when presented with carbohydrate in large quantities tend to ferment this. Fermentation by gram positive bacteria is associated with a fall in pH of the caecal liquor. As a means of providing themselves with increased intracellular buffering capacity, these bacteria produce amino acid decarboxylase enzymes which convert amino acids present in the caecal fluid into primary amines which can act as intracellular buffers. The reason we thought this might be the case was that foods formed by bacterial fermentation processes (e.g. cheese and wines) have a high content of amines. Primary amines derived from some amino acids have vasoactive properties. In the 1960s it was recognised that human patients taking drugs that inhibit the metabolism of amines (monoamine oxidase inhibitors) could suffer from severe hypertensive crises if they ate cheese or drank red wines with high tyramine content. This so called ‘cheese effect’ is the result of the indirect sympathomimetic effect of tyramine which displaces norepinephrine from sympathetic nerve endings leading to a rise in blood pressure. Monoamine oxidase enzymes present in the epithelial cells lining the gut wall and in liver cells normally protect individuals from suffering these hypertensive crises. We wondered whether amines released from the gut in response to ingestion of excessive amounts of carbohydrate might lead to a similar reaction in ponies whereby dietary amines caused vasoconstriction of the digital vasculature, leading to the prodromal phases of laminitis.

Over the last 10 years we have gathered circumstantial evidence that the amine theory may contribute to laminitis. We showed that amines are present in the caecal fluid of horses and ponies, the concentrations being related to diet and increasing when carbohydrate rich pasture is consumed. We also showed that feeding an in vitro model of the equine caecum with starch and inulin led to concentration and time related increases in concentration of vasoactive amines and gram positive bacteria proliferated and the pH decreased. The amines produced in the caecum could be measured in the plasma. Furthermore they were found at higher concentrations in the systemic circulation in ponies turned out onto spring/summer pasture as compared to when the same ponies were fed winter pasture supplemented with hay. In addition, dietary amines can stimulate the release of 5-hydroxytryptamine from platelets and cause constriction of isolated digital blood vessels. In some cases, the plasma concentrations of these amines in the spring/summer are close to the threshold for causing constriction of the digital circulation. Infusion of some of these amines into the systemic circulation was associated with a reduced digital blood flow and a concomitant rise in plasma 5-HT concentration and inhibitors of 5-HT receptors have been shown to prevent dietary amine-induced digital vasoconstriction.

These data, whilst interesting, do not prove the link between these phenomena and pasture-induced laminitis. Nor do they explain why some ponies are prone to recurrent bouts of laminitis whereas others eating exactly the same pastures year after year never suffer from this debilitating problem. The underlying phenotype of a pony prone to laminitis has recently been suggested to be associated with a resistance to the hormone insulin. The insulin resistance appears to become much more pronounced as the laminitis prone ponies eat carbohydrate rich grass in the spring-summer months. Laminitis prone ponies seem to have higher blood pressure than their ‘normal’ counterparts in these months whereas in the winter months there is no difference between these two groups in their blood pressure. Furthermore, laminitis prone ponies have higher circulating triglyceride and uric acid concentrations when compared to their non-laminitis prone counterparts eating the same pasture. These observations are substantiated by a number of different groups working on laminitis throughout the world yet the reason for the association between this metabolic phenotype (which shares some similarities with ‘metabolic syndrome’ in people) remains to be determined. It is interesting to speculate that the insulin resistant state causes a state of endothelial cell dysfunction, predisposing these ponies to excessive vasoconstriction and platelet activation in the digital circulation when the circulation is exposed to more amines absorbed from the caecum as a result of rapid ingestion of carbohydrate. It is also interesting to note that the endothelium is involved in amine metabolism by an enzyme called semicarbazide sensitive amine oxidase (SSAO) which preferentially metabolises primary monoamines, including one that is not vasoactive but is highly abundant in the caecum, namely methylamine. When the endothelium metabolise primary monoamines, such as methylamine, it produces ammonia, hydrogen peroxide and the corresponding aldehyde of the amine – in the case of methylamine this is formaldehyde. The amine metabolites can be damaging to the endothelium and contribute to endothelial cell dysfunction. Intriguingly, SSAO expression is known to increase in other species in association with the diabetic state where its upregulation has been associated with the vascular complications of diabetes.

To investigate this possibility we have examined endothelial cell function in vitro in equine digital veins and arteries following incubation with non-vasoactive primary monoamines, such as benzylamine and methylamine. Preliminary data suggests that some products of the metabolism of these amines can interfere with endothelial-dependent relaxation, particularly when the nitric oxide system has been partially inhibited. Further work is necessary to investigate this phenomenon further and to determine methods whereby endothelial cell function could be assessed in vivo to test the hypothesis that ponies predisposed to laminitis have endothelial cell dysfunction that is related to their susceptibility to laminitis. In summary, a range of trigger possible trigger factors continue to be investigated in laminitis research. Dietary amines remain possible candidates, although definitive proof awaits prospective interventional clinical trials.

This talk is part of the Departmental Seminar Programme, Department of Veterinary Medicine series.

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