link between the gut and the foot:
a summary of some of the work currently being undertaken by the laminitis
research group at the Royal Veterinary College, London.
Bailey BVMS, PhD, MRCVS
is one of the most important conditions affecting the United Kingdom
horse population in terms of prevalence, the serious nature of the condition
for the individual animal and the cost of treatment. From a study involving
113 000 horses in the UK (Hinckley and Henderson, 1996), it was estimated
that the total prevalence of acute laminitis in the UK was over 8,000
cases annually, giving a prevalence of 7.1%. The majority of affected
animals are ponies (Dorn et al, 1975), particularly those at grass,
with a greater prevalence during times of high grass growth; this seasonal
occurrence has been recognised in studies of populations both in the
UK and USA (Hinckley and Henderson, 1996; Dorn et al, 1975). In a recent
study of a large charity farm in East Anglia with a population of 1140
horses and ponies, there were an average of 148 episodes of laminitis
(prevalence of 13%) occurring each year (between 1997 and 1999) involving
113 animals (Katz et al., 2000).
clinical signs of laminitis represent the end result of a systemic condition
which has many predisposing factors such as grain overload, lush pasture
and colic, leading to a common pathogenic pathway (Hood et al, 1993).
The haemodynamic theory of the pathogenesis of acute laminitis suggests
that vasoconstriction within the digital circulation causes a decreased
perfusion to the nutrient laminar capillaries, leading to ischaemia,
followed by painful reperfusion injury and enzyme activation (Hood et
al, 1993; Johnson et al, 1998). This damage may rapidly lead to tearing
of the laminar bonds and displacement of the pedal bone away from the
second theory has been proposed to explain the pathophysiology of acute
laminitis, the connective tissue theory. This proposes that degeneration
of the connective tissue of the basement membrane (Pollitt & Daradka,
1998) mediated by activation of matrix metalloproteases (MMPs) (Johnson
et al., 1998; Pollitt et al., 1998) is a primary event in acute laminitis.
These two theories are not mutually exclusive. Marked activation of
three isoforms of MMPs has been reported to occur in models of myocardial
infarction (Carlyle et al., 1997). It is possible, therefore, that ischaemia
followed by reperfusion could lead to activation of MMPs within the
trigger factor(s) linking the gastrointestinal tract disturbances with
the onset of laminitis are not known precisely. It is known, however,
that excess carbohydrate, reaching the caecum/large intestine, either
in the form of starch from grain or water-soluble fructans from the
pasture, can result in fermentation involving gram positive bacteria
with production of lactic acid and other metabolites. It was previously
thought that endotoxin, released from Gram negative bacteria, was the
cause of laminitis; however endotoxin on its own will not cause laminitis
(Hood, 1995), therefore other potential trigger factors are being investigated.
fermentation processes are undertaken in natural production of food
products, such as cheese, beer or wine, the micro-organisms involved
generate amines as a by-product of the fermentative processes, through
the oxidative decarboxylation of amino acids. Fermentation in the intestinal
tract of herbivores in general, and ruminants in particular, leads to
the formation under certain circumstances of monoamines including tyramine
(Van der Horst 1961; Dain et al., 1955) isoamylamine, phenylethylamine
and isobutylamine (Fraser & Butler 1964). Many of these amines are
vasoactive either directly or because they inhibit the uptake and metabolism
or stimulate the release of naturally occurring vasoactive substances
such as noradrenaline or serotonin (5-hydroxytryptamine).
now have direct evidence that these amines are found in high concentrations
in the caecum of the horse, particularly those on lush spring/summer
grass (Bailey et al., 2000) and are also detectable in much lower concentrations
in the plasma of healthy horses and ponies (unpublished observations).
Increased production of isoamylamine and phenylethylamine occur when
caecal cultures are fed excess carbohydrate (Bailey et al., 2001). In
addition, caecal mucosal permeability has been shown to increase dramatically
when the pH drop associated with fermentation occurs (Weiss et al.,
2000), suggesting that these amines will have free access to the systemic
circulation under these circumstances. The amines released from the
caecum may cause vasospasm in the digit, both directly and by raising
plasma serotonin concentrations (by inhibiting its uptake into endothelial
cells stimulating its release from platelets). Therefore these compounds
could trigger vascular changes in the foot leading to acute laminitis.
Further work is ongoing to study the effects of these compounds, and
to gain a better understanding of the factors controlling blood flow
in the highly specialised circulation of the horse's foot. It is hoped
that these studies will lead to novel strategies for preventing this
painful and common condition.
Bailey S.R., Elliott
5-hydroxytryptamine in equine plasma constricts digital blood vessels
in vitro: implications for the pathogenesis of acute laminitis
Equine Veterinary Journal 30, 124-130.
Bailey, S.R., Rycroft,
A., Marr, C.M., Elliott, J. (2000) Identification and quantification of
amines in equine caecal liquor. Proceedings of the 39th British Equine
Veterinary Association Congress, p206-207
Bailey, S.R., Rycroft,
A., Marr, C.M., Elliott, J. (2001) Effect of carbohydrate oerload on production
of vasoactive amines in equine caecal contents in vitro. Proceedings of
the 40th British Equine Veterinary Association Congress, p213
Carlyle, WC, Jacobson,
AW, Judd, DL, et al., (1997)
Delayed reperfusion alters matrix metalloprotease activity and fibronectin
mRNA expression in the infarct zone of the ligated rat heart.
Journal of Molecular and Cellular Cardiology., 29, 2451-2463.
Dain, J.A., Neal,
A.L., Dougherty. R.W. (1955)
The occurrence of histamine and tyramine in rumen ingesta of experimentally
Journal of Animal Science, 14, 930-935.
Dorn C.R., Garner
H.E., Coffman J.R., Hahn A.W., Tritschler L.G. (1975)
Castration and other factors affecting the risk of equine laminitis
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Fraser J.G, Butler,
Steam-volatile amines in rumen liquor from cattle and sheep.
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Gas liquid chromatography of amines produced by the enterobacteriacae.
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Hinckley K.A., Henderson
The epidemiology of equine laminitis in the UK
Proceedings of the 35th congress of the British Equine Veterinary Association,
Hood D.M., Grosenbaugh
D.A., Mostafa M.B., Morgan S.J., Thomas B.C. (1993)
The role of vascular mechanisms in the development of acute equine laminitis
Journal of Veterinary Internal Medicine 7, 228-233
Hood, D.M. 1995.
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Johnson P.J., Tyagi
S.C., Katwa L.C., Ganjam V.K., Moore L.A., Kreeger J.M. (1998)
Activation of extracellular matrix metalloproteinases in equine laminitis
The Veterinary Record 142, 392-396
Pollitt, CC &
Daradka, M (1998)
Equine laminitis basement membrane pathology: loss of type IV, type VII
collagen and laminin immunostaining.
Equine Veterinary Journal, Suppl. 26, 139-144.
Pollitt, CC, Pass,
MA, Pollitt, S. (1998)
Batimastat (BB-94) inhibits matrix metalloproteases of equine laminitis.
Equine Veterinary Journal, Suppl. 26, 119-124.
Tavakkol A &
Drucker D.B. (1984)
Qualitative gas chromatographic analysis of bacterial amines as their
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Van der Horst, C.J.G.
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