Is the sugar metabolite methylglyoxal the villain in laminitis in horses?

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Findings of laboratory study point to the role of methylglyxol in weakening the hoof structure.
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High levels of a sugar metabolite called methylglyxol could be responsible for the irreversible hoof damage seen in some cases of laminitis in horses, laboratory findings suggest.

Laminitis, which can lead to disability or even death, is one of the most devastating diseases in equine medicine. It is characterized by deterioration of the lamellar tissue that connects the hoof wall to the underlying third phalanx in the equine hoof. There is associated inflammation, heat, digital pulses, pain and lameness, and, in some cases, rotation of the coffin bone.

The condition can be classified as either acute or chronic, and it is not usually readily reversible.

Although several mechanisms have been proposed for development of the disease, few clear answers have been identified to date.

Several lines of evidence point towards its underlying pathology as being metabolism-related, Cristina Vercelli and her fellow researchers at Italy’s University of Turin noted in the journal PLOS ONE. The most common cause involves gastrointestinal or metabolic disease.

“For a number of reasons, laminitis is considered a metabolism-related pathology, resembling the human diabetic foot, since hormonal influences, weight and pressure are involved,” the study team said.

Gastrointestinal disturbances resulting from ingestion of excess carbohydrates play a pivotal role in sepsis-related laminitis.

Feeds rich in starch are used as highly digestible energy sources in horses. During digestion in the small bowel, starch is primarily broken down by amylase enzymes, leading to glucose liberation.

Extremely large quantities of starch in the diet can result in starch overload; which means that undigested starch passes from the small to the large intestine, which can lead to a decrease in colon and caecal pH, often followed by colic laminitis.

In this scenario, release of toxins from the hindgut is suspected to occur, which in theory triggers degradation of the lamellar basement membrane and a loss of strength.

Specifically, starch overload in the gut can lead to rapid, devastating changes that result in the formation of toxins and other substances:  Bacteria in the gut undergo carbonyl stress, leading to biosynthesis of methylglyoxal.

Methylglyoxal is a highly reactive α-oxoaldehyde which would be detoxified into D-lactate under healthy physiological conditions.

In equines, feeding large amounts of fermentable carbohydrates with subsequent acidosis increases the plasma levels of D-lactate, which can be considered a clinical marker of the development of laminitis, because it is more specific and more stable than methylglyoxal.

The study team noted that one common hypothesis is that methylglyoxal could be synthesized during the digestive process in horses, and excessive levels absorbed into the bloodstream could be delivered to the foot and lead to alterations in the hoof lamellar structure.

The study team set out to investigate the effects of methylglyoxal on the equine hoof in a laboratory setting, using hooves from nine draft horses who died for reasons unrelated to the study.

In their experiment, different concentrations of methylglyoxal were applied to the hoof explants, which were then incubated and maintained in a specific medium for 24 hours and 48 hours.

The study team looked for changes in appearance, including at a microscopic level, and also applied a separation force test 24 and 48 hours after applying methylglyoxal.

The authors reported that high concentrations of methylglyoxal induced changes in the tissue, mimicking laminitis.

“The separation force test revealed that hoof tissue samples incubated for 24 hours in a high concentration of methylglyoxal, or with lower doses but for a longer period (48 hours), demonstrated significant weaknesses, and samples were easily separated,” they reported.

“All results support that high levels of methylglyoxal could induce irreversible damage in hoof explants, mimicking laminitis in an ex vivo (laboratory) model.”

Discussing their findings, the researchers said the results in the separation force test support the hypothesis that methylglyoxal can lead to modification of the hoof lamellae, rendering them less robust and unable to resist separation.

“This evaluation confirmed that higher concentrations of methylglyoxal and a longer incubation period (48 hours) can cause irreversible damage that weakens hoof tissues.”

These results, they said, were confirmed by microscopic examination of the hooves, which revealed major alterations in the basal lamella, the severity of which correlated with increasing concentrations of methylglyoxal.

They said it would be interesting to apply the same laboratory model for laminitis to older horses of different breeds, such as pony breeds, to assess any differences in the studied parameters.

Vercelli C, Tursi M, Miretti S, Giusto G, Gandini M, Re G, et al. (2021) Effect of sugar metabolite methylglyoxal on equine lamellar explants: An ex vivo model of laminitis. PLoS ONE 16(7): e0253840. https://doi.org/10.1371/journal.pone.0253840

The study, published under a Creative Commons License, can be read here

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