The role of microbial metabolites in the health, wellbeing, and performance of the horse

It is estimated that approximately 80% of the immune system interacts directly with the digestive tract as this is where most pathogens potentially can enter the body. The epithelial lining of the digestive tract is only one cell thick, facilitating digestion and absorption of nutrients. The role of the immune system in the gut is to protect the body from the potentially dangerous pathogens present in the digestive tract. On its own, the immune system is incapable of regulating such a system. This is where beneficial microbes, and their metabolites, within the gut’s microbiome come into play.

Within the hindgut of the horse there resides approximately one quadrillion bacteria, fungi, viruses, protozoa and helminths. The main role that these microbes perform is the breakdown of the ingesta, mostly fibrous grasses, into substances that the microbes can utilise themselves. These microbes then convert these substances into end products or “metabolites” that the horse can utilise – vitamins, volatile fatty acids, hormones and factorial precursors. Research in the last 20+ years has shown that the produced volatile fatty acids (also known as Short-Chain Fatty Acids (SCFA)) and factorial precursors play a far greater role in the horse’s overall health than previously thought.

There are three main SCFA – Acetate, butyrate, and propionate. These three make up nearly 90% of all the SCFA produced from microbial fermentation of fibrous feeds. They provide up to 70% of a horse’s daily energy requirement. Both acetate and butyrate are metabolised and enter the TCA cycle, producing ATP cellular energy, while propionate can be converted into glucose for immediate use through gluconeogenesis. Butyrate though performs even great functions than just providing a high-quality energy source for the horse.

The monolayer which makes up the intestinal epithelial lining contain several different types of specialised cells. These cells are held together by tight junctions, forming a physical barrier between the body and the gut, regulating epithelial permeability. Butyrate is the preferred nutrient for these cells, supplying approximately two thirds of their normal energy requirements, helping to improve both nutrient absorption but also helping to maintain the tight junction integrity of the gut epithelium. Maintenance of a healthy tight junction within the gut epithelium significantly reduces the incidence of unwanted compounds, such as undesirable microorganisms, endotoxins, and digesta, entering the body. Butyrate also appears to play a significant role in the production of protective mucus. Providing a sufficient supply of butyrate could significantly reduce the potential of systemic inflammation and associated negative impacts on the immune system and health of the animal.

Leaky gut syndrome involves both epithelial barrier dysfunction and abnormal immune-cell activation. Butyrate has been found to not only play an important role in maintaining gut epithelial barrier function, but also immune homeostasis. It also plays an important role in inhibiting abnormal immune-cell activation and, as such, works as a strong anti-inflammatory responder, reducing the abundance of inflammatory cytokines, such as IL-6, IL-17A, IL-17F, IL-21, and TNF-α. Such inflammatory markers have all been implicated in the development of insulin dysregulation (ID) in horses (and Type-2 diabetes in humans).

Butyrate upregulates gene expression within the epithelial cells towards a greater production of anti-inflammatory producing Treg cells and suppressing inflammatory producing Nuclear Factor-Kappa B (NF-kB) cells through gene expression resulting in the inhibition of histone deacetylase. The result is a significant downregulation of inflammatory compounds like IL-1β, IL-6, IL-12, and TNF-α. The same ability to alter gene expression within the gut wall cells through inhibition of histone deacetylase, allows butyrate to easily pass through the gut epithelial, into the blood, and through the highly protective blood-brain barrier. Within the brain, butyrate has been shown to enhance positive mood through the formation of serotonin as well as ensuring adequate dopamine concentrations within the cerebral, preventing against dopaminergic neural death.

Recent research has shown SCFA to be “key inductors within the gut-brain axis communication” Ahmed, H., et. al. (2022). Research is starting to show that SCFA produced from microbial fermentation are very much associated with not only a healthy gut but also a healthy mind and body, limiting neurological and physiological disorders. Butyrate, produced by microbes through insoluble fibre fermentation, is capable of elevating tryptophan levels, not only in the digestive tract, but also within the body (plasma), leading to increased serotonin production. Serotonin plays numerous physiological roles in the body including modulation of mood, perception, sleep, neurological disorders, wound healing, and suppressing appetite by increasing satiation.

In recent years it has been discovered that butyrate acts as a direct substrate for skeletal muscle metabolism. Acting as a histone deacetylase inhibitor (modulating gene expression in the gut cells), butyrate has been shown to improve metabolism and reduce muscle atrophy during aging and diabetes. Butyrate has been found to reduce cellular oxidative stress and reduction in atrophy of the skeletal muscle tissues and enhanced intestinal barrier function in animals and humans suffering from diabetes. Through the same process, butyrate can inhibit a protective effect on muscle mass, reduce fat mass (deposition) within the body including the liver (preventing Non-Alcoholic Fatty Liver disease), and improve glucose metabolism. This suggests not only a beneficial mechanism in ameliorating the impacts of ID/EMS through reduced fat deposition and improved glucose metabolism, butyrate may have positive impacts on the preservation and development of skeletal muscle of performance animals and (perhaps) horses suffering from exertional rhabdomyolysis (tying up).

In summary, butyrate is a key metabolite produced from microbial fermentation of fibrous material that plays key roles in the integrity, protection and functioning of the gut; specific gene expression; production of anti-inflammatory cytokines and prevention of systemic inflammation; mediator and (at times) up regulator of the immune system; appetite suppressant; mood enhancer and mediator of neurological disorders; enhancer of glucose metabolism while reducing fat deposition; protectant of skeletal muscle against excessive degradation; protector against oxidative stress; plus more, it would seem, as research continues.

Ahmed, H., et. al. (2022) Gut Microbes; 14(1)

Dr Mark Barnett PhD - MTB Equine Consultancy Services

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