Health and productive performance are closely related to nutrition. If animals are properly fed, they will develop and maintain a proper immunity and, furthermore, they will be able to develop their systems, grow and produce optimally. There are different stages in the nutrition process, and those that take place in the intestine are especially important. In this organ, nutrients reach the organism through different mechanisms. However, not only nutrients reach the intestinal epithelium, certain microorganisms, antigens and toxins, among others, also reach this organ. This epithelium is the main separation between the lumen or external environment and the organism or internal environment and, integrity, both of its structure and of its functions, is essential in order to allow only the passage of nutrients, and avoid the entry of harmful agents or compounds.

Maintaining the integrity of the intestinal epithelium has been a great ongoing challenge in animal farming. There are many factors that simultaneously affect the intestinal integrity, making its maintenance difficult. It is crucial to identify these factors and implement measures that minimize their impact on the intestinal epithelium.

1. Characteristics of the intestinal epithelium in animals

Structure

The intestinal epithelium is composed of a single layer of epithelial-like cells. Most of them are enterocytes, but there are also Paneth cells, goblet cells and enteroendocrine cells, such as the S cells.

Intestinal epithelial cells remain adhered thanks to intercellular junction complexes that can be of 4 different types: gap junctions, desmosomes, adherent junctions and tight junctions. All these junction complexes are of great importance, since they are responsible for closing the intercellular space and keeping the cells attached. However, among all of them, tight junctions are especially important since they are responsible

Functions

The intestinal epithelium has two essential functions:

• Protective function: this epithelium acts as a physical barrier that prevents the passage of microorganisms, toxins, including mycotoxins, and antigens, among others. This function is especially important, since it protects the intestine against direct damage caused by these agents and, secondarily, prevents them from reaching other organic locations where they can cause damage.
• The intestinal epithelium is supported by other auxiliary tools that contribute to this function:

Mucus: it is produced by goblet cells and is mainly composed of mucin. It avoids or hinders the contact of large molecules with the intestinal epithelium

Paneth cells: they secrete many substances such as defensins, lysozymes and antimicrobial peptides, which have a direct action on the microorganisms and prevent them from contacting the intestinal epithelium.

Secretions from other organs: such as bile, which also helps the intestinal epithelium in its defensive function with its antimicrobial action.

Immunoglobulin A: it blocks specific receptors on some pathogens.

Gut microbiota: it helps stimulating the proliferation of epithelial cells.

• Nutritional function: the intestinal epithelium acts as a selective barrier, which in physiological conditions only allows the passage of water, electrolytes, nutrients, and other beneficial substances for the organism. This function is essential for the growth of the animals and for the correct development of their immunity and the rest of their systems.
  There are two different pathways for the passage of substances through the intestinal epithelium:

Transcellular pathway: some molecules enter the organism through the membrane of the enterocytes using different mechanisms, such as passive transport through the lipid bilayer, active transport mediated by transporters, endocytosis, transcytosis and exocytosis.

Paracellular pathway: it is regulated by the tight junctions and is particularly important in the passive transport of molecules. Its selective nature is especially important to avoid the passage of antigens and toxins. However, it must be considered that its functionality is dynamic, since tight junctions are sensitive to variable lumen conditions, whose changes can be caused by food scraps, bacteria, or toxins, among others.

3. Main factors affecting the integrity of the intestinal epithelium

Farm animals are subjected to a strong genetic selection pressure and have reached high demanding levels in terms of feed conversion rate and feed consumption. Due to this, the digestive system and, especially, the intestine, are under stress conditions. In addition, usually there are many other factors that directly affect the integrity of the intestinal epithelium.

Microorganisms

• Virus: there are several types that usually cause damage to the intestinal epithelium, especially in young animals that have not yet fully developed their immunity or their intercellular junction complexes. Some of the most common are rotavirus, reovirus and picornavirus, among many others.
• Bacteria: they damage the intestinal epithelium, either due to their multiplication or due to the toxins they produce, which have multiple pathological effects. coli (although its pathogenic capacity will depend on concomitant factors), different species of Clostridium and Campylobacter, or Salmonella, are particularly important.
• Parasites: protozoa are especially important among these. They cause damage to the enterocytes due to their multiplication inside these cells. One of the most important protozoan parasites is coccidia, which affect multiple farm animal species, especially birds. Other parasites such as flatworms and nematodes are also commonly found in farm animals and cause damage to the epithelium by irritating and inflaming the intestinal mucosa.

Mycotoxins

Mycotoxins of the sesquiterpene group cause tissue necrosis. Trichothecenes, such as T-2 toxin, initially damage the microvilli of the enterocytes, but can subsequently destroy these cells, and even the villi, completely.

Proinflammatory factors

The tight junctions between enterocytes are extremely sensitive to slight changes in the intestinal lumen conditions, especially to inflammation. Any proinflammatory factor will cause variations in the tight junctions and, therefore, the paracellular permeability will be affected. Consequently, the protective function of the epithelium will also be affected, and harmful agents can penetrate the organism.

Some of the most important proinflammatory factors are:

• Physicochemical changes in feed: abnormal pH levels of the feed or some of its ingredients, especially fats, can cause inflammation and alter the tight junctions of the intestinal epithelium.
• Inadequate feed treatments: the addition of highly irritating substances, such as formaldehyde or high concentrations of organic and inorganic acids can also lead to this situation.

Heat stress

Under these conditions, blood is mobilized to the skin and peripheral organs in order to control the thermal stress by dissipating heat, while there is a decrease in the blood flow in the internal organs and epithelia, including the intestinal one. This epithelium suffers more from this situation as it is composed of a single cell layer. Because of this decrease in the blood supply, tight junctions break, which facilitates the entry of harmful agents into the organism.

Enzymatic deficiencies

Both deficiencies, in the enzymatic production and in the addition of exogenous enzymes in feed, that is, the enzymatic formulation does not adapt to the composition of the diet, will lead to the increase of non-assimilable substrates in the intestine. However, the substrates will be available for multiple microorganisms and facilitate their multiplication and the production of toxins that will damage the intestinal epithelium.

Anti-nutritional factors

The excess of these factors in the diet, especially non-starch polysaccharides or NSP, negatively influences the integrity of the intestinal epithelium. They are resistant to enzymes and decrease the transit which increases the viscosity of the intestinal content. This activity favours the multiplication of microorganisms and, in addition, increases the exposure time of the intestine to other possible adverse factors is increased.

4. Maintaining the integrity of the epithelium

As described in the introduction of this article, maintaining intestinal integrity is an important challenge in farm animals. On one hand, the fast growth and development determined by the genetic lines are stressful factors for both the gut and the intestinal epithelium. On the other hand, the factors listed in the previous section negatively affect the intestinal epithelium. Therefore, the identification of these factors and the implementation of different measures that minimize their impact on the intestinal epithelium are essential. In addition, measures must be implemented to maintain and optimize the physiology of the enterocytes, the main cells of the intestinal epithelium.

Measures on factors that alter the integrity of the epithelium

• Use of microbicides: As described in the previous section, many microorganisms damage the intestinal epithelium, such as bacteria, which cause damage due to their multiplication or the toxins they produce. In order to limit the effect of these microorganisms, traditionally, different types of antibiotics have been used, such as AGP, which, in addition to controlling the microorganisms in the intestine, favour productive performance. However, due to bacterial resistances, their use has been limited. An effective alternative is the use of additives based on the cimenol ring, a compound with a broad-spectrum microbicidal capacity that not only affects bacteria, but also most fungi and yeasts that usually colonize the epithelium.
• Implementation of anticoccidial programs: Coccidia is one of the main microorganisms that damage the intestinal epithelium. These protozoa destroy the enterocytes during the asexual phase of their reproductive cycle, which develops inside these cells. Therefore, it is important to implement adequate anticoccidial programs for the control of these parasites. Traditionally, synthetic, both chemical and ionophore, coccidiostats have been used, as well as different types of vaccines. However, different natural alternatives have become particularly important for the control of coccidiosis, such as additives based on intestinal optimizer pronutrients. These molecules stimulate the local immunity of the intestine, favouring the elimination of these parasites by interrupting their reproductive cycle during the asexual phase.
• Addition of mycotoxin binders in feed: The damage caused by mycotoxins on the intestinal epithelium can be prevented by using molecules that bind mycotoxins and prevent them from causing damage as they pass through the digestive tract. It is important that this union is stable at different pH levels along the digestive tract, and that they do not adsorb nutrients from the diet. In this sense, the mycotoxin binders based on the molecule called Silicoglycidol have shown great efficacy.
• Formulation of qualitatively and quantitatively appropriate diets: When formulating diets, it is essential to consider other factors apart from than the nutritional profile. Factors that may have a negative effect on the intestinal epithelium, that is on the enterocytes and their binding complexes, have to be avoided.

Therefore, try to:

Use good quality raw materials with a low content of anti-nutritional factors.

Control the pH levels of the ingredients of the diet, so that they are adequate and do not cause irritation nor inflammation.

Avoid the use of preservatives based on irritating compounds such as formaldehyde.

Adjust the amount and type of enzymes to each type of diet, to avoid the presence of undigested substrates in the intestine, which may change the conditions of the lumen or be available for the microorganisms.

• Implement measures for the detection and control of heat stress: Feed and water consumption must be monitored, as well as the environmental conditions of the shed, in order to detect heat stress problems as early as possible. Then, appropriate nutritional and management measures can be applied to prevent animals from activating mechanisms to dissipate heat and redirect blood from internal organs, such as the intestine, to the skin and peripheral organs.

Maintenance and optimization of the physiology of the enterocytes

The implementation of the measures described in the previous section will help to minimize the impact of the different factors on the integrity of the intestinal epithelium. However, these factors cannot always be controlled due to there are many that may be simultaneously involved. In addition, the high productive performance itself is a factor that can affect the digestive health and is always present if highly selected breeds are used, as it occurs in current animal farming. Therefore, it is necessary that the enterocytes are in optimal physiological conditions to be able to face different challenges.

To maintain the physiology of the enterocyte, the addition of intestinal conditioner pronutrients in the diet is essential.

These are active molecules that come from different plant extracts. In the enterocytes, they stimulate the synthesis of many functional proteins with different effects:

• Increase of the enterocyte regeneration rate, so that the intestinal epithelium is renewed faster. Furthermore, microorganisms and other debris attached to aging enterocytes will be eliminated with them and bacterial growth will be reduced.
• Improvement of the tight junctions between enterocytes, so that paracellular permeability remains intact to allow the passage of nutrients and avoid pathogens.
• Increase of enterocytes metabolic rate to increase nutrient absorption (vitamins, aminoacids) and prevent toxin absorption.

Therefore, if measures are established to control the factors that alter the epithelium and pronutrients optimize enterocyte physiology, it is unlikely that the intestinal epithelium will be altered.

5. Conclusions

The intestinal epithelium in animals plays an essential role in the growth and maintenance their health. It allows the selective passage of nutrients and avoids that of pathogens and harmful molecules. However, under the current intensive farming conditions, there are multiple factors that can directly or indirectly affect the integrity of the intestinal epithelium and hinder its function and its positive activity on growth and health. It is important to identify these factors and implement measures that minimize their impact, as well as to stimulate the physiology of the enterocytes so that the epithelium can face these challenges.