What You Need to Know About the Current State of Absorption of Food Peptides

The absorption of most of the digested foods usually takes place in the jejunum. This is normally where the chyme enters from the stomach, pending it being broken down to its constituent nutrients, which are then taken into systemic circulation across the walls of the small intestines. For a very long time, the traditional belief was that once a peptide is ingested, through the processes of digestion, the peptides could be broken down by the digestive enzymes into their constituent amino acids, which could then be easily assimilated through the epithelial cells of the small intestines.

It was also held that both the proteins and the peptides got absorbed through the walls of the small intestines through pathological conditions. But, with more insights, research, and science into the absorption of food peptides, there is a whole new set of beliefs regarding the absorption of food peptides. Recent studies show that a majority of the peptides are usually absorbed through the walls of the small intestines under normal conditions, and not pathological conditions, as had been earlier believed. Presently, four different methods of absorption of food peptides have been discovered, and comprehensively described. The four include the following:

Paracellular Diffusion

In paracellular diffusion, the movement of molecules takes place through water-filled pores or channels between the cells. Nearly 0.1% of the total intestinal surface area comprises these water-filled pores or sacks that facilitate the movement of molecules through the cells. This surface of the cells is believed to be large enough to allow small quantities of peptides to be absorbed through them, hence, the surface is just large enough to allow the peptides to exert their biological activities.

It should be noted that the paracellular pathways are normally under the control of tight junctions that act as the divide between the basolateral and the apical membranes of the epithelial cells of the small intestines. The tight junctions, commonly known as TJs, refer to various multiprotein complexes that have claudins, occulins, and occuldens proteins, which are usually part of the biological barrier responsible for stopping the paracellular flux of ions, water, and solutes.

In other words, they are responsible for preventing the crossing of substances through the tiny spaces that usually exist between the membranes of the plasma cells, and the adjacent cells. Additionally, they are also responsible for restricting most of the processes associated with macromolecule penetrations.

As such, all the peptides that are absorbed through the epithelial cells of the small intestines, usually go through the processes of diffusion or active transport. This process primarily depends on the physicochemical properties of the peptides, with properties such as the ionic charge, and the molecular weight being some of the most important ones.

Hence, it has been reported that this method is mostly preferred by hydrophilic negative charged low-molecular-weight peptides. It has also been observed that various bioactive food oligopeptides can also utilize passive diffusion through paracellular TJs. Also, it has been observed that this same route is used by 43-amino acid peptide lunasin, which is usually released through gastrointestinal digestion to move through the epithelial barrier on the walls of the small intestines.

Transcellular Passive Diffusion

This process involves the transportation of molecules across the basolateral and the apical membranes in a manner that doesn’t rely on any form of energy, but uses the concentration potential between the contents inside and outside the membranes. With passive diffusion, the transportation of bioactive peptides is usually a factor of the peptide characteristics, with the major characteristics being the hydrophobicity, the charge, and the weight of the peptide.

Hence, due to the presence of a lipid layer present in the composition of the cells, it has become to be widely believed that the lipophilicity of the peptide has a major role to play in this transport mechanism. Normally, hydrophilic peptides tend to use paracellular diffusion as their preferred method of crossing the epithelial membrane of the small intestines, lipophilic peptides, on the other hand, prefer transcellular transport as the method of choice for crossing the epithelial wall of the small intestines.

The passive diffusions of bioactive peptides may also be dependent on other factors, such as the number of polar groups in that peptide, as well as the predominant peptidic chain. Also, the transcellular absorption of peptides is dependent upon the amount of energy needed to break the water-peptide hydrogen bonds. The breaking of these bonds is necessary since after they have been broken, it now becomes possible for the molecules to enter the cell membranes.

Transcytosis

Transcytosis refers to the transportation of materials from one side of the polarized cells to the other side using energy. This route normally features transcytotic transport and endocytic uptake through internalized vesicles known as basolateral secretion and endosomes. Because peptides have to interact with the apical bilayer of the epithelial cells before they are internalized by the cells, transcytosis seems to be the preferred transport for the majority of the long-chain, as well as the highly hydrophobic peptides.

As such, it has been recently shown in a study that the high contents of hydrophobic amino acids in most of the antioxidative peptides may determine how the peptides are transported across the Caco-2 cell monolayers, through the processes of transcytosis. Apart from the immense importance of hydrophobicity, there are other factors that play equally important roles when it comes to the transcytosis transportation of peptides.

Consequently, it has been observed and reported in various cell models that the number of polar groups, as well as the net charge of peptides, especially the positive charge, display certain positive effects on their ability to be transported through the endothelial membrane of the small intestines through transcytosis.

Carrier-mediated Transportation

In carrier-mediated transportation, the movement of the peptides is against the concentration gradient, a process usually facilitated by a specific cell membrane protein that works through antiporter and uniporter mechanisms. The function of antiporters is to transport peptides in the opposite direction while the work of symporters is to transport peptides through cotransport in a similar direction to the flow of blood over the cell membranes. Uniporters, on the other hand, can work in all directions.

Carrier-mediated transportation depends on the concentration of the substance and may be inhibited by factors such as the size of the molecular structure. When considering the various peptide carriers, transporter 1 – pepT1, is well known to be a low-affinity and high-capacity carrier to have the ability to push peptides into the epithelium of the intestines from the gastrointestinal lumen. This ability, however, is dependent on the membrane potential, and as well, as the proton gradient between the two surfaces.

Although it is already a known fact that PepT1 prefers to bind in the short-chain bioactive peptides that portray neutral charge and high hydrophobicity, it has also been observed that it has the ability to recognize dipeptides that portray extreme bulk or two positive charges. But PepT1 is not likely to bind to hydrogen or hydrophilic regions. In a recent study, the Caco-2 cell monolayer model was used for studying the various transport routes likely to be used by casein-derived peptides.

The study showed that PepT1 played a major role in the transportation of low molecular weight peptides, while the high molecular weight particles moved through the intestinal barrier, through mechanisms such as paracellular diffusion. Additionally, it was noted that the peptides that were transported by PepT1 had a higher bioavailability, in comparison to those that were transported through paracellular diffusion.

Also, PepT1 has been referred to as the preferred carrier for angiotensin-converting enzyme – ACE inhibitory peptide. This peptide is usually obtained from milk and fish/chicken muscle proteins. Other than PepT1, the other peptide carriers that may be found in the basolateral membrane are also believed to have a huge role to play in the transportation of hydrolysis-resistant small peptides through the epithelial cell membrane, into the bloodstream.

The Common Factors Limiting Food Peptide Absorption

Some of the peptide characteristics, known to hinder their transportation across the walls of the cell membrane include their primary and secondary structures, the peptide lengths, lipophilicity, hydrophobicity, and the net charge of the peptide. In addition to these factors, there are other factors that have been reported to hinder the smooth transportation of the food-derived peptides across the walls of the cell membranes.

To begin with, the mechanisms of food processing may elicit certain unwanted reactions between the peptides, and the already co-existing compounds that are present within the food matrix. These have a way of limiting the ability of the peptides to be easily absorbed across the cell membranes. However, the data available on this is still very scarce. During a study featuring a placebo-controlled crossover human, it was observed that there was a delay in the plasma clearance, as well as the rate of bioaccessibility of the antihypertensive peptide, usually found in yogurt, when taken as the base of a breakfast meal compared to the peptide that was delivered in the fasted state.

In a recent study by Lacroix et al., it was observed that there was a higher rate of degradation of dipeptidyl peptidase IV (DPP-IV) inhibitory peptide obtained from whey proteins by the peptides generally found on the apical side of Caco-2 cell monolayers.

Additionally, the same study observed that the interactions that happen between free radicals obtained from food phenolic compounds can lead to the formation of new peptide derivatives, hence, introducing the possibility to modify the bioavailability of those peptides.

Also, it is possible to modify the rate of absorption of peptides, due to the effects of the co-existing compounds found in the food matrix on the transportation routes of the peptides. Therefore, compounds that rely on PepT1 transportation routes, such as small peptides, also have the potential of competing with the peptides, and also reducing their rates of absorption. The polyphenols present in black tea have been shown to downgrade PepT1 expression. This usually leads to a decrease in the rate of dipeptide absorption taking place across Caco-2 cell monolayers.

 It is also possible to modify both the peptide’s bioavailability and digestibility by altering the luminal environment, the composition of the gut microbiome, and the intestinal barrier function, which are usually influenced by food components. It has been observed that it is possible for even peptides obtained from the degradation of dietary peptides, through the actions of digestive enzymes to also act locally.

This phenomenon has potentiated the actions of other bioactive peptides through enhancing processes, such as pathway signaling, and the enhancement of the functions of the intestinal cells. Apart from the food properties, there are other non-dietary factors that can influence the bioavailability of the bioactive peptides.

For instance, studies have shown that the bioavailability of bioactive peptides can be influenced by an altered intestinal environment, occasioned by diseases or illnesses or factors relating to pharmacological treatments, the actions of endogenous hormones, and colon cancer. Therefore, it is important to consider these factors when trying to interpret data obtained from in vivo studies, targeting the bioavailability of bioactive peptides.

It has already been noted that the digestive enzymes found in the gut lumen have the ability to effectively degrade bioactive peptides into free amino acids and smaller molecules. However, there are other barriers that must be overcome by peptides in their quest to move across the gastrointestinal membrane. The first of these barriers is the mucus barrier.

This barrier comprises a hydrogel layer made of glycoproteins whose function is to act as a lubricant of the passage for chyme, and also to offer protection to the epithelial walls from mechanical damage. The walls of the small intestines are usually covered by a single layer of epithelial cells. When the peptides reach these cells, they can be transformed, degraded, or absorbed into the bloodstream depending on their individual properties. Beneath the epithelium, the peptides must also overcome the subepithelial tissue before being fully absorbed into the bloodstream.

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