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Bioactive Peptides and Nutrition Therapy

By Heather Davis, MS, RDN, LDN

Beyond a classic appreciation of its nutritive value, protein exerts specialized physiochemical action that expands its health impact. Bioactive peptides (BPs) are specific protein fragments, often three to 20 amino acids long, with unique health effects.1

Since many bodily functions are guided by amino acid interactions between peptide fragments or small protein chains, BPs offer potential for targeted therapeutic applications, including use in nutrition therapy.2

All About BPs
BPs are classified into two main groups: endogenous and exogenous. Endogenous forms are produced in certain cells, such as neural and immune cells, or in the pituitary and adrenal glands; exogenous forms are found in foods, dietary supplements, and pharmaceutical drugs.1 It’s also possible to synthesize BPs in a lab with the help of chemical reagents.

Some of the earliest syntheses of BPs took place in 1953 to produce prescription insulin. However, some of the synthetic processes, such as ones involving dimethylformamide and dichloromethane, have been criticized for their environmental harm and the fact that these compounds are difficult to remove from nature.1

The role of BPs in the body includes, but is not limited to, the following activities2:

• immunomodulatory;
• antithrombotic;
• antioxidant;
• antihypertensive;
• antimicrobial;
• mineral-binding;
• antiaging;
• antiobesity; and
• antidiabetic.

These different activities are directed by the sequence of the amino acids and their molecular weight, inviting interest in identifying sequences with desired effects and then developing nutraceuticals, functional foods, or even drugs.

Extraction
Common foods used for extracting BPs include eggs, milk (casein and whey), fish/seafood, and other meat proteins. Plant-based sources are typically soy, oats, chickpeas, peas, lentils, canola, wheat, flaxseed, and hemp seed.1 BPs from food proteins can be produced by enzymatic hydrolysis using proteolytic enzymes like pepsin and chymotrypsin. Enzymes may be derived from plants or microbes, including by fermentation using starter cultures.1

Fermentation involves growing yeasts, fungi, or bacteria on cultures with the protein of interest to break down the protein into shorter peptides with the enzymes produced naturally by these processes.1 Several studies have also used in vitro simulated gastrointestinal (GI) digestion techniques to produce BPs from food proteins.3

Gastrointestinal Considerations
Absorption from the GI tract is the first step in allowing BPs to get to work systemically. The main barriers to intact peptide absorption are the gastric and intestinal environments wherein enzymes may degrade peptides, the mucosal barrier, the tight junctions, and the epithelial cells of the GI tract.4

Once upon a time, it was believed that all peptides and proteins were broken down into their constituent amino acids, and only these amino acids could then cross the intestinal epithelial barrier.2 This also made sense when appreciating how larger peptides and proteins making their way across the barrier were often considered key pathological factors in food allergy development.4

However, researchers have since learned that some peptides do cross the intestinal epithelium under normal, nonpathological conditions through mechanisms such as paracellular transport through intercellular tight junctions, endocytosis/phagocytosis, and active transport by specific carrier proteins.1 These processes are rarely simple or straightforward, though, and often involve a protein utilizing multiple routes simultaneously.

With particular interest in improving peptide-based drug bioavailability, ambitious researchers also attempt to create absorption enhancers that can improve the uptake of BPs.4 Nevertheless, some critics push back on this approach and feel this effort to hack the system might be risky business, potentially inviting intestinal barrier permeability changes that could be difficult to control and may lead to localized inflammation and long-term damage to the epithelium.1

Gut-Focused Applications
Even if all peptides aren’t readily crossing the epithelium intact, BPs don’t necessarily need to be absorbed from the GI tract to have an impact on health. Chronic diseases of the GI tract, especially inflammatory bowel disease (IBD) such as Crohn’s and ulcerative colitis, are a prime target for GI-focused BP therapeutics. Through inhibiting several known pathways of inflammation in these conditions, some researchers are optimistic that BPs can serve local anti-inflammatory roles in intestinal cells.5 An increasing number of food-derived BPs have proven anti-inflammatory and antioxidant properties, and preliminary animal models show promise in alleviating IBD-related GI tract inflammation.1

Highlighting BPs of Interest
Where are the most interesting BPs coming from? Many of them are derived from marine origin, the oceans offering a wealth of biodiversity including organisms that endure extreme environments and that may have adapted in unique ways for survival. BPs isolated from marine organisms like sponges and mollusks have known anticancer properties and are in various phases of related clinical trials.6

Relatively more notorious in the world of BPs is the antioxidant activity of whey hydrolysate due to the presence of the amino acid cysteine and its role in glutathione synthesis.6 Additionally, opioid peptides found in milk may have morphinelike effects on the central nervous system.6 Milk-based BPs may also have angiotensin-converting enzyme inhibitory, antithrombotic, and anticancer activity, as demonstrated in animal studies.6

Drug or Food?
Though it may sound like BPs have arrived on the scene only recently, their modern terminology veils the fact that they’ve been in use for centuries around the world throughout various cultures. Traditional fermented foods like kefir, pickles, tempeh, and natto are rich in BPs that have many therapeutic applications, and they contend with the least regulatory requirements.1 You'll also find BPs in infant formula, which, unlike fermented foods, is one of the most highly regulated foods sold globally.1 However, scientists point out that there’s a food-to-drug continuum, and it’s not always easy to know exactly where BPs land on the spectrum.

Others argue that BPs are more suitably classified as nutraceuticals, falling under the dietary supplements umbrella and regulated—or not—accordingly. The FDA’s current list of new dietary ingredients related to BPs includes peptides derived from fish, shrimp, sesame, and silk fibroin protein, as well as egg albumin hydrolysate.6

Playing Devil’s Advocate
Many may wonder if there’s a need to generate BPs through high-tech in vitro enzymatic procedures since orally ingested proteins are fated to be digested into these fragments anyway. When asked this question, some researchers fire back with examples of BPs with different profiles than what might be created in vivo through natural digestive processes.1 Selective cleavage of the same protein at different target sites may yield different biological activities. For example, in one study, investigators used different enzymes to yield a variety of chicken collagen hydrolysates with notably different biological actions.1

Concerns and Limitations
As with almost any emerging area of science, the ability to translate laboratory findings into practical or commercial use is challenging. Much of the published research to date on BPs hasn’t taken a systematic approach to standardized purification or production of peptides.1 In this way, it makes it harder to understand how to scale findings or even repeat certain findings. Addressing questions of absorption and bioavailability may also fail to offer simple solutions.

The lack of human clinical trials regarding designer BPs and BPs used for highly specific medical treatments, including cancer treatment, must be considered. Additionally, extracting BPs from the food matrix may confront hurdles involving the influence of other variables in the food matrix and tricky processing conditions that could result in unwanted protein degradation.1 For example, lipids, carbohydrates, and secondary metabolites from foods may interact with the proteins in the whole food matrix and affect the type of BPs generated upon hydrolysis.1

Even so, many experts feel there’s enough reason to remain hopeful and continue exploring this exciting area of research, including the potential application of specialized BPs in nutrition therapy along the food-to-drug continuum.

— Heather Davis, MS, RDN, LDN, is editor of Today’s Dietitian.

References
1. Chakrabarti S, Guha S, Majumder K. Food-derived bioactive peptides in human health: challenges and opportunities. Nutrients. 2018;10(11):1738.

2. Purohit K, Reddy N, Sunna A. Exploring the potential of bioactive peptides: from natural sources to therapeutics. Int J Mol Sci. 2024;25(3):1391. 

3. Brodkorb A, Egger L, Alminger M, et al. INFOGEST static in vitro simulation of gastrointestinal food digestion. Nat Protoc. 2019;14(4):991-1014.

4. Muheem A, Shakeel F, Jahangir MA, et al. A review on the strategies for oral delivery of proteins and peptides and their clinical perspectives. Saudi Pharm J. 2016;24(4):413-428.

5. Zhu W, Ren L, Zhang L, Qiao Q, Farooq MZ, Xu Q. The potential of food protein-derived bioactive peptides against chronic intestinal inflammation. Mediators Inflamm. 2020;2020:6817156.

6. Akbarian M, Khani A, Eghbalpour S, Uversky VN. Bioactive peptides: synthesis, sources, applications, and proposed mechanisms of action. Int J Mol Sci. 2022;23(3):1445.