Food-Derived ACE and DPP-4 Inhibitory Peptides Survive Digestion but Struggle to Cross the Intestinal Wall | Research

The takeaway

Bioactive peptides from poultry by-products that inhibit both ACE-1 and DPP-4 survived simulated gastrointestinal digestion but were not transported across intestinal cell layers, raising questions about their oral bioavailability.

Survived digestion, failed absorption
Bioactive dipeptides resisted gastric and intestinal enzymes but were not transported across the Caco-2 intestinal cell monolayer — they were taken up by cells without reaching the other side

What the researchers found

Bioactive dipeptides YA, VL, and IY from poultry hydrolysates resisted simulated gastrointestinal digestion. However, Caco-2 cell monolayer absorption tests showed peptide concentrations decreased on the apical side but were not detected basolaterally — indicating cellular uptake/metabolism rather than transcellular transport. The peptides downregulated peptide transporter expression, CDX2 transcription factor, and tight junction protein TJP1.

Why it matters

Many food-derived peptides show impressive activity in lab tests but fail to deliver benefits when consumed orally because they can't reach the bloodstream in sufficient quantities. This study provides an important reality check: even peptides that survive digestion face a second major barrier — crossing the intestinal wall. Understanding this bottleneck is essential for developing effective nutraceutical peptide products.

The numbers in context

The low molecular weight peptide fraction (LMWPF) showed dual ACE-1 and DPP-4 inhibitory activity with good digestive stability.

How the study worked

In vitro study using INFOGEST static digestion model for gastrointestinal stability and Caco-2 cell monolayers for intestinal absorption. Peptide identification by LC-MS. Gene expression analysis of Caco-2 cells after peptide stimulation. 4-hour incubation period for transport studies.

Who was studied

Simulated gastrointestinal and intestinal absorption models

What this study cannot tell us

Caco-2 cells, while the gold standard for intestinal absorption studies, are cancer-derived cells that may not perfectly represent normal intestinal epithelium. The 4-hour timeframe may be insufficient to capture slow transcellular transport. The study used individual dipeptides rather than the complete hydrolysate, which may behave differently. No in vivo absorption data was collected.

How to read the evidence

Preliminary evidence from a well-designed in vitro study using gold-standard methods (INFOGEST digestion, Caco-2 transport). However, in vitro absorption results don't always predict in vivo bioavailability.

When this study was published

Published in 2024, adding critical bioavailability data to the growing literature on food-derived bioactive peptides.

The bigger picture

The bioactive peptide field is booming with thousands of peptides showing enzyme-inhibiting activity in vitro. However, this study highlights the critical gap between test tube activity and real-world bioavailability. The food and nutraceutical industry needs to address intestinal absorption, not just enzyme inhibition, to deliver on the promise of bioactive peptide ingredients.

Questions still open

Could formulation strategies like encapsulation or permeation enhancers improve the intestinal absorption of these bioactive dipeptides?
Do these peptides exert local effects on intestinal cells (e.g., local DPP-4 inhibition in the gut) even without systemic absorption?

Common questions

Does this mean food-derived peptides don't work?

Not necessarily. This study tested specific dipeptides in a lab model — real-world absorption may differ. Also, some peptides may have beneficial effects locally in the gut (like inhibiting DPP-4 in the intestinal wall) without needing to reach the bloodstream. More research with animal and human studies is needed.

What are ACE and DPP-4 inhibitors and why do they matter?

ACE inhibitors lower blood pressure (like the drug lisinopril), and DPP-4 inhibitors help manage blood sugar (like sitagliptin). Finding food-derived peptides that inhibit both enzymes is exciting because it could mean a single natural ingredient helps with both blood pressure and blood sugar — but only if the peptides can actually get into the body.

Read the original research

In vitro gastrointestinal stability and intestinal absorption of ACE-1 and DPP4 inhibitory peptides from poultry by-product hydrolysates.

Food & function, 15(14), 7364-7374

View on PubMed ↗Publisher’s paper ↗

Citation

Sorokina, Liudmila; Solberg, Nina Therese; Koga, Shiori; Rønning, Sissel Beate; Afseth, Nils Kristian; Wilson, Steven Ray; Rieder, Anne; Wubshet, Sileshi Gizachew. (2024). In vitro gastrointestinal stability and intestinal absorption of ACE-1 and DPP4 inhibitory peptides from poultry by-product hydrolysates.. Food & function, 15(14), 7364-7374. https://doi.org/10.1039/d4fo01214c