Tier 3 — preclinical

Oral ingestion of collagen hydrolysate leads to the transportation of highly concentrated Gly-Pro-Hyp and its hydrolyzed form of Pro-Hyp into the bloodstream and skin

Misato Yazaki, Yukihiko Ito, Masayoshi Yamada, Spyros Goulas, Sachiyuki Teramoto, Masa-aki Nakaya, Shigeo Ohno, Kohji Yamaguchi

Journal of Agricultural and Food Chemistry 2017 65(11):2315–2322

Bibliography

PubMed: PMID 28244315
DOI: 10.1021/acs.jafc.6b05679
Funding: Funding statement (verbatim): "This work was partially supported by the fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation System from Ministry of Education, Culture, Science and Technology."
Competing interests: The paper states that the authors declared no competing financial interest. Five of the eight authors — Misato Yazaki, Yukihiko Ito, Masayoshi Yamada, Sachiyuki Teramoto and Kohji Yamaguchi — were affiliated with FANCL Corporation's Research Institute; Yazaki also held a Yokohama City University affiliation. The tested collagen hydrolysates HACP-01 and CPAH-5 were supplied by Jellice. These corporate affiliations and product-supply relationships remain relevant context when interpreting the findings, but they should not be misreported as an undeclared conflict.

Study snapshot

Design	Human single-blind, two-arm crossover for plasma kinetics; parallel murine dose-ranging and pure-peptide administration arms for tissue distribution
Model	Healthy adult humans (4 M, 8 F); male BALB/c mice for tissue distribution
Sample	Human arm: n=12, mean age 31.5 ± 6.5 years. Mouse arm 1: 5 mice per dose per time point. Mouse arm 2: 5 mice per pure peptide per time point.
Intervention	Human arm: single oral dose of 300 mg/kg body weight of either high-tripeptide-content porcine collagen hydrolysate (HTC-col, HACP-01, avg MW 1,500–1,800 Da) or low-tripeptide porcine collagen hydrolysate (LTC-col, CPAH-5, avg MW 4,500–5,500 Da), ≥7-day washout between arms. Mouse arm 1: 900 or 1,800 mg/kg HTC-col by oral gavage after 16 h fast. Mouse arm 2: pure Gly-Pro-Hyp or pure Pro-Hyp at 0.2 mmol/kg. All hydrolysates supplied by Jellice (Miyagi, Japan).
Duration	Single-dose kinetics. Human plasma sampling 0–300 min. Mouse plasma and perfused-skin sampling 0–360 min (Arm 1) and 0–120 min (Arm 2).
Endpoints	Plasma concentration of 17 targeted collagen-derived peptides in humans by LC-MS/MS; Cmax; AUC and Tmax per peptide; Peptide concentration in perfused mouse skin tissue; Comparative bioavailability between HTC-col and LTC-col; Metabolic conversion of Gly-Pro-Hyp to Pro-Hyp in vivo

What the study showed, in plain terms

By 2017, researchers had already shown that some collagen peptides survive digestion and reach the bloodstream. What remained unclear was whether those peptides then actually reached the skin, where most people take collagen hoping to see a benefit. This paper set out to answer that question directly, and to test whether a newer type of collagen hydrolysate — one deliberately manufactured to contain more three-amino-acid pieces than the older two-amino-acid-dominated products — behaves differently in the body.

Twelve healthy volunteers took a single dose of one of two collagen hydrolysates, both made from pig skin but processed differently. One had a high proportion of tripeptides (three amino acids stuck together, HTC-col); the other had almost none (LTC-col). Blood samples were then taken over five hours to measure exactly which peptides showed up and at what levels. The researchers also ran a parallel experiment in mice, where they could take skin samples as well as blood samples, and they even tested what happens when you give the pure tripeptide Gly-Pro-Hyp on its own.

Two findings stand out. First, the high-tripeptide hydrolysate produced roughly ten times more Gly-Pro-Hyp in the bloodstream than the standard product — a genuinely large difference. Second, in mice, both Gly-Pro-Hyp and its two-amino-acid breakdown product Pro-Hyp did reach the skin, appearing there within about half an hour of ingestion. Giving pure Gly-Pro-Hyp also raised skin Pro-Hyp, showing that the tripeptide is partly broken down into the dipeptide inside the body. Together these findings are the closest thing yet to a direct chain of evidence from swallowed collagen supplement to peptides reaching skin tissue — though the crucial skin-uptake step was measured in mice, not humans.

Key findings

In humans, HTC-col produced a plasma Cmax of Gly-Pro-Hyp of 21.1 nmol/mL versus 2.1 nmol/mL after LTC-col — approximately 10-fold higher. AUC was also approximately 8-fold higher (2,599.88 vs 323.17 min·nmol/mL).
Ala-Hyp was the most abundant plasma peptide overall in humans across both hydrolysates (Cmax ~26 nmol/mL for HTC-col, ~24 nmol/mL for LTC-col — not significantly different).
Of 24 candidate peptides screened, 17 were reliably detected in human plasma after collagen ingestion.
In mice at 900 mg/kg HTC-col, plasma Gly-Pro-Hyp reached Cmax 103 nmol/mL at Tmax 15 min; at 1,800 mg/kg it reached 191 nmol/mL — dose-dependent absorption.
Both Gly-Pro-Hyp and Pro-Hyp accumulated in perfused mouse skin tissue, with Pro-Hyp reaching approximately 15 nmol/g (900 mg/kg dose) — measurable evidence that ingested collagen peptides reach skin.
Tmax in skin (30–45 min) lagged Tmax in plasma (15 min), consistent with peptides moving from blood into skin tissue.
The plasma-to-skin ratio inverted between peptides: Gly-Pro-Hyp was 1.78–2.63-fold more concentrated in plasma than in skin, whereas Pro-Hyp was 3–5-fold more concentrated in skin than in plasma — consistent with Gly-Pro-Hyp being partially hydrolysed to Pro-Hyp during or after skin uptake.
Administration of pure Gly-Pro-Hyp raised both Gly-Pro-Hyp and Pro-Hyp in plasma and skin, directly confirming in vivo conversion of the tripeptide to the dipeptide.

What this study can and cannot tell us

The human sample was small (n=12), and multiple peptide comparisons were made; the large Gly-Pro-Hyp difference is more persuasive than smaller exploratory peptide signals.
This was a single-dose kinetics study, so it does not establish how plasma or tissue exposure behaves during chronic daily supplementation.
The key tissue-distribution evidence was measured in mice, not humans. Human plasma kinetics do not by themselves prove that the same peptide concentrations reach human skin.
Detecting Gly-Pro-Hyp or Pro-Hyp in skin tissue does not demonstrate a clinical skin benefit; the study did not measure wrinkles, elasticity, fibroblast activity or collagen synthesis as outcomes.
Five of the eight authors (Misato Yazaki, Yukihiko Ito, Masayoshi Yamada, Sachiyuki Teramoto and Kohji Yamaguchi) were affiliated with FANCL Corporation. The paper nevertheless explicitly states that the authors declared no competing financial interest; the corporate affiliations are relevant context and should not be misreported as an undeclared conflict.
Both hydrolysates in the human comparison were porcine type I collagen preparations, so the findings do not establish equivalent kinetics for marine, bovine or chicken collagen products.
The mouse doses (900–1,800 mg/kg) were much higher on a body-weight basis than typical human supplemental intakes, so direct dose translation is inappropriate.

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