Lactotripeptides

Lactotripeptides (IPP and VPP): A Comprehensive Reference

1. Identity and Chemical Characterization

Names and Nomenclature

Lactotripeptides are bioactive tripeptides derived from the casein fraction of bovine milk proteins, consisting primarily of the sequences isoleucine-proline-proline (IPP) and valine-proline-proline (VPP), which exhibit angiotensin-converting enzyme (ACE) inhibitory activity and are associated with potential blood pressure-lowering effects in humans. The standard abbreviations used throughout scientific and regulatory literature are IPP (Ile-Pro-Pro) and VPP (Val-Pro-Pro). The collective term "lactotripeptides" or "LTPs" refers to both peptides together. A commercially branded form is sold under the trade name AmealPeptide®.

Molecular Origins Within Casein

Valine-proline-proline (VPP) and isoleucine-proline-proline (IPP) can be released from β-casein and κ-casein, and are the two most investigated casein-derived peptides in both animal and human studies. More specifically, the VPP sequence is embedded in the β-casein fraction at positions 84–86, while IPP appears in β-casein at positions 74–76 and in κ-casein at positions 108–110. Caseins are characterized by high proline content that protects embedded tripeptides from premature degradation.

Common Preparations and Dosage Forms

LTPs are obtained from either fermented or enzymatically treated milk (FLTPs or ELTPs). The fermented milk product may be in the form of solids such as powders, granules, and tablets, or of fluids such as paste, gel, and liquid. Similar peptides are added to yogurts and cheeses, typically providing 0.1 to 1 mg of VPP and IPP per serving, and in dietary supplements lactotripeptides are available as capsules or tablets, often dosed at 3 to 10 mg of combined VPP and IPP per daily serving.

2. Natural Sources and Production

Primary Biological Source

These peptides are released through enzymatic hydrolysis or microbial fermentation during the production of fermented dairy products such as yogurt, cheese, and milk drinks, where lactic acid bacteria like Lactobacillus helveticus play a key role in their generation. The exact IPP and VPP sequences occur in ruminant milks such as bovine, goat, and sheep due to similar casein structures.

Microbial Production Mechanism

Lactobacillus helveticus can release the antihypertensive peptides Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP) from casein in fermented milk by a specific proteolytic system. Lb. helveticus is one of the most efficient proteolytic Lactobacillus species. The breakdown process is staged: initially the breakdown of casein is performed by extracellular proteinases, followed by the uptake of di/tripeptides and oligopeptides using specific uptake mechanisms; in the last stage, peptides are further degraded by intracellular peptidases, yielding small peptides and amino acids for bacterial growth.

Commercial Products

A commercially available fermented milk product claimed to be "suitable for those with mild hypertension" is Calpis sour milk, fermented with Lactobacillus helveticus and Saccharomyces cerevisiae, produced by Calpis Food Industry, Japan. Another commercially available fermented milk product is Evolus, produced by Valio, Finland, which claims to be "the first European functional food to help lower blood pressure." Lactotripeptides (AmealPeptide®) are certified as a "food for specified health use" (FOSHU) in Japan and have been granted GRAS approval in the US.

3. Historical and Traditional Context

The origin of fermented milk consumption in Japan can be traced back to about 100 years ago, when it was observed that Mongolians who consumed fermented milk products enjoyed good health. The Asahi Group's research on lactic acid bacteria and fermented milk can be traced back to Calpis, a company that produced and released Japan's first lactic acid bacteria beverage in 1919.

While the isolation of lactotripeptides as distinct compounds is relatively recent, the broader use of milk-based preparations for health dates back centuries, with traditional medicinal systems in various cultures extolling the virtues of dairy for vitality, stress relief, and cardiovascular well-being. Ancient remedies often included fermented milk products, which naturally contain increased levels of bioactive peptides, including lactotripeptides, due to enzymatic breakdown during fermentation.

The specific identification of IPP and VPP as the active antihypertensive constituents of fermented milk was a product of 20th-century Japanese scientific research. AmealPeptide® was discovered over the course of around 40 years of continuous research into the physiological functions of fermented milk, produced during the process of manufacturing the CALPIS® lactic acid drink. Consumption of products enriched with lactotripeptides has risen slowly since their introduction into the Japanese market in 1997. Japan's Food for Specified Health Uses (FOSHU) system approved VPP/IPP-containing products for blood pressure claims in 1997.

4. Key Constituents and Active Compounds

Structural Features Conferring Stability

Their stability in the gastrointestinal tract, attributed to structural features like C-terminal proline residues and branched-chain N-terminal amino acids, allows them to reach target tissues intact and exert physiological effects. IPP, VPP, and LPP (Leucine-Proline-Proline) are relatively resistant against breakdown in the gastrointestinal tract and therefore expected to be similar in their kinetics.

Additional Peptides

While IPP and VPP are the primary lactotripeptides studied, production processes also generate leucine-proline-proline (LPP) and other minor tripeptide fragments. In most products, more VPP is present than IPP, giving a ratio of approximately 1.1–1.8 VPP:IPP. Data from a study that assessed the bioavailability of IPP and VPP suggest that IPP may have a better bioavailability than VPP.

5. Mechanisms of Action

ACE Inhibition (Primary Proposed Mechanism)

Because IPP and VPP were first isolated and identified as angiotensin-converting enzyme (ACE) inhibitory peptides and were shown to exert antihypertensive effects after oral administration in spontaneously hypertensive rats, both peptides had been thought to act through ACE inhibition. Renin converts angiotensinogen to the biologically inactive angiotensin I, which in turn undergoes proteolytic cleavage by ACE to the vasoconstrictor angiotensin II; inhibition of ACE leads to an increase of the angiotensin I/angiotensin II ratio and a subsequent compensatory increase in renin activity.

These lactotripeptides inhibit ACE in vitro at micromolar concentrations, protect endothelial function in vitro, and reduce arterial stiffness in humans. However, the in vivo significance of ACE inhibition remains contested. IPP and VPP were poorly absorbed and rapidly eliminated in one human study; they did not inhibit plasma or endothelial ACE in vivo at the selected doses and had no specific effect on the N-terminal or C-terminal ACE domains.

Additional Proposed Mechanisms

The precise mechanisms responsible for the antihypertensive effect are still unknown; other mechanisms might also be involved, such as production of vasodilative substances or an effect on sympathetic nervous activity. A plausible mechanism is thought to be the effect of lactotripeptides in inhibiting the activity of angiotensin-converting enzyme (ACE), which results in inhibition of conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, and also an increase in the release of vasodilatory peptides such as bradykinins; these actions provide beneficial effects on the vasculature and kidney function.

Another possible mechanism for antihypertensive action of milk protein-derived peptides is stimulation of nitric oxide production by endothelial cells. A standardized LTP product has been shown in both in vitro and animal models to induce nitric oxide (NO) production and attenuate atherosclerosis.

Absorption and Bioavailability

Di- and tripeptides are efficiently absorbed intact via the PepT1 transporter in the small intestinal epithelium; this is why the ACE-inhibitory tripeptides VPP and IPP are among the best-validated food peptides, as their small size matches the transporter's substrate preference. Portal availability of synthetic XPP was 0.08 ± 0.01% of intake and increased when a protein matrix was present. A casein hydrolysate (CasH) matrix prolonged portal bioavailability by 18 minutes (absorption half-life: synthetic XPP 15 ± 2 min vs. CasH 33 ± 3 min, p<0.0001) and increased systemic elimination by 20 minutes.

Preclinical and in vitro studies suggest that a portion of the orally ingested dose of these peptides can be absorbed in the intact form from the gastrointestinal tract, can inhibit the tissue renin-angiotensin system, and can produce significant reductions in blood pressure. One of the few studies that support their in vivo action demonstrated the presence of IPP and VPP as well as a decreased ACE activity in the aorta after a single oral administration to spontaneously hypertensive rats.

6. Scientific Evidence by Area of Use

6.1 Blood Pressure Reduction

Overview and Magnitude of Evidence

The effects of milk protein-derived peptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP) on blood pressure have been reported in more than 20 randomized, placebo-controlled clinical studies. The number of meta-analyses that have pooled this evidence is substantial, with consistent but moderate and sometimes contested effect sizes.

Meta-Analyses: Pooled Effect Sizes

Nineteen randomized clinical intervention trials with small daily doses (2.0–10.2 mg) of milk casein-derived tripeptides showed an overall lowering of systolic blood pressure (4.0 mmHg) and diastolic blood pressure (1.9 mmHg) in mildly hypertensive subjects in a random effects meta-analysis.

A second important meta-analysis reported similar overall effects: in a general analysis of 24 studies with 28 trials on 1,919 human subjects, there are small reductions in both systolic BP (SBP) and diastolic BP (DBP), with pooled mean effects of 1.66 mmHg (95% CI: −2.48 to −0.84) and 0.76 mmHg (−1.31 to −0.20), respectively.

A 2015 Nutrients meta-analysis by Fekete, Givens, and Lovegrove (University of Reading), which searched Medline, Cochrane, EMBASE, and Web of Science until May 2014, found a small but significant decrease in BP after lactotripeptides ingestion, although the data are inconsistent.

The 2010 meta-analysis by Cicero et al. in the Journal of Human Hypertension found: pooled effect of peptides was a reduction of −3.73 mmHg (95% CI: −6.70, −1.76) for systolic blood pressure and 1.97 mmHg (95% CI: −3.85, −0.64) for diastolic blood pressure.

Asian vs. European Populations: Ethnic Heterogeneity

A major and consistent finding across meta-analyses is an ethnic difference in response. The effect was more evident in Asian patients (SBP: −6.93 mmHg, 95% CI: −10.95 to −2.94; DBP: −3.98 mmHg, 95% CI: −5.38 to −2.44) than in Caucasian ones (SBP: −1.17 mmHg, 95% CI: −2.82 to 0.72; DBP: −0.52 mmHg, 95% CI: −1.39 to 0.13).

For European populations specifically, a dedicated meta-analysis found: the decrease in SBP with IPP/VPP was 1.28 mmHg (95% CI: −2.09 to −0.48, P = 0.0017) and the decrease in diastolic BP was 0.59 mmHg (95% CI: −1.18 to −0.01, P = 0.047). A significant effect was seen for age, with each additional year of age reducing the effect on SBP by 0.09 mmHg; this might be related to isolated systolic hypertension, a condition often encountered in the elderly, who may be poorly responsive to first-line treatments for hypertension.

However, this evidence for Europeans was qualified by independent assessment: the authors concluded that IPP and VPP were effective in moderately reducing systolic blood pressure in European subjects, but limitations of the evidence base and review methodology suggest that these conclusions may be unreliable.

Japanese Populations

The strongest and most consistent evidence is from Japanese subjects. Eighteen studies including a total of 1,194 subjects were included in one meta-analysis; a random effect model showed that consumption of IPP/VPP induced a significant reduction in SBP compared with placebo in Japanese subjects, with an estimated effect of −5.63 mmHg (95% CI: −6.87 to −4.39). A significant heterogeneity between series was evident, which could be explained by a significant influence of the baseline blood pressure status of the subjects; the effect of IPP/VPP on SBP was stronger in hypertensive subjects (−8.35 mmHg, P<0.0001) than in non-hypertensive subjects (−3.42 mmHg, P<0.0001).

Baseline Blood Pressure as a Predictor

Lactotripeptides, in particular VPP and IPP, appear more effective in reducing BP of subjects with a higher starting BP; in none of the trials with normotensives were any statistically significant BP changes found. A 164-subject double-blind RCT in European participants found: when compared with baseline, office systolic BP (−3.42 mmHg, P < .001) and diastolic BP (−2.35 mmHg, P < .001) significantly decreased in LTP-treated patients only, with baseline BP being the main predictor of the LTP antihypertensive effect.

Negative and Null Findings

Not all clinical data support a blood pressure effect. Six double-blind, placebo-controlled trials involving a total of 780 subjects with high-normal blood pressure or untreated hypertension from the UK and The Netherlands, with intervention periods of 4–8 weeks and IPP + VPP intake ranging from 2 to 10 mg/day, showed little evidence for an antihypertensive effect of IPP + VPP. Furthermore, no ACE inhibition was observed in vivo. These recent data did not support a role for lactotripeptides in blood pressure regulation, though the authors could not exclude a beneficial effect in hypertensive subjects from specific populations such as Finland and Japan.

While the number of clinical trials testing the efficacy of LTPs continues to increase, the results have been inconsistent, especially in the last few years.

Maximum Effects and Onset

Maximum BP-lowering effects of lactotripeptides approximated 13 mmHg SBP and 8 mmHg DBP with active treatment versus placebo, and were likely to reach the maximum after 8–12 weeks of treatment. The first significant effects on BP in hypertensive subjects have been observed after 1–2 weeks of treatment with dosages as low as 3.8 mg/day.

Regulatory Position

The European Food Safety Authority (EFSA) has been more cautious, declining similar claims in 2012, citing insufficient evidence of a cause-and-effect relationship. By contrast, in Japan, FOSHU approval for blood pressure claims has remained in place since 1997.

6.2 Arterial Stiffness and Vascular Function

Beyond systolic and diastolic blood pressure, several human studies have examined effects on vascular structure and function. Clinical research has confirmed that LTP can promote vasodilation, improve endothelial function, and mitigate arterial stiffness in prehypertensive and hypertensive subjects.

One randomized, double-blind, placebo-controlled clinical trial investigated the effects of standardized LTP tablets containing 3.4 mg each of VPP and IPP on central blood pressure and arterial stiffness in 70 subjects with untreated stage 1 hypertension; central blood pressure and brachial-ankle pulse wave velocity (baPWV) were measured at the beginning and end of the 8-week study; central SBP, baPWV, brachial SBP, and radial mean blood pressure were significantly reduced in the treatment group compared with placebo; overall, these results suggest that VPP and IPP might have beneficial effects on arterial health.

In a trial of metabolic syndrome patients, a randomized, double-blind, placebo-controlled, crossover clinical trial was conducted in 40 nonsmoking volunteers with metabolic syndrome; treatment periods were 4 weeks long, separated by a 4-week washout period; daily administration of LTPs from casein at 10.2 mg/day was compared with placebo; during LTP treatment, patients experienced a significant mean decrease in systolic BP (−3.4 ± 4.4 mmHg, P = 0.041), diastolic BP (−3.1 ± 3.2 mmHg, P = 0.049), and pulse wave velocity (−0.7 ± 0.3 m/sec, P = 0.001).

Administration of casein hydrolysate containing Ile-Pro-Pro and Val-Pro-Pro four times a day for one week in capsules increased maximum blood flow of the upper forearm during reactive hyperemia, demonstrating an improvement in vascular endothelial dysfunction in subjects with mild hypertension; interestingly, this effect was apparently not related to a blood pressure-lowering effect, as no significant changes were detected in systemic blood pressure.

6.3 Arterial Compliance in Postmenopausal Women

A randomized controlled trial examined LTP in combination with aerobic exercise. The effects of LTP ingestion alone or in combination with regular aerobic exercise on arterial compliance were determined; a total of 55 postmenopausal women (50–65 years old) were randomly divided into four groups: placebo, LTP, exercise and placebo, or exercise and LTP; LTP or placebo was administered orally for 8 weeks; the exercise groups completed an 8-week moderate aerobic exercise intervention.

6.4 Normotensive Individuals

In clinical studies, no significant effect on blood pressure was observed in normotensives. In none of the trials with normotensives were any statistically significant BP changes found. This is broadly consistent with the behavior of ACE inhibitors and other antihypertensive interventions that show baseline-dependent effects.

7. Body Systems and Health Areas of Association

Cardiovascular System

The primary and most-studied area is the cardiovascular system. In vitro and experimental studies conducted since the 1980s have demonstrated the wide functionality of bioactive peptides released from bovine milk proteins, suggesting that such peptides may exert physiological effects on the gastrointestinal, cardiovascular, endocrine, immune, nervous, and other body systems. The key cardiovascular areas of evidence include blood pressure regulation, arterial stiffness (pulse wave velocity), central aortic pressure, and endothelial function.

Renin-Angiotensin-Aldosterone System (RAAS)

Inhibition of ACE is generally believed to be the underlying working mechanism of lactotripeptides. ACE is an enzyme that plays a crucial role in the renin-angiotensin system, which regulates blood pressure and fluid and electrolyte balance. The ACE inhibitory activity of lactotripeptides has mainly been determined in vitro.

Potential Vascular and Endothelial Effects

Lactotripeptides have additionally been shown to exert beneficial effects other than lowering systemic BP, such as improvement of vascular endothelial function in subjects with mild hypertension; since there was no change in systemic BP in this study, the authors suggest that the improvement of vascular endothelial function attributable to VPP and IPP is independent of hemodynamic changes.

8. Dosage Forms and Dosages Reported in Studies

Effective dosages of lactotripeptides (VPP and IPP) range from 3.07 to 52.5 mg/d; blood pressure-lowering effects of lactotripeptides are typically measured after 4–6 weeks of treatment.

Nineteen randomized clinical intervention trials used small daily doses of 2.0–10.2 mg of milk casein-derived tripeptides.

In the metabolic syndrome crossover trial described above, the dietary supplementation was made by daily administration of LTPs from casein at 10.2 mg/day.

In the IPP-rich hydrolysate study: a randomized, placebo-controlled, double-blind, crossover study included 70 Caucasian subjects with prehypertension or stage 1 hypertension; study treatments consisted of daily consumption of two capsules of MPH1 (each containing 7.5 mg Isoleucine-Proline-Proline) or MPH2 (each containing 6.6 mg Methionine-Alanine-Proline, 2.3 mg Leucine-Proline-Proline, and 1.8 mg IPP), or placebo for 4 weeks.

In the arterial stiffness trial cited above, standardized LTP tablets containing 3.4 mg each of VPP and IPP were administered for 8 weeks.

Maximum blood pressure reductions approximating 13 mmHg of SBP and 8 mmHg of DBP, respectively, after active treatment compared with placebo, are likely reached after 8–12 weeks of treatment.

9. Safety Considerations

General Safety Profile

Food protein-derived bioactive peptides have attracted increasing attention in functional foods due to their advantages of high bioactivity, low toxicity, and easy metabolism in the human body. The doses used in multiple clinical studies did not exert any significant effects on blood and urine parameters, adverse events, and other adverse effects, and were thus considered safe; previous studies confirmed that even high daily dosages of VPP and IPP were safe.

No-Observable-Adverse-Effect Level (NOAEL)

In the sub-chronic toxicity test in rats exposed to casein hydrolysate product, the "no observable adverse effect level" (NOAEL) resulted in >1,000 mg casein hydrolysate/kg body weight per day, corresponding to 3 mg IPP + 3 mg VPP/kg body weight per day.

GRAS and Regulatory Status

The valine-proline-proline (VPP) and isoleucine-proline-proline (IPP) tripeptides were generally recognised as safe (GRAS) by the United States Food and Drug Administration (USFDA) and were approved for use as functional components in food to reduce blood vessel constriction.

Regulatory Health Claim Limitations

Casein and caseinates are covered under EU regulations (EC 2921/90; EC 760/2008), but casein hydrolysates do not currently possess approved health claims in Europe per EFSA's position. The EFSA declined similar claims in 2012, citing insufficient evidence of a cause-and-effect relationship; this regulatory divergence illustrates a broader challenge for bioactive food peptides, as the evidence threshold for food health claims varies by jurisdiction.

Milk Protein Allergy Consideration

Lactotripeptides are derived from cow's milk casein. As such, individuals with confirmed cow's milk protein allergy should be aware that even hydrolyzed casein products retain immunogenic potential for highly sensitive individuals, as documented in the allergy literature (Wal JM, 2001, Allergy 56:35–8, cited in multiple clinical trial reference lists). This is a factual precautionary consideration supported by the published allergy literature referenced in LTP clinical trials.

Confounding Mineral Content

All products tested in human studies so far contain a number of minerals with known effects on BP, such as calcium, potassium, magnesium, and phosphorus. Some lactotripeptide products administered in capsules in various studies contained varying quantities of potassium and calcium per mg of IPP; researchers have argued it is very unlikely that minerals contributed to observed blood pressure-lowering effects in mineral-depleted preparations.

Potential Interaction with Antihypertensive Medications

Milk-derived small peptides have held promise for reducing angiotensin II-mediated vasoconstriction because mechanistically they imitate angiotensin-converting enzyme inhibitors (ACEIs). Because LTPs share the mechanistic pathway of pharmaceutical ACE inhibitors (e.g., lisinopril, enalapril), additive blood pressure lowering is mechanistically plausible in subjects already on ACE inhibitor therapy, though no specific human drug interaction trial has been published in the available peer-reviewed literature. Hypertensive subjects who are pharmacologically treated were generally excluded from LTP intervention studies.

10. Limitations and Quality of Evidence

The overall body of clinical evidence has several acknowledged limitations that must be understood when interpreting LTP research:

• Lactotripeptides have held promise in the framework of lifestyle modification for prevention and control of hypertension, but while the number of clinical trials continues to increase, the results have been inconsistent, especially in recent years.
• The blood pressure decrease is convincingly shown in subjects of Asian origin, but less consistent results have been obtained in European populations.
• Lactotripeptides may exert BP-lowering effects either via ACE inhibition or via non-ACE-dependent pathways, but only limited in vivo evidence is currently available for the physiological basis of their antihypertensive action.
• Several systematic reviews in this field were funded by or conducted in collaboration with commercial lactotripeptide manufacturers, including Calpis, which presents a potential source of bias that should be considered when interpreting the results.
• All products tested in human studies contain a number of minerals with known effects on BP, making it difficult to fully isolate the peptide-specific effect in non-mineral-depleted preparations.
• Study populations across trials are heterogeneous in terms of baseline blood pressure, ethnicity, dietary background, product matrix (fermented milk vs. capsule vs. tablet), and duration, making cross-trial comparisons difficult.

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