What is nattokinase?
Nattokinase, a large enzyme of the serine protease family, is isolated from the fermented food product known as nattō (boiled soybeans fermented with the bacterium Bacillus subtilis). Interest in using nattokinase as a supplement has grown because of its cardiovascular benefits of reducing blood clotting and blood pressure.[1][2][3] Although there’s some concern of an increased bleeding risk, reports of bleeding have been very rare and limited to people with chronic conditions or who are already taking blood thinning medications.[8][9]
What are nattokinase’s main benefits?
There is interest in using nattokinase for its cardiovascular benefits such as reducing blood clotting and lowering blood pressure.[1][2][3] However, nattokinase does not seem to lower cholesterol nor reduce atherosclerosis. In a randomized trial in 265 adults with an average age of 65 years, taking 100 mg (2,000 fibrinolytic units (FU)) of nattokinase daily for about 3 years did not slow the progression of atherosclerosis compared to a placebo.[10] The same dose taken for 6 months also did not lower cholesterol levels compared to a placebo,[11] except when it was used in combination with red yeast rice, which is a natural source for the cholesterol-lowering drug lovastatin.[12] Some researchers insist that higher doses of nattokinase may have a benefit for cholesterol. In fact, one large observational study in Chinese patients found that taking 10,800 FU of nattokinase daily for a year was associated with a reduction in cholesterol, while a lower dose of 3,600 FU daily was not associated with a reduction in cholesterol.[6] This observational study cannot show cause and effect, so further interventional research is needed. It’s unclear if these effects are generalizable to other geographic locations.
What are nattokinase’s main drawbacks?
Generally, nattokinase seems to be safe in adults when taken by mouth in doses of 100 mg (2,000 fibrinolytic units) daily.[5] Although this dose may reduce blood coagulability biomarkers (e.g., prolonged activated partial thromboplastin time (aPTT), a measure of how long it takes blood to clot),[3] there have been no reports of bleeding in adults without apparent health conditions even at doses up to 552 mg daily for four weeks.[2] However, in older adults with chronic conditions, there have been rare reports of bleeding.[8][9]
There have been reports of severe allergic reactions to nattokinase, including FAQ:What is anaphylaxis?, an itchy rash, and difficulty breathing. This can occur in people allergic to either polygamma glutamic acid (PGA, a sticky substance also found in jellyfish) or to nattokinase itself.[13] However, the European Commission concluded that the risk of allergic reactions with nattokinase is no higher than the risk with soy products.[5]
How does nattokinase work?
Nattokinase seems to have some anti-inflammatory and antioxidant effects that can contribute to cardioprotection,[4] but its claim to fame is its ability to reduce blood clotting. Nattokinase seems to reduce blood clotting by breaking down fibrin (a molecule that entangles platelets and creates blood clots) by degrading plasminogen activator inhibitor-1 (PAI-1, a protein that makes clotting more efficient). PAI-1 disables plasminogen activators (PAs), including tissue-type plasminogen activator (tPA), a serine protease which is administered therapeutically to break up blood clots in conditions such as ischemic stroke and heart attack.[4][14] Studies in humans have shown that ingesting a single dose of nattokinase increases blood levels of tPA for about 3 hours,[15] while regular administration (taking 1,300 mg of nattokinase 3 times daily for 8 days) seems to gradually increase tPA in the blood over time.[7] Small studies conducted in generally healthy people, as well as people on dialysis and with cardiovascular disease, showed that taking 800 mg (4,000 fibrinolytic units) of enteric-coated nattokinase 30 minutes after dinner every day for 2 months reduced serum fibrinogen by 7%–10%, factor VII by 7%–14%, and factor VIII by 17%–19% compared to baseline. The reduction in fibrinogen in people with cardiovascular disease and the reduction in factor VII in people on dialysis did not reach statistical significance, possibly due to insufficient power in the study.[16]
What are other names for Nattokinase
- Natto extract
- subtilisin NAT
- Orokinase
- NSK-SD
- NKCP
- Nattō (food product)
Dosage information
Most commonly, 100 mg (2,000 fibrinolytic units (FU)) of nattokinase are taken by mouth daily.[1][2][3][4] This dose is reported to not cause adverse effects by the European Food Safety Authority (EFSA).[5] Limited research using higher doses of nattokinase also reported no adverse effects. People living in China have taken 540 mg (10,800 FU) of nattokinase daily for a year,[6] and adults living in the United States have taken 552 mg of nattokinase daily for four weeks[2] without any reported adverse effects. Nattō itself can be used, and some anti-clotting effects have been noted with 12 grams of nattō daily over 2 weeks.[7]
Examine Database: Nattokinase
Frequently asked questions
Nattokinase, a large enzyme of the serine protease family, is isolated from the fermented food product known as nattō (boiled soybeans fermented with the bacterium Bacillus subtilis). Interest in using nattokinase as a supplement has grown because of its cardiovascular benefits of reducing blood clotting and blood pressure.[1][2][3] Although there’s some concern of an increased bleeding risk, reports of bleeding have been very rare and limited to people with chronic conditions or who are already taking blood thinning medications.[8][9]
Nattokinase is extracted from nattō, a food made of boiled soybeans fermented with the bacterial strain Bacillus subtilis natto.[2] To extract nattokinase from the fermentation broth, processes such as protein salting-out, organic solvent distillation, microfiltration, and ultrafiltration are used.[20] Because of increasing interest in nattokinase, methods of production that increase yield and stability have been explored. For example, irradiation of the bacterial strain B. subtilis natto with gamma or ultraviolet rays seems to improve its heat stability and to increase the yield of nattokinase. Furthermore, using glucose (instead of sucrose or maltose), adding soy milk, and adding certain ions such as calcium and magnesium sulfate to the fermentation medium has been shown to increase the yield of nattokinase.[20]
There is interest in using nattokinase for its cardiovascular benefits such as reducing blood clotting and lowering blood pressure.[1][2][3] However, nattokinase does not seem to lower cholesterol nor reduce atherosclerosis. In a randomized trial in 265 adults with an average age of 65 years, taking 100 mg (2,000 fibrinolytic units (FU)) of nattokinase daily for about 3 years did not slow the progression of atherosclerosis compared to a placebo.[10] The same dose taken for 6 months also did not lower cholesterol levels compared to a placebo,[11] except when it was used in combination with red yeast rice, which is a natural source for the cholesterol-lowering drug lovastatin.[12] Some researchers insist that higher doses of nattokinase may have a benefit for cholesterol. In fact, one large observational study in Chinese patients found that taking 10,800 FU of nattokinase daily for a year was associated with a reduction in cholesterol, while a lower dose of 3,600 FU daily was not associated with a reduction in cholesterol.[6] This observational study cannot show cause and effect, so further interventional research is needed. It’s unclear if these effects are generalizable to other geographic locations.
Small studies suggest that nattokinase can mildly lower blood pressure in some people; however, it's not clear if this effect persists in the long term. A clinical study in 86 patients with high blood pressure showed that taking 100 mg (2,000 fibrinolytic units (FU)) of nattokinase daily for 8 weeks reduced systolic blood pressure by about 6 mmHg and diastolic blood pressure by about 3 mmHg compared to a placebo.[1] Another small study in adults without known health conditions showed that taking 552 mg (11,040 FU) of nattokinase (NSK-SD) daily for four weeks resulted in small and variable decreases in blood pressure. However, the reduction in diastolic blood pressure was only statistically significant in female participants.[2]
The blood-pressure-lowering effect has been attributed to peptides in denatured nattokinase which inhibit the angiotensin-I-converting enzyme (ACE). Denaturing the nattokinase enzyme with heat and simulated stomach contents seems to yield more of these peptides, as shown in animal and in vitro research.[17][18] A laboratory study using simulated digestion, or exposing nattokinase to the stomach digestive enzymes pepsin and trypsin, showed that the enzyme fragments had greater ACE-inhibitory activity than nattokinase itself.[19]
Generally, nattokinase seems to be safe in adults when taken by mouth in doses of 100 mg (2,000 fibrinolytic units) daily.[5] Although this dose may reduce blood coagulability biomarkers (e.g., prolonged activated partial thromboplastin time (aPTT), a measure of how long it takes blood to clot),[3] there have been no reports of bleeding in adults without apparent health conditions even at doses up to 552 mg daily for four weeks.[2] However, in older adults with chronic conditions, there have been rare reports of bleeding.[8][9]
There have been reports of severe allergic reactions to nattokinase, including FAQ:What is anaphylaxis?, an itchy rash, and difficulty breathing. This can occur in people allergic to either polygamma glutamic acid (PGA, a sticky substance also found in jellyfish) or to nattokinase itself.[13] However, the European Commission concluded that the risk of allergic reactions with nattokinase is no higher than the risk with soy products.[5]
Nattokinase seems to alter blood coagulation chemistry, and there’s a concern it may increase the risk of bleeding. In people with mildly elevated cholesterol levels, taking 2,000 fibrinolytic units (FU) of nattokinase daily for 8 weeks prolonged the aPTT (activated partial thromboplastin time — a measure of how long it takes blood to clot).[3]
However, there have been only 2 reported cases of bleeding with nattokinase in older adults with cardiovascular conditions. In one case, 400 mg of nattokinase was taken daily for 7 days with aspirin (a blood thinner).[8] In the other case, an unknown, likely large dose of nattokinase (sometimes a “handful” of capsules) was taken daily.[9]
Nattokinase seems to have some anti-inflammatory and antioxidant effects that can contribute to cardioprotection,[4] but its claim to fame is its ability to reduce blood clotting. Nattokinase seems to reduce blood clotting by breaking down fibrin (a molecule that entangles platelets and creates blood clots) by degrading plasminogen activator inhibitor-1 (PAI-1, a protein that makes clotting more efficient). PAI-1 disables plasminogen activators (PAs), including tissue-type plasminogen activator (tPA), a serine protease which is administered therapeutically to break up blood clots in conditions such as ischemic stroke and heart attack.[4][14] Studies in humans have shown that ingesting a single dose of nattokinase increases blood levels of tPA for about 3 hours,[15] while regular administration (taking 1,300 mg of nattokinase 3 times daily for 8 days) seems to gradually increase tPA in the blood over time.[7] Small studies conducted in generally healthy people, as well as people on dialysis and with cardiovascular disease, showed that taking 800 mg (4,000 fibrinolytic units) of enteric-coated nattokinase 30 minutes after dinner every day for 2 months reduced serum fibrinogen by 7%–10%, factor VII by 7%–14%, and factor VIII by 17%–19% compared to baseline. The reduction in fibrinogen in people with cardiovascular disease and the reduction in factor VII in people on dialysis did not reach statistical significance, possibly due to insufficient power in the study.[16]
Limited research in humans suggests that nattokinase is absorbed and present in the blood between 2 and 24 hours after ingestion.[21][2] However, nattokinase can be degraded by stomach acid and exposure to high temperatures (over 50 degrees Celsius (122 degrees Fahrenheit)), which could reduce its fibrinolytic effect. Nattokinase seems to be stable at pH values of 6 to 9 and temperatures of 30 to 50 degrees Celsius.[21][22] To improve its stability in the stomach, nattokinase is often formulated with various protective ingredients. Formulations of nattokinase to protect it from being denatured by gastric acid include encapsulation (coatings) and nanoemulsion (dispersing and coating submicron particles). Inactive ingredients used to coat or immobilize the enzyme include chitosan, mesoporous silica, polyglutamic acid peptide, hydroxypropyl cellulose, polylactic-co-glycolic acid, and others.[20][22]
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References
- ^Kim JY, Gum SN, Paik JK, Lim HH, Kim KC, Ogasawara K, Inoue K, Park S, Jang Y, Lee JHEffects of nattokinase on blood pressure: a randomized, controlled trialHypertens Res.(2008 Aug)
- ^Lampe BJ, English JCToxicological assessment of nattokinase derived from Bacillus subtilis var. natto.Food Chem Toxicol.(2016 Feb)
- ^Yoo HJ , Kim M , Kim M , Lee A , Jin C , Lee SP , Kim TS , Lee SH , Lee JHThe effects of nattokinase supplementation on collagen-epinephrine closure time, prothrombin time and activated partial thromboplastin time in nondiabetic and hypercholesterolemic subjects.Food Funct.(2019 May 22)
- ^Gallelli G, Di Mizio G, Palleria C, Siniscalchi A, Rubino P, Muraca L, Cione E, Salerno M, De Sarro G, Gallelli LData Recorded in Real Life Support the Safety of Nattokinase in Patients with Vascular Diseases.Nutrients.(2021 Jun 13)
- ^Turck D, Bresson J-L, et alSafety of fermented soybean extract NSK-SD® as a novel food pursuant to Regulation (EC) No 258/97(28 July 2016)
- ^Chen H, Chen J, Zhang F, Li Y, Wang R, Zheng Q, Zhang X, Zeng J, Xu F, Lin YEffective management of atherosclerosis progress and hyperlipidemia with nattokinase: A clinical study with 1,062 participants.Front Cardiovasc Med.(2022)
- ^Sumi H, Hamada H, Nakanishi K, Hiratani HEnhancement of the fibrinolytic activity in plasma by oral administration of nattokinaseActa Haematol.(1990)
- ^Chang YY, Liu JS, Lai SL, Wu HS, Lan MYCerebellar hemorrhage provoked by combined use of nattokinase and aspirin in a patient with cerebral microbleeds.Intern Med.(2008)
- ^Ramachandran L, Aqeel A, Jafri A, Sidhu Y, Mohamed Djirdeh TNattokinase-Associated Hemoperitoneum in an Elderly Woman.Cureus.(2021 Dec)
- ^Hodis HN, Mack WJ, Meiselman HJ, Kalra V, Liebman H, Hwang-Levine J, Dustin L, Kono N, Mert M, Wenby RB, Huesca E, Rochanda L, Li Y, Yan M, St John JA, Whitfield LNattokinase atherothrombotic prevention study: A randomized controlled trial.Clin Hemorheol Microcirc.(2021)
- ^Yang NC, Chou CW, Chen CY, Hwang KL, Yang YCCombined nattokinase with red yeast rice but not nattokinase alone has potent effects on blood lipids in human subjects with hyperlipidemia.Asia Pac J Clin Nutr.(2009)
- ^Liu X, Zeng X, Mahe J, Guo K, He P, Yang Q, Zhang Z, Li Z, Wang D, Zhang Z, Wang L, Jing LThe Effect of Nattokinase-Monascus Supplements on Dyslipidemia: A Four-Month Randomized, Double-Blind, Placebo-Controlled Clinical Trial.Nutrients.(2023 Sep 30)
- ^Suzuki K, Nakamura M, Sato N, Futamura K, Matsunaga K, Yagami ANattokinase (Bac s 1), a subtilisin family serine protease, is a novel allergen contained in the traditional Japanese fermented food natto.Allergol Int.(2023 Apr)
- ^Jilani TN, Siddiqui AHTissue Plasminogen Activator.StatPearls.(2024 Jan)
- ^Tai MW, Sweet BVNattokinase for prevention of thrombosis.Am J Health Syst Pharm.(2006 Jun 15)
- ^Hsia CH, Shen MC, Lin JS, Wen YK, Hwang KL, Cham TM, Yang NCNattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjectsNutr Res.(2009 Mar)
- ^Fujita M, Ohnishi K, Takaoka S, Ogasawara K, Fukuyama R, Nakamuta HAntihypertensive effects of continuous oral administration of nattokinase and its fragments in spontaneously hypertensive rats.Biol Pharm Bull.(2011)
- ^Murakami K, Yamanaka N, Ohnishi K, Fukayama M, Yoshino MInhibition of angiotensin I converting enzyme by subtilisin NAT (nattokinase) in natto, a Japanese traditional fermented food.Food Funct.(2012 Jun)
- ^Ramlal A, Nautiyal A, Baweja P, Kumar V, Mehta S, Mahto RK, Tripathi S, Shanmugam A, Pujari Mallikarjuna B, Raman P, Lal SK, Raju D, Rajendran AAngiotensin-converting enzyme inhibitory peptides and isoflavonoids from soybean Glycine max (L.) Merr..Front Nutr.(2022)
- ^Li D, Hou L, Hu M, Gao Y, Tian Z, Fan B, Li S, Wang FRecent Advances in Nattokinase-Enriched Fermented Soybean Foods: A Review.Foods.(2022 Jun 24)
- ^Ero MP, Ng CM, Mihailovski T, Harvey NR, Lewis BHA pilot study on the serum pharmacokinetics of nattokinase in humans following a single, oral, daily dose.Altern Ther Health Med.(2013 May-Jun)
- ^Wang C, Du M, Zheng D, Kong F, Zu G, Feng YPurification and characterization of nattokinase from Bacillus subtilis natto B-12.J Agric Food Chem.(2009 Oct 28)
Examine Database References
- Fibrinolysis - Sumi H, Hamada H, Nakanishi K, Hiratani HEnhancement of the fibrinolytic activity in plasma by oral administration of nattokinaseActa Haematol.(1990)
- Factor VIII - Hsia CH, Shen MC, Lin JS, Wen YK, Hwang KL, Cham TM, Yang NCNattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjectsNutr Res.(2009 Mar)
- Liver Enzymes - Yang NC, Chou CW, Chen CY, Hwang KL, Yang YCCombined nattokinase with red yeast rice but not nattokinase alone has potent effects on blood lipids in human subjects with hyperlipidemia.Asia Pac J Clin Nutr.(2009)
- Blood Pressure - Kim JY, Gum SN, Paik JK, Lim HH, Kim KC, Ogasawara K, Inoue K, Park S, Jang Y, Lee JHEffects of nattokinase on blood pressure: a randomized, controlled trialHypertens Res.(2008 Aug)