Nattokinase & Vitamin K2 (MK-7) — The Natto Connection

Natto is the world's most concentrated dietary source of vitamin K2 menaquinone-7 (MK-7), delivering approximately 1,000 mcg of MK-7 per 100 g serving — an order of magnitude higher than any cheese, fermented dairy, or organ meat. MK-7 is the long-chain menaquinone with a 72-hour serum half-life (versus approximately 6 hours for MK-4), which makes a single daily dose sufficient to maintain stable circulating levels and tissue saturation. The biology that matters is the matrix Gla protein (MGP) axis: MGP is the body's principal endogenous inhibitor of arterial calcification, it requires gamma-carboxylation by vitamin K2 to become functional, and its job is to bind free calcium ions in the vascular wall and direct them out of arterial tissue and into bone matrix. The Rotterdam Study (Geleijnse 2004), the Knapen 2015 RCT in postmenopausal women, and the Beulens 2009 coronary calcification cohort all support a meaningful cardiovascular protective effect of dietary or supplemental MK-7. The clinical convergence is striking: natto delivers BOTH the fibrinolytic enzyme nattokinase that dissolves fibrin clots AND the matrix-Gla-protein-activating vitamin MK-7 that prevents arterial calcification — two fundamentally different mechanisms operating on the same end target (cardiovascular disease) in a single traditional food. This deep-dive walks through MK-7 chemistry, the MGP arterial calcification axis, the pivotal RCTs, the practical question of whether to use whole natto vs. isolated nattokinase vs. isolated MK-7, and the warfarin compatibility considerations.

Table of Contents

  1. Vitamin K1 vs. K2 — Two Vitamins, Different Jobs
  2. MK-4 vs. MK-7 vs. MK-9 — The Menaquinone Series
  3. Why Natto Is Uniquely Concentrated in MK-7
  4. The Matrix Gla Protein (MGP) Arterial Calcification Axis
  5. Osteocalcin and Bone — The Other K2-Dependent Gla Protein
  6. The Rotterdam Study — K2 and Coronary Heart Disease
  7. The Knapen 2015 RCT — MK-7 and Arterial Stiffness
  8. The ECKO Trial — K1 vs. K2 in Osteoporosis
  9. Whole Natto vs. Isolated Nattokinase vs. Isolated MK-7 — Practical Decisions
  10. Dosing for MK-7 Alone or in Combination
  11. Warfarin Compatibility — A Real Concern
  12. Key Research Papers
  13. Connections

Vitamin K1 vs. K2 — Two Vitamins, Different Jobs

"Vitamin K" is actually a family of related fat-soluble compounds with different sources, kinetics, and biological roles. The two principal forms are:

The clinical distinction matters because the cardiovascular and skeletal effects associated with vitamin K2 are NOT well-replicated by vitamin K1 supplementation. Dietary K1 intake from leafy greens is associated with improved hemostasis but not with the same cardiovascular calcification protection or the same fracture-risk reduction. K2 is required for the activation of matrix Gla protein and the calcification-relevant fraction of osteocalcin; K1 cannot fully substitute for these functions in peripheral tissues.

This is why the cardiovascular and bone literature has increasingly distinguished K1 from K2 over the last two decades, and why food sources of K2 (fermented foods, particularly natto; aged cheeses; egg yolks and animal fats from grass-fed sources; and some organ meats) have received attention disproportionate to their absolute K content compared to leafy greens.

For more on vitamin K generally, see our Vitamin K page.

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MK-4 vs. MK-7 vs. MK-9 — The Menaquinone Series

Within the vitamin K2 family, the different menaquinones (MK-n) are distinguished by the length of their isoprenoid side chain. The relevant variants for human nutrition are:

The Sato 2012 comparative bioavailability study and the Schurgers 2007 lipoprotein-transport study both established that MK-7 reaches the peripheral tissues (bone, arterial wall, kidney) more efficiently than either K1 or MK-4 from typical dietary doses. MK-4 is rapidly metabolized in the liver and has limited peripheral distribution; MK-7 partitions into LDL and reaches peripheral tissues in proportionally higher amounts.

This is why MK-7 has become the dominant form in vitamin K2 supplements over the last 15 years: the longer half-life makes once-daily dosing feasible, and the better peripheral distribution supports the cardiovascular and skeletal applications that motivated supplement use in the first place. Most current "vitamin K2" supplements specify MK-7, often derived from natto fermentation.

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Why Natto Is Uniquely Concentrated in MK-7

The reason natto is so uniquely concentrated in MK-7 is the specific bacterial strain used in its fermentation. Bacillus subtilis var. natto is an unusual MK-7 producer — most fermentation bacteria produce smaller amounts of various menaquinones, but this particular strain converts a substantial fraction of its carbon flux into MK-7 specifically as part of its respiratory metabolism. The fermentation of cooked soybeans by this bacterium therefore produces, alongside the now-famous nattokinase enzyme, an exceptional concentration of MK-7.

The Kaneki 2001 paper documented the geographic implications of this. Japanese populations who regularly eat natto have markedly higher circulating MK-7 levels than populations in other countries (and than Japanese populations in regions where natto is less commonly consumed). The eastern Japanese regional preference for natto (vs. the relative aversion in western Japan) correlates with regional differences in circulating MK-7 and is one of the proposed contributors to the regional differences in cardiovascular event rates within Japan.

The practical implication: a single serving of natto (~30–50 g for a typical Japanese breakfast portion) delivers approximately 300–500 mcg of MK-7, which is a substantial fraction of even the most aggressive supplemental dose. Daily natto consumption produces MK-7 saturation that is genuinely difficult to achieve through other dietary means in non-Japanese populations.

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The Matrix Gla Protein (MGP) Arterial Calcification Axis

The cardiovascular protective effect of vitamin K2 is mediated primarily through matrix Gla protein (MGP), a small (84 amino acid) calcium-binding protein expressed at high levels in vascular smooth muscle cells, chondrocytes, and several other tissues. MGP requires post-translational gamma-carboxylation of five specific glutamic acid residues (converting them to gamma-carboxyglutamic acid, or "Gla" residues) to become functional. This carboxylation reaction requires vitamin K2 as cofactor for the enzyme gamma-glutamyl carboxylase.

Functional (carboxylated) MGP serves as the body's principal endogenous inhibitor of arterial calcification. The mechanism is direct: carboxylated MGP binds free calcium ions and calcium-phosphate nucleation sites in the vascular wall, physically preventing the precipitation of hydroxyapatite-like calcium-phosphate mineral that constitutes vascular calcification. MGP-knockout mice develop massive arterial calcification within weeks of birth and die from arterial rupture; rare humans with Keutel syndrome (a genetic deficiency in MGP) develop similar arterial calcification phenotypes.

The clinical relevance for vitamin K2 nutrition: in K2-insufficient subjects (the typical Western diet), a substantial fraction of MGP circulates in the uncarboxylated, dysfunctional form. The "uncarboxylated MGP" fraction (sometimes measured as the dp-ucMGP biomarker, "desphospho-uncarboxylated MGP") is elevated in K2-insufficient subjects and correlates with cardiovascular risk in observational studies. Supplementation with MK-7 reduces dp-ucMGP, increases the carboxylated/functional fraction, and is the principal mechanism by which K2 protects against arterial calcification.

This is a fundamentally different mechanism from the fibrinolytic activity of nattokinase. Nattokinase dissolves fibrin that has already formed (and modulates the fibrinolytic system to prevent future fibrin accumulation). MK-7 prevents calcium from precipitating in the arterial wall in the first place. The two mechanisms address different aspects of cardiovascular pathology and are mechanistically additive. The fact that nature has conveniently packaged both in a single food (natto) is one of the more elegant examples of how traditional fermented foods can deliver multiple bioactive compounds that turn out to be synergistic for a single end goal.

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Osteocalcin and Bone — The Other K2-Dependent Gla Protein

The second major vitamin K2-dependent Gla protein is osteocalcin (also called bone Gla protein, BGP). Osteocalcin is produced by osteoblasts during bone formation and requires gamma-carboxylation by vitamin K2 to bind calcium in the bone matrix. Uncarboxylated osteocalcin (ucOC) is the dysfunctional form; it does not adequately mineralize bone matrix, and elevated ucOC fraction is independently associated with fracture risk in postmenopausal women.

The clinical implication is that vitamin K2 (and specifically MK-7) supplementation supports bone mineralization independent of its effects on calcium and vitamin D status. Several RCTs have documented improvements in bone mineral density and reduced fracture risk with MK-7 supplementation in postmenopausal women. The Knapen 2013 trial in 244 postmenopausal women given 180 mcg/day MK-7 for 3 years showed reduced age-related bone loss compared to placebo, with corresponding reduction in ucOC.

The complementarity with the cardiovascular calcification mechanism is striking: vitamin K2 directs calcium AWAY from arterial walls (via carboxylated MGP) and INTO bone (via carboxylated osteocalcin). Insufficient K2 has the inverse effect — calcium accumulates in arterial walls (calcification) and is lost from bone (osteoporosis). The clinical picture of an elderly patient with severe osteoporosis AND severe coronary artery calcification ("calcium paradox") is the visible expression of long-term vitamin K2 insufficiency interacting with calcium supplementation and aging.

For more on bone health and calcium metabolism, see our pages on Vitamin K and Magnesium.

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The Rotterdam Study — K2 and Coronary Heart Disease

The Rotterdam Study (Geleijnse 2004, Journal of Nutrition) is the foundational prospective cohort study linking dietary vitamin K2 intake to cardiovascular outcomes. Design:

Results:

The Rotterdam Study established the K2-cardiovascular protection association at the population level, and importantly demonstrated that the effect was specific to K2 rather than to vitamin K generally. The principal dietary sources of K2 in the Dutch cohort were aged cheese (rich in MK-8 and MK-9) and curd cheese, not natto (which is not commonly consumed in the Netherlands), so the protective effect appears to be a property of K2 as a class rather than specific to MK-7.

The Beulens 2009 follow-up paper from the Rotterdam group examined coronary calcification specifically (using electron-beam CT) and found similar protective associations with higher K2 intake. Together these papers form the strongest observational evidence base for K2 as a cardiovascular protective nutrient.

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The Knapen 2015 RCT — MK-7 and Arterial Stiffness

The Knapen 2015 trial in Thrombosis and Haemostasis is the most important RCT of MK-7 specifically for cardiovascular outcomes. Design:

Results:

The Knapen trial is the strongest RCT evidence to date that MK-7 supplementation has measurable benefit on arterial-wall properties in healthy postmenopausal women. The 180 mcg/day dose used in the trial is achievable with daily natto consumption (well within the ~300–500 mcg per serving) or with a single MK-7 capsule (most products provide 100–180 mcg per capsule).

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The ECKO Trial — K1 vs. K2 in Osteoporosis

The ECKO trial (Cheung 2008, PLoS Medicine) is an important reference point for the K1 vs. K2 distinction in bone health. Design:

Results were modestly positive: although the primary bone mineral density endpoint did not show large changes, the clinical fracture incidence was significantly reduced in the K1 group (relative risk approximately 0.45 for clinical fractures over 2 years). This suggested that high-dose K1 has some skeletal benefit even though K1 is less directly active in peripheral tissues than K2.

The interpretation that has become standard: K1 at high doses can produce some K2 effects, probably via partial enzymatic conversion to MK-4 in tissues including bone. But MK-7 supplementation at much lower doses (180–360 mcg) produces equivalent or greater peripheral effects with much better tissue-distribution kinetics. For practical supplementation purposes, MK-7 is the better choice over high-dose K1.

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Whole Natto vs. Isolated Nattokinase vs. Isolated MK-7 — Practical Decisions

Once you understand that natto delivers two distinct cardiovascular-relevant bioactive compounds (nattokinase the enzyme + MK-7 the vitamin), the practical question becomes which delivery vehicle is right for which goal. Several scenarios:

For the practical food considerations of natto itself — sourcing, preparation, seasonings, comparison to other fermented soy foods — see our Natto food page.

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Dosing for MK-7 Alone or in Combination

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Warfarin Compatibility — A Real Concern

Warfarin works by inhibiting the vitamin K cycle, blocking the regeneration of reduced vitamin K (the active form for gamma-glutamyl carboxylase). This reduces the gamma-carboxylation of clotting factors II, VII, IX, and X, producing the anticoagulant effect. The clinical effect of warfarin is therefore highly sensitive to vitamin K intake — large changes in dietary vitamin K (from any source) disrupt INR control and require dose adjustment.

The clinical implications for warfarin patients considering nattokinase or vitamin K2:

The DOAC drugs (apixaban, rivaroxaban, edoxaban, dabigatran) act downstream of the vitamin-K-dependent carboxylation step — they directly inhibit either factor Xa or factor IIa (thrombin). They are not affected by dietary vitamin K intake, so the K2-supplementation question is much simpler in DOAC-treated patients than in warfarin-treated patients. The bleeding-risk caution still applies to nattokinase combined with DOACs, but the K2 itself does not interfere with the anticoagulant.

For more on warfarin and anticoagulation, see our Coagulation Panel page.

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Key Research Papers

  1. Geleijnse JM et al. (2004). Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr 134(11):3100-3105. — PubMed
  2. Knapen MHJ et al. (2015). Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women: a double-blind randomised clinical trial. Thromb Haemost. — PubMed
  3. Beulens JWJ et al. (2009). High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. — PubMed
  4. Schurgers LJ et al. (2007). Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood. — PubMed
  5. Sato T et al. (2012). Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women. Nutr J. — PubMed
  6. Cheung AM et al. (2008). Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial). PLoS Med. — PubMed
  7. Knapen MHJ et al. (2013). Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. — PubMed
  8. Schurgers LJ, Vermeer C (2002). Differential lipoprotein transport pathways of K-vitamins in healthy subjects. Biochim Biophys Acta. — PubMed
  9. Kaneki M et al. (2001). Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2. Nutrition. — PubMed
  10. Maresz K (2015). Proper calcium use: vitamin K2 as a promoter of bone and cardiovascular health. Integr Med (Encinitas). — PubMed
  11. Theuwissen E et al. (2014). Vitamin K status in healthy volunteers. Food Funct. — PubMed
  12. Luo G et al. (1997). Spontaneous calcification of arteries and cartilage in mice lacking matrix Gla protein. Nature. — PubMed

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Connections

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