Am J Gastroenterol. 1994 Jun;89(6):915-23.
The contribution of vitamin K2 (menaquinones) produced by the intestinal microflora to human nutritional requirements for vitamin K.
Conly JM, Stein K, Worobetz L, Rutledge-Harding S.
Coagulopathy manifest by elevation of the prothrombin time (PT) in patients receiving broad spectrum antimicrobials indirectly suggests a role for intestinal microflora synthesized menaquinone (MK) in the maintenance of normal coagulation. Nonetheless, no direct evidence is available to support this contention.
Our objective was therefore to provide evidence that bacterially produced MK may be absorbed by the distal small bowel of humans.
Using a cell harvester, Staphylococcus aureus (ATCC 29213) was grown in 12-L batches, harvested, and extracted by high performance liquid chromatography (HPLC) to obtain 8 mg of pure MK. Four normal volunteers were placed on a diet severely restricted in vitamin K1 (median 32-40 U/day), and were given warfarin to maintain an International Normalized Ratio of approximately 2.0. On the 10th day of warfarin administration, naso-ileal intubation was performed and 1.5 mg of MK was delivered into the ileum. PT, factor VII, II and serum vitamin K1 levels were monitored throughout the study.
Mean serum vitamin K1 levels were reduced to 30% of the pre-diet value at the time of MK administration. Within 24 h of ileal MK administration, there was a significant (p < 0.05) increase in the factor VII level of 0.28 +/- 0.10 U/ml (mean +/- SEM) and a significant decrease of 2.5 (+/- 0.1) s in the PT, whereas in the control phase (during which no MK was administered), there were no significant changes in the PT or factor VII at corresponding time intervals.
These data provide direct evidence for the absorption of vitamin K2 from the distal small bowel, supporting a definite role for bacterially synthesized vitamin K2 in contributing to the human nutritional requirements of this vitamin.
Prog Food Nutr Sci. 1992 Oct-Dec;16(4):307-43.
The production of menaquinones (vitamin K2) by intestinal bacteria and their role in maintaining coagulation homeostasis.
Conly JM, Stein K.
Vitamin K is an essential cofactor necessary for the production of clotting factors II, VII, IX, and X in humans and has recently been found to be an essential factor for many other proteins in the body. There are two sources of this essential vitamin, including vitamin K1, or phylloquinone which is primarily found in green leafy vegetables and vitamin K2 or menaquinone which is synthesized by certain intestinal bacteria. The precise contribution of the bacterially synthesized menaquinone to overall vitamin K requirements in man is unknown. This paper reviews the available literature regarding the production and liberation of menaquinones from bacteria, the animal experiments which have been done to examine the absorption of menaquinones and the indirect and direct evidence in humans regarding utilization of menaquinones. The preponderance of the evidence suggests that bacterially synthesized menaquinones, particularly in the ileum can and do play a significant role in contributing to vitamin K requirements in humans to prevent clinically significant coagulopathy, especially during periods of episodic dietary lack of the vitamin.
Clin Invest Med. 1993 Feb;16(1):45-57.
The absorption and bioactivity of bacterially synthesized menaquinones.
Conly JM, Stein KE.
After optimizing conditions for maximal production of menaquinones (MK), S. aureus and B. vulgatus were grown in batches, harvested and extracted for qualitative and quantitative MK content utilizing HPLC (high performance liquid chromatography) until a total of 6 mg was available. Five normal healthy male volunteers were placed on a vitamin K1 deficient diet (< or = 25 micrograms/day) and were subsequently warfarinized to maintain a prothrombin time (PT) 1.5-2 times control. Following stabilization of daily warfarin dosage 1 mg doses of the extracted MK were orally administered. As a control, the same volunteers were later warfarinized but no MK was given. Within 24 h of MK administration the prothrombin time (PT) decreased (mean +/- SEM) 3.6 +/- 1.0 s (p < 0.005) and the Factor VII level increased 0.36 +/- 0.3 u/ml (p < 0.005) vs a PT increase of 1.0 +/- 1.0 s (p > 0.1) and a Factor VII level increase of 0.03 +/- 0.1 u/ml (p > 0.1) in the control phase. Within 48 h of MK administration the PT was normal in all subjects but remained > or = 1.5 times control in the control phase. These data demonstrate for the first time the absorption and bioactivity of bacterially synthesized vitamin K in humans.
Some of the benefit from antibiotics probably results from the reduced endotoxin stress when intestinal bacteria are suppressed. However, antibiotics can kill the intestinal bacteria that produce vitamin K, so it’s important to include that in the diet when antibiotics are used. -Ray Peat, PhD
Clin Invest Med. 1994 Dec;17(6):531-9.
Reduction of vitamin K2 concentrations in human liver associated with the use of broad spectrum antimicrobials.
Conly J, Stein K.
It is unclear whether menaquinones produced by the intestinal microflora play any role in human nutrition. Reports of coagulopathy due to vitamin K deficiency occurring in patients receiving broad spectrum antibiotics indirectly suggest that vitamin K2 produced by the gut microflora may be utilized by the host. We analyzed the vitamin K1 (phylloquinone) and vitamin K2 (menaquinone) content in a convenience sample of 22 human post-mortem liver samples, including 9 individuals who had been receiving broad spectrum antimicrobials prior to death and 13 individuals who had been victims of sudden, unexpected deaths. There were no significant differences in the mean (+/- SEM) phylloquinone content between the 2 groups [21.9 (+/- 15.5) vs. 16.0 (+/- 9.3) pmol/g wet weight (excluding those who had received supplemental vitamin K1)] but there was a significant difference (p < 0.05) in the total menaquinone (MK) content, 70.0 (+/- 23.3) vs. 423.1 (+/- 141) pmol/g between the 2 groups. These findings suggest an association between receipt of broad spectrum antibiotics and a reduction in hepatic menaquinone concentration, lending support to the hypothesis that a reduction in the gut microflora responsible for their production leads to reduced hepatic stores of this form of the vitamin.
Biochim Biophys Acta. 1999 Jan 4;1426(1):43-52.
Gender differences in hepatic phylloquinone and menaquinones in the vitamin K-deficient and -supplemented rat.
Huber AM, Davidson KW, O’Brien-Morse ME, Sadowski JA.
Gender differences in relation to vitamin K were investigated in the rat. Hepatic phylloquinone and menaquinone (MK-1 to MK-10) concentrations, gamma-carboxyglutamic acid (Gla) excretion, plasma phylloquinone and percent prothrombin were measured in male and female rats on a chow diet (24.5 ng phylloquinone and 8.8 microgram menadione), and on phylloquinone-deficient and -supplemented purified diets (0.38 and 1400 ng phylloquinone/g, respectively). Mean hepatic phylloquinone concentrations varied with dietary intake and ranged from 6.8+/-9.0 pmol/g in the deficient male, to 171. 1+/-56.9 pmol/g in the supplemented female. Menaquinones accounted for a large proportion of total vitamin K in the liver of males and females with MK-4, MK-6, and MK-10 present in highest concentrations. On the chow and supplemented diets, females had significantly higher MK-4, MK-6, and MK-10 concentrations in their livers (P<0.05). On the phylloquinone-deficient diet (-K1), hepatic phylloquinone, MK-4, and to a lesser extent MK-6 (but not MK-10) were significantly reduced (P<0.05). In the phylloquinone-supplemented male and female groups, which did not receive menadione during the experimental period, MK-4 increased above that in the chow groups suggesting synthesis of MK-4 from phylloquinone which was statistically significant in the female (P<0.01). A significant gender difference (P<0.05) was also observed for urinary Gla excretion with less Gla excreted by the females indicating that females may require less dietary phylloquinone than males of the same body weight.