The Metabolism of Plant Lignans via Human Intestinal Microbiota

Thinkingbact1 GutBacteriaFactory1

Introduction

Hey kiddos! I’m working on a series of posts on gut bacteria and I thought I’d start off with a post about the gut bacterial metabolism of plant lignans and its role in health and disease, primarily because it is something I know a great deal about. Or should I say “it is something about which I know a great deal”? Probably the latter. Proper use of prepositional phrases confounds me sometimes. Wait, this isn’t a blog about grammar; it’s about nutrition! Moving on…

What are lignans?

Lignans are polyphenolic compounds found in many plants that play a role in plant defense. It’s really quite extraordinary what lignans do for the plant. They have quite an array of defensive properties, protecting the plant from harmful pests and pathogens.1 For example, lignans have been shown to have insecticidal properties comparable to that of pyrethrins.2 If you have ever used that to kill aphids in your home garden then you know how powerful that is. They also have other properties that protect plants such as antifungal properties and somewhat paradoxically antimicrobial properties.3,4 I say “paradoxically” because I am about to discuss the fact that some species of bacteria that can live in the gut go nuts for these lignans.

Lignans are not to be confused with their homophone lignins, which are kinda similar in that they are also found in plants and are chemically related. However, lignins are much larger polymers that intercalate with cellulose and hemicellulose within the cell wall to provide structure and support. Interestingly though, since there are lignan structures within the larger lignin molecule, gut bacteria are able to metabolize lignins to some degree and “release” lignans for further metabolism.5,6

lignins

lignin_lignan3

What Foods are Lignans Found In?

Or maybe I should say “In What Foods are Lignans Found?” Damn those prepositional phrases! So they are found in a variety of foods. You can find a fair amount in cereal grains (corn, oats, wheat, rye), cruciferous vegetables, fruits (like apricots, oranges, kiwi, strawberries), and you can even find small amounts in beverages like coffee, tea, beer, and wine.7–31 But by far the largest concentration of lignans can be found in seeds, particularly flaxseeds. Seriously. A handful of flaxseeds contain about ten thousand times more lignans than an equivalent amount of broccoli, and about a hundred thousand times the lignans of, say, an orange.

flax-seeds

So Where do Gut Bacteria Come In?

Or should I say “In Where do Gut –“ ah, forget it. So it turns out that plant lignans can be converted to what are sometimes called mammalian lignans or enterolignans by bacteria found in the gut.8,32–68 There are several steps involved when converting a plant lignan to an enterolignan, however, and as far as we know there is not one bacterium that can catalyze all the reactions. Rather, a consortium of bacteria is needed to complete the conversion to the enterolignans enterodiol and/or enterolactone. These more physiologically active enterolignans then get absorbed via colonic epithelial cells.69

But the thing is that not everyone possesses the bacterial community necessary to complete this transformation. According to research by Possemiers and others maybe about 2/3rds of the population has the appropriate species in their gut to convert lignans to enterodiol and far fewer are able to convert lignans to enterolactone.70

Metabolism of isoflavones, lignans and prenylflavonoids by intestinal bacteria producer phenotyping and relation with intestinal community.

 

diagram w bacteria
Here’s a little diagram I made of common food lignans and the bacteria that convert them. Or at least some of them.

I made a diagram of sesaminol if you’d like to see that, too.

Why Should I Care About Lignans Anyway?

There is quite a bit of evidence that lignans have a variety of beneficial health effects.71–90 Let’s look at all these bennies in slightly more detail.

In Vitro Evidence

  • Lignans inhibit the proliferation of cancer cells.91–107
  • Lignans suppress the flu virus.108
  • Lignans have antimicrobial activity.109
  • Provide therapeutic effects to cardiovascular tissue by promoting vasorelaxation and reducing fibrosis, inflammation, apoptosis, and oxidative stress.110,111
  • Have neuroprotective effects.112,113
  • General antioxidant and anti-inflammatory effects.114
  • Prevents angiogenesis.115

Evidence from Animal Studies

  • A topical cream made with flax lignans aid in wound healing by their antioxidant activity and stimulating collagen synthesis.116
  • Reduced breast tumors.117–121
  • Protects bone tissue.122
  • Can reduce pain and inflammation.123
  • Improves vascular biomarkers.124–126
  • Reduces radiation damage.127
  • Reduced colon cancer biomarkers.128
  • Reduced biomarkers of liver cancer.129

Human Studies

Epidemiological Evidence

  • Lignan intake is negatively associated with esophageal cancer.130
  • Enterolignans are associated with a reduced risk of type 2 diabetes.131
  • Enterolactone levels are negatively associated with asthma.132
  • Lignan intake is negatively associated with bladder cancer, especially urothelial cell carcinoma.133
  • Reduced risk of breast cancer.117,134–144
  • Associated with reduced risk of colon cancer.140,145–148
  • Associated with a decreased risk of prostate cancer.140,148–150
  • Lignans are associated with a reduction in cardiovascular disease risk factors.151–153
  • Inversely associated with obesity and overweight.154

Clinical Trials

  • Flaxseed intake improves lipid profiles and reduces CVD risk factors.155–157
  • Might reduce breast tumor growth.117,158
  • Small reductions in prostate cancer biomarkers.159
  • Lignans attenuate blood glucose levels.160

Not-So-Good Outcomes

There is some evidence that lignans might not be so beneficial, particularly in men. This may be due to the fact that plant lignans and enterolignans are considered to be phytoestrogens with weak estrogenic and antiestrogenic properties.56,161–163

  • Associated with male infertility.164
  • Associated with an increase in prostate cancer.165,166

Conclusion

Despite the bit of evidence that dietary lignans may not be so good for men, I would say that the benefits outweigh the risks, especially if you are one of the lucky people to have the gut bacterial community that makes for efficient lignan conversion.

Refs

1            Pan J-Y, Chen S-L, Yang M-H, Wu J, Sinkkonen J, Zou K. An update on lignans: natural products and synthesis. Nat Prod Rep 2009; 26: 1251–92.

2            Harmatha J, Dinan L. Biological activities of lignans and stilbenoids associated with plant-insect chemical interactions. Phytochem Rev 2003; 2: 321–30.

3            Gang DR, Dinkova-Kostova AT, Davin LB, Lewis NG. Phylogenetic Links in Plant Defense Systems: Lignans, Isoflavonoids, and Their Reductases. In: Hedin PA, Hollingworth RM, Masler EP, Miyamoto J, eds. Phytochemicals for Pest Control. Washington, DC, American Chemical Society, 1997: 59–89.

4            Lewis NG, Kato MJ, Lopes N, Davin LB. Lignans: Diversity, Biosynthesis, and Function. In: Seidl PR, Gottlieb OR, Kaplan MAC, eds. Chemistry of the Amazon. Washington, DC, American Chemical Society, 1995: 135–67.

5            Niemi P, Aura A-M, Maukonen J, et al. Interactions of a Lignin-Rich Fraction from Brewer’s Spent Grain with Gut Microbiota In Vitro. J Agric Food Chem 2013. doi:10.1021/jf401738x.

6            Begum AN, Nicolle C, Mila I, et al. Dietary lignins are precursors of mammalian lignans in rats. J Nutr 2004; 134: 120–7.

7            Blitz CL, Murphy SP, Au DLM. Adding lignan values to a food composition database. J Food Compos Anal 2007; 20: 99–105.

8            Coulman KD, Liu Z, Hum WQ, Michaelides J, Thompson LU. Whole sesame seed is as rich a source of mammalian lignan precursors as whole flaxseed. Nutr Cancer 2005; 52: 156–65.

9            Hao M, Beta T. Qualitative and quantitative analysis of the major phenolic compounds as antioxidants in barley and flaxseed hulls using HPLC/MS/MS. J Sci Food Agric 2012; 92: 2062–8.

10         Horn-Ross PL, Barnes S, Lee M, et al. Assessing phytoestrogen exposure in epidemiologic studies: development of a database (United States). Cancer Causes Control 2000; 11: 289–98.

11         Huang M-H, Norris J, Han W, et al. Development of an updated phytoestrogen database for use with the SWAN food frequency questionnaire: intakes and food sources in a community-based, multiethnic cohort study. Nutr Cancer 2012; 64: 228–44.

12         Johnsson P, Kamal-Eldin A, Lundgren LN, Aman P. HPLC method for analysis of secoisolariciresinol diglucoside in flaxseeds. J Agric Food Chem 2000; 48: 5216–9.

13         Kraushofer T, Sontag G. Determination of some phenolic compounds in flax seed and nettle roots by HPLC with coulometric electrode array detection. Eur Food Res Technol 2002; 215: 529–33.

14         Mazur W. Phytoestrogen content in foods. Baillieres Clin Endocrinol Metab 1998; 12: 729–42.

15         Mazur W, Adlercreutz H. Naturally occurring oestrogens in food. Pure Appl Chem 1998; 70: 1759–76.

16         Mazur WM, Duke JA, Wähälä K, Rasku S, Adlercreutz H. Isoflavonoids and Lignans in Legumes: Nutritional and Health Aspects in Humans. J Nutr Biochem 1998; 9: 193–200.

17         Meagher LP, Beecher GR. Assessment of Data on the Lignan Content of Foods. J Food Compos Anal 2000; 13: 935–47.

18         Milder IEJ, Arts ICW, van de Putte B, Venema DP, Hollman PCH. Lignan contents of Dutch plant foods: a database including lariciresinol, pinoresinol, secoisolariciresinol and matairesinol. Br J Nutr 2005; 93: 393–402.

19         Owen RW, Mier W, Giacosa A, Hull WE, Spiegelhalder B, Bartsch H. Identification of lignans as major components in the phenolic fraction of olive oil. Clin Chem 2000; 46: 976–88.

20         Peñalvo JL, Haajanen KM, Botting N, Adlercreutz H. Quantification of lignans in food using isotope dilution gas chromatography/mass spectrometry. J Agric Food Chem 2005; 53: 9342–7.

21         Smeds AI, Eklund PC, Sjöholm RE, et al. Quantification of a broad spectrum of lignans in cereals, oilseeds, and nuts. J Agric Food Chem 2007; 55: 1337–46.

22         Smeds AI, Jauhiainen L, Tuomola E, Peltonen-Sainio P. Characterization of variation in the lignan content and composition of winter rye, spring wheat, and spring oat. J Agric Food Chem 2009; 57: 5837–42.

23         Kuhnle GGC, Dell’Aquila C, Aspinall SM, Runswick S a, Mulligan A a, Bingham S a. Phytoestrogen content of beverages, nuts, seeds, and oils. J Agric Food Chem 2008; 56: 7311–5.

24         Kuhnle GGC, Dell’aquila C, Aspinall SM, Runswick S a, Mulligan A a, Bingham S a. Phytoestrogen content of cereals and cereal-based foods consumed in the UK. Nutr Cancer 2009; 61: 302–9.

25         Mazur WM, Wähälä K, Rasku S, Salakka A, Hase T, Adlercreutz H. Lignan and isoflavonoid concentrations in tea and coffee. Br J Nutr 1998; 79: 37–45.

26         Peñalvo JL, Adlercreutz H, Uehara M, Ristimaki A, Watanabe S. Lignan content of selected foods from Japan. J Agric Food Chem 2008; 56: 401–9.

27         Smeds AI, Eklund PC, Willför SM. Content, composition, and stereochemical characterisation of lignans in berries and seeds. Food Chem 2012; 134: 1991–8.

28         Thompson LU, Boucher B a, Liu Z, Cotterchio M, Kreiger N. Phytoestrogen content of foods consumed in Canada, including isoflavones, lignans, and coumestan. Nutr Cancer 2006; 54: 184–201.

29         Valsta LM, Kilkkinen A, Mazur W, et al. Phyto-oestrogen database of foods and average intake in Finland. Br J Nutr 2003; 89 Suppl 1: S31–8.

30         Tetens I, Turrini A, Tapanainen H, et al. Dietary intake and main sources of plant lignans in five European countries. Food Nutr Res 2013; 57. doi:10.3402/fnr.v57i0.19805.

31         Meija L, Söderholm P, Samaletdin A, et al. Dietary intake and major sources of plant lignans in Latvian men and women. Int J Food Sci Nutr 2013; 64: 622–30.

32         Aura A-M, Karppinen S, Virtanen H, et al. Processing of rye bran influences both the fermentation of dietary fibre and the bioconversion of lignans by human faecal florain vitro. J Sci Food Agric 2005; 85: 2085–93.

33         Aura A-M, Myllymäki O, Bailey M, Penalvo JL, Adlercreutz H, Poutanen K. Interrelationships between carbohydrate type, phenolic acids and initial pH on in vitro conversion of enterolactone from rye lignans. In: Salovaara H, Gates F, Tenkanen M, eds. Dietary Fibre: Components and Functions. Wageningen, The Netherlands, Wageningen Academic Publishers, 2007: 235–45.

34         Aura A-M, Oikarinen S, Mutanen M, et al. Suitability of a batch in vitro fermentation model using human faecal microbiota for prediction of conversion of flaxseed lignans to enterolactone with reference to an in vivo rat model. Eur J Nutr 2006; 45: 45–51.

35         Bartkiene E, Juodeikiene G, Basinskiene L. In Vitro Fermentative Production of Plant Lignans from Cereal Products in Relationship with Constituents of Non-Starch Polysaccharides. Food Technol Biotechnol 2012; 50: 237–45.

36         Bartkiene E, Juodeikiene G, Basinskiene L, Liukkonen K-H, Adlercreutz H, Kluge H. Enterolignans enterolactone and enterodiol formation from their precursors by the action of intestinal microflora and their relationship with non-starch polysaccharides in various berries and vegetables. LWT–Food Sci Technol 2011; 44: 48–53.

37         Borriello SP, Setchell KD, Axelson M, Lawson AM. Production and metabolism of lignans by the human faecal flora. J Appl Bacteriol 1985; 58: 37–43.

38         Clavel T, Borrmann D, Braune A, Doré J, Blaut M. Occurrence and activity of human intestinal bacteria involved in the conversion of dietary lignans. Anaerobe 2006; 12: 140–7.

39         Clavel T, Lippman R, Gavini F, Doré J, Blaut M. Clostridium saccharogumia sp. nov. and Lactonifactor longoviformis gen. nov., sp. nov., two novel human faecal bacteria involved in the conversion of the dietary phytoestrogen secoisolariciresinol diglucoside. Syst Appl Microbiol 2007; 30: 16–26.

40         Clavel T, Henderson G, Engst W, Doré J, Blaut M. Phylogeny of human intestinal bacteria that activate the dietary lignan secoisolariciresinol diglucoside. FEMS Microbiol Ecol 2006; 55: 471–8.

41         Clavel T, Henderson G, Alpert C-A, et al. Intestinal bacterial communities that produce active estrogen-like compounds enterodiol and enterolactone in humans. Appl Env Microbiol 2005; 71: 6077–85.

42         Clavel T, Doré J, Blaut M. Bioavailability of lignans in human subjects. Nutr Res Rev 2006; 19: 187–96.

43         Heinonen S, Nurmi T, Liukkonen K, et al. In vitro metabolism of plant lignans: new precursors of mammalian lignans enterolactone and enterodiol. J Agric Food Chem 2001; 49: 3178–86.

44         Jan K-C, Hwang LS, Ho C-T. Biotransformation of sesaminol triglucoside to mammalian lignans by intestinal microbiota. J Agric Food Chem 2009; 57: 6101–6.

45         Jin J-S, Zhao Y-F, Nakamura N, et al. Enantioselective dehydroxylation of enterodiol and enterolactone precursors by human intestinal bacteria. Biol Pharm Bull 2007; 30: 2113–9.

46         Jin J-S, Kakiuchi N, Hattori M. Enantioselective oxidation of enterodiol to enterolactone by human intestinal bacteria. Biol Pharm Bull 2007; 30: 2204–6.

47         Jin J-S, Hattori M. Human intestinal bacterium, strain END-2 is responsible for demethylation as well as lactonization during plant lignan metabolism. Biol Pharm Bull 2010; 33: 1443–7.

48         Jin J-S, Hattori M. Further studies on a human intestinal bacterium Ruminococcus sp. END-1 for transformation of plant lignans to mammalian lignans. J Agric Food Chem 2009; 57: 7537–42.

49         Li M-X, Zhu H-Y, Yang D-H, et al. Production of secoisolariciresinol from defatted flaxseed by bacterial biotransformation. J Appl Microbiol 2012; 113: 1352–61.

50         Roncaglia L, Amaretti A, Raimondi S, Leonardi A, Rossi M. Role of bifidobacteria in the activation of the lignan secoisolariciresinol diglucoside. Appl Microbiol Biotechnol 2011; 92: 159–68.

51         Setchell KDR, Brown NM, Zimmer-Nechemias L, Wolfe B, Jha P, Heubi JE. Metabolism of secoisolariciresinol-diglycoside the dietary precursor to the intestinally derived lignan enterolactone in humans. Food Funct 2014; 5: 491–501.

52         Struijs K, Vincken J-P, Gruppen H. Bacterial conversion of secoisolariciresinol and anhydrosecoisolariciresinol. J Appl Microbiol 2009; 107: 308–17.

53         Eeckhaut E, Struijs K, Possemiers S, Vincken J-P, Keukeleire D De, Verstraete W. Metabolism of the lignan macromolecule into enterolignans in the gastrointestinal lumen as determined in the simulator of the human intestinal microbial ecosystem. J Agric Food Chem 2008; 56: 4806–12.

54         Wang C-Z, Ma X-Q, Yang D-H, et al. Production of enterodiol from defatted flaxseeds through biotransformation by human intestinal bacteria. BMC Microbiol 2010; 10: 115.

55         Wang LQ, Meselhy MR, Li Y, Qin GW, Hattori M. Human intestinal bacteria capable of transforming secoisolariciresinol diglucoside to mammalian lignans, enterodiol and enterolactone. Chem Pharm Bull 2000; 48: 1606–10.

56         Xie L-H, Ahn E-M, Akao T, Abdel-Hafez AA-M, Nakamura N, Hattori M. Transformation of arctiin to estrogenic and antiestrogenic substances by human intestinal bacteria. Chem Pharm Bull 2003; 51: 378–84.

57         Xie L-H, Akao T, Hamasaki K, Deyama T, Hattori M. Biotransformation of pinoresinol diglucoside to mammalian lignans by human intestinal microflora, and isolation of Enterococcus faecalis strain PDG-1 responsible for the transformation of (+)-pinoresinol to (+)-lariciresinol. Chem Pharm Bull 2003; 51: 508–15.

58         Horner NK, Kristal AR, Prunty J, Skor HE, Potter JD, Lampe JW. Dietary determinants of plasma enterolactone. Cancer Epidemiol Biomarkers Prev 2002; 11: 121–6.

59         Hutchins AM, Martini MC, Olson BA, Thomas W, Slavin JL. Flaxseed influences urinary lignan excretion in a dose-dependent manner in postmenopausal women. Cancer Epidemiol Biomarkers Prev 2000; 9: 1113–8.

60         Juntunen KS, Mazur WM, Liukkonen KH, et al. Consumption of wholemeal rye bread increases serum concentrations and urinary excretion of enterolactone compared with consumption of white wheat bread in healthy Finnish men and women. Br J Nutr 2000; 84: 839–46.

61         Kilkkinen A, Stumpf K, Pietinen P, Valsta LM, Tapanainen H, Adlercreutz H. Determinants of serum enterolactone concentration. Am J Clin Nutr 2001; 73: 1094–100.

62         Kilkkinen A, Valsta LM, Virtamo J, Stumpf K, Adlercreutz H, Pietinen P. Intake of lignans is associated with serum enterolactone concentration in Finnish men and women. J Nutr 2003; 133: 1830–3.

63         Kilkkinen A, Pietinen P, Klaukka T, Virtamo J, Korhonen P, Adlercreutz H. Use of oral antimicrobials decreases serum enterolactone concentration. Am J Epidemiol 2002; 155: 472–7.

64         Knust U, Spiegelhalder B, Strowitzki T, Owen RW. Contribution of linseed intake to urine and serum enterolignan levels in German females: a randomised controlled intervention trial. Food Chem Toxicol 2006; 44: 1057–64.

65         Kurzer MS, Lampe JW, Martini MC, Adlercreutz H. Fecal lignan and isoflavonoid excretion in premenopausal women consuming flaxseed powder. Cancer Epidemiol Biomarkers Prev 1995; 4: 353–8.

66         Lampe JW, Martini MC, Kurzer MS, Adlercreutz H, Slavin JL. Urinary lignan and isoflavonoid excretion in premenopausal women consuming flaxseed powder. Am J Clin Nutr 1994; 60: 122–8.

67         Nesbitt PD, Lam Y, Thompson LU. Human metabolism of mammalian lignan precursors in raw and processed flaxseed. Am J Clin Nutr 1999; 69: 549–55.

68         Peñalvo JL, Heinonen S-M, Aura A-M, Adlercreutz H. Dietary sesamin is converted to enterolactone in humans. J Nutr 2005; 135: 1056–62.

69         Jansen GHE, Arts ICW, Nielen MWF, Müller M, Hollman PCH, Keijer J. Uptake and metabolism of enterolactone and enterodiol by human colon epithelial cells. Arch Biochem Biophys 2005; 435: 74–82.

70         Possemiers S, Bolca S, Eeckhaut E, Depypere H, Verstraete W. Metabolism of isoflavones, lignans and prenylflavonoids by intestinal bacteria: producer phenotyping and relation with intestinal community. FEMS Microbiol Ecol 2007; 61: 372–83.

71         Wang L. Mammalian phytoestrogens: enterodiol and enterolactone. J Chromatogr, B Anal Technol Biomed Life Sci 2002; 777: 289–309.

72         Westcott ND, Muir AD. Flax seed lignan in disease prevention and health promotion. Phytochem Rev 2003; 2: 401–17.

73         Touré A, Xueming X. Flaxseed Lignans: Source, Biosynthesis, Metabolism, Antioxidant Activity, Bio-Active Components, and Health Benefits. Compr Rev Food Sci Food Saf 2010; 9: 261–9.

74         Thompson LU. Experimental studies on lignans and cancer. Baillieres Clin Endocrinol Metab 1998; 12: 691–705.

75         Tham DM, Gardner CD, Haskell WL. Potential health benefits of dietary phytoestrogens: a review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrinol Metab 1998; 83: 2223–35.

76         Peterson J, Dwyer J, Adlercreutz H, Scalbert A, Jacques P, McCullough ML. Dietary lignans: physiology and potential for cardiovascular disease risk reduction. Nutr Rev 2010; 68: 571–603.

77         Landete JM. Plant and mammalian lignans: A review of source, intake, metabolism, intestinal bacteria and health. Food Res Int 2012; 46: 410–24.

78         Kurzer MS, Xu X. Dietary phytoestrogens. Annu Rev Nutr 1997; 17: 353–81.

79         Dar AA, Arumugam N. Lignans of sesame: purification methods, biological activities and biosynthesis–a review. Bioorg Chem 2013; 50: 1–10.

80         Adolphe JL, Whiting SJ, Juurlink BHJ, Thorpe LU, Alcorn J. Health effects with consumption of the flax lignan secoisolariciresinol diglucoside. Br J Nutr 2010; 103: 929–38.

81         Adlercreutz H. Phyto-oestrogens and cancer. Lancet Oncol 2002; 3: 364–73.

82         Adlercreutz H. Lignans and human health. Crit Rev Clin Lab Sci 2007; 44: 483–525.

83         Adlercreutz H, Heinonen S-M, Penalvo-Garcia J. Phytoestrogens, cancer and coronary heart disease. BioFactors 2004; 22: 229–36.

84         Sok D-E, Cui HS, Kim MR. Isolation and bioactivities of furfuran type lignan compounds from edible plants. Recent Pat Food, Nutr Agric 2009; 1: 87–95.

85         Sainvitu P, Nott K, Richard G, et al. Structure , properties and obtention routes of flaxseed lignan secoisolariciresinol : a review. Biotechnol, Agron, Soc Env 2012; 16: 115–24.

86         Bolca S, Van de Wiele T, Possemiers S. Gut metabotypes govern health effects of dietary polyphenols. Curr Opin Biotechnol 2013; 24: 220–5.

87         Adlercreutz H, Mazur W, Bartels P, et al. Phytoestrogens and prostate disease. J Nutr 2000; 130: 658S – 9S.

88         Cardoso Carraro JC, Dantas MI de S, Espeschit ACR, Martino HSD, Ribeiro SMR. Flaxseed and Human Health: Reviewing Benefits and Adverse Effects. Food Rev Int 2012; 28: 203–30.

89         Adlercreutz H. Phytoestrogens: epidemiology and a possible role in cancer protection. Env Heal Perspect 1995; 103 Suppl: 103–12.

90         Bedell S, Nachtigall M, Naftolin F. The pros and cons of plant estrogens for menopause. J Steroid Biochem Mol Biol 2014; 139: 225–36.

91         Jafari S, Saeidnia S, Abdollahi M. Role of Natural Phenolic Compounds in Cancer Chemoprevention via Regulation of the Cell Cycle. Curr Pharm Biotechnol 2014; 15: 409–21.

92         Casarin E, Dall’Acqua S, Smejkal K, Slapetová T, Innocenti G, Carrara M. Molecular mechanisms of antiproliferative effects induced by Schisandra-derived dibenzocyclooctadiene lignans (+)-deoxyschisandrin and (-)-gomisin N in human tumour cell lines. Fitoterapia 2014; 98: 241–7.

93         Kong X, Ma M, Zhang Y, et al. Differentiation therapy: sesamin as an effective agent in targeting cancer stem-like side population cells of human gallbladder carcinoma. BMC Complement Altern Med 2014; 14: 254.

94         Kim KH, Woo KW, Moon E, et al. Identification of antitumor lignans from the seeds of morning glory (Pharbitis nil). J Agric Food Chem 2014; 62: 7746–52.

95         Kong P, Zhang L, Guo Y, Lu Y, Lin D. Phillyrin, a natural lignan, attenuates tumor necrosis factor α-mediated insulin resistance and lipolytic acceleration in 3T3-L1 adipocytes. Planta Med 2014; 80: 880–6.

96         Kang K, Nho CW, Kim ND, et al. Daurinol, a catalytic inhibitor of topoisomerase IIα, suppresses SNU-840 ovarian cancer cell proliferation through cell cycle arrest in S phase. Int J Oncol 2014; 45: 558–66.

97         Shimizu S, Fujii G, Takahashi M, et al. Sesamol suppresses cyclooxygenase-2 transcriptional activity in colon cancer cells and modifies intestinal polyp development in Apc (Min/+) mice. J Clin Biochem Nutr 2014; 54: 95–101.

98         Luo J, Hu Y, Kong W, Yang M. Evaluation and structure-activity relationship analysis of a new series of arylnaphthalene lignans as potential anti-tumor agents. PLoS One 2014; 9: e93516.

99         Saeed M, Khalid H, Sugimoto Y, Efferth T. The lignan, (-)-sesamin reveals cytotoxicity toward cancer cells: pharmacogenomic determination of genes associated with sensitivity or resistance. Phytomedicine 2014; 21: 689–96.

100      Qu H, Madl RL, Takemoto DJ, Baybutt RC, Wang W. Lignans are involved in the antitumor activity of wheat bran in colon cancer SW480 cells. J Nutr 2005; 135: 598–602.

101      Saggar JK, Chen J, Corey P, Thompson LU. The effect of secoisolariciresinol diglucoside and flaxseed oil, alone and in combination, on MCF-7 tumor growth and signaling pathways. Nutr Cancer 2010; 62: 533–42.

102      Wada-Hiraike O, Warner M, Gustafsson J. New developments in oestrogen signalling in colonic epithelium. Biochem Soc Trans 2006; 34: 1114–6.

103      Ford JD, Huang KS, Wang HB, Davin LB, Lewis NG. Biosynthetic pathway to the cancer chemopreventive secoisolariciresinol diglucoside-hydroxymethyl glutaryl ester-linked lignan oligomers in flax (Linum usitatissimum) seed. J Nat Prod 2001; 64: 1388–97.

104      Bailly F, Toillon R-A, Tomavo O, Jouy N, Hondermarck H, Cotelle P. Antiproliferative and apoptotic effects of the oxidative dimerization product of methyl caffeate on human breast cancer cells. Bioorg Med Chem Lett 2013; 23: 574–8.

105      Mali A V, Wagh U V, Hegde M V, Chandorkar SS, Surve S V, Patole M V. In vitro anti-metastatic activity of enterolactone, a mammalian lignan derived from flax lignan, and down-regulation of matrix metalloproteinases in MCF-7 and MDA MB 231 cell lines. Indian J Cancer 2012; 49: 181–7.

106      Macdonald RS, Wagner K. Influence of Dietary Phytochemicals and Microbiota on Colon Cancer Risk. J Agric Food Chem 2012. doi:10.1021/jf204230r.

107      McCann MJ, Rowland IR, Roy NC. Anti-proliferative effects of physiological concentrations of enterolactone in models of prostate tumourigenesis. Mol Nutr Food Res 2013; 57: 212–24.

108      Parhira S, Yang Z-F, Zhu G-Y, et al. In vitro anti-influenza virus activities of a new lignan glycoside from the latex of Calotropis gigantea. PLoS One 2014; 9: e104544.

109      Zuk M, Dorotkiewicz-Jach A, Drulis-Kawa Z, Arendt M, Kulma A, Szopa J. Bactericidal activities of GM flax seedcake extract on pathogenic bacteria clinical strains. BMC Biotechnol 2014; 14: 70.

110      Chun JN, Cho M, So I, Jeon J-H. The protective effects of Schisandra chinensis fruit extract and its lignans against cardiovascular disease: a review of the molecular mechanisms. Fitoterapia 2014; 97: 224–33.

111      Lee W, Ku S-K, Kim JA, Lee T, Bae J-S. Inhibitory effects of epi-sesamin on HMGB1-induced vascular barrier disruptive responses in vitro and in vivo. Toxicol Appl Pharmacol 2013; 267: 201–8.

112      Yu H-Y, Chen Z-Y, Sun B, et al. Lignans from the fruit of Schisandra glaucescens with antioxidant and neuroprotective properties. J Nat Prod 2014; 77: 1311–20.

113      Jung Y-J, Park J-H, Cho J-G, et al. Lignan and flavonoids from the stems of Zea mays and their anti-inflammatory and neuroprotective activities. Arch Pharm Res 2014. doi:10.1007/s12272-014-0387-4.

114      Zheng J, Piao MJ, Kim KC, et al. Americanin B protects cultured human keratinocytes against oxidative stress by exerting antioxidant effects. In Vitro Cell Dev Biol Anim 2014; 50: 766–77.

115      Liu J-X, Luo M-Q, Xia M, et al. Marine compound catunaregin inhibits angiogenesis through the modulation of phosphorylation of akt and eNOS in vivo and in vitro. Mar Drugs 2014; 12: 2790–801.

116      Draganescu D, Ibanescu C, Tamba BI, Andritoiu C V, Dodi G, Popa MI. Flaxseed lignan wound healing formulation: Characterization and in vivo therapeutic evaluation. Int J Biol Macromol 2015; 72: 614–23.

117      Mason JK, Thompson LU. Flaxseed and its lignan and oil components: can they play a role in reducing the risk of and improving the treatment of breast cancer? Appl Physiol Nutr Metab 2014; 39: 663–78.

118      Truan JS, Chen J-M, Thompson LU. Comparative effects of sesame seed lignan and flaxseed lignan in reducing the growth of human breast tumors (MCF-7) at high levels of circulating estrogen in athymic mice. Nutr Cancer 2012; 64: 65–71.

119      Mabrok HB, Klopfleisch R, Ghanem KZ, Clavel T, Blaut M, Loh G. Lignan transformation by gut bacteria lowers tumor burden in a gnotobiotic rat model of breast cancer. Carcinogenesis 2012; 33: 203–8.

120      Chen J, Saggar JK, Corey P, Thompson LU. Flaxseed and pure secoisolariciresinol diglucoside, but not flaxseed hull, reduce human breast tumor growth (MCF-7) in athymic mice. J Nutr 2009; 139: 2061–6.

121      Delman D, Kimler BF, Fabian CJ, Petroff BK. Secoisolariciresinol diglucoside (SDG, flaxseed lignan) improves biomarkers of early mammary gland cancer progression in a rat model of breast and ovarian cancer. Cancer Res 2013; 73: 185–185.

122      Sacco SM, Chen J, Ganss B, Thompson LU, Ward WE. Flaxseed enhances the beneficial effect of low-dose estrogen therapy at reducing bone turnover and preserving bone microarchitecture in ovariectomized rats. Appl Physiol Nutr Metab 2014; 39: 801–10.

123      Monteiro EMH, Chibli LA, Yamamoto CH, et al. Antinociceptive and anti-inflammatory activities of the sesame oil and sesamin. Nutrients 2014; 6: 1931–44.

124      Baluchnejadmojarad T, Roghani M, Jalali Nadoushan M-R, et al. The sesame lignan sesamin attenuates vascular dysfunction in streptozotocin diabetic rats: involvement of nitric oxide and oxidative stress. Eur J Pharmacol 2013; 698: 316–21.

125      Zanwar A, Hegde M, Bodhankar S. Cardioprotective effect of flax lignan concentrate and omega-3-fatty acid alone and in combination in ischemia/reperfusion injury in isolated rat heart. Atherosclerosis 2014; 235: e251.

126      Zanwar A a., Hegde M V., Bodhankar SL. Protective role of concomitant administration of flax lignan concentrate and omega-3-fatty acid on myocardial damage in doxorubicin-induced cardiotoxicity. Food Sci Hum Wellness 2013; 2: 29–38.

127      Pietrofesa R, Turowski J, Tyagi S, et al. Radiation mitigating properties of the lignan component in flaxseed. BMC Cancer 2013; 13: 179.

128      Jenab M, Thompson LU. The influence of flaxseed and lignans on colon carcinogenesis and beta-glucuronidase activity. Carcinogenesis 1996; 17: 1343–8.

129      Shousha W, El-mezayen HA, Abdul-halim SS, Elham A. Antioxidant effect of Flaxseed against liver Cirrhosis induced in Thioacetamide intoxicated rats. Egypt J Hosp Med 2013; 51: 448–60.

130      Lin Y, Yngve A, Lagergren J, Lu Y. A dietary pattern rich in lignans, quercetin and resveratrol decreases the risk of oesophageal cancer. Br J Nutr 2014; 112: 2002–9.

131      Sun Q, Wedick NM, Pan A, et al. Gut microbiota metabolites of dietary lignans and risk of type 2 diabetes: a prospective investigation in two cohorts of U.S. women. Diabetes Care 2014; 37: 1287–95.

132      Cardet J-C, Johns CB, Savage JH. Bacterial metabolites of diet-derived lignans and isoflavones inversely associate with asthma and wheezing. J Allergy Clin Immunol 2014. doi:10.1016/j.jaci.2014.07.035.

133      Zamora-Ros R, Sacerdote C, Ricceri F, et al. Flavonoid and lignan intake in relation to bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Br J Cancer 2014; 111: 1870–80.

134      Buck K, Zaineddin AK, Vrieling A, et al. Estimated enterolignans, lignan-rich foods, and fibre in relation to survival after postmenopausal breast cancer. Br J Cancer 2011; 105: 1151–7.

135      Velentzis LS, Cantwell MM, Cardwell C, Keshtgar MR, Leathem AJ, Woodside J V. Lignans and breast cancer risk in pre- and post-menopausal women: meta-analyses of observational studies. Br J Cancer 2009; 100: 1492–8.

136      Torres-Sanchez L, Galvan-Portillo M, Wolff MS, Lopez-Carrillo L. Dietary consumption of phytochemicals and breast cancer risk in Mexican women. Public Heal Nutr 2009; 12: 825–31.

137      Anderson LN, Cotterchio M, Boucher BA, Kreiger N. Phytoestrogen intake from foods, during adolescence and adulthood, and risk of breast cancer by estrogen and progesterone receptor tumor subgroup among Ontario women. Int J Cancer 2013; 132: 1683–92.

138      Guglielmini P, Rubagotti A, Boccardo F. Serum enterolactone levels and mortality outcome in women with early breast cancer: a retrospective cohort study. Breast Cancer Res Treat 2012; 132: 661–8.

139      McCann SE, Hootman KC, Weaver AM, et al. Dietary intakes of total and specific lignans are associated with clinical breast tumor characteristics. J Nutr 2012; 142: 91–8.

140      Lof M, Weiderpass E. Epidemiologic evidence suggests that dietary phytoestrogen intake is associated with reduced risk of breast, endometrial, and prostate cancers. Nutr Res 2006; 26: 609–19.

141      Dai Q, Franke AA, Jin F, et al. Urinary excretion of phytoestrogens and risk of breast cancer among Chinese women in Shanghai. Cancer Epidemiol Biomarkers Prev 2002; 11: 815–21.

142      Pietinen P, Stumpf K, Männistö S, Kataja V, Uusitupa M, Adlercreutz H. Serum enterolactone and risk of breast cancer: a case-control study in eastern Finland. Cancer Epidemiol Biomarkers Prev 2001; 10: 339–44.

143      Hultén K, Winkvist A, Lenner P, Johansson R, Adlercreutz H, Hallmans G. An incident case-referent study on plasma enterolactone and breast cancer risk. Eur J Nutr 2002; 41: 168–76.

144      Xie J, Tworoger SS, Franke A a, et al. Plasma enterolactone and breast cancer risk in the Nurses’ Health Study II. Breast Cancer Res Treat 2013. doi:10.1007/s10549-013-2586-y.

145      Kuijsten A, Arts ICW, Hollman PCH, van’t Veer P, Kampman E. Plasma enterolignans are associated with lower colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev 2006; 15: 1132–6.

146      Cotterchio M, Boucher BA, Manno M, Gallinger S, Okey A, Harper P. Dietary phytoestrogen intake is associated with reduced colorectal cancer risk. J Nutr 2006; 136: 3046–53.

147      Johnsen NF, Olsen A, Thomsen BLR, et al. Plasma enterolactone and risk of colon and rectal cancer in a case-cohort study of Danish men and women. Cancer Causes Control 2010; 21: 153–62.

148      Ward HA, Kuhnle GGC, Mulligan AA, Lentjes MAH, Luben RN, Khaw K. Breast, colorectal, and prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition-Norfolk in relation to phytoestrogen intake derived from an improved database. Am J Clin Nutr 2010; 91: 440–8.

149      McCann MJ, Gill CIR, McGlynn H, Rowland IR. Role of mammalian lignans in the prevention and treatment of prostate cancer. Nutr Cancer 2005; 52: 1–14.

150      Demark-Wahnefried W, Price DT, Polascik TJ, et al. Pilot study of dietary fat restriction and flaxseed supplementation in men with prostate cancer before surgery: exploring the effects on hormonal levels, prostate-specific antigen, and histopathologic features. Urology 2001; 58: 47–52.

151      Pellegrini N, Valtueña S, Ardigò D, et al. Intake of the plant lignans matairesinol, secoisolariciresinol, pinoresinol, and lariciresinol in relation to vascular inflammation and endothelial dysfunction in middle age-elderly men and post-menopausal women living in Northern Italy. Nutr Metab Cardiovasc Dis 2010; 20: 64–71.

152      Vanharanta M, Voutilainen S, Lakka TA, van der Lee M, Adlercreutz H, Salonen JT. Risk of acute coronary events according to serum concentrations of enterolactone: a prospective population-based case-control study. Lancet 1999; 354: 2112–5.

153      Vanharanta M, Voutilainen S, Rissanen TH, Adlercreutz H, Salonen JT. Risk of cardiovascular disease-related and all-cause death according to serum concentrations of enterolactone: Kuopio Ischaemic Heart Disease Risk Factor Study. Arch Intern Med 2003; 163: 1099–104.

154      Frankenfeld CL. Relationship of obesity and high urinary enterolignan concentrations in 6806 children and adults: analysis of National Health and Nutrition Examination Survey data. Eur J Clin Nutr 2013; : 1–3.

155      Saxena S, Katare C. Evaluation of flaxseed formulation as a potential therapeutic agent in mitigation of dyslipidemia. Biomed J 2014; 37: 386–90.

156      Wong H, Chahal N, Manlhiot C, Niedra E, McCrindle BW. Flaxseed in Pediatric Hyperlipidemia: A Placebo-Controlled, Blinded, Randomized Clinical Trial of Dietary Flaxseed Supplementation for Children and Adolescents With Hypercholesterolemia. JAMA Pediatr 2013; : 1–5.

157      Almario RU, Karakas SE. Lignan content of the flaxseed influences its biological effects in healthy men and women. J Am Coll Nutr 2013; 32: 194–9.

158      Thompson LU, Chen JM, Li T, Strasser-Weippl K, Goss PE. Dietary flaxseed alters tumor biological markers in postmenopausal breast cancer. Clin Cancer Res 2005; 11: 3828–35.

159      Bylund A, Lundin E, Zhang JX, et al. Randomised controlled short-term intervention pilot study on rye bran bread in prostate cancer. Eur J Cancer Prev 2003; 12: 407–15.

160      Shousha W, El-mezayen HA, Abdul-halim SS, Elham A. Effect of whole and ground Salba seeds (Salvia Hispanica L.) on postprandial glycemia in healthy volunteers: a randomized controlled, dose-response trial. Eur J Clin Nutr 2013; 2009: 1–3.

161      Gao J, Hattori M. Metabolic activation of lignans to estrogenic and antiestrogenic substances by human intestinal bacteria. J Tradit Med 2005; 22: 213–21.

162      Saleem M, Kim HJ, Ali MS, Lee YS. An update on bioactive plant lignans. Nat Prod Rep 2005; 22: 696–716.

163      Dixon R a. Phytoestrogens. Annu Rev Plant Biol 2004; 55: 225–61.

164      Xia Y, Chen M, Zhu P, et al. Urinary phytoestrogen levels related to idiopathic male infertility in Chinese men. Env Int 2013; 59: 161–7.

165      Jackson MD, McFarlane-Anderson ND, Simon GA, Bennett FI, Walker SP. Urinary phytoestrogens and risk of prostate cancer in Jamaican men. Cancer Causes Control 2010; 21: 2249–57.

166      Ward HA, Kuhnle GGC. Phytoestrogen consumption and association with breast, prostate and colorectal cancer in EPIC Norfolk. Arch Biochem Biophys 2010; 501: 170–5.

 

Comments

  1. Reijo Laatikainen (@pronutritionist)

    Very informative post, thanks.

    Finnish Food Safety Authority, Evira recommends not to consume flaxseeds more than 2 tablespoonfuls per day due to cadmium content of flaxseeds (and cyanogenic substances). I’m not aware of if Finnish soil contains more cadmium than North American but I’m a bit puzzled that no other country than Finland seems to be concerned about cadmium. My further question is, might it be cadmium content of flaxseeds that causes variation in the outcomes in different cancer types?

    Flaxseeds are well tolerated and have improved some gastrointestinal symptoms in irritable bowel syndrome according to two randomized trials.

    1. Post
      Author
      Seth

      I do not know much about cadmium in flaxseeds so I can’t really comment intelligently on the matter. You raise an interesting question, though. I’ll have to look into it.

Comments are closed.