Nativa, Sinop, v. 9, n. 4, p. 373-381, 2021.
Pesquisas Agrárias e Ambientais
DOI: https://doi.org/10.31413/nativa.v9i4.11809 ISSN: 2318-7670
Flaxseed meal feeding to dairy cows as a strategy to improve milk
enterolactone concentration: a literature review
Caren Paludo GHEDINI1*; Daiane Caroline de MOURA1
1 Department of Agriculture, Nutrition, and Food Systems, University of New Hampshire, Durham, USA.
2 Dairy Cattle Research Lab, Universidade Federal de Mato Grosso, Sinop, MT, Brazil.
*E-mail: caren_pg@hotmail.com
(ORCID: 0000-0001-8532-4087; 0000-0002-8276-2089)
Recebido em 10/02/2021; Aceito em 18/08/2021; Publicado em 20/09/2021.
ABSTRACT: Flaxseed (Linum usitatissimum) is the richest source of the plant lignan secoisolariciresinol
diglucoside (SDG). In mammals, including bovine, SDG is converted to the mammalian lignans enterolactone
(EL) and enterodiol (ED) by the action of gastrointestinal microbes. There is a great deal of interest in
promoting increased intakes of lignans in humans’ diet due to the potential health benefits of mammalian
lignans, especially in the prevention of cardiovascular diseases, hypercholesterolaemia, breast and prostate
cancers, and osteoporosis. Consumption of milk and dairy products enriched in EL could be an excellent
strategy to increase the intake of lignans by humans. This literature review will focus on presenting feeding
strategies capable to improve milk enterolactone concentration. Research has demonstrated the potential of
flaxseed meal (FM) feeding to dairy cows as a strategy to improve milk EL concentration, therefore enhancing
milk nutraceutical proprieties. A considerable number of studies have demonstrated that feeding vegetable
lignans-rich sources, such as FM, to dairy cows improves EL in milk. Additionally, it has been reported that
changes in the carbohydrate profile of FM-based diets fed to dairy cows can alter the output of milk EL. The
application of animal nutrition as a tool to increase nutraceutical properties of milk (i.e. increased EL
concentration) is a valuable strategy for promoting the association of milk with humans’ health benefits and is
of great interest in contemporary society.
Keywords: milk nutraceutical proprieties; bioactive compounds; lignans; disease risk reduction; dairy cattle
production.
O farelo de linhaça na dieta de vacas leiteiras como estratégia para aumentar
a concentração de enterolactona no leite: revisão de literatura
RESUMO: A linhaça (Linum usitatissimum) é a principal fonte da lignana vegetal secoisolariciresinol
diglucosídeo (SDG). Em mamíferos, incluindo bovinos, SDG é precursor para a síntese das lignanas de
mamíferos enterolactona (EL) e enterodiol (ED) pelos microrganismos gastrointestinais. Existe um grande
interesse em promover o aumento da ingestão de lignanas na dieta humana devido aos potenciais benefícios da
EL a saúde, incluindo principalmente a prevenção de doenças cardiovasculares, hipercolesterolemia, câncer de
mama e de próstata e osteoporose. Assim, objetivou-se fazer uma revisão de literatura sobre estratégias de
alimentação capazes de melhorar a concentração de enterolactona no leite, melhorando assim a atividade
biológica e os benefícios do leite para a saúde humana. A alimentação de vacas leiteiras com fontes ricas em
lignanas vegetais, como o farelo de linhaça (FM), aumenta a concentração de EL no leite. Além disso, estudos
têm demonstrado que mudanças no perfil de carboidratos de dietas à base de FM fornecidas a vacas leiteiras
alteram a concentração de EL do leite. A aplicação da nutrição animal como ferramenta para aumentar as
propriedades nutracêuticas do leite (ex. aumentar a concentração de EL) é uma estratégia valiosa para promover
a associação do leite com benefícios à saúde humana e é de grande interesse na sociedade moderna.
Palavras-chave: propriedades nutracêuticas do leite; compostos bioativos; lignanas; redução do risco de
doenças; bovinocultura leiteira.
1. INTRODUCTION
Flaxseed has been consumed by humans since ancient
times and it has establishing importance as a functional food
mainly due to the presence of three main bioactive
compounds: α-linolenic acid (ALA), dietary fiber, and lignans
(TOURE; XUEMING, 2010; KAJLA et al., 2015). In dairy
cows diets, flaxseed can be fed as a source of both energy and
protein (PETIT, 2011). Whole flaxseed and flaxseed oil are
excellent sources of ALA and the outer fiber-containing
layers of flaxseed is the richest source of lignans, which are
polyphenolic compounds known as phytoestrogens
(THOMPSON et al., 1991; KAJLA et al., 2015).
Feeding flaxseed to dairy cows contributes to favorable
changes in milk composition for better human health by
enhancing milk nutraceutical compounds. For instance,
improved amounts of polyunsaturated fatty acids (PUFA) in
milk of dairy cows have been reported with feeding extruded
Flaxseed meal feeding to dairy cows as a strategy to improve milk enterolactone concentration: a literature review
Nativa, Sinop, v. 9, n. 4, p. 373-381, 2021.
374
flaxseed (ZACHUT et al., 2010) and flaxseed oil
(CAROPRESE et al., 2010) to dairy cows.
Additionally, supplementation with flaxseed oil has been
shown to increase the concentration of conjugated linoleic
acid in milk of dairy cows (GLASSER et al., 2008). Whereas,
improved concentration of mammalian lignans in milk has
been reported with feeding flaxseed meal (FM), a lignan-rich
source, to dairy cows (PETIT; GAGNON, 2009; BRITO et
al., 2015; LIMA et al., 2016). Mammalian lignans are bioactive
compounds with a wide range of biological activities,
including: antioxidant, antitumor, and weakly estrogen-linked
proprieties. There is great deal of interest in promoting the
inclusion of lignan-rich foods in humans’ diets due to the
potential humans’ health benefits of mamalians lignans,
including prevention of cardiovascular diseases,
hypercholesterolemia, breast and prostate cancers,
menopausal symptoms, and osteoporosis (MURKIES et al.,
1998; ADLERCREUTZ, 2002).
Secoisolariciresinol diglucoside (SDG) is the major lignan
in flaxseed, accounting for more than 95% of the total
lignans. It is mostly concentrated in the outer fiber-
containing layers of the seed (ADLERCREUTZ; MAZUR,
1997), thus resulting in greater concentration of SDG in hulls
compared to seeds. Secoisolariciresinol diglycoside is the
major precursor for synthesis of the mammalian lignans
enterolactone (EL) and enterodiol (ED) by the gut
microbiota in humans (THOMPSON et al., 1991) and
ruminants (CÔRTES et al., 2008; GAGNON et al., 2009a).
In dairy cows, EL is the predominant mammalian lignan
found in the rumen and physiological fluids, including
plasma, urine, and milk (CÔRTES et al., 2008; GAGNON et
al., 2009a).
Saarinen et al. (2002) reported that rats fed pure EL had
a 5-fold increase in urinary excretion of EL compared with
those fed plant lignans. These findings indicate that prior
absorption, plant lignans must be converted to EL by
microbes in the colon, whereas deconjugated EL may be
passively absorbed along the intestine of mammals . The
concentration of EL in milk of dairy cows can be modulated
by dietary changes and EL-enriched milk or dairy products
could be used as a source of EL for humans (PETIT;
GAGNON, 2009; BRITO et al., 2015). Humans rely on gut
microbes to convert plant lignans to mammalian lignans
(THOMPSON et al., 1991). Therefore, the intake of EL-
enriched milk or dairy products may be more efficient in
providing EL for humans, than the intake of plant lignans.
In this sense, there is a growing interest in improving milk
EL concentration and dietary strategies have been
investigated in order to produce EL-enriched milk. Feeding
SDG-rich sources to dairy cows is one of the dietary
strategies that can be applied to improve milk EL
concentration. Indeed, supplementation with FM (PETIT;
GAGNON, 2009; PETIT et al., 2009b; BRITO et al., 2015;
LIMA et al., 2016) and flaxseed hulls (GAGNON et al.,
2009a; PETIT et al., 2009a) have been reported to improve
the concentration of EL in milk of dairy cows. It has also
been reported that changes in the carbohydrate profile of
FM-based diets fed to dairy cows can potentially alter the
output of milk EL (BRITO et al., 2015).
This literature review will focus on presenting feeding
strategies capable to improve milk enterolactone
concentration. Additionally, this literature review will
describe the chemical composition of flaxseed, specifically
regarding lignans content while discussing the metabolism of
mammalian lignans in both non-ruminant and ruminant
animals. Biological activities and potential human health
benefits of mammalian lignans will be briefly addressed.
2. LITERATURE REVIEW
2.1 Flaxseed
Flaxseed is a blue flowering annual herb that belongs to
the family Lineaceae (RUBILAR et al., 2010; SIGH et al.,
2011). Flaxseed is cultivated for fiber, medicinal purposes,
and as nutritional product in more than 50 countries (SIGH
et al., 2011). Currently, Canada is the largest producer in the
world and India, China, United States, and Ethiopia can also
be cited as important flaxseed growing countries (SIGH et
al., 2011; KAJLA et al., 2015).
The chemical composition of whole-grain flaxseed is
detailed on Table 1. Flaxseed chemical composition varies
upon growing environment, genetics, processing conditions,
and method of analysis (MORRIS, 2007). The major
component of flaxseed is its oil. It has around 40% fat found
manly as triglycerides (98%) with lower contents of
phospholipids (0.9 %) and free fatty acids (0.1%)
(MUELLER et al., 2010). Flaxseed is a rich source of n-3 fatty
acids, especially ALA which can constitute up to 55% of the
total fatty acids in flaxseed (MUSTAFA et al. 2003;
MUELLER et al., 2010). The content of neutral detergent
fibre (NDF) of flaxseed is around 30% (CHUNG et al.,
2005). Flaxseed is also a good protein source. It contains
around 20% of crude protein (CP), mainly globulin (26–58%)
and albumin (20–42%). Regarding amino acid profile,
flaxseed is rich in arginine, aspartic acid, and glutamic acid,
and limiting in lysine (CHUNG et al., 2005).
Table 1. Nutritional composition of whole flaxseed
Tabela 1. Composição nutricional da semente de linhaça
Nutrients Amount¹
Moisture, g 6.5
Protein, g 20.3
Fat, g 37.1
Minerals, g 2.4
Crude fiber, g 4.8
Total dietary fiber, g 24.5
Carbohydrates, g 28.9
Energy, kcal 530.0
Potassium, mg 750.0
Calcium, mg 170.0
Phosphorus, mg 370.0
Iron, mg 2.7
Vitamin A, µg 30
Vitamin E, mg 0.6
Thiamine (B1), mg 0.23
Riboflavin (B2), mg 0.07
Niacin, mg 1.0
Pyridoxine, mg 0.61
Pantothenic acid, µg 0.57
Biotin, µg 0.6
Folic acid, µg 112
Source: (Kajda et al., 2015)
¹ Amount per 100 g of edible Flaxseed
Fonte: (Kajda et al., 2015)
¹ Quantidade por 100 g de linhaça
Flaxseed can be fed to dairy cows as whole flaxseed,
flaxseed oil, and FM. Flaxseed meal is the residue remaining
after flaxseed oil extraction. Compared to whole flaxseed, FM
is greater in fiber and protein and lower in crude fat
Ghedini & Moura
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375
(GAGNON et al., 2009). Therefore, FM is fed to dairy cows
mainly as a protein source. Chemical composition of FM and
other protein supplements fed to dairy cows are detailed in
Table 2.
Table 2. Chemical composition of flaxseed meal, canola meal,
soybean meal and cottonseed meal. Value are expressed as % DM
except amino acids, which are expressed as % crude protein
Tabela 2. Composição química do farelo de linhaça, farelo de
canola, farelo de soja e farelo de algodão. Os valores são expressos
como% DM exceto aminoácidos, que são expressos como %
proteína bruta
Item
Protein Supplements
Flaxseed
meal Canola
meal Soybean
meal Cottonseed
meal
DM 91.6 90.1 88.6 90.2
CP 34.3 40.0 48.8 35.0
EE 1.32 1.32 1.71 1.38
NDF 25.0 30.7 14.6 28.5
ADF
16.4 21.77 9.86 28.8
Lysine 3.85 2.36 2.82 1.45
Methionine 1.86 0.83 0.63 0.62
Cysteine 1.56 1.02 0.66 0.51
Threonine 3.65 1.67 1.8 1.27
Tryptophan 1.66 0.48 0.67 0.55
Phenylalanine
4.93 1.56 2.34 2.00
Leucine 6.00 2.69 3.62 2.21
Isoleucine 4.18 1.41 2.07 1.11
Valine
4.99 1.64 2.16 1.64
Histidine 2.15 1.00 1.16 1.00
Arginine
9.10 3.94 5.5 3.94
Tyrosine 2.71 1.21 1.5 1.21
Alanine
4.50 1.64 2.06 1.64
Aspartate
9.14 3.17 5.50 3.17
Glutamate 18.3 7.10 8.70 7.10
Glycine 5.84 1.64 1.97 1.64
Serine 3.88 1.66 2.47 1.66
Source: Valadares Filho et al. (2006)
Fonte: Valadares Filho et al. (2006)
2.1.1 Flaxseed lignans
One of the most interesting characteristics of flaxseed is
its content of complex phenols, known as phytoestrogens,
primarily lignans. Phytoestrogens are a diverse group of
compounds found naturally in many edible plants and their
seeds that have a phenolic group shared with estrogenic
steroids (WANG et al., 2002). Phytoestrogens are known as
plant compounds with estrogen-like biological activity and
are classified according to their chemical structure in three
major categories: isoflavones, cousmestans, and lignans
(ADLERCREUTZ; MAZUR, 1997).
Plant lignans are defined as diphenolic compounds
produced by the coupling of 2 coniferyl alcohol residues
existing in cell wall of high plants (TOUREAND;
XUEMING, 2010). They are found in fibrous rich plants:
cereals (barley, wheat and oats), vegetables (broccoli, garlic,
asparagus and carrots), legumes (bean, lentil and soybean),
fruits, berries, tea, and alcoholic beverages (WANG et al.,
2002).
Flaxseed is the richest source of plant lignans. Flaxseed
lignans are mostly concentrated in the outer fiber-containing
layers of the seed (ADLERCREUTZ; MAZUR, 1997). The
concentration of SDG in flaxseed hulls has been reported to
be 3.4-times greater than in whole flaxseeds (CORTES et al.,
2012). The chemical structure of flaxseed lignans is detailed
in Figure 1. Secoisolariciresinol diglycoside is the major
lignan of flaxseed, representing over 95% of the total lignans
(DAUN et al., 2003; LIU et al., 2006). Minor concentrations
of other lignans including matairesinol, pinoresinol,
lariciresinol, and isolariciresinol are also present in flaxseed
(RAFFAELLI et al., 2002). Table 3 details the concentration
of lignans in whole-grain flaxseed. According to Johnsson et
al. (2000) SDG concentration in flaxseed ranges from 1.7 to
2.4 % in defatted flour and 0.6 to 1.3 % in whole flaxseed
flour. Flaxseed meal SDG concentration were 1.66% and
1.64% of DM in the studies done by Brito et al. (2015) and
Petit and Gagnon (2009), respectively.
Figure 1. Chemical structure of flaxseed lignans (Adapted from Landete, 2012 and Kajla et al., 2015).
Figura 1. Estrutura química das lignanas de linhaça (adaptado de Landete, 2012 e Kajla et al., 2015).
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376
Table 3. Lignan content of flaxseed
Tabela 3. Conteúdo de Lignanas da linhaça
Serving
Size SDG1 MAT2 LAR2 PINO2 SECO2
Total²
mg³ 82-2600 0.15 2.8 0.7 375 379
mg4 11-286 0.02 0.3 0.1 41 42
mg5 8-208 0.01 0.2 0.1 30 30
Abreviations: LAR: lariciresinol; MAT: matairesinol; PINO: pinoresinol.
1 data adapted from Muir, 2006; 2 data adapted from Thompson et al., 2006.
The values for total lignans were calculated by summing the values for MAT,
LAR, PINO and SECO. ³ 100 g; 4 one tbsp. (11g) of whole seed; 5 one tbsp.
of milled flax (8 g).
Source: adapted from Muir, (2006) and Thompson et al. (2006).
Abreviações: LAR: lariciresinol; MAT: matairesinol; PINO: pinoresinol.
1 dados adaptados de Muir, 2006; 2 dados adaptados de Thompson et al.,
2006. Os valores para lignanas totais foram calculados somando os valores
de MAT, LAR, PINO e SECO. ³ 100 g; 4 uma colher de sopa. (11g) de
semente inteira; 5 uma colher de sopa. de linho moído (8 g).
Fonte: adaptado de Muir, (2006) e Thompson et al. (2006)
2.2 Lignans metabolism in non-ruminant and ruminant
animals
2.2.1 Non-ruminant animals
In mammals, plant lignans are metabolized by the
gastrointestinal microbiota to the mammalian lignans: EL
and ED (THOMPSON et al., 1991; CHEN et al., 2007;
CÔRTES et al., 2008; GAGNON et al., 2009) (Figure 2).
Figure 3 shows the pathways for mammalian lignans
synthesis from different plant lignans. The pathway for
conversion of SDG, the major lignan found inflaxseed, to
mammalian lignans is detailed in Figure 4. The conversion of
plant SGD to mammalian lignans involves basically 3 steps
that take place in the gut of non-ruminant animals:
Figure 2. Chemical structure of the mammalian lignans
Fonte: Landete, 2012.
Figura 2. Estrutura química dos lignanos mamíferos
Fonte: Landete, 2012.
Figure 3. Pathways for mammalian lignans synthesis from plant lignans. Numbers indicate the reactions catalyzed by intestinal bacteria in humans: (1)
indicates reduction reaction, (2) deglycosylation, (3) demethylation, (4) dihydroxylation, and (5) dehydrogenation (adapted from
Source: Clavel et al. (2006).
Figura 3. Vias para a síntese de lignanas de mamíferos a partir de lignanas de plantas. Os números indicam as reações catalisadas por bactérias intestinais
em humanos: (1) indica reação de redução, (2) desglicosilação, (3) desmetilação, (4) dihidroxilação e (5) desidrogenação (adaptado de
Fonte: Clavel et al. (2006).
Figure 4. Metabolism of SDG to mammalian lignans
Source: Clavel et al. (2006).
Figura 4. Metabolismo de SDG para lignanos de mamíferos
Fonte: Clavel et al. (2006).
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(1) first, SDG is hydrolyzed under the action of intestinal
glycosidases to SECO, which is the non-sugar moiety of
SGD (CLAVEL et al., 2006; CHEN et al., 2007). Bacteroides
and Clostridia have been reported to release the glucosyl
moieties from SDG to yield SECO (CLAVEL et al. 2006).
(2) Further, colonic microbes convert SECO to ED by
demethylation and dehydrogenation. (3) Finally, ED can be
converted to EL by dihydroxylation (CLAVEL et al., 2006;
CHEN et al., 2007). Peptostreptococcus productus, Eubacterium
callanderi, Eubacterium limosum, and Bacteroides methylotrophicum
have been identified as the major bacteria responsible for
demethylation reactions, whereas dehydrogenation reactions
are carried out mainly by Eubacterium lentum (WANG et al.,
2000; CLAVEL et al., 2007). Several Clostridia and
Ruminococcus spp. have been cited as the major microorganisms
responsible for converting ED to EL by dihydroxylation as
cited above (CLAVEL et al., 2007).
Mammalian lignans formed from plant lignans by the gut
microbiota have three metabolic fates: (1) they are directly
excreted in feces, (2) they are taken up by epithelial cells lining
of the colon and conjugated with glucuronic acid or sulfate.
After conjugation, EL and ED enter the circulation and can
eventually be excreted in feces, and (3) they can be absorbed
from the gut in their deconjugated form and reach the liver,
where free forms are conjugated and released into the
bloodstream. Eventually, the conjugated mammalian lignans
are excreted into physiological fluids (e.g., plasma and urine)
or return to the intestine via enterohepatic circulation
(WANG, 2002; LANDETE, 2012). The conjugated forms of
mammalian lignans that reach the intestine via enterohepatic
circulation are poorly absorbed. The microbial enzyme β-
glucuronidase converts mammalians lignans to their
deconjugated forms, allowing them to be reabsorbed in the
intestine (RAFFAELI et al., 2002). The activity of β-
glucuronidase in humans has been attributed to intestinal-
dominant bacteria belonging to Bacteroides, Bifidobacterium,
Eubacterium, and Ruminococcus genera (AKAO et al., 2000).
2.2.2 Ruminant animals
The metabolism of lignans in ruminant aminals is not
completely elucidated. It is known that plant lignans are
metabolized to mammalian lignans by both ruminal and fecal
microbiota (CORTES et al., 2008). Recent studies have
demonstrated that lignans metabolism in ruminants occurs
mainly into the rumen, where plant lignans are converted to
mammalian lignans by ruminal microbes (CORTES et al.,
2008; GAGNON et al., 2009a).
The study done by Gagnon et al. (2009a) was the first in
vivo study to investigate the role of ruminal microorganisms
in flaxseed lignans metabolism in lactating dairy cows.
Ruminally-cannulated dairy cows were assigned to the
following experimental treatments: (1) Flaxseed oil and
flaxseed hulls administration into the rumen and water
infusion in the abomasum; (2) oil and hulls administration
into the abomasum; oil infusion in the abomasum and hulls
placed in the rumen; or (4) oil placed in the rumen and hulls
administered in the abomasum. Enterolactone concentration
on milk and urine were 12 and 16 times greater, respectively,
with flaxseed hulls administration in the rumen compared to
administration of flaxseed hulls in the abomasum. Similarly,
plasma EL concentration was three times higher in cows
receiving flaxseed hulls in the rumen than those receiving
flaxseed hulls in the abomasum. These results demonstrated
that ruminal microbiota plays an important role in converting
flaxseed lignans to mammalian lignans in dairy cows.
Despite the importance of ruminal microbes on lignans
metabolism in dairy cows, just few studies have investigated
lignans metabolism in the rumen and how dietary changes
could impact this process. Recently, Schogor et al. (2014)
studied lignans metabolism using selected pure cultures of
ruminal bacteria incubated in vitro with SDG. It was reported
that 11 ruminal bacteria, mainly Prevotella spp. were able to
convert SDG to SECO, which is formed as an intermediate
in the ruminal metabolim of SDG to EL. These findings
suggest that Prevotella spp. may play an important role in lignan
metabolism in dairy cows (SCHOGOR et al., 2014).
Enterolactone has been identified as the major lignan
metabolite present in ruminal fluid, urine, plasma, and milk
of dairy cows (PETIT; GAGNON, 2009; GAGNON et al.,
2009a; BRITO et al., 2015). Gagnon et al. (2009b)
investigated the length of time to obtain peak EL
concentration in milk of dairy cows fed FM (20% of diet
DM). The length of time need for EL to return to baseline
level was also evaluated in this study. It was reported that the
conversion of SDG to EL and the transfer of EL to the
mammary gland are established after one week of FM
supplementation, whereas milk concentration of EL returned
to baseline level after one week of FM deprivation.
Studies have investigated β- glucuronidase activity in
lignans metabolism in dairy cows. Petit et al. (2009) evaluated
the effect of feeding monensin and flaxseed hulls on β-
glucuronidase activity in rumen fluid and feces. Monensin is
known to decrease the growth of Gram-positive bacteria and
could potentially impact β- glucuronidase activity,
considering that strains of ruminal bacteria with β-
glucuronidase activity (e.g. Ruminococcus and Eubacterium)
are Gram positive bacteria (JENAB; THOMPSON, 1996).
Indeed, the activity of β- glucuronidase in ruminal fluid
tended to decrease when cows received monensin. Flaxseed
hulls supplementation decreased β- glucuronidase activity in
both ruminal fluid and feces (PETIT et al.,2009).
Similar results were reported with ruminal infusion of
flaxseed oil in the study done by Gagnon et al. (2009a) and
could be explained by the high content of omega-3 FA o
these flax products which can negatively affect the growth of
ruminal bacteria (MAIA et al. 2007). A subsequent study,
(LIMA et al., 2016) investigated the effects of dietary FM and
abomasal infusion of flaxseed oil and their interaction on
activity of β-glucuronidase. It was reported that abomasal
infusion of flaxseed oil, which is a PUFA rich source, had no
effect on β-glucuronidase activity. These results suggest that
polyunsaturated fatty acids do not interfere with the
absorption of mammalian lignans in ruminants. No effect of
FM supplementation was reported on activity of β-
glucuronidase. The author also reported higher activity of β-
glucoronidase in feces than in ruminal fluid suggesting that
the deconjugation reactions may be more important in the
large intestine than in the rumen of ruminant animals (LIMA
et al., 2016).
2.3 Biological activities and potential human health
benefits of mammalian lignans
There is a growing interest in promoting the inclusion of
lignans-rich sources in human diets due to the potential
health benefits of mammalian lignans. Flaxseed lignans and
the mammalian lignans ED and EL are biologically active
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substances that elicit a wide range of biological activities
including weak estrogenic and cardioprotective effects, as
well as antiestrogenic, antioxidant, anti-inflammatory, and
anticarcinogenic properties (ADOLPHE et al., 2010;
HÖGGER, 2013; IMRAN et al., 2015; LANDETE, 2012).
Lignans and mammalian lignans are known to be strong
antioxidants and their antioxidant proprieties are presumably
the main reason for the anticancer activity of these
components in humans (PRASAD, 2000; LANDETE,
2012). Prasad (2000) studied the antioxidant activity of
SECO, ED, and EL using chemiluminescence of zymosan-
activated polymorphonuclear leukocytes. SDG and vitamin
E were used for comparison. The highest antioxidant activity
was reported with SECO and ED, whereas, vitamin E
resulted in the lowest antioxidant activity. The antioxidant
potency of SECO, ED, EL, and SDG was 4.86, 5.02, 4.35,
and 1.27 respectively, compared to vitamin E (PRASAD,
2000). Phytoestrogens, including lignans exhibit both in vitro
and in vivo weak estrogenic and antiestrogenic actions
(LANDETE, 2012). Mammalian lignans have an aromatic
structure similar to the endogenous estrogen, estradiol
(MORRIS, 2007). It is believed that mammalian lignans act
by binding to estrogen receptors (ER) on cell membranes
(LANDETE, 2012; MORRIS, 2007).
Enterolactone can function as weak estrogen, in this
circumstance EL binds to ER and mimic the action of
endogenous estrogen working as an agonist (LANDETE,
2012). For example, EL can stimulate growth of breast cancer
cells as reported by Wang and Kurzer (1997). Anti-estrogenic
proprieties of EL have also been reported. In cell-based
studies EL binds the ER inhibiting breast cancer cells growth
(BUCK et al., 2010). In this situation, EL blocks the action
of endogenous estrogen, working as antagonists
(LANDETE, 2012).
In addition to the estrogen-like activity of mammalian
lignans, studies have also reported that mammalian lignans
exhibit effects on hormone metabolism and availability. For
example, EL has been shown to stimulate the synthesis of sex
hormone binding globulin, which binds sex hormones and
reduce their circulation in blood, thus decreasing their
biological activity (THOMPSON et al., 1996). Furthermore,
mammalian lignans are believed to influence enzyme activity.
For instance, EL inhibit the activity of aromatase, an enzyme
involved in the production of estrogens (LANDETE, 2012,
ADLERCREUTZ et al., 1993).
Research has reported the important role of mammalian
lignans in preventing various types of cancer specially the
hormone sensitive ones, primarily breast and prostate cancer.
In vitro studies have reported that mammalian lignans are
possibly responsible for growth inhibition of human prostate
cancer (WESTCOTT; MUIR, 2003) and breast cancer cells
(BUCK et al., 2010). Additionally, epidemiological studies
have linked high lignan intake to lower cancer risk.
For instance, Touilland et al. (2007) conducted a seven
years long study with 58,049 female participants and reported
that high dietary intake of plant lignans were associated with
reduced risks of postmenopausal breast cancer. Buck et al.
(2010) conducted a meta-analysis to investigate the
association between lignans and breast cancer risk. The meta-
analysis investigated a total of 21 studies, in which high
lignans intake was associated with a significant reduction in
breast cancer risk in postmenopausal women (BUCK et al.,
2010). Despite the potential human health benefits of
mammalian lignans, intake of phytoestrogens may also have
adverse health effects, particularly in critical stages of infant
development (SETCHELl, 1998; ZUNG et al., 2008;
LANDETE, 2012) and timing of exposure is crucial to
maximize potential health benefits while minimizing adverse
health effects.
2.4 Improving enterolactone concentration in milk
The concentration of EL in milk of dairy cows can be
modulated by dietary changes. Improved concentrations of
EL have been reported with feeding SDG-rich sources, such
as, FM and flaxseed hulls to dairy cows. Petit et al. (2009b),
conducted a study to determine the effects of feeding FM and
whole flaxseed (both fed at 10% of DM) on concentrations
of ED and EL in milk of Holstein cows. The mammalian
lignan ED was not detected in milk. Milk enterolactone
concentration was higher in cows receiving FM (0.713 mg/d
of EL in milk) than those fed whole flaxseed (0.505 mg/d)
and the control diet (no flaxseed products, 0.231 mg/d).
Feeding the two flaxseed products resulted in different
intakes of SDG: 15280 mg/d in cows receiving FM and 8050
mg/d in cows receiving whole flaxseed which is explain by
the fact that lignans are concentrated in the outer fibre
containing layers of grains (ADLERCREUTZ; MAZUR,
1997) which leads to higher SDG concentration in flax
products with lower concentrations of oil. Lower SDG intake
in cows receiving whole flaxseed explains the lower EL
concentration in milk reported in this study in cows fed
whole flaxseed at 10% of the DM (PETIT et al., 2009b). Petit
and Gagnon (2009b) fed Holstein cows with incremental
amounts of FM: 0, 5, 10 and 15% of DM and reported that
the concentration of EL in milk increased linearly.
Concentration of EL in milk, expressed as mg/d, was 0.175,
0.312, 0.393 and 0.535 for cows receiving 0, 5, 10 and 15%
of FM, respectively. Concentration of ED in milk was below
detection level. Similarly, Petit and Gagnon (2011) reported
linear increase on milk EL concentration with feeding
increasing levels of flaxseed hulls (0, 5, 10, 15, 20% of DM)
to Holstein cows (PETIT; GAGNON, 2011).
Lima et al. (2016) investigated the effects of dietary FM
and abomasal infusion of flaxseed oil and their interaction on
milk enterolactone concentration in rumen-fistulated
Holstein cows. Cows received four different diets: (1) control
diet with no FM (CON); (2) diet containing 12.4 % of FM in
the dry matter; (3) no FM and 250 g of flaxseed oil/day
infused in the abomasum; and (4) 12.4% of FM and 250 g
flaxseed oil/day infused in the abomasum.
Dietary FM increased concentrations of EL in milk. Milk
EL concentration were 2.11 mg/d and 2.61 mg/d in cows
fed 12.4% of FM and no oil (diet 2) and those fed 12.4% of
FM and flaxseed oil infusion in the abomasum (diet 4),
respectively (LIMA et al., 2016).
Recently, it was reported that the concentration of EL in
milk can be modified by the type of NSC source
supplemented to dairy cows fed diets containing FM, with
LM resulting in greater milk EL than GRC (BRITO et al.,
2015). In this study, Jersey cows were fed mixed mostly grass
hay and one of the following 4 concentrate blends: (1) GRC
(12% of DM) plus a protein mix containing soybean meal
(11% of DM) and sunflower meal (5% of DM); (2) GRC
(12% of DM) plus flaxseed meal (16% of DM); (3) LM (12%
of DM) plus the same protein mix of diet 1; or LM (12% of
DM) plus flaxseed meal (16% of DM). Milk EL
concentration were: 0.37, 1.68, 0.75 and 2.40 mg/d in cows
fed diets 1, 2, 3 e 4, respectively. Increased milk EL
Ghedini & Moura
Nativa, Sinop, v. 9, n. 4, p. 373-381, 2021.
379
concentration was observed when FM was fed to the cows.
Additionally, it was reported that cows fed LM and FM had
higher concentration and yield of milk EL than those fed
GRC and FM. This finding suggests that LM, which is a
sucrose source, may be more efficient in selecting for ruminal
microbes with higher capacity to metabolize plant lignans to
mammalian lignans in the rumen than GRC, which is a starch
source (BRITO et al., 2015).
A subsequent study was carried to better understand how
changes in diet NSC profile could impact EL output in milk
of dairy cows fed FM (GHEDINI et al., 2017). This study
investigated the effects of replacing GRC with incremental
amounts of LM on milk enterolactone concentration in
Jersey cows fed FM (15% DM) and low-starch diets (GRC-
to-LM dietary ratio were: 12:0, 8:4, 4:8, and 0:12, dry matter
basis). The concentration of EL in milk tended to respond
cubically with replacing GRC by incremental amounts of LM
in FM-based diets. Based on their results, the authors suggest
that further studies are needed to fully elucidate how FM-
SDG is affected by changes in ruminal microbiome and diet
composition (GHEDINI et al., 2017).
Considering that Prevotella spp. may play a role in lignan
metabolism in dairy cows (SCHOGOR et al., 2014) as
described previosly, dietary changes that favor or result in a
greater prevalence of Prevotella spp. in the rumen could
improve EL secretion on milk. Li et al. (2015) reported that
when steers were fed diets containing 4% flaxseed oil the
genus Prevotella dominated the ruminal bacterial community,
suggesting that PUFA supplementation favors Prevotella spp.
growth in the rumen. The effect of feeding sucrose and FO
alone or in association (sucrose + FO) on milk EL
concentration of dairy cows fed 15% FM was investigated by
Ghedini et al (2017). Holstein cows were fed four different
treatments: 1) 8% soybean meal (control); (2) 5% sucrose +
15% FM; (3) 3% FO + 15% FM; and (4) 5% sucrose + 3%
FO + 15% FM. The authors hypothesized that sucrose and
FO could synergistically interact to increase the
concentration of EL in milk as both,sugars and FO, have
been shown to promote growth of Prevotella spp. The
average concentration of EL in milk increased 4-fold in cows
fed 15% FM compared with the control diet (diet with no
FM). However, no differences in milk EL concentration were
observed among the treatments containing FM
supplemented with sucrose or FO or their association
(GHEDINI, 2017). Despite these findings, the effect of
PUFA on SDG metabolism and subsequent milk EL
concentration has not been fully investigated.
3. CONCLUSIONS
Milk concentration of EL, a nutraceutical component
with humans’ health benefits can be modulated by altering
diets of dairy cows. Feeding FM improves milk EL
concentration as it is a lignan-rich source. In ruminants, plant
lignans (SDG) are converted to mammalian lignans (EL and
ED) mainly in the rumen by the action of rumen microbes.
Increased concentration of EL with FM feeding to dairy
cows demonstrates that EL produced in the rumen reaches
the mammary gland and is transferred to milk. Therefore, FM
feeding to dairy cows improves the capacity of milk to favor
humans´ health. Research has also demonstrated that
changing carbohydrate profile of FM-based diets fed to dairy
cows can potentially alter the output of milk EL. Considering
the importance of rumen microbes on lignans metabolism,
changes in diversity and function of the ruminal microbiome
have the potential to alter the concentration of EL in milk.
4. ACKNOLEDGMENTS
The authors thank the scientific and technical advice
from Dr. André Fonseca de Brito (Department of
Agriculture, Nutrition, and Food Systems, University of New
Hampshire).
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