Lignans are polyphenolic compounds with a wide spectrum of biological functions including antioxidant, anti-inflammatory, and anticarcinogenic activities, therefore, there is an increasing interest in promoting the inclusion of lignan-rich foods in humans’ diets. Flaxseed is the richest source of the lignan secoisolariciresinol diglucoside—a compound found in the outer fibrous-containing layers of flax. The rumen appears to be the major site for the conversion of secoisolariciresinol diglucoside to the enterolignans enterodiol and enterolactone, but only enterolactone has been detected in milk of dairy cows fed flaxseed products (whole seeds, hulls, meal). However, there is limited information regarding the ruminal microbiota species involved in the metabolism of secoisolariciresinol diglucoside. Likewise, little is known about how dietary manipulation such as varying the nonstructural carbohydrate profile of rations affects milk enterolactone in dairy cows. Our review covers the gastrointestinal tract metabolism of lignans in humans and animals and presents an in-depth assessment of research that have investigated the impacts of flaxseed products on milk enterolactone concentration and animal health. It also addresses the pharmacokinetics of enterolactone consumed through milk, which may have implications to ruminants and humans’ health.

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Dairy cows consume inadequate amounts of feed in early lactation and during conditions and diseases such as excessive fatness, heat stress, and infectious diseases. Affected cows often experience increases in plasma concentrations of acute phase proteins consistent with the negative effect of inflammation on appetite. The acute phase protein orosomucoid 1 (ORM1), also known as alpha-1-acid glycoprotein, was recently reported to reduce appetite in the mouse through its ability to bind the full-length leptin receptor (Ob-Rb) and activate appetite-suppressing signal transducer and activator of transcription 3 (STAT3) signaling. These observations raise the possibility that ORM1 exerts appetitesuppressing effects in dairy cattle during periods of increased inflammatory tone. The applicability of this model was assessed in 2 ways. First, we asked whether ORM1 is regulated during periods of inadequate appetite such as the transition from late pregnancy to early lactation and periods of increased inflammatory tone. Plasma ORM1 was invariant in late pregnancy but increased 2.5-fold between parturition and d 7 of lactation. Gene expression studies showed that liver was the major source of this elevation with little contribution by adipose tissue or mammary gland. Additional studies showed that plasma ORM1 was not increased further by excessive fatness or by reproductive dysfunction in early lactation and was completely unresponsive to inflammatory stimuli such as heat stress or intravascular administration of the endotoxin lipopolysaccharide during established lactation. Second, we tested the ability of ORM1 to trigger STAT3 signaling through Ob-Rb using Chinese hamster ovary K1 (CHO-K1) cells transfected with a STAT3 expression plasmid. In this configuration, CHO-K1 cells did not express Ob-Rb and were incapable of leptin-induced STAT3 phosphorylation. Leptin responsiveness was conferred by co-transfecting with bovine Ob-Rb, with leptin causing increases of 5.7-fold in STAT3 phosphorylation and 2.1fold in the expression of the STAT3-dependent gene, SOCS3. In contrast, neither bovine or human ORM1 triggered STAT3 phosphorylation irrespective of dose and period of incubation tested. In summary, bovine ORM1 is not increased during periods of increased inflammatory tone except in early lactation and is incapable of Ob-Rb-dependent STAT3 signaling. Overall, these data are inconsistent with ORM1 mediating the appetite-suppressing effects of inflammation in cattle through Ob-Rb.

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Defects in mitochondrial fatty acid processing are associated with the development of fatty liver disease, inflammation, and insulin resistance in overweight nonruminants. Surplus fatty acids (FA) and defects in FA oxidation favor the accumulation of fatty acylcarnitines (FAC) and the sphingolipid ceramide. Moreover, elevated circulating FAC and ceramide concentrations are inversely related to insulin action. Because we have previously demonstrated that plasma ceramide levels increase during the transition from gestation to lactation, our aim was to determine whether changes in plasma medium- and long-chain FAC levels are related to circulating FA and sphingolipids in peripartal dairy cows. We hypothesized that plasma FAC levels would be higher in overweight cows experiencing increased lipolysis, and that FAC levels would be positively associated with elevations in plasma ceramides. Twenty-one multiparous Holstein cows were grouped according to body condition score (BCS) at d -30 prepartum as lean (BCS <3.0; n = 10) or overweight (BCS >4.0; n = 11). Blood was collected at d -30, -15, -7, and 4, relative to parturition. Circulating FAC and ceramide levels were determined using liquid chromatography and tandem mass spectrometry. To investigate the potential contributions of sphingomyelin (SM) hydrolysis to ceramide accrual, we also determined plasma SM levels during the peripartum period. Data were analyzed under a mixed model with the fixed effects of adiposity and time, and the random effect of cow. Relative to lean cows, overweight cows had elevated FAC during the transition from gestation to lactation. Circulating FAC levels were positively associated with FA, ceramide, and dihydro-SM levels. Although circulating FAC levels increased in all cows during the peripartum, enhanced prepartum adiposity contributed to a greater rise in plasma FA and FAC. Our results support on-going efforts to determine whether altered mitochondrial FA processing promotes the accumulation of the insulin resistance biomarker ceramide in blood and liver.

The dairy industry can benefit from low crude protein (CP) diets due to reduced N excretion, but shortages of Met, Lys, and His may limit milk protein synthesis. We studied the effect of incremental amounts of rumen-protected (RP)-His on plasma and muscle AA profile, nutrient utilization, and yields of milk and milk true protein in dairy cows. Eight multiparous Holstein cows (130 ± 30 d in milk) were randomly assigned to treatment sequences in a replicated 4 × 4 Latin square design with 28-d experimental periods. Treatments included a basal diet composed (dry matter basis) of 50% corn silage, 15% haylage, and 35% concentrate supplemented with 0, 82, 164, and 246 g/d of RP-His and 11 g/d of RP-Met. Milk, plasma, and muscle samples were collected weekly or every other week during all 4 periods, whereas spot urine and fecal grab samples were taken only in wk 4 of each period. Data were analyzed individually by week using linear, quadratic, and cubic orthogonal polynomials and repeated measures. Plasma His increased linearly with RP-His during wk 1 (30.3 to 57.2 µM) to wk 4 (33.2 to 63.1 µM). Plasma carnosine increased linearly with supplemental RP-His except in wk 2. No treatment effect was observed for plasma 3-methylhistidine except a quadratic effect in wk 3. Inclusion of RP-His showed linear effects on muscle His in wk 2 (20.1 to 32.5 µM) and 4 (20.3 to 35.5 µM). Whereas muscle anserine and carnosine concentrations were not affected by treatments in wk 4, anserine responded quadratically and carnosine showed a trend for a quadratic response to RP-His in wk 2. During wk 4, treatments did not affect urinary excretion of total purine derivatives, as well as dry matter intake and milk concentrations of fat and true protein. In contrast, milk yield tended to increase linearly (31.2 to 32.7 kg/d) and milk true protein yield responded linearly (0.93 to 0.98 kg/d) and tended to increase quadratically to RP-His supplementation in wk 4. Also, milk urea-N (11.7 to 12.9 mg/dL) and urinary excretion of urea-N (23.7 to 27.0% of N intake) increased linearly with feeding RP-His in wk 4. Overall, RP-His was effective to enhance plasma and muscle concentrations of His and milk protein synthesis. Elevated milk urea-N and urinary excretion of urea-N suggest that plasma His may have exceeded the requirement with excess N converted to urea in the liver. Future research is needed to determine the bioavailability of RP-His supplements to improve the accuracy of diet formulation for AA.

Co-supplementation of methyl donors may lower hepatic lipid content in transition cows. To define the ability of methyl donor supplementation (MDS) to reduce hepatic lipid content and modify the plasma lipidome, 30 multiparous Holstein cows (2.04 ± 0.69 lactations; 689 ± 58 kg of body weight; 3.48 ± 0.10 units of body condition score) were fed a ration with or without rumen-protected methyl donors (22 g/d of Met, 10 g/d of choline chloride, 3 g/d of betaine, 96 mg/d of riboflavin, and 1.4 mg/d of vitamin B 12 ) from d −28 before expected calving through d 14 postpartum. Cows were randomly enrolled based on predefined selection criteria (body condition score and parity). Base diets without MDS were formulated for gestation (15.4% crude protein with a predicted Lys-to-Met ratio of 3.25; 1.44 Mcal of net energy for lactation/ kg of dry matter) and lactation (16.6% crude protein with a predicted Lys-to-Met ratio of 3.36; 1.64 Mcal of net energy for lactation/kg of dry matter). Blood sampling occurred from d −28 relative to expected calving through d 14 postpartum. Liver tissue was biopsied at d −28 relative to expected calving and on d 5 and 14 postpartum. In addition to routine analyses, serum AA concentrations on d 10 and 12 were quantified using mass spectrometry. Plasma triacylglycerol (TAG) and cholesteryl esters (CE) were qualitatively measured using time-of-flight mass spectrometry. Data were analyzed using a mixed model with repeated measures. Dry matter intake and milk yield were not modified by MDS. The transition from d −28 relative to expected parturition to d 14 postpartum was characterized by increased plasma fatty acid (0.15 to 0.71 mmol/L) and β-hydroxybutyrate (0.34 to 0.43 mmol/L) levels and liver lipid content (3.91 to 9.16%). Methyl donor supplementation increased the serum Met level by 26% and decreased the serum Lys-to-Met ratio by 21% on d 10 and 12, respectively. Moreover, the increase in hepatic lipid content from d 5 through 14 postpartum was suppressed with MDS relative to control (3.57 vs. −0.29%). Dietary MDS modified the TAG and CE lipidome. For example, MDS increased plasma TAG 46:3 (carbon number: double bond) by 116% relative to control cows on d 5 postpartum. Moreover, MDS tended to increase plasma CE 34:6. In contrast, MDS lowered plasma TAG 54:8 by 39% relative to control cows on d 5 postpartum. We concluded that in the absence of gains in dry matter intake and milk and milk protein yields, dietary MDS slows the progression of hepatic lipid accumulation and modifies the plasma TAG lipidome in transition cows.