Grasslands: A Source of Secondary Metabolites ... - ACS Publications

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Grasslands: A Source of Secondary Metabolites for Livestock Health Anne Poutaraud,*,† Alice Michelot-Antalik,§ and Sylvain Plantureux§ †

Laboratoire Agronomie et Environnement, INRA, UMR 1121, Colmar, 29 rue de Herrlisheim, F-68021 Colmar Cedex, France Laboratoire Agronomie et Environnement, Université de Lorraine, UMR 1121, 2 Avenue de la forêt de Haye - TSA 40602, F-54518 Vandœuvre-lès-Nancy Cedex, France

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ABSTRACT: The need for environmentally friendly practices in animal husbandry, in conjunction with the reduction of the use of synthetic chemicals, leads us to reconsider our agricultural production systems. In that context, grassland secondary metabolites (GSMs) could offer an alternative way to support to livestock health. In fact, grasslands, especially those with high dicotyledonous plant species, present a large, pharmacologically active reservoir of secondary metabolites (e.g., phenolic compounds, alkaloids, saponins, terpenoids, carotenoids, and quinones). These molecules have activities that could improve or deteriorate health and production. This Review presents the main families of GSMs and uses examples to describe their known impact on animal health in husbandry. Techniques involved for their study are also described. A particular focus is put on antioxidant activities of GSMs. In fact, numerous husbandry pathologies, such as inflammation, are linked to oxidative stress and can be managed by a diet rich in anti-oxidants. The different approaches and techniques used to evaluate grassland quality for livestock health highlight the lack of efficient and reliable technics to study the activities of this complex phytococktail. Better knowledge and management of this animal health resource constitute a new multidisciplinary research field and a challenge to maintain and valorize grasslands. KEYWORDS: grasslands, secondary metabolites, anti-oxidant, plants, chemical composition, animal health

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INTRODUCTION Agricultural practices need to turn toward alternative, more environmentally friendly food production for more sustainable agriculture. Furthermore, the need to restrain costs has led to decreased use of medicines and concentrates in animal husbandry. Natural sources of secondary metabolites (SMs) from permanent grasslands might contribute to limit pharmaceutical input and improve animal health. Grasslands represent 30% of the agricultural area in Europe.1 However, permanent grassland acreage has declined steadily over the past 30 years in Europe. The European Union encourages grasslands maintenance2 because of its economic and environmental importance in low-cost forage, landscape, soil fertility, air and water quality, carbon sequestration, and flora and fauna biodiversity conservation. Therefore, grasslands could be of great importance for the development of innovative thinking in “metabolic” and “ecosystemic” approaches.3 In fact, the use of synthetic chemicals could be reduced by the therapeutic potential of plants to treat chronic and recurrent diseases and to stimulate the immune system and growth. This is of importance in the context of antibiotic resistance and the prohibition of the use of antibiotics as growth promoters in farming systems in the European Union since 2006.4 According to the World Organisation for Animal Health, 30% of the production of animal products is currently lost due to diseases, infectious or not, at the farm level in Europe as well as around the world. In that context, improved valorization of grassland secondary metabolites (GSMs) is of interest.5−7 Formerly used as a traditional source of medicinal plants, grasslands offer a huge reservoir of SMs. Indeed, many existing drugs originated from grasslands (e.g., aspirin from Filipendula ulmaria L. and colchicine from Colchicum autumnale L.). These therapeutic molecules can also contribute to quality products © 2017 American Chemical Society

and human health. For example, intake of plant phenolic compounds by cattle decreases plasma and meat lipoperoxidation.8,9 GSMs are also known to promote livestock health, as in the case of condensed tannins (CTs), which present anthelmintic activity against some gastrointestinal nematodes.10 However, some GSMs, such as numerous alkaloids, are highly toxic, and the effects of others on health remain unknown, in part because animal health is a multifactorial and complex concept that is difficult to measure. Animal health is often considered from the point of view of productivity. Maxin et al. (2015)11 presented criteria of interest related to animal health, such as digestive pathologies (e.g., acidosis, bloat), parasitism, and the risk of poisoning. Numerous pathologies and various livestock stresses, such as heat and cold environment and physical, chronic, or nutritional diseases, strongly influence animal health by inducing oxidative stress. Oxidative stress is a physiological condition linked to an imbalance between concentrations of reactive oxygen species (ROS) and anti-oxidants. However, excessive ROS accumulation will lead to cellular injury, such as damage to DNA, proteins, and lipid membranes, which is implicated in the development of many diseases. Husbandry conditions induce oxidative stress, meaning a high production of ROS which could be counterbalanced by intake of anti-oxidants.12 Thus, based on their anti-oxidant properties, GSMs can prevent acute pathologies.13−16 The improvement of livestock breeding diets has focused on primary metabolites for rapid production and simplification of Received: Revised: Accepted: Published: 6535

April 13, 2017 July 13, 2017 July 13, 2017 July 13, 2017 DOI: 10.1021/acs.jafc.7b00425 J. Agric. Food Chem. 2017, 65, 6535−6553

Review

Journal of Agricultural and Food Chemistry

Plants elaborate a vast array of SMs, which have evolved to confer selective advantages against biotic and abiotic environmental stresses.25 Diverse arrays of over 100 000 of these molecules have been isolated from higher plants.26 Generally defined in opposition to primary metabolites, delineation between these two categories of molecules is not always easy. In fact, SMs are derived from primary metabolites, especially from three main pathways: (1) the shikimate pathway for phenylpropanoids (e.g., flavonoids, coumarins, cinnamic and benzoic acids, aromatic volatile molecules) and alkaloids; (2) the mevalonate and deoxyxylulose pathways for saponins, carotenoids, and terpenoids; and (3) the acetate pathway for anthraquinones.27 SM production is often low (less than 1% dry weight) but in certain cases can reach 10%. These molecules are constitutive in the plant and/or inducible by biotic (e.g., pathogens) and abiotic (e.g., climatic conditions) stresses.25,28 SMs are low-molecular-weight molecules and can be lipo-soluble, water-soluble, and/or volatile. Grassland plant species emit volatile organic compounds (VOCs), which are defined as organic molecules with a high vapor pressure at ordinary room temperature (e.g., monoterpenes, coumarins). VOCs are numerous, varied, and ubiquitous. For example, essential oils are composed of several hundreds of aromatic VOCs. SMs exhibit variations of composition and content among plant organs and with time and are not necessarily synthesized by all plant cells or consistently over time. Most plants concentrate their SMs in certain organs or parts of the plant. However, the sites of maximum metabolite accumulation are not necessarily the sites of synthesis. Phenolic Compounds. Phenolic compounds are a large SM family. More than 8000 molecules are currently known.29 They are involved in plant responses to various biotic and abiotic stresses. They are generally localized in cells (insoluble phenolics) or vacuoles (soluble). In vacuoles, they are conjugated with sugar or organic acids to increase their solubility and are highly suspected to play a ROS-mitigating role.30 Phenylalanine, which is produced by the shikimate route, is the precursor of phenylpropanoid metabolism, which, in turn, feeds the diverse specific flavonoid pathway.31 Some polyphenol biosynthesis pathways are well known (i.e., flavonoid quercetin), but others, such as those of CTs, remain unclear.32 Phenolic compounds range from simple phenolic molecules to highly polymerized compounds such as CTs. They are classified depending on their carbon skeleton: C6, simple phenols, benzoquinone (catechol); C6−C1, hydroxybenzoic acids (p-hydroxybenzoic acid); C6−C2, acetophenones and phenylacetic acids; C6−C3, hydroxycinnamic acids (caffeic acid); C6−C4, hydroxyanthraquinones (physcion); C6−C2− C6, stilbenes (resveratrol); C6−C3−C6, flavonoids (quercetin); (C6−C3)2, lignans (matairesinol); (C6−C3−C6)2, biflavonoids (agathisflavone); (C6−C3)n, lignins; and (C6− C3−C6)n, CTs.33 The main GSM hydroxycinnamic acids are neochlorogenic, chlorogenic, and dicaffeoylquinic acids.34 Ferulic acid and pcoumaric acid are widely distributed in graminaceous plant cell walls; values of up to 2% in cell wall have been reported.35 Some hydroxycinnamic acids exhibit strong anti-oxidant properties and affect the expression and activity of enzymes involved in the production of inflammatory pathway mediators.36 The biological properties of phenolic compounds are greatly influenced by digestive processes and metabolism,37 which differ between monogastric and polygastric organisms.

agricultural practices, whereas GSMs were essentially considered toxins.17 The term “forage quality” encompasses nutritive value, including high digestibility or metabolizable energy, crude protein content,18 and amounts of fiber and minerals, as well as forage sanitary status linked to the absence of dust, allergens, noxious weeds, nitrates, prussic acid, ergot alkaloids, and insect infestation. Although primary metabolites are well known to be essential for energy and growing livestock,2 SMs are increasingly recognized as a means to improve animal health.6,7 In fact, the input of primary metabolites has been extensively studied and is well documented in feed tables. However, new quality criteria have appeared. In Northern European countries, the dietary habits of cattle (NorFor) include anti-oxidant molecules such as vitamins A and E.19 Synergistic effects have been shown in the case of nonenzymatic lipoperoxidation, which impacts animal health,20 but there are still no quality criteria for GSMs involved in animal health in feed tables. An analysis based on the collection of expert opinion highlighted the need for research to identify and measure criteria evaluating the impact of forage nutritional characteristics on animal health.11 This is a novel but complex issue due to the large number of grasslands and forage types, molecules, and animal metabolisms. In fact, the impact of GSMs on animal health depends significantly on animal physiological status, production, and species (cattle, horses, goats, sheep), particularly their digestive systems. GSMs enable health through nutrition.21 This relationship is now well documented for human health but remains highly complex.22 A new field of research is opening with the interest in the valorization of GSMs in livestock health. There is a need to develop tools to quantify permanent grassland forage quality precisely and to identify the key factors determining the value of permanent grasslands.2,11 The aim in this field of research would be to establish global indicators to develop tools to manage grasslands (i.e., biodiversity, stage, and interactions between plants and their environment). This Review focuses on the complex topic of GSMs linked to animal health. Three aspects will be treated: (1) an overview of the main families of SMs found in grasslands species, (2) an inventory of the impacts of these compounds on animal health (large herbivores), and (3) approaches and techniques used to study GSMs and their activities on animal health, with a particular emphasis on anti-oxidants.

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GRASSLAND SECONDARY METABOLITES There are a great variety of grasslands with various levels of biodiversity, characterized by species richness (R). Grasses and legumes (R between 1 and 20 species) dominate temporary grasslands (i.e., sown) and intensified permanent grasslands (i.e., highly fertilized or grazed). Extensified permanent grasslands (semi-natural grasslands) generally contain more species (R between 20 and 100 species), especially dicotyledonous (legumes and forbs). Botanical families in permanent grasslands (% of biomass) comprise approximately 85% monocotyledonous species and 15% dicotyledonous (legumes) and others (7%).23 Another national survey of 200 permanent grasslands in France reported the following contributions of plant families in the grassland biomass: Poaceae 70%, Fabaceae 12%, Asteraceae 5%, and others (i.e., Ericaceae, Ranunculaceae, Iridaceae, Cyperaceae, Plantaginaceae) 13%.24 This diversity in grassland types and flora results in a variety of GSM amounts and compositions. 6536

DOI: 10.1021/acs.jafc.7b00425 J. Agric. Food Chem. 2017, 65, 6535−6553

Review


and thus are difficult to characterize. Tannins can precipitate gelatin and other proteins.49 This group contains polyhydroxyflavan-3-ol oligomers and polymers linked by carbon−carbon bonds between flavanol subunits.50 They can be classified into two subgroups, CTs (also called proanthocyanidins) and hydrolyzable tannins.51 Both classes have been described as having adverse or beneficial effects, especially on feed digestibility and animal performance, depending on the tannin concentration and structure, plant source, animal species, and physiological state and diet.10 They have often been described as anti-nutritional factors due to depression of feed intake and decreased palatability, as well as reduction of dry matter (DM) and fiber and nitrogen digestibility, but are now described as molecules presenting beneficial effects on animals and the environment.52 The term “condensed tannin” is derived from the condensation of flavan-3-ol units and their capacity to bind with protein to preserve (tan) leather. They are monomeric or oligomeric end products of the flavonoid pathway or products of the branch pathway of anthocyanin biosynthesis (flower pigments).32 CTs are common in forage leaves and in seed coats and foliage of legumes. They are usually absent or have very low concentrations in foliage of Poaceae. CTs are confined to intracellular vacuoles and are essentially unreactive until released by cell rupture, resulting in extensive binding with proteins.28,53 Some temperate legumes produce CT in foliage, such as lotus (Lotus spp.), sainfoin (Onobrychis viciifolia Scop.), sulla (Hedysarum coronarium L.), as do other species such as dock (Rumex obtusifolius L.). These forages perform well under conditions of average and poor soil fertility and can be tolerant of acid soils.53 Another class of tannins is hydrolyzable tannins. It consists, as their name indicates, of molecules that are easily hydrolyzed with acid, alkali, and hot water and by enzymatic action, yielding polyhydric alcohol and phenylcarboxylic acid. They are composed of gallic acid and its dimeric condensation product, hexahydroxydiphenic acid, esterified to a polyol, which is mainly glucose. These metabolites can oxidatively condense to other galloyl or hexahydroxydiphenic molecules and form high-molecular-weight polymers.54 Hydrolyzable tannins are essentially present in tree leaves.53 They have been shown to be effective antagonists against viruses, bacteria, and eukaryotic micro-organisms.55 Terpenoids. This largest family of plant SMs (approximately 16 000)40 is also called isoprenoids because all of these molecules originate through the condensation of the universal five-carbon precursors: isopentenyl diphosphate and dimethylallyl diphosphate. Monoterpenoids (C10) are formed from two such units, whereas sesquiterpenoids (C15) are formed from three units. They tend to accumulate in certain species of grassland families, such as Labiatae, Rutaceae, and Apiaceae.56 Some of these aromatic compounds are deleterious for herbivores, such as sesquiterpene lactones, which are widely found in the Asteraceae family. Iridoids represent a large group of monoterpenoid compounds. Some herbivores avoid deleterious nutritional effects by absorbing the terpenes from the stomach and small intestine and then detoxifying them via the liver.56 Several medicinal plants rich in iridoid glucosides have been used to treat infections, rheumatism, and inflammation (Plantago sp., Scrophularia nodosa).40 Many terpenoids are essential oils with a strong odor. Terpenoid phenols (thymol, carvacrol) present in aromatic plants such as thyme or oregano are highly anti-infectious molecules; they disrupt the lipid bilayer structure of bacterial membranes and denature bacterial proteins. Furthermore,

Flavonoids are a large class of SMs encompassing more than 4000 structures38 and are widely distributed in the plant kingdom and grassland species (Figure 1). Numerous studies of

Figure 1. Basic structure and numbering system of flavonoids.

these flavonoids and their glycosides have shown (e.g., kaempferol) a wide range of pharmacological activities, including anti-oxidant (in vitro as well as in vivo), antiinflammatory, anti-microbial, anti-cancer, cardio-protective (by inhibiting platelet aggregation and protecting against oxidation of low-density lipoprotein), neuro-protective, anti-diabetic, antiosteoporotic, estrogenic/anti-estrogenic, anxiolytic, analgesic, and anti-allergic activities.39 In a study of phenolic compounds in 43 grassland species of a permanent mountain pasture in the Massif Central (France), Fraisse et al. (2007)34 demonstrated that they are mainly composed of dihydroxycinnamic derivatives (3,5-di-O-caffeoylquinic, chlorogenic, and 1,5-di-Ocaffeoylquinic acids) and flavonoids in lesser proportions (schaftoside, homo-orientin, luteolin-7-glucoside, luteolin-7rutinoside, and apigenin). The identified compounds accounted for half of the total quantified amount. This total amount reached approximately 31 g/kg DM in the first two harvest stages and then decreased to 19 g/kg DM. Some polyphenols were peculiar to a few species, and others were ubiquitous. Coumarins and furo- and pyranocoumarins are common phenylpropanoids, and more than 700 structures have been determined. Coumarins can reach concentrations of up to 2% in plants and are present in certain genera of Apiaceae (most genera), Fabaceae (e.g., Melilotus of f icinalis (L.) Lam.), Poaceae (e.g., Anthoxanthum odoratum L.), and Rubiaceae (e.g., Galium odoratum L.).40 Many coumarins have pharmacological use as anti-inflammatory agents.41 Sweetclover (Melilotus off icinalis (L.) Lam.) and sweet vernal (Anthoxanthum odoratum L.)42 are forages with therapeutic properties essentially linked to the presence of coumarin (1,2-benzopyrone). Extensive studies have shown that coumarin possesses dose-dependent antiinflammatory and anti-edema activities and improves blood circulation. However, the content of coumarin in fresh plants is very low. Like other phenylpropanoids, coumarin arises from the metabolism of phenylalanine via cinnamic acid, i.e., pcoumaric acid. Free coumarin is derived from β-D-glucosyl trans- and cis-O-hydroxycinnamic acids (β-GOHCA), which are stored in vacuoles.43,44 trans-β-GOHCA is isomerized under UV light to the cis form; this molecule is hydrolyzed by an inter-cellular and specific β-glucosidase to cis-OHCA, which is lactonized spontaneously to produce free coumarin. The reaction occurs upon disruption of the tissue, generally during harvest and drying.43 Furthermore, coumarin can be rapidly transformed into dicoumarol (4-hydroxycoumarin) during long drying under low temperatures and high humidity. In fact, these conditions improve the activities of micro-organisms responsible for the formation of dicoumarol. This vitamin K antagonist is a powerful anti-coagulant that is highly toxic in livestock.45−48 Tannins are a heterogeneous group of polyphenolic polymers of varying molecular weight (larger than 500) and complexity 6537


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Table 1. Examples of Grassland Secondary Metabolites with Potential Positive Activities on Livestock Health and Their Frequency in Grasslands and Reported Dry Weight Content from the Literature subclass

GSM

examples of grassland plants containing the GSM

main activity

flavonols

kaempferol myricetin quercetin

Phenolic Compounds hepato-protective Origanum vulgare L. anti-bacterial Equisetum arvense L. anti-oxidant anti-oxidant Sonchus oleraceus L. anti-oxidant Knautia arvernensis L. Achillea millefolium L. anti-oxidant Thymus vulgaris L. anti-bacterial anti-viral acetylcholinesterase Achillea millefolium L. inhibitor anti-oxidant Trifolium pratense L. anti-oxidant Trifolium pratense L. anti-oxidant Trifolium repens L.

flavonol glycosides

rutin

anti-oxidant

flavones

apigenin

HCAc

caffeic acid

chicoric acid dihydroxycinnamic acid derivatives, (e.g., chlorogenic acid) HCA derivatives

rosmarinic acid

luteolin

daidzein thymol

reported contentb (g/kg DM)

0d 2

5.56 ± 0.003

0d 0d 45 2

12.5 ± 1.3 0−36.2 0.39−33.1 23.5 ± 0.5 ap

45 58 58 70

0.8 ± 0.02 fl 1.4 ± 0.02 fl 0−1.16 10.3 ± 0.2 fl 45.8 ± 1.1 fl 19.94 ± 12.07 yl 24.5 l

anti-bacterial

70 3 0d 2

anti-oxidant

Mentha arvensis L. (Lamiaceae)

1

0.8

anti-bacterial anti-oxidant

Trifolium pratense L. Thymus vulgaris L.

58 0d

16.7 ± 0.8 fl 1.12 ap

1

0−9.4

12

0−6.6

0d

7−11

Rumex acetosella L. (Polygonaceae) anti-microbial Galium verum L. (Rubiaceae) improve reproductive performance anti-oxidant Thymus vulgaris L. anti-bacterial

carvacrol

anti-oxidant anti-bacterial

diterpene phenolics

carnosic acid

sesquiterpene lactones

lactucin 8-deoxylactucin lactucopicrin

anti-oxidant anti-microbial anti-nematodes

xanthophylls

lutein violaxanthin

anti-oxidant

refs 183 184 185 186 34 187 188 189 190

Trifolium repens L. Onobrychis viciifolia Scop. Amaranthus hybridus L. Thymus serpyllum L.

anti-oxidant

isoflavones terpenoid phenols

species frequencya (%)

13 13 193 13 13 194 85 191 183 189 34 183 192 34 34 72 119 195 183 104 183 104

Thymus vulgaris L.

0d

Terpenoids Salvia verticillata L.

0d

4.4

69

Inula salsoloides L. Cichorium intybus L.

0d 0d

0.42−3.65 0.43−3.96 0.53−9.36

102 196 174

Carotenoids Lolium perenne L. (Poaceae)

69

2.08 0.49

63

a

Species frequency corresponds to the percentage of grasslands where the species is present. Data from the e-FLORA-sys Grassland Database (http://eflorasys.univ-lorraine.fr/). bap, aerial part; fl, flowers; l, leaves; yl, young leaflet. cHCA = hydroxycinnamic acid. dSpecies present but lower than 1% frequency.

Carotenoids. The 600 carotenoid structures are split into two classes: xanthophylls and carotenes. They are fat-soluble yellow, orange, and red pigments that participate in photosynthesis in higher plants, algae, bacteria, and fungi.63 Forage represents the main source of carotenoids for ruminants.64 The literature highlights a large diversity of forage carotenoids, such as neoxanthin, violaxanthin, zeaxanthin, lutein, all-E-β-carotene, 9Z- and 13Z-β-carotene, and, occasionally and in small

carvacrol exhibits strong anti-oxidative properties as well as hydrophobic properties associated with the substituted aromatic ring and hydrophilic properties associated with the phenolic OH group. Numerous studies have reported antioxidative, anti-inflammatory, anti-bacterial, anti-viral, antifungal, anti-protozoal, anti-carcinogenic, anti-diabetic, antinociceptive, cardio-protective, and neuro-protective properties of carvacrol.57 6538


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Table 2. Examples of Grassland Secondary Metabolites Toxic for Livestock and Their Frequency in Grasslands and Reported Dry Weight Content from the Literature subclass

GSM

flavonols

quercetin

flavones

apigenin luteolin biochanin A daidzein formononetin

isoflavones

genistein coumestan

coumestrol

furanocoumarins

psoralen

benzofuran ketones

tremetone and derivatives

naphthodianthrones

hypericins

iridoid glycosides diterpenes

catalpol, aucubin delphinine, nudicauline, staphisine

examples of grassland plants containing the GSM

main activity

Phenolic Compounds phytoestrogen, temporally or Medicago sativa L. permanent infertility phytoestrogen Medicago sativa L. phytoestrogen Medicago sativa L. phytoestrogen Trifolium subterraneum L. phytoestrogen Trifolium pratense L. phytoestrogen Trifolium subterraneum L. Trifolium pratense L. phytoestrogen Trifolium subterraneum L. Trifolium pratense L. phytoestrogen Medicago sativa L. Trifolium repens L. photosensitization by contact Biserrula pelecinus L. Ruta graveolens L. Psoralea cinerea L. dehydration Isocoma plurif lora Greene muscle fatigue Ageratina altissima L. photosensitization by ingestion Hypericum perforatum L.

species frequencya (%)

indicative content (g/kg DM)

2

30−75

198

2 2 1 58 1 58 1 58 2 70 − − − − − 0

55−225 15−85

198 198 53

0.6−1.13 0−0.3 50−135

4 lv 137 fr

5 fl

120, 201

19.2 ± 0.66

213 121

norsesquiterpene glucosides

ptaquiloside

indolizidines

swainsonine

locoism

locoweed (Fabaceae family) Oxytropis sericea Nutt. Astragalus lentiginosus Dougl.

−

0−4

isoquinoline tropolonics

colchicine and derivatives

Colchicum autumnale L.

10

1−4.5

piperidines

coniine, γ-coniceine palustrine N5-formylpalustrine palustridine N5-acetylpalustrine N5-formylpalustridiene coniine, γ-coniceine heliosupine seneciphylline senecionine jacozine, jacobine, jacoline jaconine jervine cyclopamine scopolamine hyoscyamine atropine

colic, abdominal pain, diarrhea, fetid feces with tenesmus; death occurs from cardiorespiratory collapse fetal abnormalities intoxication, lack of appetite, diarrhea, or neurological disorders

Conium maculatum L. Equisetum palustre L.

0 2

10 13.3−16.7 (FW)

50 0

53 193 53 193 198 53, 193 199 200 197

Terpenoids toxic to generalist herbivores Plantago lanceolata L. Delphinium sp. skin irritation, nausea, disturbance of gastrointestinal tract and kidneys allergy/dermatitis Ranunculus acris L. Caltha palustris L. acute hemorrhagic syndrome Pteridium aquilinum L.

sesquiterpenes

refs

59 4 1

0−5.79

214 215 211,212

Alkaloids

pyrrolizidines

steroidal alkaloids tropanics

thioglucosides enzymes amino acid

thiaminase polyphenol oxidase hypoglycin A

Equisetum arvense L. (Equisetaceae) Conium maculatum L. Cynoglossum of f icinale L. Senecio vulgaris DC. Jacobaea vulgaris L. Jacobaea aquatica L.

fetal abnormalities poisoning hepatotoxic photosensitization CNS derangement

chronic lethal dose: 2.5 mg/kg body weight embryonic death Veratrum sp. lengthened postpartum interval anti-cholinergic effects Datura stramonium L.

Glucosinolates hepatotoxicity Brassica napus L. photosensitization inactivation of thiamine (vitamin B1) Pteridium aquilinum L. high fever Equisetum palustre L. Acer pseudoplatanus L. 6539

202 203 120 148 120, 138, 204 122, 205 124

0.15 (FW)

0 − 2

5−22 6.3−20.2

122 120, 206 206 120 207 58 122

0 0

1 sd

135 120 208

0

9.6

209 210 120

0.04−2.81 sd

216


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Journal of Agricultural and Food Chemistry Table 2. continued a

Species frequency corresponds to the percentage of grasslands where the species is present. Data from the e-FLORA-sys grassland database (http:// eflorasys.univ-lorraine.fr/). bMost abundant and toxic: lv, leaves; sd, seeds.

quantities, β-cryptoxanthin and antheraxanthin. Susceptible to drying, these molecules present a higher content in grass silage than in hay.64,65 Carotenoids are liposoluble terpenoids and include provitamin A as well as all-E-β-carotene. In fact vitamin A is formed from β-carotene.66 Twenty-three LC peaks of carotenoids were identified in forages by Chauveau-Duriot et al. (2010);66 the lutein content reached 230 mg/kg, followed by all-E-β-carotene at 60 mg/kg. Composed of long carbon chains (C40 isoprenoid compounds), their conjugated double bounds confer anti-oxidant properties. Carotenoids also present anticancer activities and stimulate the immune system. Alkaloids. Alkaloids (about 27 000) are not a chemically homogeneous group, and generalizations about them are subject to many exceptions.40 They all contain one or several nitrogen atoms, and many, but not all, are basic, as their name indicates. They are derived from amino acids. They are often toxic GSMs. They can be classified into two groups: nonheterocyclic alkaloids and heterocyclic alkaloids. In the first group, the best-known and most problematic GSM is colchicine, an alkaloid with a tropolone nucleus and sidechain nitrogen found in Colchicum spp. and related genera (Liliaceae). The second group contains the important class of indole alkaloids, such as toxins present in grassland fungi (e.g., ergotamine), pyrrolizidine alkaloids (e.g., symphitine from Symphytum spp. or senecionine from Senecio spp.), pyridine alkaloids (e.g., trigoneline from Leguminoseae), tropane alkaloids (e.g., atropine from Atropa spp., scopolamine), isoquinoline alkaloids (e.g., corydaline from Corydalis spp.), quinolizidine alkaloids, which occur particularly in Leguminosae such as Genista tinctoria L., and terpenoid alkaloids (e.g., aconitine from Aconitum spp.). The pyrrolizidine alkaloids of Senecio aquaticus Huds, which grows in wet grasslands, primarily affect the liver and other organs and exhibit carcinogenic potency.58 Alkaloids are commonly found in the grassland orders Chenopodiaceae, Ranunculaceae, Fumariaceae, Fabaceae, Apocynaceae, Solanaceae, and Asteraceae and subfamily Senecioneae.59 Saponins. The word “saponin” is derived from the Latin “sapo”, meaning soap, and saponin-containing plants have traditionally been utilized for washing, such as the genus Saponaria (Caryophyllaceae).60 Saponins are an important group of high-molecular-weight SMs consisting of glycosylated triterpenes and steroids. Steroid saponins are typical of several monocotyledonous families and are less frequent in dicotyledonous families. Triterpene saponins are abundant in several dicotyledonous families, such as Chenopodiaceae, Caryophyllaceae, Primulaceae, and Ranunculaceae.40 Poaceae, including cereals, appears to be generally saponin-deficient, with the exception of oats (Avena spp.).61,62 Saponin biosynthesis is not yet completely understood. Alfalfa contains several medicagenic acid saponins that appear to be responsible for its antinutritional effects. The biological roles of saponins include membrane-permeabilizing, immunostimulant, and hypocholesterolemic properties, and saponins have been found to affect growth and feed intake in animals. These compounds have been observed to kill protozoans, to impair protein digestion and the uptake of vitamins and minerals in the gut, and to act as hypoglycemic agents. These compounds affect animals in both

positive and negative ways.60 Many saponins present antimicrobial activity, suggesting involvement in plant defense. Quinones. Quinones are oxidized derivatives of aromatic compounds. They are widespread plant pigments and include benzoquinones, naphthoquinones, anthraquinones, and polycyclic quinones. Polygonaceae and Rubiaceae produce anthraquinones, especially in glycosylated form in roots.67 Anthraquinones are SMs with systemic toxicity to mammals and induce skin irritation or sensitization. The naphthodianthrone hypericins are phototoxic extended quinones from Hypericum perforatum L.68 Others. Although vitamins and enzymes are not considered SMs, we will mention some here. Some vitamins and enzymes are highly anti-oxidant, act as ROS scavengers, and counteract the damage caused by free radicals. These molecules can interact with phenolic compounds such as vitamin E (a lipidsoluble anti-oxidant that stops the formation of ROS when lipids undergo oxidation and prevent cancer) or vitamin C.66 In a study of 60 species of the genus Salvia, α-tocopherol (an active form of vitamin E) levels were shown to be 2-fold higher in species lacking phenolic diterpenes than in species containing these SMs.69

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GRASSLAND SECONDARY METABOLITES AND HERBIVORE HEALTH Each grassland contains a reservoir of a multitude of known and still unknown SMs, which is also referred to as a “phytococktail”.70 In contrast to primary metabolites, the health value of GSMs is currently difficult to measure and thus badly managed. Indeed, each grassland species contains many SMs with positive and/or negative impacts on health. GSMs use different molecular targets to connect with animals. Many of these receptors have important roles in the central nervous system, such as disturbing the three-dimensional structures of proteins (e.g., alkaloids and some sesquiterpenes), covalent bonding of RNA and DNA (e.g., inhibition of mitosis for colchicine), modifying gene expression and changing membrane permeability and the function of membrane proteins.71 Health-Promoting Molecules. Numerous studies have shown the involvement of GSMs, especially phenolic compounds (e.g., tannins, flavonoids), in a wide range of pharmacological activities, such as anti-inflammatory, antimicrobial, anti-cancer, cardio-protective, neuro-protective, anti-osteoporotic, estrogenic/anti-estrogenic, anxiolytic, analgesic, and anti-oxidant activities in laboratory animals and/or herbivores.38,39 Table 1 presents some GSMs involved in positive activities on herbivore health status. The majority of these GSMs belong to the polyphenol family. None belong to the alkaloid family, which are generally considered toxic and are presented in Table 2. Anti-oxidant. Breathing (oxygen intake) generates the production of energy by cells via the mitochondrial process called oxidative phosphorylation. The production of energy (ATP) is coupled with a reaction in which oxygen (O2) is reduced to H2O. In this reaction, four electrons and four protons are added to O2 to form two molecules of H2O. 6540


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pathways by modulating gene expression in protein and lipid kinase signaling pathways.82 Bravo (1998)54 in her review on polyphenols noted that their efficiency as anti-oxidants greatly depends on their chemical structure. Phenol itself is inactive as an anti-oxidant, but orthoand para-diphenolics have anti-oxidant capacity, which increases with the substitution of hydrogen atoms by ethyl or n-butyl groups.83 Flavonoids (Figure 1) are among the most potent plant anti-oxidants because they possess one or more of the following structural elements involved in antiradical activity: an o-diphenol group (in ring B), a 2−3 double bond conjugated with a 4-oxo moiety, and hydroxyl groups in positions 3 and 5. Quercetin, a flavonol that combines all of these characteristics, is one of the most potent natural anti-oxidants. In addition, the anti-oxidant efficiency of flavonoids is directly correlated with their degree of hydroxylation and decreases with the presence of a sugar moiety (glycosides are not anti-oxidants, whereas their corresponding aglycones are anti-oxidant). For example, flavonoids with multiple hydroxyl groups have high anti-oxidant activity (e.g., quercetin, myricetin, and kaempferol), and the glycosylation of flavonoids reduces their activity (e.g., rutin, myricitrin, and astragalin).84 However, Kraujalis et al. (2013)85 found that rutin was the main radical scavenger in amaranth extracts. Flavonoids are very effective scavengers of hydroxyl and peroxyl radicals, although their efficiency as scavengers of superoxide anion is not yet clear.54 An interesting example of the importance of phenolic compounds in cattle diet was described by Gobert et al. (2011).86 With the aim of protecting animal unsaturated fatty acids from oxidation, different plant extracts rich in polyphenolic compounds (10 g/kg of diet DM per day) were added to the cattle diet in combination with vitamin E. This combination was able to protect cattle from lipoperoxidation (particularly in plasma) via complementary mechanisms of action in the lipoperoxidation chain reaction. The protective anti-oxidant action was probably due to the combination of the hydrophilic properties of polyphenol acting at the initiation step to limit the propagation phase and reduce the quantity of ROS and the lipophilic properties of vitamin E breaking the lipoperoxidation propagation chain.86 The same kind of result was obtained in sheep and goats. These animals fed with 10− 20% pellets rich in phenolic compounds (byproduct of distilled rosemary or thyme) in the diet for several months exhibited higher anti-oxidant stability in meat, a higher concentration of polyphenolic anti-oxidants in meat, a higher concentration of polyphenolic anti-oxidants in milk, a lower susceptibility to oxidative stress in suckling goat kids, and an increased content of polyphenols with anti-oxidant capacity in cheese.87 Thus, the anti-oxidant active components were transferred into the meat without detriment to animal productivity.88,89 Currently, there is no accurate information available on dietary intake of polyphenols for herbivore husbandry. This is of interest because an excess of polyphenols can invert their action and provoke pro-oxidant activities. The switch of some SMs from anti-oxidant to pro-oxidant activity is a conflicting and important topic.90 Flavonoids are known anti-oxidants but can also act as pro-oxidant agents under specific conditions. Thus, kaempferol presents anti-mutagenic activities but also genotoxic effects due to its pro-oxidant effects. This phenomenon is linked to the concentration of the molecule. At low concentrations, kaempferol acts as anti-oxidant, whereas at high concentrations, it may generate ROS and act as a prooxidant that generally induces apoptosis of the cell.39 This pro-

However, when a molecule of O2 gains only one electron, superoxide anion (O2•−) is formed. This potent ROS tends to gain three more electrons and four protons to form H2O; this process involves several reactions and results in the production of other ROS such as hydrogen peroxide (H2O2), hydroxyl radical (OH•), and peroxynitrite (ONOO−). Of the oxygen consumed by mitochondria, 2% is transformed into superoxide radical. The controlled production of ROS has an important physiological role. Basal ROS production is necessary for the cell, and could be involved in cell signaling, but high production of ROS that is not counterbalanced by anti-oxidant defense increases cellular levels of ROS and produces oxidative stress.39 Thus, oxidative stress corresponds to an overproduction of ROS (especially peroxynitrites and hydroxyl radical), which cause oxidative damage to all macromolecules (DNA, proteins, lipids) within the cell. Free radicals are the main cause of more than 60 health problems.72 Oxidative stress has been associated with the deterioration of many physiological functions, such as growth, reproduction, and immunity, and metabolic diseases such as inflammation, hyperglycemia, carcinogenesis cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative disorders, rheumatoid arthritis,73 and parasites.74,75 Anti-oxidants can act at different levels in an oxidative sequence and counterbalance this phenomenon. An anti-oxidant is a substance that, when present at low concentrations compared to an oxidizable substrate, significantly delays or inhibits the oxidation of that substrate.76 Polyunsaturated fatty acids are one of the favored oxidation targets for ROS. Numerous anti-oxidants act as ROS scavengers: non-enzymatic small-molecular-weight molecules such as glutathione, NADPH, thioredoxin, vitamins E and C; SMs and trace metals, such as selenium; and high-molecularweight enzymes such as superoxide dismutase, glutathione peroxidase, and catalase. Thus, anti-oxidant agents can reduce oxidative stress and may play a protective role in the prevention of the formation and action of ROS.77,78 In fact, anti-oxidants may decrease superoxide anion, hydroxyl radical, and peroxynitrite levels, inhibit the activities of enzymes that generate ROS, such as xanthine oxidase, and increase the expression of anti-oxidant enzymes such as superoxide dismutase or catalase.39 The number of publications on this complex topic has increased considerably in the past decade.79 A large body of evidence suggests that the beneficial effects of SMs in livestock might depend on their anti-oxidant functions (reducing activities).80 The presence of double bonds in their structure may trap the ROS (superoxide anion, hydroxyl free radical). Anti-oxidants can be classified physically by solubility into two groups: hydrophilic anti-oxidants, such as vitamin C and a majority of polyphenolic compounds, and lipophilic antioxidants, such as vitamin E and carotenoids.81 The most common anti-oxidants present in grassland plants are vitamins C and E, carotenoids, phenolic compounds, and thiol (SH) compounds. Plant volatile molecules such as the monoterpenoid phenol carvacrol also exhibit high anti-oxidant properties.57 Phenolic compounds present anti-oxidant capacity and contribute to the defense mechanisms of plants against oxidative stress damage. Their structure allows them to react with free radicals and chelate metals. They prevent oxidation by rapid donation of a hydrogen atom. Intermediate phenoxy radicals are stable and may end oxidative chain reactions.54 They could also inhibit or stimulate endogenous anti-oxidant 6541


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Teladorsagia/Ostertagia circumcincta) and the trematodes Fasciola hepatica (the liver fluke) and rumen fluke species (Paramphistomum spp. and Calicophoron spp.). Other nematodes, such as Cooperia spp., Chabertia spp., and Oesophagostomum spp., can be important in some circumstances but usually as part of a mixed burden.94,95 Classic treatments against parasites are based on synthetic macrocyclic lactones such as ivermectin, but resistance is now a common problem in nematode parasites of livestock.96 Infection induces oxidative stress.74 Thus, goats naturally infected with Anaplasma ovis show a decrease in total anti-oxidant capacity (TAC) and superoxide dismutase (SOD) activity.75 The main anthelminthic GSM family is CT. Numerous studies present their activities. (Please also see the section Benefits and Adverse Function of SMs: Example of Condensed Tannins.) Compared to the large number of studies investigating effects of CT against parasitic nematodes, there are fewer reports on the anthelmintic activities of other SM families as flavonoids and terpenes.97 The most common flavonoids for which antinematode effects have been investigated are flavones and flavonols. Luteolin-7-O-glucoside and quercetin-3-O-glucoside were identified as the active compounds from Vicia pannonica and showed a comparable efficacy in inhibiting the motility of Trichostrongylosis colubriformis larvae in rumen fluid.98 Other SM families such as terpene peroxide (e.g., ascaridole from Chenopodium sp.,99,100 sesquiterpenes lactones (e.g., Cichorium intybus,101 Inula sp.102) have shown anthelminthic activities. Anti-microbial. Infectious diseases of livestock are a major health problem, and their control is crucial for animal breeding.103 Numerous constitutive and inducible SMs play important roles against pathogen invasions (e.g., flavonoids, tannins, essential oils, saponins).5,104 Flavonoids are traditionally used to treat infectious diseases. In fact, plants containing kaempferol and its glycosides present anti-bacterial, anti-viral, anti-fungal, and anti-protozoal activities. 39 Furthermore, kaempferol can act in synergy with antibiotics against antibiotic-resistant bacteria,39 as can some volatile molecules (terpenes, alcohol, aldehydes, ketones, oxides)87 present in numerous grassland plants, such as chamomile and Achillea millefolium L. Essential oils comprising a phenol moiety (carvacrol, thymol) present high anti-microbial activities and include VOCs present in grasslands. These lipophilic compounds interfere with the double-layer phospholipid microbial membrane. Compared with Gram-negative bacteria, which feature an outer membrane containing lipopolysaccharides, Gram-positive bacteria are more susceptible to essential oils. However, thymol is active against Gram-positive and Gram-negative bacteria.27 Essential oils enhance antibiotic activity by disrupting the bacterial membrane, thus facilitating antibiotic penetration, induction of enzyme inhibition, reduced ATP and DNA synthesis, and alteration of metabolic pathways.105 Treating Metabolic Disorders. Nutrition is essential in preventing metabolic disorders. Common problems encountered in farming are bloat (pathology often associated with feeding highly fermentable protein-rich forages to ruminants) and acidosis (increased acidity in the blood and other body tissues due to incorrect diet or feeding). Bloat generally occurs when plants degrade too fast in the rumen.6 The single most important plant factor predisposing cattle to bloat is the presence of highly soluble plant proteins, especially ribulose1,5-bisphosphate carboxylase/oxygenase. These ubiquitous and abundant proteins are particularly associated with the leaves of

oxidant capacity may be linked to the formation of a phenoxyl radical after hydrogen atom donation or the reduction of iron and copper ions (these reduced metals may participate in the formation of hydroxyl radicals and lipid peroxidation).39 Thus, plants rich in polyphenols could represent interesting anti-oxidant sources, and intake of such plants by livestock might be an efficient means to enhance plasma total antioxidant status. However, the use of these plants in livestock diets requires further experiments, particularly to determine the optimum dose of administration and to characterize the bioactive molecules.8 Anti-inflammatory. Inflammation is a physiological immune defense reaction of the body to causes such as bacterial or viral infections, burns, chemical irritations, or allergies. After tissue injury, a multifactorial network of chemical signals initiates and maintains a host response designed to heal the damaged tissue. The activation and migration of leukocytes to the site of damage and the release of growth factors, cytokines, and reactive oxygen and nitrogen species play crucial roles in the inflammatory response.39 Chronic inflammation occurs if inflammation persists for a long period of time, potentially causing a predisposition to neurological, auto-immune, and cardiovascular diseases.91 Some SMs presenting anti-inflammatory properties can act directly by limiting the expression of enzymes involved in inflammation, such as nuclear factor kappa B, which increases the expression of pro-inflammatory cytokines or chemokines as well as cyclooxygenases or lipoxygenases. GSMs can act indirectly by decreasing ROS. Numerous in vitro and in vivo studies have shown anti-inflammatory activities of several phenolic compounds.91 Flavonoids such as kaempferol and quercetin present strong anti-inflammatory properties, and their transfer into plasma after oral ingestion at nanomolar concentrations has been shown.39 A recent study92 of twoweek daily quercetin supplementation in horses (10 mg/kg body weight) showed a significant increase in total plasma flavonols and plasma concentrations of anti-inflammatory cytokines (interleukin-10, interleukin-1 receptor antagonist). In horses, quercetin is rapidly absorbed from the gastrointestinal tract and undergoes intensive metabolic transformation, resulting in maximum total flavonol concentrations within 1 h after the ingestion of a single quercetin dose in the test meal. Thus, quercetin may be useful for controlling inflammatory disorders in horses. Anti-cancer. Cancer is caused by DNA alterations. Accumulating evidence suggests that ROS play an important role in the development of cancer via chronic inflammation and the immune system. The key role of ROS in carcinogenesis is supported by experimental data showing that cancer cells commonly have increased levels of ROS, that ROS can induce cell malignant transformation, and that the malignant phenotype of cancer cells can be reversed by reducing cellular levels of ROS.39 Livestock suffer from different types of cancer (malignant tumors), although most are rare. The most common cattle, sheep, and horse cancers affect the skin and eyes and are generally caused by irritation from ultraviolet radiation from the sun. In their review on essential oils, Patel and Gogna (2015)93 summarized the activities of volatile fractions of plants against cancer cell lines. Anti-parasitics. Parasitism is a huge problem in husbandry and is among the main limitations to livestock production. The main economically important helminth parasites in sheep and cattle in Ireland are the nematodes (e.g., Nematodirus spp., 6542


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Journal of Agricultural and Food Chemistry plants of Medicago sativa, Trifolium repens, and Trifolium pratense.106 The rapid disintegration produces stable proteinaceous foam that traps fermentation gases (CO2, CH4), which can no longer be eructed by the animal.107 Some plants from Rosaceae, Onagraceae, Polygonaceae, and Dipsacaceae allow the reduction of CH4 and NH3-N (marker of nitrogen use efficiency).108 Factors in plants that suppress bloat include CTs.106 Rumen protozoa are proteolytic and cause the most important protein turnover in the rumen. The manipulation of rumen flora through modification by SMs such as saponins or essential oils has been attempted to improve N metabolism.109,110 A large number of grassland plants are known to improve digestion. These plants act directly by stimulating digestive secretion (e.g., saliva, bile, mucus) and enhancing enzyme activity or indirectly by improving and modulating the bacterial flora via the production of aromatic compounds.110,111 Increasing proportions of dicotyledonous plants and legumes reduce biomass production but improve the nutritive value of the herbage (organic matter digestibility, crude protein content).2 Thus, a steady increase in food intake was observed as the number of plant species offered to sheep and goats increased.112 Some herbs such as garlic, coriander, and oregano have been shown to have prebiotic-type effects. They stimulate the growth of certain rumen bacteria and thus may be used to manipulate rumen metabolism to, for example, promote the growth of Gram-negative fiber-digesting bacterial populations.27 In ruminants, essential oils and aromatic plants have been shown to improve appetite and digestion. These SMs influence rumen metabolism by reducing methanogenesis and nitrogen excretion.87 In vitro studies have shown that extracts of Lavandula of ficinalis promote rumen fermentation, whereas Salvia off icinalis extracts have possible inhibitory effects on methane production.113 These plants could also limit rumen ammonia concentrations and consequently lead to more efficient utilization of dietary nitrogen.114 However, these responses were often observed with high doses of aromatic compounds, which also can inhibit the process of ruminal fermentation, thus causing a decline in total volatile fatty acid production. Grassland medicinal plant mixtures of Taraxacum of f icinale L., Acorus calamus L., Calendula of f icinalis L., Hypericum perforatum L., Achillea millefolium L., Urtica dioica L., and Cichorium intybus L. containing tannin, phenol, steroid, flavonoid, saponin, terpenoid, and glycoside GSMs have been used as high-concentrate supplement diets in vitro. The major effects of this supplement were beneficial (higher DM digestibility and lower methanogenesis) and included interesting effects on unsaturated fatty acids.115 Activity on Production and Growth. More than 300 plant species with estrogenic activity have been identified.116 Estrogen can elicit growth responses and modify carcass composition.27 Many SMs possess hormone-like bioactive properties and could be involved in animal performance. They belong to different SM classes, including phytoestrogens, phytosterols, insulin-like SMs, and catecholamine analogues.27 The well-known classes of phytoestrogens are phenolic compounds with structures similar to endogenous steroids and may induce or inhibit the response of hormone receptors. They include isoflavones (daidzein, genistein, formononetin, and biochanin) synthesized from phenylalanine that resemble estradiol and act as estrogens or anti-estrogens (competition),116 coumestan (coumestrol), and lignans (secoisolariciresinol and matairesinol). 117 In sheep, high intake of

phytoestrogens, especially formononetin, has been found to impair fertility, whereas in cattle, the effects are not consistent. The isoflavones formononetin and daidzein are largely converted by rumen microorganisms to the mammalian isoflavone equol. Equol is a metabolite which results from bacterial metabolism of an isoflavone; it is an isoflavan which has much higher estrogen capacity then daidzein.27 Leguminosae such as alfalfa and clovers are the most important family with regard to the isoflavone content. The flavonoid kaempferol can also act as a weak estrogen receptor agonist and may cause estrogen or anti-estrogen effects, mainly depending on the concentration of endogenous estrogens. The hydroxyl group at C4′ appears to be crucial for its estrogenic activity.39 More than 400 plant species and 200 SMs have been documented as having hypoglycemic activity. In their review, Greathead et al. (2003)27 described experiments showing the influence of extracts of Coriandrum sativum, Sambucus nigra, Medicago sativa, and Agrimony eupatoria on the stimulation of insulin secretion, enhancement of the uptake and metabolism of glucose by muscle, and stimulation of glycogenesis.27 Toxic Molecules. Diverse Types of Toxic GSMs. Grazing ruminants generally avoid toxic plants.118 However, poisoning by plants is a relatively common veterinary problem and may occur when the fresh plant is ingested in grasslands (especially during low grazing) or when the plant contaminates hay, silage, and feed. Table 2 provides examples of toxic GSMs and GSMcontaining plants. Studies of the toxicities of GSMs are much more common than those reporting positive effects on animal health. Some GSMs and plants may be present in both tables. For example, phytoestrogens in husbandry may have, depending to the dose, a negative effect on reproductive performance, or a positive one (e.g., daidzein119), promote animal growth, enhance body immunity, and improve milk performance. These opposing effects illustrate the complexity of the subject. Clinical signs may vary from mild gastrointestinal irritation to sudden death, and diagnosis can rarely be made by clinical syndrome alone.120 Molecule toxicity is linked to chemical structure but also to the dose ingested. As early as 1537, Paracelsus postulated sola dosis facet venenum (“it is the dose that makes a poison”).120,121 Furthermore, the potential for intoxication is dependent on other variables such as animal species, physiological status (weight, health), ability of the toxin to diffuse across membranes, manner of excretion (e.g., urine, feces), and ability of the animal system to detoxify the compound.122 Indeed, the rumen contains a consortium of microorganisms involved in detoxification.123 Toxins are classified into four categories according to their oral toxicity as determined in rat experiments: class Ia, extremely hazardous (5 mg or less per kg body weight); class Ib, highly hazardous (5−50 mg per kg body weight); class II, moderately hazardous (50−500 mg/kg body weight); and class III, slightly hazardous (500 mg and more per kg body weight). Toxins that fall into classes Ia, Ib, and II interfere with central functions in an animal. The most poisonous substances are neurotoxins, which affect the nervous system (e.g., alkaloids from Equisetum arvense,124 mycotoxins produced by endophytes within ryegrass 125,126), followed by cytotoxins (e.g., repin, a sesquiterpene lactone from Centaurea repens127 or colchicine from Colchicum autumnale128) and metabolic poisons that disturb the liver (e.g., pyrrolizidine alkaloids of Jacobaea aquatica58), heart (e.g., phytoestrogens116), kidneys, respiration, and muscles.121 SM plant toxins also affect nearly all reproductive processes: spermatogenesis and oogenesis, fertil6543


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latter group of animals, the former animals do not develop diarrhea. The species difference in the enterotoxicity of Colchicum autumnale L. may be closely associated with the physiological mechanism of eliminating the effects on enterocytes. Clinical signs appear 48 h after ingestion and, because of the rapid turnover of intestinal epithelial cells, are predominantly related to the digestive tract (colic, abdominal pain, diarrhea, fetid feces with tenesmus). Death occurs from cardiorespiratory collapse.138 In Europe, several cases of horse poisoning by meadow saffron have been reported.138,139 Colic was the most common clinical sign observed in affected horses.120 2. Doses. In humans, colchicine causes death when absorbed at more than 0.8 mg/kg, and 40 mg is always fatal within 3 days after ingestion.140 Intoxication of horses was described by Kamphues et al.,139 and death occurred 3−4 h after ingestion of hay containing 1.48% Colchicum autumnale.139 Based on these data, a calculation of the lethal dose could be attempted. Consumption of a daily ration of 5 kg of DM hay per horse corresponded in this case to an input of 74 g of meadow saffron dry weight. If the colchicine content is arbitrarily fixed at 0.5%, the colchicine input per horse was 0.370 g. In the case of a 500kg horse, the lethal dose would be 0.74 mg of colchicine per kilogram of horse weight, which is very close to the human lethal dose. 3. Distribution of the Plant. Largely distributed in Europe, this grassland species is widespread in Central and Eastern Europe, where seeds used for processing by the pharmaceutical industry are collected manually. Meadow saffron could represent as much as 10% of species in permanent grasslands (http://eflorasys.univ-lorraine.fr/). A study of six natural sites in eastern France containing a high Colchicum autumnale density (3−49 fruiting plants/m2), showed high spatial heterogeneity of the distribution.141 This implies a risk of high Colchicum content in certain haystacks. Benefits and Adverse Function: Example of Condensed Tannins. Waghorn et al. (2003)53 summarized in a review the benefits and costs attributable to CTs in forages fed to ruminants. This family of molecules improves live-weight gain without affecting carcass composition, wool growth, lambing percentage (ovulation rate), and milk production and protein concentration in sheep. These effects could be due to reduction by CTs of proteolysis in the rumen, thus increasing bypass protein reaching the intestine. CTs contain a large number of phenolic hydroxyl groups and thus can form stable protein−tannin complexes.40 Therefore, CTs protect proteins from degradation by rumen microbes as well as NH 3 production. CTs also prevent bloat in cattle (i.e., reduction of CH4 production). The aggregation of soluble proteins with CTs interferes with the formation of stable foam and is often sufficient to reduce its severity. The concentration of CTs needed to achieve bloat protection has been estimated by extrapolation at 5 g/kg DM but depends on nutrition and dietary composition.142 The propensity for alfalfa and white clover to cause bloat has been a major incentive for attempting to express CTs in the foliage of these plants. Alfalfa and white clover contain very low amounts of CTs in leaf and stem tissues, which are high in protein. Ironically, the aim to select high-value legumes with high CT content is a result of excessive concentrations of readily degradable protein in these species resulting from earlier selections.53 Condensed tannins also improve tolerance of intestinal helminths and parasite burdens in sheep and minimize the

ization, fertility, placentation, embryonic and fetal development, pregnancy (abortions and embryonic deaths), and neonatal survival.122 Due to their bitter taste, pyrrolizidine alkaloidcontaining plants, mostly belonging to the families Boraginaceae, Asteraceae, and Fabaceae, are generally unpalatable and, as a result, avoided by grazing animals in the field. Among livestock, cattle and horses are especially susceptible to the toxic effects of pyrrolizidine alkaloids. In preserved and composed feeds, this recognition is lost, and the toxic pyrrolizidine alkaloids may be consumed. The most undesirable aspect of poisoning with pyrrolizidine alkaloids is that the disease develops undetected for a long time, which means that at the moment of symptom onset, the process of liver damage is so advanced that the animal dies within a few days.129 Phytoestrogens (e.g., coumestrol) already presented as potential growth promotors could cause temporary infertility, whereas those produced by Fusarium fungi found in grasslands, silage, or stored grains can cause permanent infertility.53 In some cases, depending on the molecules, plants lose their toxicity during drying from fresh grass to hay, such as Ranunculus acris130 a toxic plant which is widespread on grasslands (59% frequency http://eflorasys.univ-lorraine.fr/ index.php/fr/species/index) that is avoided by livestock because of the production of the toxic, blistering, unstable glucoside agent ranunculin, which is converted to the reactive protoanemonin (sometimes called anemonol or ranunculol) after enzymatic cleavage.131 In hay, this molecule is not present because, during drying of aerial parts of Ranunculus acris, the toxin protoanemonin comes into contact with air and dimerizes to anemonin, which is further hydrolyzed to a non-toxic carboxylic acid. The toxin protoanemonin can form covalent bonds with the free sulfhydryl groups of proteins or glutathione, resulting in cytotoxic and allergenic effects. Symptoms include severe skin and mucosal irritation with blisters and ulceration, internal diarrhea, abdominal pain, and death from respiratory and cardiac arrest.121 Protoanemonin can also alkylate DNA and is therefore mutagenic.40 Example of Colchicum Alkaloids. 1. Mode of Action and Clinical Signs. The genus Colchicum is characterized by the presence of tropolonic alkaloids widely distributed in all plant parts.132 The best known is colchicine, which has numerous derivatives, such as demethylcolchicine or colchicoside (3glucosyl-3-demethylcolchcine).133,134 Colchicine is widely used in human medicine and in biology for its capacity to block mitosis by inhibiting microtubule polymerization. In fact, colchicine binds to the cell protein tubulin, disrupts spindle formation, and arrests mitosis in metaphase. This phenomenon alters cell morphology, decreases cellular motility, and interrupts cardiac myocyte conduction and contractility. The culmination of these mechanisms leads to multi-organ dysfunctions and failures. Colchicine is excreted into milk and crosses the placenta.128 These toxins are easily absorbed from mucous membranes and the gastrointestinal tract. The peripheral receptors are on exocrine glands, resulting in effects on sweating, salivation, and smooth and cardiac muscle.135 In experiments, feeding cattle with meadow saffron corms induce severe diarrhea, followed by death. Autopsies reported enterotoxic cellular lesions closely associated with apoptosis.136 However, differences in sensitivity between animal species have been observed. Yamada et al. (2000)137 demonstrated that the physiological mechanism of the apoptotic process for eliminating enterocytes in mice and rats differs from that of guinea pigs, monkeys, cattle, and horses. In contrast to the 6544


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kaempferol could be hydrolyzed by microflora which break the C3 ring of the aglycone to form simple phenolic compounds such as 4-hydroxyphenlacetic acid, phloroglucinol and 4methylphenol, which can either be absorbed or excreted in feces.39,147 Kaempferol could also be metabolized in the liver in glucurono- and sulfo-conjugated forms which can reach the systemic circulation and tissues and are excreted in urine.39 Many SMs are excreted in urine as conjugated amino acids, glucuronic acids or sulfates.21 Monogastric versus Polygastric. The digestive system of monogastric or polygastric herbivores interacts differently with SMs. Several differences have been observed between cattle/ sheep and horses.148 In fact, due to this rumen microbiota potent detoxifier, cattle are less susceptible to toxic molecules than horses or other monogastric herbivores. Furthermore, this microbiota can greatly influence the absorption and metabolism of SMs.27 Hence, in contrast to monogastrics, ruminants can benefit from the anti-oxidant effects of polymeric proanthocyanidins by producing new polyphenols, which can be detected in the plasma.120,149,150 Cattle appear also less susceptible to the phytoestrogen formononetin than sheep because, in cattle, this phytoestrogen is excreted rapidly.53 In contrast to cattle, in horses, pyrrolizidine alkaloids are bioactivated in the liver into metabolites known as pyrroles, which are cumulative hepatotoxins.120 However, in certain cases, ruminants can be more susceptible than monogastric. This is the case for Scontaining GSMs, such as glucosinolates and S-methyl-cysteine sulfoxide, which are found in all Brassica species. This latter molecule is fermented in the rumen to dimethyl disulfide, which causes hemolytic anemia and depressed voluntary feed intake. Glucosinolates are decomposed to iso-thiocyanate and nitrites, with the latter having the potential to depress voluntary feed intake.151 GSM Choice and Sequence of Ingestion. On highbiodiversity grasslands, livestock may seek out plants for selfmedication, to rectify nutritional imbalances or avoid toxics.17,152 In his review of plants for improving animal productivity, Greathead (2003)27 noted the difficulty of characterizing highly complex mixtures of SMs and considered that the simplest method of delivering bioactive SMs to animals outdoors would be to grow the relevant plants in a field and let the animals graze the plants in a controlled manner, assuming that the plants are palatable. Self-medication has the potential to improve the health and welfare of animals.17 Livestock have the ability to learn rapidly about the negative consequences of foods and to choose diets that ameliorate these negative consequences.153 In fact, many herbivores can detect plant toxins and avoid them because of their taste receptors (e.g., for bitter molecules or amino acids154). Otherwise, livestock can avoid intoxication by detoxifying the toxic molecules, even if it is energetically expensive. There are two routes of detoxification: oxidation, such as the detoxification of terpenes by a suite of cytochrome-P450-dependent monooxygenases, or conjugation and excretion. In certain cases, saturation of specific detoxification pathways could limit feeding.155 To decrease the effect of toxic molecules, livestock have also the abilities to select the sequence of ingestion among highly diverse and changing biochemical diversity.21 Sequences in which plant species containing GSMs are ingested by livestock markedly influence the intake of forages, satiation, satiety, and toxicity.17,21,156 For example, in sheep, white clover is more nutritious and digestible than grass, but after eating clover, sheep switch to grass; their mild aversion to clover subsides

detrimental effects associated with a heavy load of internal parasites.10 However, in contrast to observations in vitro, there is no evidence in vivo of complete suppression of larval development. However, Waghorn et al. (2003)53 emphasized that ruminants grazing tropical browse can be heavily parasitized, despite a high dietary CT content. CTs are thought to act directly against the parasites because of their ability to form strong complexes with proline-rich proteins present on nematode surfaces.143 Recent studies have also shown the potential for indirect effects because CTs can stimulate the immune response in T cells in ruminants.144 This is particularly important as helminths are inherently immunosuppressive, and down-regulation inappropriately skews the host immune system.6 Some forage species contain high amounts of CTs in leaves and stems, such as birdsfoot trefoil (Lotus corniculatus L.), which contains 10−40 g/kg DM, sulla (Hedysarum coronarium L.), which contains 20−110 g/kg DM,53 and Onobrychis viciifolia Scop., which contains 30−80 g/kg DM.145 However, the benefits of CTs do not apply to all sources of CTs. Accordingly, L. corniculatus provides consistent benefits for production, and sulla (Hedysarum coronarium L.) reduces gastrointestinal parasite numbers.53 CTs’ beneficial effects are dependent on their physical and chemical structure and content in the diet.53 Furthermore, the estimate of CT content is dependent on the analytical technique as well as drying techniques. A moderate amount of CT (20−49 g/kg DM) in forage significantly reduces the level of protein digestion during ensiling and rumen fermentation due to a great affinity for leaf protein after mastication, which inhibits protein degradation, thereby protecting ruminants against grassland bloat.146 However, the “optimal” type or concentration of a CT will vary depending on the duration over which it is fed.53 The concentration and the structure of a CT strongly affect the palatability and the nutritional value of forage legumes.142 High levels of CTs (60−120 g/kg DM) have negative effects on non-ruminant livestock. CTs can decrease the palatably of forages and negatively impact nutritive value, including forage digestibility, by binding bacterial enzymes or forming complexes with cell-wall polysaccharides.146 High concentrations and astringent CTs reduce live-weight gain (i.e., reduce digestibility) and productivity and can cause death. CTs lower voluntary feed intake, the nutritive value of other dietary constituents, and the bioavailability of essential micronutrients (iron, zinc) through their ability to complex them.146 Giraffes, goats, and deer are more tolerant to diets rich in CT than sheep or cattle because their high-proline salivary proteins reduce the effect of CTs in the rumen.53 GSM Metabolism. Bioavailability. The bioavailability of a substance is determined by its absorption, disposition (distribution and elimination) in the systemic circulation, metabolism, and excretion and differs greatly among SMs. Their activity depends also on their biochemical form and environment. Numerous SMs are stored in the plant vacuole in glucoside forms, as is the case for flavonols. The highly polar glucoside moiety hinders their absorption, whereas the intermediate-polarity aglycone facilitates absorption. Glycosides must be hydrolyzed to the aglycone form to be absorbed. Absorption could also occur by passive diffusion for lipophilic molecules or active transport. The gut, gut wall, and liver can extensively metabolize SMs before they reach the systemic circulation.27 The microflora has an important impact on SM transformation and, consequently, absorption. For example, 6545


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Journal of Agricultural and Food Chemistry Table 3. Assay Methods for the Measurement of Anti-oxidant Capacity assay method name

assay method type

Folin−Ciocalteu or Folin−Denis; also called the gallic acid equivalence method (GAE) 2,2-diphenyl-1-picrylhydrazyl (DPPH) ferric reducing/anti-oxidant power (FRAP) cupric reducing anti-oxidant capacity (CUPRAC) Trolox equivalent anti-oxidant capacity assay (TEAC/ABTS) oxygen radical absorption capacity (ORAC) hydroxyl radical averting capacity (HORAC) total radical absorption potentials (TRAP) lipid peroxidation inhibition assay

measured

refs

absorbance measurement

electron transfer

79, 217, 218

absorbance measurement absorbance measurement absorbance measurement absorbance measurement fluorescence decay (fluorescein) fluorescence decay (fluorescein) fluorescence decay (phycoerythrin) absorbance measurement

electron transfer electron transfer electron transfer electron transfer hydrogen atom transfer hydrogen atom transfer hydrogen atom transfer

81, 167 167, 219 49 79, 220−224 49, 79, 81, 167 81 79, 81

hydrogen atom transfer

81, 225

incubated with rumen fluid in vitro to evaluate digestibility as well as methane and ammonia production.108,162 Nevertheless, concentrations of potentially active substances used in vitro do not always correspond to in vivo bioavailability.163 So, given the difficulty of measuring valid grassland markers linked to animal health, directly on grasslands or in vitro direct tests on animals are of interest. Different kinds of markers could be followed on the animal. Physiological parameters such as heart rate, blood pressure, body temperature, weight, serum levels of various stress hormones (e.g., cortisol) and immunological functions (e.g., suppression of lymphocyte activity) could be used to assess health and welfare. For example, pH reveals the status of acidity of the animal, whereas immunoglobulin levels reflect immunity.164 For inflammation pathologies, the plasma concentration of pro-inflammatory and anti-inflammatory cytokines could be measured.165 With the advent of genomics, another approach to study activities of molecules on animal health has emerged based on the examination of the molecular signatures of all genes and proteins using high-throughput techniques (e.g., transcriptomics and proteomics).166 Due to this progress, molecular targets (i.e., genes involved in health disorders) have increasingly been identified. Some of these new targets will become available for testing SMs.40 Different types of anti-oxidant measurements can be performed in various systems: in vitro, on laboratory animals or directly on herbivores. However, in vitro anti-oxidant measurements are only an approximation of the in vivo reality. In fact, there are numerous sources of variation, such as solubility differences, bioavailability in the digestive tract, and interactions and conjugation with other molecules, such as fiber/lignin.53 However, in vitro studies constitute a first approach to better understand GSM activities.78 The antioxidant capacities of compounds and their mixtures should be assessed on the basis of their effects on the levels of plasma lipid peroxidation in vitro and biomarkers of oxidative stress in vivo.167 Among different markers of oxidative stress in animals, malondialdehyde and the natural anti-oxidant metalloenzymes Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and seleniumdependent glutathione peroxidase are currently considered the most important markers.12 Other non-enzymatic endogenous anti-oxidants of importance include bilirubin, a bile pigment bound to albumin that may protect albumin-bound fatty acids from peroxidation,76 uric acid, and coenzyme Q10.168 Global anti-oxidant capacity could be measured in plasma using the same techniques described for grasslands (Table 3) or in vitro susceptibility to peroxidation (kinetics of conjugated diene production after copper induction).169

during the afternoon and evening, and by morning, they return to eating clover. The transient aversion is due to feedback from primary (organic acids from soluble carbohydrates and ammonia from highly digestible protein) and secondary (cyanogenic glycosides) compounds.21,157

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APPROACHES AND TECHNIQUES ALLOWING THE EVALUATION OF GSMS IN HERBIVORE HEALTH Currently, no technology can provide a “holistic” view of all compounds in forage and their effects on animal health. Several approaches are commonly used to characterized plant material composition or activities and to study their impact on animal health. Generally, tests of the activity of the plant extract or molecules are first performed in vitro or on animal models such as murine models, followed by small livestock.87 Characterization of Plant GSM. The most widespread approach to characterize the complex GSM phytococktail is targeted on a molecule or a class of molecule. For that, GSMs are extracted from forage to get a precise content of each known GMS presents on grasslands. A combination of several extraction, separation, and detection techniques (e.g., gas or liquid chromatography coupled with mass spectrometers) are required to provide an overview of most metabolites present in a sample.158 Another approach is targeted on the activity of a grassland extract. In the current state of science, anti-oxidant capacity appears to be a good candidate. Numerous techniques have been developed to study this activity (Table 3) but no one is sufficient to establish it. This is the topic of different extensive reviews.79,81,159,160 A new approach to study GSMs is linked to the development of metabolomics. This approach provides a very fine description of GSMs by assessing all molecules extracted from the plant that are analyzable by mass spectrometry or nuclear magnetic resonance. The resultant diverse list of chemical structures16,158,161 is treated with chemometrics methods based on mathematical modeling (multivariate data analysis). These highly precise and costly analyses generate a large amount of data that is difficult to directly link to health but provide the best description of GSM composition. Metabolomic approaches are generally used to study differences in a forage species under different conditions158 by identifying the metabolites influenced by the conditions studied. However, the number, complexity, and probable interactions between components of the GSM phytococktail complicate the association of these sets of data with animal health. Studies of GSMs on Animal Health Activities. In vitro tests representing part of the animal are an appropriate initial method for GSM studies. For example, a plant extract can be 6546


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DISCUSSION The recent papers presented in this Review reveal an increasing focus on livestock diet as a tool to maintain health and prevent disease. Having achieved significant improvements in grassland quality for livestock production based on nutritive value (primary metabolites), research is now turning to the “nonnutritive value” of feed components, including GSMs, that impact animal health status87 and quality of products. Grassland produces a rich phytococktail of SMs, especially linked to the presence of dicotyledonous. So, GSMs appear to be a low-cost, environmentally friendly, and accessible source of pharmacologically active molecules to improve animal health without the use of medicines. However, a huge gap in knowledge about the GSM phytococktail remains. The challenge today is to describe and understand the diversity of SMs and their modes of action alone or in natural combinations.40 Several studies have examined toxic GSMs, including poisoning, mode of action, critical dose (e.g., meadow saffron/colchicine/intoxication),136,137 while others have evaluated their benefits for a specific pathology that can be evaluated in a quantifiable manner (e.g., Hedysarum coronarium L./condensed tannins/ parasitism).170−173 Other GSM classes, such as CTs, are complex and not yet accurately identified. In the case of Cichorium intybus L., the aspect of anthelminthic activity related to sesquiterpene lactones and CTs is not clear,174 as is also the case for CT and flavonol glucosides in Onobrychis viciifolia Scop.175 Thus, the health-promoting activity of a plant could be attributed to several molecules and families of molecules. Therefore, current scientific knowledge on the function of these substances and their interactions (synergy, additivity, antagonism) is poor. Furthermore, the same GSM could have positive or negative effects on animal health, depending generally on dose (e.g., phytoestrogens), but also possibly depending on the characteristics of the animal, such as monogastric/polygastric, stage, and production status. Numerous other factors also affect intake: palatability or refusal of the plant, bioavailability of the molecule, absorption (microbiota, digestive system).87 A new focus of the study grassland species for animal health concerns their anti-oxidant activity. In fact, current breeding conditions are well known to create unbalanced oxidative stress,169 originating from free radical production. This is a major source of complications in metabolic pathologies that have been linked to many diseases.72 It is currently accepted that intake of anti-oxidants improves health because these molecules reduce oxidative stress.12,104 For example, phenolic compounds, which are present in large amounts in grasslands, scavenge free radicals by H-atom transfer and may thus decrease noxious effects due to oxidative stress.176 Phenolic content is generally well correlated with anti-oxidant capacity.34,85,177−179 Anti-oxidant studies are generally performed on a specific plant species,180,181 and very few are performed directly on grasslands.34,182 A simple and universal method for assessing anti-oxidant capacity accurately and quantitatively167 has to be developed to aggregate and compare results. Combined measures of anti-oxidant GSM intake, antioxidant status of the animal, and health criteria are needed to determine optimal dose in diet and GSM type and to avoid prooxidant activity. So, studies are required to better understand the role of GSM in livestock farming systems and health in order to identify a link between analytical grassland data and animal health criteria. As concluded by Mueller-Harvey (2006)143 in her review on tannins: “Our ability to predict

whether [GSM] feeds confer positive or negative effects will depend on interdisciplinary research between animal nutritionists and plant chemists.” An effort to organize multidisciplinary data with techniques to integrate the complexity of GSM phytococktail effects on herbivore heath is necessary to provide farmers indicators on which to make decisions aimed at better grassland valorization and practices. The first step in such research is to clearly identify the grassland markers (e.g., grassland anti-oxidant activity) conferring animal health and to then evaluate grassland animal health potential for a wide range of forages to adapt grassland management toward optimal GSM production. The integration of GSM criteria for forage as valuable for health could be a new challenge to maintain and valorize grasslands, especially permanent ones.

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +33 3 89 22 49 23. Fax: +33 3 89 22 49 20. E-mail: anne. [email protected]. ORCID

Anne Poutaraud: 0000-0002-1496-3196 Notes

The authors declare no competing financial interest.

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ABBREVIATIONS USED CT, condensed tannin DM, dry matter GSM, grassland secondary metabolite ROS, reactive oxygen species SM, secondary metabolite VOC, volatile organic compound REFERENCES

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