Nutraceutical Potential of the Low Deciduous Forest to Improve Small Ruminant Nutrition and Health: a Systematic Review

agronomy

Review Nutraceutical Potential of the Low Deciduous Forest to Improve Small Ruminant Nutrition and Health: A Systematic Review

Rafael Arturo Torres-Fajardo , Pedro Geraldo González-Pech , Juan Felipe de Jesús Torres-Acosta and Carlos Alfredo Sandoval-Castro *

Facultad de Medicina Veterinaria y Zootecnia, Universidad Autónoma de Yucatán, Mérida 97000, Mexico; [email protected] (R.A.T.-F.); [email protected] (P.G.G.-P.); [email protected] (J.F.d.J.T.-A.) * Correspondence: [email protected]; Tel.: +52-999-9423-200

Simple Summary: There is strong interest in identifying plant species with potential benefits for small ruminant production systems but, despite its importance, there are limited reports systematically exploring such properties. Previously, we proposed an interdisciplinary approach to evaluate the nutraceutical properties of plant species under a heterogeneous context, such as the low deciduous forest. Continuing this effort, we present here a systematic review gathering two decades of research devoted to identifying plant species from such an ecosystem that could influence the nutrition and health of sheep and goats. Encouragingly, the evaluation of plant species from diverse agroecosystems has steadily increased, resulting in the identification of some candidates with nutraceutical properties. Under the heterogeneous conditions of the low decid-

Citation: Torres-Fajardo, R.A.; uous forest, small ruminants consume up to 61 plant species in their grazing circuits. Amongst González-Pech, P.G.; Torres-Acosta, these, 13 have been tested in in vitro and/or in vivo trials, showing promising properties for both J.F.d.J.; Sandoval-Castro, C.A. enhancing nutrition and controlling gastrointestinal nematode infections. The objective of this Nutraceutical Potential of the Low review was to gather relevant information supporting the revalorization and potential use of Deciduous Forest to Improve Small plants that naturally occur in the tropical forest, which could enhance small ruminants’ welfare Ruminant Nutrition and Health: A and production. Systematic Review. Agronomy 2021, 11, 1403. https://doi.org/10.3390/ Abstract: Nutraceuticals are defined as livestock feeds that combine their nutritional value with agronomy11071403 their beneficial effects on animal health. We analyzed the outcomes from nearly 20 years of research assessing the nutraceutical properties of plants consumed by sheep and goats in low deciduous Academic Editors: Juan J. Villalba and forests. A systematic review of different databases suggested 31 peer-reviewed manuscripts ac- Jennifer MacAdam cording to pre-established criteria. Amongst these, 16 manuscripts described in vitro evaluations

Received: 26 May 2021 investigating the bioactivity of plant secondary compounds in the extracts of 12 plant species. Accepted: 9 July 2021 Most of these studies used the abomasal nematode Haemonchus contortus as the parasite model. Published: 13 July 2021 Meanwhile, 11 manuscripts reported in vivo trials under controlled pen conditions, evaluating the relationships between the intake of leaves from different plant species and their secondary Publisher’s Note: MDPI stays neutral compounds and animal nutrition, performance, and gastrointestinal nematode infections. Ad- with regard to jurisdictional claims in ditionally, four manuscripts described studies under natural feeding conditions. Altogether, the published maps and institutional afﬁl- studies showed the inherent complexity of the relationship between small ruminants, plants, iations. nutrients, secondary compounds, and gastrointestinal nematodes in natural feeding systems. Several plant species can be considered good candidates for nutraceutical use. Our findings warrant future work to understand the relationship between plants, ruminants, and their parasites, with the aim to improve the sustainability of production systems based on the native vegetation Copyright: © 2021 by the authors. of tropical forests. Licensee MDPI, Basel, Switzerland. This article is an open access article Keywords: anthelmintic plants; bioactive compounds; gastrointestinal nematodes; goat; native distributed under the terms and vegetation; nutraceutical; plant secondary compounds; sheep; sustainable grazing system conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Agronomy 2021, 11, 1403. https://doi.org/10.3390/agronomy11071403 https://www.mdpi.com/journal/agronomy Agronomy 2021, 11, 1403 Agronomy 2021, 11, x 2 of 20 2 of 21 Agronomy 2021 , 11, x 2 of 21

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1. Introduction 1. Introduction1. Introduction The low deciduous forest (LDF) is a heterogeneous vegetation system that predomi- 1. Introduction1. Introduction1. Introduction 1. Introduction1. Introduction1. IntroductionThe low deciduous forest (LDF) is a heterogeneous vegetation system that predomi- The low deciduous forest (LDF) is a heterogeneous vegetation system that predomi- 1. Introduction nates in the tropical regions of México [1,2]. This ecosystem covers ~8% of the country’s nates in the tropical regions of México [1,2]. This ecosystem covers ~8% of the country’s TheThe lowThe low deciduous low deciduous deciduousThe Theforest low forestThe low deciduousforest(LDF) low (LDF)deciduous deciduous(LDF) is ais heteroforesta ishetero forest a hetero(LDF)forestgeneousgeneous (LDF) geneous(LDF)is a vegetationis hetero vegetationa is hetero vegetationa heterogeneous geneoussystem systemgeneous vegetationsystem that vegetation that vegetationpredomi- that predomi- system predomi- system system that that predomi- that predomi- predomi-nates in the tropical regions of México [1,2]. This ecosystem covers ~8% of the country’s The low deciduous forestsurface (LDF) area is and a hetero is a featuregeneous in 15vegetation of 32 states system of the that country predomi- [3,4]. The LDF plant inventory surface area and is a feature in 15 of 32 states of the country [3,4]. The LDF plant inventory natesnates natesin inthe the intropical thetropicalnates tropicalnates regions innatesregions thein regions the inoftropical of theMéxicotropical México oftropical Méxicoregions [1,2]. regions [1,2]. regions This[1,2].of This Méxicoof ecosystem This México ofecosystem México ecosystem[1,2]. [1,2]. covers This[1,2]. covers This ecosystemcovers This~8% ecosystem ~8% ecosystemof ~8% ofthe coversthe ofcountry’s covers thecountry’s covers ~8%country’s ~8% of ~8% theof the ofcountry’s thecountry’s country’s surface area and is a feature in 15 of 32 states of the country [3,4]. The LDF plant inventory nates in the tropical regionsis ample, of México with [1,2]. some This studies ecosystem reporting covers the existence ~8% of the of up country’s to 2200 plant species [5], of which is ample, with some studies reporting the existence of up to 2200 plant species [5], of which surface areasurface andsurface issurface areaa feature area and area and isin anda 15is feature a of isfeature 32a feature statin 15ines of 15of in 32ofthe 15 stat32 ofcountry stat 32es ofstates theof [3,4].es the countryof theThecountry country LDF [3,4]. [3,4]. plant The [3,4]. The inventoryLDF The LDF plant LDF plant inventory plant inventory inventory is ample, with some studies reporting the existence of up to 2200 plant species [5], of which surfacesurfacesurface area areaand area isand aand feature is ais feature athe feature in Fabaceae 15 in of in15 32 15of stat (Leguminosae) of32es 32stat of stat esthe esof country ofthe the family country country [3,4]. is [3,4]. theThe [3,4]. most LDFThe The abundant LDFplant LDF plant inventory plant [ 6inventory]. inventory From this large biodiversity, the Fabaceae (Leguminosae) family is the most abundant [6]. From this large biodiversity, is ample, withis ample,is some ample,is ample, studieswith with some with reporting some studies some studies studiesthe reporting existencereporting reporting the of the existence up theexistence to existence 2200 of plantup of upto of species2200 toup 2200 to plant 2200 [5], plant species ofplant whichspecies species [5], [5], of which [5],of which of whichthe Fabaceae (Leguminosae) family is the most abundant [6]. From this large biodiversity, is ample,is ample,is ample,with with some with some studies some studiesdecades studies reporting reporting ofreporting experimentation the existence the the existence existence of up have of to ofup 2200 allowed up to to 2200plant 2200 researchersplant species plant species species [5], to of [5], identify which [5], of ofwhich which approximately 260 plant decades of experimentation have allowed researchers to identify approximately 260 plant the Fabaceaethe (Leguminosae)the Fabaceae theFabaceae Fabaceae (Leguminosae) (Leguminosae) family (Leguminosae) is the family most family family isabundant the is the mostis themost [6]. abundant most abundantFrom abundant this [6]. [6].large From [6].From biodiversity, thisFrom this large this large biodiversity, large biodiversity, biodiversity, decades of experimentation have allowed researchers to identify approximately 260 plant the Fabaceaethethe Fabaceae Fabaceae (Leguminosae) (Leguminosae) (Leguminosae)species family family as familyis potential the is most theis the feedmost abundant most resourcesabundant abundant [6]. From for[6]. [6]. ruminant From this From largethis this livestock large biodiversity, large biodiversity, biodiversity, [7]. Recent studies have deter- species as potential feed resources for ruminant livestock [7]. Recent studies have deter- decades of decadesexperimentationdecadesdecades of experimentationof experimentation of haveexperimentation allowed have haveresearchers allowed have allowed allowed researchers to researchers identify researchers toapproximately identifyto identify to identify approximately approximately 260 approximately plant 260 260 plant 260 plant plantspecies as potential feed resources for ruminant livestock [7]. Recent studies have deter- decadesdecadesdecades of experimentation of ofexperimentation experimentationmined have have theallowed have consumption allowed allowed researchers researchers researchers of to up identify to to 61toidentify identify plant approximately approximately species approximately of 260 the plant LDF260 260 plant by plant sheep and goats [8,9]. mined the consumption of up to 61 plant species of the LDF by sheep and goats [8,9]. species as potentialspeciesspeciesspecies as feed potentialas potential asresources potential feed feed for resources feed ruminantresources resources for livestock forruminant forruminant ruminant [7]. livestock Recentlivestock livestock [7].studies [7]. Recent [7].Recent have Recent studies deter-studies studies have have deter- have deter- deter-mined the consumption of up to 61 plant species of the LDF by sheep and goats [8,9]. speciesspeciesspecies as potential as aspotential potential feed feedresourcesUnder feed resources resources this for context, ruminant for for ruminant ruminant the livestock LDF livestock representslivestock [7]. Recent [7]. [7]. aRecent valuable Recentstudies studies studies resourcehave have deter- havefor deter- deter- small ruminant produc- Under this context, the LDF represents a valuable resource for small ruminant production mined the minedconsumptionminedmined the the consumption the consumptionof upconsumption to 61 of plant upof upofto sp up61toecies 61plantto plantof61 thespplant eciessp LDFecies sp of eciesby theof sheep the ofLDF theLDF and by LDF by sheepgoats bysheep sheep[8,9].and and goats and goats [8,9].goats [8,9]. Under[8,9]. this context, the LDF represents a valuable resource for small ruminant production minedmined minedthe consumptionthe the consumption consumption oftion up of systems to ofup 61up to plant to in61 61severalplant spplantecies sp regions species ofecies the of of LDFofthe M theé LDFxicoby LDF sheep whereby by sheep andsheep a large andgoats and majority goats [8,9].goats [8,9]. of[8,9]. small ruminant herds systems in several regions of México where a large majority of small ruminant herds de- Under this Undercontext,UnderUnder this the this context, LDF this context, representscontext, the the LDF theLDF representsa LDFvalu represents ablerepresents resourcea valu a valu ablea valu forable resource smallable resource resource ruminant for forsmall forsmall production ruminantsmall ruminant ruminant production production production systems in several regions of México where a large majority of small ruminant herds de- UnderUnder Underthis context,this this context, context, the LDF thedepend the LDFrepresents LDF represents exclusivelyrepresents a valu a ablevalu a on valu able thisresourceable vegetationresource resource for small for systemfor small ruminant small ruminant as ruminant their production feed production production source [7, 10–12]. Therefore, pend exclusively on this vegetation system as their feed source [7,10–12]. Therefore, systems in systemsseveralsystemssystems regionsin severalin several in of several Méxicoregions regions regions whereof Méxicoof México ofa largeMéxico where wheremajority where a large a large ofa majority largesmall majority majority ruminant of smallof small of herds ruminantsmall ruminant de- ruminant herds herds herdsde- de-pend de- exclusively on this vegetation system as their feed source [7,10–12]. Therefore, systemssystemssystems in several in inseveral several regions regions regionsdeeper of México of insightofMéxico México whereinto where wherea thelarge arelationship large amajority large majority majority of betweensmall of ofsmall ruminant small herbivores ruminant ruminant herds andherds de-herds the de- environmentde- can help deeper insight into the relationship between herbivores and the environment can help to pend exclusivelypendpend exclusivelypend on exclusively this exclusively vegetation on onthis onthis vegetation systemthis vegetation vegetation as systemtheir system feedsystem as astheirsource theiras feedtheir [7,10–12].feed sourcefeed source source Therefore,[7,10–12]. [7,10–12]. [7,10–12]. Therefore, Therefore, Therefore, deeper insight into the relationship between herbivores and the environment can help to pendpend exclusivelypend exclusively exclusively on thison on tothisvegetation design,this vegetation vegetation develop, system system system andas their improveas astheir feed their resilientfeedsource feed source source[7,10–12]. forage–livestock [7,10–12]. [7,10–12]. Therefore, Therefore, Therefore, systems, which could ﬁnally design, develop, and improve resilient forage–livestock systems, which could finally en- deeper insightdeeperdeeper intodeeper insight the insight relationship insight into into the into the relationship between therelationship relationship herbivores between between between herbivoresand herbivores the herbivores environment and and the and the environment thecanenvironment environmenthelp to can can help can help to help todesign, to develop, and improve resilient forage–livestock systems, which could finally en- deeperdeeperdeeper insight insight insight into intothe into relationship theenhance the relationship relationship ruminant between between between productionherbivores herbivores herbivores (Figureand theand and1 environment). the the environment environment can helpcan can helpto help to to hance ruminant production (Figure 1). design, develop,design,design, design,and develop, develop,improve develop, and resilientand improve and improve improve forage resilient resilient–livestock resilient forage forage systems,forage–livestock–livestock–livestock which systems, systems, could systems, which finally which whichcould en-could couldfinally finally finally en- en-hance en- ruminant production (Figure 1). design,design,design, develop, develop, develop, and improveand and improve improve resilient resilient resilient forage forage –livestockforage–livestock–livestock systems, systems, systems, which which whichcould could finallycould finally finallyen- en- enhance ruminanthancehance production hanceruminant ruminant ruminant production (Figure production production 1). (Figure (Figure (Figure 1). 1). 1). hancehance ruminanthance ruminant ruminant production production production (Figure (Figure (Figure 1). 1). 1).

Figure 1. A brief depiction of the natural scenario in the low deciduous forest. Within this heterogenous context, temper- Figure 1. A brief depiction of the natural scenario in the low deciduous forest. Within this heterogenous context, temper-

FigureFigureFigure Figure1. A 1. brief 1.A 1. Abrief A depiction brief brief depiction depiction depiction of the of ofthenatural of the thenatural natural natural scenario scenario scenarioscenario in the in thelow inin thethelow decidu low decidu ous deciduousdeciduous forest. ousforest. Withinforest. Within Within this Within this heterogenous this heterogenous this heterogenous heterogenous context, context, context, context,temper- temper- temper- tem- FigureFigureFigure 1. A1. briefA 1. brief A depiction brief depiction depiction of ofthe the naturalof naturalthe natural scenario scenario scenario in inthe the lowin lowthe decidu lowdecidu deciduousous forest. ousforest. forest.Within Within Within this this heterogenous thisheterogenous heterogenous context, context, context, temper- temper- temperature/solar radiation ( ), humidity ( ), and rainfall ( ) are variable throughout the year. Approxi- Figure 1. A brief depiction of the natural scenario in the low deciduous forest. Within this heterogenous context, temperature/solar radiation ( ), humidity ( ), and rainfall ( ) are variable throughout the year. Approxi- perature/solar radiation ( ), humidity ( ), and rainfall ( ) are variable throughout the year. Approximately,mately, 260 plant species have been considered as valuable resources for ruminant feeding. There are 80 plants verified as ature/solarature/solarature/solar radiation radiation radiation ( ( ( ), humidity ), humidity ), humidity ( ( ( ), and ), and ra ), infalland rainfall ra ( infall ( ( ) are ) are variable ) arevariable variable throughout throughout throughoutmately, the theyear. 260 theyear. Approxi-plant year. Approxi- species Approxi- have been considered as valuable resources for ruminant feeding. There are 80 plants verified as ature/solarature/solarature/solar radiation radiation radiation ( ( ( ), humidity ), humidity ), humidity ( ( ( ), and ), and ra ), andinfallrainfall ra (infall ( ( ) are ) are variable ) variableare variable throughout throughout throughout the the year. year.the Approxi- year. Approxi- Approxi- consumed by sheep and goats through direct observation. Each one containing different levels and concentrations of nu- ature/solar radiation ( 260 ), planthumidityspecies ( have been ), and considered rainfall ( as valuable ) are resources variable for throughout ruminant feeding. the year. There Approxi- are 80 plantsconsumed veriﬁed by as sheep consumed and goats through direct observation. Each one containing different levels and concentrations of nu- mately,mately,mately, 260 260 plant plant260 species plantmately, speciesmately, species havemately, 260 have 260 plantbeen have been 260plant consideredspecies beenplant considered species considered species have haveas been asvaluable have beenvaluable asconsidered beenvaluable considered reso consideredresources resourcesas valuable forasurces forvaluable ruminantas ruminantvaluablefor reso ruminant resources feeding. resofeeding.urces for urcesfeeding. forruminantThere There ruminantfor are Thereruminant are feeding.80 80 plantsarefeeding. plants 80feeding. There plantsverified Thereverified are Thereverified as are80 as plants80are asplants 80 verifiedplants verified verified as as as mately, 260 plant species haveby been sheep considered and goats as through valuable direct reso observation.urces for ruminant Each one feeding. containing There different are 80 plants levels verified and concentrations as of nutrients ( ), consumedconsumedconsumed by bysheep sheep byconsumed andsheepconsumed and goatsconsumed andgoats by through goats sheep bythrough sheepby through anddirectsheep directand goats observation.anddirect goats observation. through goats observation.through through direct Each directEach one observation. directEach one observation. containing onecontainingobservation. containing Each different Each differentone Each onedifferent containing leve onecontaining levels containing andlevels anddifferent lsconcentrations different andconcentrations different concentrations leve levels and levelsof andofnu- concentrationsls nu- and ofconcentrations nu- concentrationstrients of nu- of ( nu- of nu- ), plant secondary compounds like terpenes ( ), alkaloids ( ), and phenolic compounds ( consumed by sheep and goats through direct observation. Each one containing different levels and concentrations of nutrients ( ), plant secondary compounds like terpenes ( ), alkaloids ( ), and phenolic compounds ( plant secondary compounds like terpenes ( ), alkaloids ( ), and phenolic compounds ( ). In addition,). In addition, there are there are other components making part of the grazing paddock such as gastrointestinal nematodes’ eggs ( trients ( trients ), planttrients trients( secondary ( ), ( plant ), plant compounds ), secondary plant secondary secondary compoundslike compounds terpenes compounds like ( like terpenes liketerpenes ), terpenesalkaloids ( ( ( ( ), alkaloids ), alkaloids ), alkaloids ), and ( (phenolic ( ), and ),compounds and phenolic ), and phenolic phenolic). Incompounds( addition, compounds compounds there( ( are ( other components making part of the grazing paddock such as gastrointestinal nematodes’ eggs ( trientstrients (trients ( ), (plant ), plant ),secondary plant secondary secondary compounds compounds compounds like terpenes like like terpenes terpenes ( ( ( ), alkaloids ), alkaloids ), alkaloids ( ( ( ), and ), phenolic and ), and phenolic phenolic compounds compounds compounds ( ( ( ). In). 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In addition, there are other components making part of the grazing paddock such as gastrointestinal nematodes’ eggs ( ), and infective larvae ( ). Other herbivores such as domestic cattle, white-tailed deer (Odocoileus virginianus yucatanensis), reptiles, birds, and insects are part of the landscape. Also, farmer management and human (non-farmer) ), and infective ( ), and ),larvae and ).infective ), Other and infective ( infective herbivores larvae ).larvae Other (larvae ( such herbivores ( ). as Other domestic ). Other ).such herbivoresOther herbivores cattle,as herbivoresdomestic white-tailedsuch such ascattle, such domestic as domestic white-tailed deeras domestic (Odocoileuscattle, cattle, white-tailed cattle,deer white-tailed (Odocoileus virginianus white-tailed deer deer (Odocoileus yucatanensis),virginianus deer (Odocoileusyucatanensis), (Odocoileus virginianus reptiles, virginianus reptiles, virginianus birds, birds, and insects are part of the landscape. 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Also, mana and Also, humanfarmer gementAlso, farmer farmermana (non-farmer) and management humanmanagementgement and impacts(non-farmer) and humanimpacts and human are human (non-farmer) importantare (non-farmer) important (non-farmer) factors factors which must be studied and understood in order to improve its utilization and design more yucatanensis),yucatanensis),yucatanensis), reptiles, reptiles, reptiles, birds, birds, and birds, insectsand and insects areinsects part are are ofpart thpart eof landscape. ofth eth landscape.e landscape. Also, Also, farmer Also, farmer manafarmer management management gementand humanand and human human(non-farmer) (non-farmer) (non-farmer) sustainable production systems in this “ever-changing” environment. impacts are impactsimportantimpactsimpacts are factors areimportant areimportant which important factors must factors factors whichbe whichstudied mustwhich must and be must studiedbeunders studied be studiedtood and and undersin andorder unders understood totood improve intood order in order in itsto order improveutilization to improve to improve its and utilizationits designutilization its utilizationsustainable moreand and design and designproduction designmore more more systems in this “ever-changing” environment. impactsimpactsimpacts are important are are important important factors factorswhich whichfactors mustwhich must which be mustbe studied must studied be bestudied and studiedand understood unders and and understood unders in toodin order toodorder in to inorder improveto order improve to toimprove its improve its utilization utilization its itsutilization utilization and and design design and and more design moredesign sustainable more more production systems sustainablesustainablesustainable production production productionsustainablesustainable insystemssustainable thissystems “ever-changing”systemsproduction in production thisin thisproduction in“ever-changing” this“ever-changing” systems systems“ever-changing” environment. systems in this in environment.this “ever-changing”in environment. this “ever-changing” environment. “ever-changing” environment. environment. environment. sustainable production systems in this “ever-changing” environment. The term nutraceuticalThe term nutraceutical has been coined has been by coinedcombining by combining the word “nutritional”the word “nutritional” with with “pharmaceutical”, and it represents “any livestock feed which combines nutritional value The term nutraceuticalTheThe ThetermThe term term nutraceutical term nutraceuticalhas nutraceutical nutraceutical been coined has has been has hasby been been combining coinedbeen coined coined coined by by combiningthe by combiningby combiningword combining “nutritional”the the word the theword word “nutritional”word with“nutritional” “nutritional” “nutritional” with with with “pharmaceutical”,with and it represents “any livestock feed which combines nutritional value The termTheThe term nutraceutical term nutraceutical nutraceutical has beenhas has been coined been coined coinedby combining by by combining combining the wordthe the word “nutritional”word “nutritional” “nutritional” with with with with beneficial effects on animal health” [13–15]. This implies that its validation depends “pharmaceutical”,“pharmaceutical”,“pharmaceutical”,“pharmaceutical”,“pharmaceutical”, and it represents and and andit andrepresents“any it itrepresents representsit livestock represents “any “any feed “any livestock “any livestockwhich livestock livestock feed combines feed feedwhich feed which which nutritional whichcombines combines combines combines nutritionalvalue nutritional nutritional nutritional value value value valuewith beneficial effects on animal health” [13–15]. This implies that its validation depends “pharmaceutical”,“pharmaceutical”,“pharmaceutical”, and itand represents and it representsit represents “any “any livestock “any livestock livestock feed feedwhich feed which combineswhich combines combines nutritional nutritional nutritional value value value on the development of methodologies capable of identifying both the nutritional and with beneficialwithwith witheffects beneficialwith beneficial beneﬁcial beneficialon animal effects effects effects effectshealth”on onanimal on animalon animal[13–15]. animal health” health” health” This health” [13–15]. implies[13–15]. [13 [13–15].– This15 that]. This Thisimplies Thisits implies impliesvalidation implies that that thatits that dependsitsvalidation its validationits validation validation depends depends depends depends on the development of methodologies capable of identifying both the nutritional and withwith beneficialwith beneficial beneficial effects effects effectson animal on on animal animal health” health” health” [13–15]. [13–15]. [13–15]. This Thisimplies This implies implies that itsthat that validation its its validation validation depends depends depends pharmaceutical properties of a given resource. However, these two aspects are not the on the developmenton onthe onthe development the developmentof developmentmethodologies of methodologiesof methodologiesof capabl methodologiese of capablidentifying capabl capable ofe identifyingof bothe identifyingof identifyingthe nutritional both both theboth the nutritionaland thenutritional nutritional and and pharmaceutical and properties of a given resource. However, these two aspects are not the on theon on developmentthe the development development of methodologies of ofmethodologies methodologies capabl capabl ecapabl of eidentifying ofe ofidentifying identifying both boththe both nutritionalthe the nutritional nutritional and and and pharmaceuticalpharmaceuticalpharmaceutical propertiespharmaceutical propertiesof propertiesa given properties ofresource. aof given aof given a However,givenresource. resource. resource. theseHowever, However, twoHowever, aspectsthese these twothese are two aspects nottwo aspects the aspects are are not arenot the not the the pharmaceuticalpharmaceuticalpharmaceutical properties properties properties of a ofgiven ofa givena resource.given resource. resource. However, However, However, these these two these twoaspects two aspects aspects are notare are thenot not the the

Agronomy 2021, 11, 1403 3 of 20

on the development of methodologies capable of identifying both the nutritional and pharmaceutical properties of a given resource. However, these two aspects are not the only ones associated with animal performance in complex production systems. Biotic and abiotic factors (either from the ecosystem itself or arising from farmer management) should also be considered, as they could influence the performance of sheep and goats. Plant secondary compounds (PSCs) and gastrointestinal nematodes (GINs) are unavoidable components of the LDF ecosystem, as they mediate its interactions with herbivores [16–18]. The PSCs play a vital role in plant defense and provide plasticity that allows for the interactions of the plants with their environment [19–21]. They are broadly categorized into three functional groups: (i) alkaloids, with up to 20,000 reported molecules [22], (ii) terpenes, with up to 80,000 molecules [23], and (iii) phenolic compounds, with up to 8000 molecules [24]. Within the last group, condensed tannins (CTs) are the most studied PSCs in relation to the nutrition and health of ruminant livestock [25–27]. The bioactive properties of CTs against helminth infections [28–30] and the capacity of CTs and GINs to modulate methane production at a ruminal level [31–33] have been recently explored. In the present review, we focused on the anthelmintic effects of PSCs because GIN infections are also a common feature in grazing ruminant production systems [34,35]. GIN infections are currently considered one of the main drawbacks for small ruminant productive systems worldwide [36–38]. Considering the above, proper and systematic validation of the nutraceutical properties of plant species should merge the nutritional and sanitary effects by studying the relationships between ruminants, their GINs, and the macronutrient/PSC content of plants. Recently, we presented an interdisciplinary proposal to identify plant species with nutraceutical potential using small ruminants and their GIN infections as a model [39]. Broadly, the methodology established that the nutraceutical validation of plant materials should involve disciplines such as botany, ecology, agronomy, ethology, ethnoveterinary, nutrition, parasitology, and chemistry. The general process, which is outlined in Figure2 , is briefly structured in ten steps, described as follows: (i) identify and classify the plant species occurring in the field, (ii) assess the plants’ biomass availability, (iii) confirm—by ethnoveterinary or direct observation—those plants freely consumed by animals, (iv) estimate the selection of plant species, (v) perform a chemical characterization of the plant material, including nutrients and PSCs, (vi) evaluate the plants’ digestibility with in vitro or in vivo techniques, (vii) establish techniques for PSC purification using specific solvents, (viii) evaluate the bioactive effect of extracts using in vitro parasitological tests in different stages of the biological cycle of GINs, (ix) perform in vivo trials under controlled— single choice or cafeteria—conditions, and (x) carry out field in vivo trials that take into consideration the natural behavior of small ruminant species. In the present work, we present a systematic review on the efforts to evaluate both in vitro and in vivo nutraceutical feed resources from such a heterogeneous vegetation scenario, with the aim to encourage future research that deepens our knowledge of the relationships between small ruminants, their GINs, plants’ nutrients, and PSCs, thus contributing to the revalorization of native vegetation systems. Agronomy 2021, 11, 1403 4 of 20

Figure 2. The ten-step proposed protocol for the identiﬁcation of plants with nutraceutical potential. The parentheses represent each step mentioned above. A cyclic conceptualization, where each component provides feedback to the other, was presented by Torres-Fajardo et al. [39].

2. Methods The process of the search and classification of bibliographic material began on 1 March 2020, a last search was performed on 1 February 2021. The web-based search comprised databases such as the Wiley Online Library (https://onlinelibrary.wiley.com/, accessed on 15 May 2021), Springer Link (https://link.springer.com/, accessed on 15 May 2021), Science Direct (https://www.sciencedirect.com/, accessed on 15 May 2021), PubMed (https://pubmed.ncbi.nlm.nih.gov/, accessed on 15 May 2021) and the Multidisciplinary Digital Publishing Institute (https://www.mdpi.com/, accessed on 15 May 2021). The database Scielo (https://scielo.org/es/, accessed on 15 May 2021) was considered for searching manuscripts in Spanish and Portuguese languages. For the data collection, the following keywords were used: “low deciduous forest OR tropical deciduous forest”, “anthelmintic activity OR anthelmintic plants OR bioactive plants”, “plant secondary compounds OR plant secondary metabolites”, “nutraceuticals”, “gastrointestinal nematodes”, “sheep”, and “goats”. The authors selected and reviewed the manuscripts to meet the pre-established inclusion criteria, as follows: (i) studies involving small ruminants (sheep and/or goats), (ii) studies evaluating plant species from an LDF, (iii) studies involving GIN species of small ruminants, (iv) in vitro studies specifying solvents/methods for PSC extraction, (v) in vitro studies reporting the use of parasitological techniques to evaluate the bioactivity of compounds on specific stages of the GIN biological cycle, (vi) in vivo studies considering a patent GIN infection, and (vii) in vivo studies administering foliage or extracts from LDF plant species. This search methodology resulted in 31 original peer-reviewed manuscripts fulfilling the criteria.

3. Results The literature search produced 31 publications from nearly 20 years of research in the LDF ecosystem. Broadly, the analyzed studies were performed in a tropical subhumid area ◦ (Aw0), with an annual average temperature of 26–27.6 C, relative humidity of 72%, and an average rainfall of 728–1000 mm. A common feature in the ecosystem is its marked dry season between November and May, causing the shrubs and tree species to lose approximately 70% of their foliage cover. In summary, 16 studies used the in vitro approach on the leaves of plants and are presented in Table1. In addition, Table2 includes 11 in vivo Agronomy 2021, 11, 1403 5 of 20

studies, with 7 of them evaluating the leaves of a single plant and the remaining 4 using a cafeteria protocol, using the leaves of different plant species. Table3 shows four in vivo studies performed under the natural field grazing/browsing conditions of the LDF. Finally, Table4 presents the anthelmintic effect ( in vitro and in vivo) of low deciduous forest plant species against different phases of gastrointestinal nematodes’ biological cycle. For the in vitro approach (16 studies), a total of 12 plants were evaluated. The most commonly incorporated species were Lysiloma latisiliquum (representing 56% of the studies), Acacia pennatula (50%), Leucaena leucocephala (37%), Senegalia gaumeri (31%), Havardia albicans (25%), and Piscidia piscipula (25%); all of these plants belong to the Fabaceae family. The Malphigiaceae and Polygonaceae families were also included in two (12.5%) of the studies, while Moraceae and Phytolaccaceae were used in one study. Most studies (81%) used acetone–water (70:30) extracts, while three studies (18%) used methanol–water (70:30) extracts. Other methodologies—or solvents—for extraction aimed at isolating certain PSCs of interest, such as flavonoids, terpenoids, triterpenoids, coumarins, saponins, flavonoid glycosides, and alkaloids. Usually, the CTs were the target PSCs that were mostly studied (81%). The screening of alkaloids, flavonoids, and saponins was considered in 12% of the studies. Regarding the GIN species used for the in vitro screening, 93% (15/16) of the studies used the abomasal nematode Haemonchus contortus, while the intestinal nematode Trichostrongylus colubriformis was used in one study. The larval exsheathment inhibition test (LEIT) was the most employed test (56%), followed by the larval motility inhibition test (LMIT) (44%), and the egg inhibition test (EHT) (37%). In the in vivo approach, which included 11 controlled experiments, goats were used in 63% of occasions (7/11), while sheep were used in 36% of the experiments (4/11). The mean body weight (± standard deviation) of experimental animals was 16.8 ± 8.36 kg. Monospecific infection with the abomasal nematode H. contortus was employed in nine studies (81%), while a natural H. contortus infection and a mixed infection of H. contortus plus T. colubriformis were studied in one trial each. Similar to the in vitro approach, the main target PSCs of the in vivo studies were the CTs, representing 81% of the trials. Within the ten plants used under this approach, L. latisiliquum was the most frequently used (45%), followed by G. floribundum (36%), H. albicans (36%), and L. leucocephala (27%). The shrub A. pennatula, which was the second-most used resource in in vitro trials (used in seven studies), was only tested once in an in vivo trial. The four studies that were performed under natural feeding conditions took place during the rainy season, when plant species have more biomass. All these studies used a natural GIN infection—mainly composed of H. contortus, T. colubriformis, and Oesophagostomum columbianum. In addition, all studies implemented a direct observational methodology with the aim of quantifying the voluntary feed intake of experimental animals [40,41]. Agronomy 2021, 11, 1403 6 of 20

Table 1. Screening the in vitro anthelmintic activity against small ruminant’s gastrointestinal nematodes using different extracts produced from the leaves of plant species present in the low deciduous forest.

GIN Species Plant(s) Family Type of Solvent PSC Type Type of Assay Salient Results Reference (Isolate(s) Origin) Acacia pennatula The four extracts showed good results Leucaena leucocephala Acetone–Water Haemonchus contortus LMIT Fabaceae CT PVPP in LEIT. In LMIT, P. piscipula did not [42] Lysiloma latisiliquum (70:30) (French isolate) LEIT show activity. Piscidia piscipula Havardia albicans Acetone–Water H. contortus S. gaumeri did not have an effect Fabaceae CT LMIT [43] Senegalia gaumeri (70:30) (Mexican temperate isolate) against larvae motility. A. pennatula The four extracts showed good results L. leucocephala Acetone–Water Trichostrongylus colubriformis LMIT Fabaceae CT PVPP in LEIT. In LMIT, P. piscipula did not [44] L. latisiliquum (70:30) (French isolate) LEIT show activity. P. piscipula A. pennatula H. contortus Sensitivity of H. contortus strains was L. leucocephala Acetone–Water Fabaceae CT PVPP (Temperate and tropical LMIT related with their origin as well as the [45] L. latisiliquum (70:30) Mexican isolates) contact with tannin-rich plants. P. piscipula H. albicans L. leucocephala Fabaceae S. gaumeri and H. albicans were Acetone–Water H. contortus LMIT S. gaumeri CT more potent inhibitors of larvae [46] (70:30) (French isolate) LEIT biology. Brosimum alicastrum Moraceae H. contortus EHT Extracts’ bioactivity on both assays Phytolacca icosandra Phytolaccaceae E, DCM, n-H F, St, T, A, C, Sp ¤ [47] (Temperate Mexican isolate) LMIT was E > DCM > n-H. Acetone–Water H. contortus CTs formed aggregates in the buccal L. latisiliquum Fabaceae CT ANM [48] (70:30) (Mexican and French isolates) capsule, female vulva, and anus. Blocking CTs with PVPP increased the Acetone–Water H. contortus L. latisiliquum Fabaceae CT PVPP EHT AH effect of the extract. [49] (70:30) (Temperate Mexican isolate) First work using EC50 values. A tropical Mexican—but not Acetone–Water A. pennatula Fabaceae CT PVPP 10 isolates of H. contortus § EHT local—strain was the least susceptible [50] (70:30) against extract. H. contortus L from 1 to LMIT Acetone–Water 3 EC and EC of L were different: A. pennatula Fabaceae CT 7 weeks of age LEIT 50 90 3 [51] (70:30) w1 < w2 = w3 = w4 = w5 < w6 = w7. (Tropical Mexican isolate) LMOT Agronomy 2021, 11, 1403 7 of 20

Table 1. Cont.

GIN Species Plant(s) Family Type of Solvent PSC Type Type of Assay Salient Results Reference (Isolate(s) Origin) Acacia collinsi A. pennatula H. albicans L. leucocephala Fabaceae Positive correlations L. latisiliquum M–W CT, H. contortus EHT were found between the EC50 of Mimosa bahamensis PVPP [52] 70:30 PP (Tropical Mexican isolate) LEIT extracts and their CT and TP contents P. piscipula in the EHT. S. gaumeri Bunchosia swartziana Malpighiaceae Gymnopodium ﬂoribundum Polygonaceae Lowest and highest EC were from a Acetone–Water 50 A. pennatula Fabaceae CT PVPP 10 isolates of H. contortus § LEIT Mexican and a French isolate, [53] (70:30) respectively (36.44 vs. 501.40 µg/mL). Acetone–Water, M–W, FG, quercitrin, H. contortus The AH activity against L was L. latisiliquum Fabaceae M, E, MChl, DCMSE, LEIT 3 [54] arbutin (Tropical Mexican isolate) A–W > M–W = M = MSE. EASE, and MSE A. collinsi A. pennatula H. albicans L. leucocephala Fabaceae Despite their low CT quantities, S. L. latisiliquum Acetone–Water H. contortus EHT CT gaumeri showed the highest AH effect [55] M. bahamensis (70:30) (Tropical Mexican isolate) LEIT P. piscipula against GIN eggs and larvae. S. gaumeri B. swartziana Malpighiaceae G. ﬂoribundum Polygonaceae Acetone–Water, and The AH activity against L was L. latisiliquum Fabaceae then compared FR, OD, CT H. contortus LEIT 3 [56] OD > LP = FR. and LP Agronomy 2021, 11, 1403 8 of 20

Table 1. Cont.

GIN Species Plant(s) Family Type of Solvent PSC Type Type of Assay Salient Results Reference (Isolate(s) Origin) Although p-coumaric acid was M–W H. contortus S. gaumeri Fabaceae F, Sp, 3T, A EHT suggested as a bioactive, it failed to [57] 70:30 (Tropical Mexican isolate) show effects alone. Type of solvent: E (ethanolic), DCM (dichloromethane), n-H (n-Hexane), M–W (methanolic–water), M (methanolic), Mch (methanol–chloroform), DCMSE (dichloromethane successive extractions), EASE (ethyl acetate successive extractions), MSE (methanol successive extractions), FR (fresh leaves), OD (oven-dried), LP (lyophilized). Target PSCs: CT (condensed tannins), F (ﬂavonoids), St (steroids), T (terpenoids), C (coumarins), Sp (saponins), PP (polyphenols), FG (ﬂavonoid glycosides), 3T (triterpenes), A (alkaloids), ¤ (assessments were qualitative), PVPP This super index represents the studies that used polyvinyl pyrrolidone to neutralize CTs and differentiate their effects. GIN (gastrointestinal nematode) species: L3 (third larvae stage), § (larvae origin: two Mexican from template climates, two Mexican from tropical climates, two from Australia, two from France, one from South Africa, and one from the United States of America). Type of assay: LMIT (larvae motility inhibition test), LEIT (larvae exsheathment inhibition test), EHT (egg hatch test), ANM (adult nematode measurements), LMOT (larvae motility observation test). Salient results: EC50 (effective concentration 50), EC90 (effective concentration 90), µg/mL (micrograms per milliliter), AH (anthelmintic). w1 (week 1), w2 (week 2), and so forth.

Table 2. Nutritional and parasitological effects reported for sheep or goats when consuming the leaves of different plants from the low deciduous forest in pen studies or cafeteria studies, either with natural or controlled GIN infections.

Type of Infection. Scenario Species n Age Plant(s) PSC Type Nutritional Effect Parasitological Effect Reference (Isolate(s) Origin) Mixed Total counts of adult GINs Controlled Goat 18 6 m Hc, Tc L. latisiliquum CT PEG NR were reduced by 70% after L. [58] (Mexican and French isolates) latisiliquum consumption. Monospecific Higher consumption of Lower GIN female size, Controlled Sheep 22 2 m Hc. L. latisiliquum CT L. latisiliquum in infected fecundity, and EPG excretion [59] (Temperate Mexican isolate) animals. in infected animals †. Monospecific Lower DMD for animals H. albicans inclusion reduced Controlled Sheep 21 3 m Hc. H. albicans CT PEG [60] consuming H. albicans. the length of female GIN †. (Temperate Mexican isolate) Monospecific Significant reduction (72%) C, F, Sp Controlled Goat 12 3 m Hc. P. icosandra NR of EPG excretion in the [61] St, T (Temperate Mexican isolate) treated group. Significant reduction (58.8%) Monospecific Lower DMD for animals Controlled Sheep 28 3 m H. albicans CT PEG of EPG excretion in the [62] Hc consuming H. albicans. treated group. Monospecific Changes in the cuticle, Controlled Goat 4 NR Hc. L. latisiliquum CT NR buccal capsule, and cephalic [48] (Mexican and French isolates) region (assessed by SEM†). Agronomy 2021, 11, 1403 9 of 20

Table 2. Cont.

Type of Infection. Scenario Species n Age Plant(s) PSC Type Nutritional Effect Parasitological Effect Reference (Isolate(s) Origin) Neither intake nor L. leucocephala selection were modified Reduction of 91.1% of EPG G. floribundum Cafeteria Goat 12 3–5 y Natural CT between experimental excretion in infected goats [63] M. bahamensis groups (infected vs. during the trial. Viguiera dentata non-infected). A. pennatula B. alicastrum Neither intake nor G. floribundum Reductions of 28.08% and Monospecific selection were modified H. albicans 13.61% of EPG during two Cafeteria Goat 12 3–5 y Hc. CT between experimental [64] L. latisiliquum experimental periods (5 days (Tropical Mexican isolate) groups (infected vs. L. leucocephala each period). non-infected). M. bahamensis P. piscipula GIN infection increased H. albicans Reduction of 70% of EPG Monospecific CT consumption. G. floribundum excretion for infected and Cafeteria Goat 22 NR Hc. CT PEG PEG administration [65] L. leucocephala non-infected goats during (Tropical Mexican isolate) reduced L. leucocephala P. piscipula the trial. and CP consumption. PP diet caused Monospecific ultrastructural changes in Controlled Goat 4 NR Hc. L. latisiliquum PP NR [66] muscular and intestinal cells, (Tropical Mexican isolate) assessed by SEM †. Monospecific G. floribundum inclusion Inclusion of plant at 40% Controlled Sheep 30 3–4 m Hc. G. floribundum CT reduced DMD reduced TFEC and number [67] (Tropical Mexican isolate) and OMD. of adult female GINs. Age: m (months), y (years), NR (not reported). N: Number of experimental animals. Type of infection: Hc (Haemonchus contortus), Tc (Trichostrongylus colubriformis). Target PSCs: CTs (condensed tannins), C (coumarins), F (flavonoids), Sp (saponins), St (steroids), T (terpenoids), PP (polyphenol), PEG This super index represents the studies that used polyethylene glycol to neutralize CTs and differentiate their effects. Nutritional effect: NR (not reported), DMD (dry matter digestibility), GIN (gastrointestinal nematodes), PEG (polyethylene glycol), OMD (organic matter digestibility), CP (crude protein). Parasitological effect: EPG (eggs per gram), SEM (scanning electron microscopy), TFEC (total fecal egg count), † (studies that assessed the relationships between PSC consumption and post-mortem adult nematode measurements). Agronomy 2021, 11, 1403 10 of 20

Table 3. Interactions between the natural gastrointestinal nematode infection and the feeding behavior of sheep or goats when browsing the foliage of the plant species present in the low deciduous forest of México. All the studies were performed during the rainy season (between June and October) and employed a continuous bite monitoring methodology for feeding behavior assessment.

Number of Species Age n GIN Infection Composition Max EPG Mean Duration (Months) % CT in Diet Salient Results Reference Plants Consumed 15.3% Hc Anthelmintic treatment did not Goat 5–9 y 12 46.1% Tc 450 3 35 1.5 modify the macronutrient [68] 38.4% Oc or CT intake. Kids consumed less low-stratum plants and more Sheep and goat 4–5 m 24 Hc, Tc, Oc † NR 3 37 NR [69] medium-stratum plants, resulting in lower GIN infections. Reduction of 78% of EPG during 44% Hc the ﬁrst experimental stage. Goat Adult 36 30% Tc 2450 3.5 45 5–9 PEG [70] Higher selectivity towards 26% Oc grass species. Reduction of 81.2% of EPG 44% Hc during experiment. Goat Adult 12 30% Tc 1300 1 NR NR [71] All goats consumed more grass 26% Oc species in the early mornings. Age: m (months), y (years). N: Number of experimental animals. GIN infection composition (composition of natural gastrointestinal nematodes infection); Hc (Haemonchus contortus), Tc (Trichostrongylus colubriformis), Oc (Oesophagostomum columbianum); † (Adult identiﬁcation was done during necropsy, fecal cultures were not performed). Max EPG mean (maximum mean of gastrointestinal nematode eggs per gram of feces; NR (not reported). Number of plants consumed: NR (not reported). % CT in diet: Percentage of condensed tannins in diet, PEG This super index represents those studies that used polyethylene glycol to neutralize CTs and differentiate their effects, NR (not reported). Salient results: GIN (gastrointestinal nematodes), EPG (eggs per gram), DM (dry matter). Agronomy 2021, 11, x 12 of 21

Table 4. Summary of the anthelmintic effect of the low deciduous forest plants species against different phases of gastrointestinal nematodes’ biological cycles 1.

Reduction of EPG Plant Species Family In Vitro Tests 2 Counts in In Vivo Agronomy 2021, 11, 1403 Trials 3 11 of 20 Eggs Larvae Adult GIN Acacia collinsi Fabaceae   nsy nsy Acacia pennatula Fabaceae   nsy  BrosimumTable alicastrum 4. Summary ofMoraceae the anthelmintic effect ofnsy the low deciduous forest plants species againstnsy different phases of gastroin- Bunchosiatestinal swartsiana nematodes’ Malpighiaceae biological cycles 1.   nsy nsy Gymnopodium flori- Polygonaceae   nsy Reduction of EPG bundumPlant Species Family In Vitro Tests 2 Counts in In Vivo Trials 3 Havardia albicans Fabaceae     Leucaena leucocephala Fabaceae  Eggs Larvae Adultnsy GIN  Lysiloma latisiliquumAcacia collinsi Fabaceae Fabaceae  √ √ nsy nsy Mimosa bahamanesisAcacia pennatula Fabaceae Fabaceae  √ √ nsynsy  PhytolaccaBrosimum icosandra alicastrum PhytolaccaceaeMoraceae  nsy  √ nsynsy  PiscidiaBunchosia piscipula swartsiana FabaceaeMalpighiaceae  √ √ nsynsy nsy SenegaliaGymnopodium gaumeri floribundumFabaceaePolygonaceae  √ √ nsynsy nsy√ ViguieraHavardia dentata albicans Asteraceae Fabaceae nsy √nsy √ √nsy  √ 1 ForLeucaena a more leucocephala detailed description Fabaceaeof this process, as well√ as other factors √ involved, pleasensy refer to previous tables and consultLysiloma the latisiliquumreferences herein. 2 In Fabaceaevitro tests: GIN (gastrointestinal√ nematodes). √  (at least √one study has reported√ some anthelminticMimosa bahamanesis effect over this biologicFabaceaeal cycle phase), nsy (not√ studied yet). √3 Reduction of EPGnsy counts in in vivo trials:  a reductionPhytolacca in eggs icosandra per gram (EPG)Phytolaccaceae excretion has been reported√, but the study √ was designednsy as a cafeteria trial, in which√ Piscidia piscipula the anthelmintic effect of a given plFabaceaeant should be interpreted√ cautiously. √ nsy Senegalia gaumeri Fabaceae √ √ nsy nsy Viguiera dentata Asteraceae nsy nsy nsy 4. Discussion 1 For a more detailed description of this process, as well as other factors involved, please refer to previous tables and consult the references herein. 2 In vitro tests: GIN (gastrointestinalThe present nematodes). work reviews√(at least the one state study of has the reported efforts some to anthelminticevaluate the effect in overvitro this and biological in vivo cycle phase), nsy (not studiednutraceutical yet). 3 Reduction potential of EPG countsof feed in inresources vivo trials: froma reduction the heterogeneous in eggs per gram vegetation (EPG) excretion of the has beenLDF. reported, but the study wasAfter designed the as literature a cafeteria trial,search, in which we classified the anthelmintic and effectanalyzed of a given 31 manuscripts plant should be produced interpreted cautiously. in almost two decades of research. It is important to highlight that the screening process of nutraceu- tical4. plants Discussion in the LDF was partly derived by the search for non-chemical alternatives for the controlThe of present GINs in work small reviews ruminants, the state which of the could efforts help to with evaluate combating the in vitroGIN andpopula-in vivo tionsnutraceutical resistant to potentialconventional of feed chemical resources therapy. from Anthelmintic the heterogeneous products vegetation emerged of in the the LDF. 1960sAfter and the had literature a continuous search, release we classified of novel and molecules analyzed for 31 three manuscripts decades produced [72,73]. During in almost thistwo period, decades the ofcontinuous research. Itrelease is important of produc to highlightts in the thatmarket the screeningoffered good process therapeutic of nutraceu- results.tical However, plants in thethis LDF strategy was partlyis now derivedconsidered by theunsustainable search for non-chemical on its own [36,74,75]. alternatives An- for thelminticthe control resistance of GINs leads in smallto poor ruminants, control of whichGIN infection, could help and withhence, combating these parasites GIN popula- still exerttions profound resistant effects to conventional on the nutrition, chemical health, therapy. and Anthelminticwelfare of their products hosts, emergedand conse- in the quently1960s threaten and had the a continuousprofitability release of grazin of novelg production molecules systems for three worldwide decades [76–78]. [72,73]. Con- During sequently,this period, alternatives the continuous to conventional release anthel of productsmintic treatment, in the market such offered as the feeding good therapeutic of PSC- richresults. plants However,or the use thisof their strategy bioactive is now co consideredmpounds, unsustainablehave been a matter on its ownof intensive [36,74,75 re-]. An- searchthelmintic [79–81]. resistance leads to poor control of GIN infection, and hence, these parasites still exertThe profoundnutraceutical effects approach on the nutrition, represents health, an in andtegral welfare view of the their plant–animal hosts, and consequently interac- tionsthreaten because the it profitabilitytakes into account of grazing elements production other systemsthan PSCs. worldwide Although [76 the–78 ].information Consequently, gatheredalternatives when toassessing conventional the nutraceutical anthelmintic pote treatment,ntial of suchplants as is the relevant feeding to of develop PSC-rich new plants productionor the use systems of their or bioactive strategies, compounds, a thorough have methodology been a matter for its of evaluation intensive research in ruminant [79–81 ]. livestockThe is still nutraceutical under construction. approachrepresents Benell et al. an [82] integral presented view of a thesystematic plant–animal approach interac- aimedtions at becauseselecting it native takes Australian into account plants elements with otherbioactive than benefits. PSCs. Although Later, Hoste the et information al. [13] establishedgathered some when guidelines assessing fo ther the nutraceutical evaluation potentialof nutraceutical of plants plant is relevant materials to using develop dif- new ferentproduction CT-rich legume systems plants or strategies, as models, a thorough and Torres-Fajardo methodology et foral. [39] its evaluation proposed inan ruminantinter- disciplinarylivestock approach is still under used construction.to identify plant Benell species et al. with [82 nutraceutical] presented a potential systematic from approach het- erogeneousaimed at vegetation selecting native scenarios, Australian also using plants GIN with infection bioactive as benefits.a model. Later, The implementa- Hoste et al. [13] tionestablished of the nutraceutical some guidelines concept foron thespecific evaluation plant species of nutraceutical has also been plant considered materials by using Peña-Espinozadifferent CT-rich et al. [83] legume in reviewing plants as the models, potential and use Torres-Fajardo of chicory (Cichorium et al. [39 intybus] proposed) as a an interdisciplinary approach used to identify plant species with nutraceutical potential from heterogeneous vegetation scenarios, also using GIN infection as a model. The implementation of the nutraceutical concept on specific plant species has also been considered by Peña-Espinoza et al. [83] in reviewing the potential use of chicory (Cichorium intybus) as a nutraceutical forage in parasitized livestock, by Marie-Magdeleine et al. [84] in evaluating the nutraceutical potential of pelleted Leucaena Leucocephala leaves in goat kids, and by Oliveira et al. [85] in reviewing the use of Mediterranean salt-tolerant plants as nutraceuti- Agronomy 2021, 11, 1403 12 of 20

cals or phytotherapeutics in ruminants. In the following discussion, we tackle the studies that have collectively evaluated the nutraceutical value of LDF plant species.

4.1. The In Vitro Experiences The use of in vitro studies as part of a nutraceutical screening process of LDF plants was first reported in 2008 by Alonso-Díaz et al. who studied the effect of four tannin-rich plant extracts against two fundamental processes of the infective larvae (L3): motility and exsheathment. In this first study, the L3 of the abomasal H. contortus [42] and the intestinal T. colubriformis [44] GIN species (French isolates) were used and showed that A. pennatula, L. latisiliquum, and L. leucocephala at 1200 micrograms per milliliter (µg/mL) had anthelmintic activity, as measured with the larval migration inhibition test (LMIT), while P. piscipula did not show such properties. On the contrary, all the plant extracts showed anthelmintic activity in the larval exsheathment inhibition test (LEIT). Subse- quently, S. gaumeri and H. albicans extracts were tested using the LMIT [43,46] and LEIT [46], showing that H. albicans caused a reduction of 48 and 68.9% in the L3 motility at 1200 and 2400 µg/mL, respectively. Meanwhile, S. gaumeri showed no effect as per the LEIT [43], but a reduction of 20.9% in the LMIT [46]. Given that all extracts exerted activity against exsheathment at 300 µg/mL in the latter study, it was concluded that the LEIT was more sensitive compared with the LMIT. The egg hatching test (EHT) was initially performed by Hernández-Villegas et al. [47], but the work of Vargas-Magaña et al. [49] suggested that the main effect of L. latisiliquum acetone–water (A–W) extracts was to prevent the larvae eclosion from eggs, which is the final step in the hatching process. This mechanism was later confirmed with A. pennatula extracts [50]. The proposed mechanism to explain this activity includes the inhibition of enzymes, the binding of egg-structural proteins, the binding of receptors, or a synergy between these processes [86,87]. It is worth mentioning that Calderón-Quintal et al. [45] and Chan-Pérez et al. [50,53] provided the first evidence of variation in susceptibility according to the GIN geographic origin. In the first work, differences in susceptibility were evidenced in three H. contortus strains from different regions of México. Strains from tropical México, which, in principle, have been in frequent contact with tropical CT-rich plants due to their regular intake by sheep and goats while browsing the LDF, were less sensitive to the extracts compared to the strain from a temperate zone of México. In the second and third works, the same tendency was found when using A. pennatula extracts against ten H. contortus isolates from diverse geographical origins (two from temperate climates in México, two from tropical climates in México, two from Australia, two from France, one from South Africa, and one from the United States of America). Another striking result that emerged from subsequent studies was the consideration of the larval age as a factor affecting the outcome of in vitro tests in tropical environments [51]. In this case, the LEIT evidenced that one-week-old H. contortus infective larvae showed higher motility and susceptibility to extracts, two to five-week-old infective larvae showed a good exsheathment ability, and older infective larvae showed greater exsheathment variability. Considering these results, it was reasonable to recommend the use of two-to-five week-old infective larvae for future studies. A recent study proposed the use of T. colubriformis infective larvae no older than 7 weeks of age [88]. As a result, the use of infective larvae, under tropical conditions should within a range of age that challenges the recommendation of three months made by other authors with larvae under temperate conditions [89]. However, a direct implication of this recommendation is the huge challenge that it represents for tropical laboratories, as they would need to produce their biological material constantly [90]. Regarding solvents for the extraction of PSCs, contrasting outcomes were noted by evaluating the bioactivity of ten plant species using methanol–water (M–W; 70:30) [52]. To begin with, the A. pennatula extract needed the highest concentrations to inhibit the 50% of egg hatching (EC50: 8180.8 µg/mL) and the 50% of larval exsheathment (EC50: 426 µg/mL). Secondly, L. leucocephala and S. gaumeri extracts showed the lowest EC50 values in the EHT and LEIT (139.9 and 186.3 µg/mL, respectively), albeit they had the lowest CT content Agronomy 2021, 11, 1403 13 of 20

among the studied plants. Finally, H. albicans, G. floribundum, and S. gaumeri showed EC50 values of 63.5, 66.9, and 184.7 µg/mL, respectively in the LEIT. Castañeda-Ramírez et al. [55] provided the first in vitro proposal to evaluate the nutraceutical value of the ten feed resources used in the previous experiment. In this protocol, the authors evaluated the macronutrient content, the in vitro dry matter, and the organic matter digestibility. The extracts were obtained with acetone–water (A–W; 70:30) solvents and subsequently employed in the EHT and LEIT. The extracts of S. gaumeri showed the lowest EC50 values in the EHT (401.8 µg/mL) and LEIT (83.1 µg/mL), together with a good macronutrient profile (21.4% crude protein and 17.0% acid detergent fiber), in vitro organic matter digestibility (53.5%), and low CT contents (1.0%). Hence, this plant was used in a forthcoming study with the aim of isolating the metabolites involved in its AH activity through a bio-guided fractionation technique [57]. This methodology allowed the identification of p-coumaric acid—a phenolic compound—as the bioactive molecule. However, when this compound was tested alone, there was no AH effect, suggesting a synergy with other PSCs. Finally, a study performed by Hernández-Bolio et al. [54] used a metabolomic approach on the shrub/tree L. latisiliquum and suggested AH effects of highly polar PSCs, such as quercitrin and arbutin. In addition, they compared different polyphenol removal and drying methods, pointing out that CT and their monomers were not related to the in vitro AH activity of L. latisiliquum [56]. In this respect, Sandoval-Castro [91] argued that such a lack of effect should be demonstrated by isolating and testing the specific CT fraction of L. latisiliquum extract, conferring anthelmintic activity.

4.2. The In Vivo Experiences The hypothesis linking PSC intake with the potential anthelmintic properties of plants that contain them has been explored since the early 2000s. In the first in vivo publication, Brunet et al. [58] used an artificial infection with GINs and evidenced that the aboma- sum and first portion of the small intestine of goats fed with L. latisiliquum foliage had lower counts of immature H. contortus and T. colubriformis than those fed with foliage of B. alicastrum, a plant with low PSC content (75 ± 23.45 vs. 258.33 ± 74.68, respectively). The authors concluded that the reduction in the establishment was driven by CTs, which avoided the exsheathment of L3. Meanwhile, Martínez-Ortiz-de-Montellano et al. [59] supplemented artificially infected sheep with L. latisiliquum foliage and noted a reduction in the fecal excretion of GIN eggs (eggs per gram, EPG), as well as a reduction in the length and fecundity of adult worms. These above-mentioned studies found no evidence to support the indirect effect of CTs, which have been hypothesized to stimulate an im- munological response mediated by an increase in the number of inflammatory cells in the mucosa [92]. Later, the previous positive in vitro effects of Phytolacca icosandra [47] led to performing an in vivo trial [61], in which its ethanolic extracts were administered for two consecutive days using gelatin capsules and caused a reduction of 66% of the EPG. Such an effect could not be attributed to any specific PSC, as the extract contained a mixture of coumarins, flavonoids, steroids, terpenoids, and saponins. The foliage of H. albicans was also studied by the authors of [60,62]. Both experiments assessed the relationships between voluntary feed intake, dry matter digestibility, and fecal GIN excretion in infected vs. dewormed lambs eating this plant. The inclusion of H. albicans caused a reduction of dry matter digestibility in both cases. In the former experiment, fecundity and the size of adult GIN were reduced in animals consuming H. albicans [60], and in the latter experiment, lambs consuming this plant increased their voluntary feed intake and showed a reduction of 58.8% of the EPG [62]. A step further in the elucidation of the mechanisms of action of PSCs—specifically CTs—was done by Martínez-Ortiz-de-Montellano et al. [48,66] through the scanning electron microscopy technique. In both works, L. latisiliquum foliage was administered to goats artificially infected with H. contortus and changes in the structure and ultrastructure of adult worms were measured. These studies allowed for identifying superficial alterations in the cuticle, buccal capsule, and aggregates in the cephalic region, Agronomy 2021, 11, 1403 14 of 20

as well as ultrastructural changes, such as vacuolization of the intestinal, muscular, and hypodermal cells. Cafeteria trials, as part of a nutraceutical screening process, were implemented in two experiments by Ventura-Cordero et al. [63,64]. Both studies evaluated the intake and selection of LDF plants in response to natural [63] or artificial [64] GIN infections using goats with many years of browsing experience. A higher GIN excretion of 2150 EPG did not change either the intake or selection of four plant species in the former study. Thus, in the latter study, the authors decided to superimpose an artificial infection with H. contortus. Nevertheless, the same intake pattern was maintained independently of high GIN egg excretions (3158 EPG). In addition, body weight gain, the mean packed cell volume, and the mean hemoglobin levels were not different between the infected and non-infected animals. Due to these findings, Torres-Fajardo et al. [65] evaluated the goats feeding behavior and their relationships with GIN infection, CT intake, and their interactions. It is worth noting that there was an increase in CT intake for GIN-infected goats and a reduction of the crude protein intake in animals that were CT-neutralized by the administration of polyethylene glycol. It is possible that the high GIN excretion in this study (nearly 5000 EPG) triggered the higher CT intake. In addition, the reduction of CP intake in polyethylene glycol- administered goats could be aimed at avoiding an excess of ruminal protein metabolism and their physiological costs. Together, these cafeteria trials allowed researchers to point out that CTs were not the only PSCs with anthelmintic properties and that the ingestive behavior of small ruminants is a multifactorial process. The study done by Méndez-Ortiz et al. [67] represents the first attempt to validate the nutraceutical value of plants under controlled in vivo conditions. Researchers used the leaves of the shrub/tree G. floribundum and assessed its macronutrient and PSC content together with the in vivo dry matter digestibility and organic matter digestibility. The authors administered different plant inclusion levels to hair sheep lambs carrying an artificial H. contortus infection. The inclusion of G. floribundum at 40% reduced the digestibility but maintain live weight gain and voluntary feed intake. In addition, it significantly reduced the EPG and female GIN burdens in post-mortem measurements. Furthermore, the bioactivity of its extracts against H. contortus was confirmed using the LEIT. The authors highlighted the nutraceutical potential of this plant species. The next scenario implies the evaluation of plants under the LDF feeding conditions. At first, Jaimez-Rodríguez et al. [69] compared the feeding behavior of inexperienced tracer kids and lambs and observed the consumption of 37 plants species. In addition, kids had a lower EPG count because of their lesser consumption of low stratum plants (<25 cm) and higher consumption of medium stratum plants (25–50 cm). The remaining studies were performed with experienced goats, which guarantee an appropriate “feed culture” acquisition [93]. Novelo-Chi et al. [68] used 12 animals to assess the effect of natural GIN infection in the macronutrient and CT intake. To do this, the authors observed the feeding behavior of the goats for two months. In the first month, all goats had a natural GIN infection and, after 30 days, the authors dewormed half of the group with a broad-spectrum commercial drug with a persistent effect of at least 28 days (moxidectin) [94]. The intake of macronutrients and CTs was not modified after deworming the animals when compared to the naturally infected animals. In addition, the EPG, packed cell volume, and live weight did not change during the experiment. In light of these results, the work of Torres-Fajardo et al. [70] evaluated GINs, CTs, and their interactions as modifiers of voluntary feed intake and selection in 32 goats. In this work, a group of animals was maintained free of GINs by means of a treatment with a broad-spectrum commercial persistent anthelmintic product, and polyethylene glycol (a neutralizing polymer) was used for CT removal. Independent of treatment, there were no changes in the goats’ feeding behavior during the two-month trial, which was attributed to the resilience of local breeds [95], and the physiological and behavioral mechanisms that goats possess to counteract the apparently harmful effects of CTs [17,96–98]. In addition, the authors reported the consumption of 45 plant species and high selectivity towards gramineous plants. In the last work, Torres-Fajardo et al. [71] Agronomy 2021, 11, 1403 15 of 20

emphasized the feeding pattern of goats in response to natural GIN infection. Then, the authors compared the pattern of voluntary feed intake of infected vs. dewormed goats, establishing two schedules (7:00–8:30 a.m. and 9:30–11:00 a.m.). There were no differences in the feeding behavior between the experimental groups during the month of observation. It is worth noting that all the goats significantly increased their grass intake during the late morning. Altogether, these findings support the hypothesis of the goats’ resiliency and suggest the expression of behaviors with an aim to (i) balance the energy–protein ratio, (ii) avoid the saturation of detoxification pathways, (iii) avoid L3 from grass in the early morning as a sign of “flight” behavior, and (iv) use PSCs from browsing in order to limit GIN establishment.

5. Final Remarks If we consider that at least 260 plants could be used as feed resources for small ruminants in the low deciduous forest, but only 13 of them have been properly evaluated under a nutraceutical approach, it represents only 5% of such biodiversity. However, this percentage has implied two decades of research and endeavors from both researchers and collaborators. The brief summary of results presented regards the anthelmintic effect of plants and their extracts. Although it is one of the biologicals effects most studied during recent years, it must be noted that it is not the only response/effect that could be associated within the nutraceutical research area. Further research is needed to explore additional nutraceutical effects. Native vegetation systems are inherently complex and relevant for domestic livestock worldwide, and researchers have a duty to understand the relationships between its biotic and abiotic components. In the present review, we gathered information from a vegetation system that has been used for centuries to sustain ruminant production. Further research should be intended to (i) evaluate the agronomic performance of potential nutraceutical plants, (ii) improve the methods for biomass estimation, (iii) focus on the ingestive behavior of ruminant species, (iv) standardize the techniques for PSC extraction and quan- tiﬁcation, (v) evaluate the bioactivity of the whole range of PSC families, (vi) study the synergy/antagonism between PSCs, (viii) identify novel candidate molecules, (ix) increase the number of in vivo trials, and (x) establish communication channels with shepherds, farmers, extensionists, and professionals.

Author Contributions: Conceptualization, R.A.T.-F.; investigation, R.A.T.-F.; data collection, R.A.T.-F.; writing—original draft preparation, R.A.T.-F.; writing—review and editing, R.A.T.-F., P.G.G.-P., C.A.S.-C. and J.F.d.J.T.-A.; supervision, P.G.G.-P., C.A.S.-C., and J.F.d.J.T.-A. All authors have read and agreed to the published version of the manuscript. Funding: This research was partially funded by CONACYT México, grant numbers CB-2013- 01/221041, CB-2013-01221608, and CB-2008/106146. Institutional Review Board Statement: Ethical review and approval were not needed as it is a literature review which do not involve additional animal experimentation. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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