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Invited review: Bioactive compounds produced during cheese ripening and health effects associated with aged cheese consumption

  • Author Footnotes
    1 These authors contributed equally to this paper.
    Lourdes Santiago-López
    Footnotes
    1 These authors contributed equally to this paper.
    Affiliations
    Laboratorio de Química y Biotecnología de Productos Lácteos, Coordinación de Tecnología de Alimentos de Origen Animal, Centro de Investigación en Alimentación y Desarrollo, A. C. (CIAD), Hermosillo, Sonora 83304, México
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  • Author Footnotes
    1 These authors contributed equally to this paper.
    Jose E. Aguilar-Toalá
    Footnotes
    1 These authors contributed equally to this paper.
    Affiliations
    Laboratorio de Química y Biotecnología de Productos Lácteos, Coordinación de Tecnología de Alimentos de Origen Animal, Centro de Investigación en Alimentación y Desarrollo, A. C. (CIAD), Hermosillo, Sonora 83304, México
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  • Adrián Hernández-Mendoza
    Affiliations
    Laboratorio de Química y Biotecnología de Productos Lácteos, Coordinación de Tecnología de Alimentos de Origen Animal, Centro de Investigación en Alimentación y Desarrollo, A. C. (CIAD), Hermosillo, Sonora 83304, México
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  • Belinda Vallejo-Cordoba
    Affiliations
    Laboratorio de Química y Biotecnología de Productos Lácteos, Coordinación de Tecnología de Alimentos de Origen Animal, Centro de Investigación en Alimentación y Desarrollo, A. C. (CIAD), Hermosillo, Sonora 83304, México
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  • Andrea M. Liceaga
    Affiliations
    Department of Food Sciences, Purdue University, West Lafayette, IN 47907
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  • Aarón F. González-Córdova
    Correspondence
    Corresponding author
    Affiliations
    Laboratorio de Química y Biotecnología de Productos Lácteos, Coordinación de Tecnología de Alimentos de Origen Animal, Centro de Investigación en Alimentación y Desarrollo, A. C. (CIAD), Hermosillo, Sonora 83304, México
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  • Author Footnotes
    1 These authors contributed equally to this paper.
Open ArchivePublished:February 21, 2018DOI:https://doi.org/10.3168/jds.2017-13465

      ABSTRACT

      Traditionally, cheese is manufactured by converting fluid milk to a semisolid mass through the use of a coagulating agent, such as rennet, acid, heat plus acid, or a combination thereof. Cheese can vary widely in its characteristics, including color, aroma, texture, flavor, and firmness, which can generally be attributed to the production technology, source of the milk, moisture content, and length of aging, in addition to the presence of specific molds, yeast, and bacteria. Among the most important bacteria, lactic acid bacteria (LAB) play a critical role during the cheese-making process. In general, LAB contain cell-envelope proteinases that contribute to the proteolysis of cheese proteins, breaking them down into oligopeptides that can be subsequently taken up by cells via specific peptide transport systems or further degraded into shorter peptides and amino acids through the collaborative action of various intracellular peptidases. Such peptides, amino acids, and their derivatives contribute to the development of texture and flavor in the final cheese. In vitro and in vivo assays have demonstrated that specific sequences of released peptides exhibit biological properties including antioxidant, antimicrobial, anti-inflammatory, immunomodulatory, and analgesic/opioid activity, in addition to angiotensin-converting enzyme inhibition and antiproliferative activity. Some LAB also produce functional lipids (e.g., conjugated linoleic acid) with anti-inflammatory and anticarcinogenic activity, synthesize vitamins and antimicrobial peptides (bacteriocins), or release γ-aminobutyric acid, a nonprotein amino acid that participates in physiological functions, such as neurotransmission and hypotension induction, with diuretic effects. This review provides an overview of the main bioactive components present or released during the ripening process of different types of cheese.

      Key words

      INTRODUCTION

      Cheese, defined as the fresh or matured product obtained from the coagulation of milk, is easily digestible and rich in nutritional components, thus constituting an important source of proteins, short-chain fatty acids, vitamins, and minerals. It is therefore an important source of a wide variety of biologically active substances (
      • Walther B.
      • Schimid A.
      • Sieber R.
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      Cheese in nutrition and health.
      ;
      • Diana M.
      • Rafecas M.
      • Arco C.
      • Quilez J.
      Free amino acid profile of Spanish artisanal cheeses: Importance of gamma-aminobutyric acid (GABA) and ornithine content.
      ). Cheese can be classified based on the type of milk used, manufacturing process, fat content, type of fermentation, and its microbiota (
      • Walther B.
      • Schimid A.
      • Sieber R.
      • Wehrmüller K.
      Cheese in nutrition and health.
      ).
      Several compounds in cheese are derived from the metabolism of lactic acid bacteria (LAB), which play an important role in the cheese-making process and contribute to the development of the texture and flavor of the final product. Lactic acid bacteria hydrolyze lactose during fermentation and produce high concentrations of lactic acid and other organic acids (
      • Settanni L.
      • Moschetti G.
      Non-starter lactic acid bacteria used to improve cheese quality and provide health benefits.
      ). Several milk enzymes, such as rennet and enzymes from LAB, participate in the ripening process, resulting in the subsequent transformations that target the diverse constituents of curds (
      • Leroy F.
      • De Vuyst L.
      Lactic acid bacteria as functional starter cultures for the food fermentation industry.
      ;
      • McSweeney P.L.H.
      Biochemistry of cheese ripening.
      ).
      The following bioactive compounds are found in cheese: peptides, exopolysaccharides, fatty acids, organic acids, vitamins, γ-aminobutyric acid (GABA), and CLA. All of these have biological activities. In vitro and in vivo studies have demonstrated that these compounds inhibit angiotensin-converting enzyme (ACE) and exhibit antioxidant, antimicrobial, and antiproliferative activities (
      • Faure M.
      • Mettraux C.
      • Moennoz D.
      • Godin J.P.
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      • Rochat F.
      • Breuille D.
      • Obled C.
      • Corthesy-Thelaz I.
      Specific amino acids increase mucin synthesis and microbiota in dextran sulfate sodium-treated rats.
      ;
      • Sprong R.C.
      • Schonewille A.J.
      • van der Meer R.
      Dietary cheese whey protein protects rats against mild dextran sulfate sodium-induced colitis: Role of mucin and microbiota.
      ;
      • Geurts L.
      • Everard A.
      • Ruyet P.
      • Delzenne N.M.
      • Cani P.D.
      Ripened dairy products differentially affect hepatic lipid content and adipose tissue oxidative stress markers in obese and type 2 diabetic mice.
      ). The above bioactivities lead to health-protective effects associated with a reduced incidence of cardiovascular disease risk factors, such as obesity, dyslipidemia, and type 2 diabetes (
      • Sullivan A.
      • Edlund C.
      • Nord C.
      Effect of antimicrobial agents on the ecological balance of human microflora.
      ), as well as reduced incidence of metabolic syndrome (MetS;
      • Bonthuis M.
      • Hughes M.C.B.
      • Ibiebele T.I.
      • Green A.C.
      • van der Pols J.C.
      Dairy consumption and patterns of mortality of Australian adults.
      ;
      • Sonestedt E.
      • Wirfa¨lt E.
      • Wallstro P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: The Malmö diet and cancer cohort.
      ). Mexican cheeses have potential benefits because of their native microflora, the type of milk used, and artisanal techniques applied during their production. A previous study (
      • Torres-Llanez M.J.
      • González-Córdova A.F.
      • Hernández-Mendoza A.
      • García H.S.
      • Vallejo-Córdoba B.
      Angiotensin-converting enzyme inhibitory activity in Mexican Fresco cheese.
      ) demonstrated the ACE-inhibitory action of peptides derived from fresh cheese and a model cheese (made at the laboratory scale). Studies in Mexico on bioactive compounds present in artisanal cheeses are limited, and those available focus primarily on the antioxidant and ACE activity of water-soluble extracts (WSE) obtained from different types of artisanal cheese (e.g., Crema de Chiapas, Cocido, and Fresco of Sonora) from different storage conditions (
      • Aguilar-Toalá J.E.
      • González-Córdova A.F.
      • Hernández-Mendoza A.
      • Torres-Llanez M.J.
      • Vallejo-Cordoba B.
      Antioxidant activity of bioactive peptides and polyphenols isolated from Mexican Artisanal Cheeses.
      ,
      • Aguilar-Toalá J.E.
      • Vallejo-Cordoba B.
      • Hernández-Mendoza A.
      • González-Córdova A.F.
      Antioxidant capacity of water soluble extracts obtained from Queso Crema de Chiapas, an Artisanal Mexican Cheese. Abstract number 023 in IFT Annual Meeting and Expo, Chicago, IL.
      ;
      • Santos-Espinosa A.
      • González-Córdova A.F.
      • Hernández-Mendoza A.
      • Estrada-Montoya M.C.
      • Vallejo-Cordoba B.
      Angiotensin-converting enzyme inhibitory activity of Mexican Artisanal Cheeses. In: Abstract number 072–05 in IFT Annual Meeting and Expo, Chicago, IL.
      ).
      This review article provides an overview of the main bioactive components present or released during the ripening process of different cheese types from different countries.

      INFLUENCE OF CHEESE PROCESSING TECHNOLOGY ON THE DEVELOPMENT OF BIOACTIVE COMPOUNDS

      Cheese is a biologically and biochemically dynamic product, in which a series of sequential changes take place during the cheese-making process. Some technological procedures such as heat treatment, homogenization, pressure application, and milk coagulation can affect the structure of the milk constituents and promote the development or the release of bioactive compounds (
      • Kumar V.V.
      • Sharma V.
      • Bector B.S.
      Effect of ripening on total conjugated linoleic acid and its isomers in buffalo Cheddar cheese.
      ;
      • Cruz A.G.
      • Faria J.A.F.
      • Pollonio M.A.R.
      • Bolini H.M.A.
      • Celeghini R.M.S.
      • Granato D.
      • Shah N.P.
      Cheese with reduced sodium content: effects on functionality, public health benefits and sensory properties.
      ).
      Some studies have reported that heat treatments alter the final milk and cheese composition and thereby determine cheese quality (
      • Albenzio M.
      • Corbo M.R.
      • Rehman S.U.
      • Fox P.F.
      • De Angelis M.
      • Corsetti A.
      • Sevi A.
      • Gobbetti M.
      Microbiological and biochemical characteristics of Canestrato Pugliese cheese made from raw milk, or by heating the curd in hot whey.
      ;
      • McSweeney P.L.H.
      Biochemistry of cheese ripening.
      ). Meanwhile, other authors have hypothesized that pasteurization could influence the amount of protein and PUFA in milk or cheese; however, the results of a study showed that heat treatment did not affect the amount of protein or the fatty acid profile of cheese (
      • Cuchillo-Hilario M.
      • Delgadillo P.G.
      • Wrage N.
      • Perez-Gil R.F.
      Feeding goats on scrubbly Mexican rangeland and pasteurization: Influence on milk and artisan cheese quality.
      ).
      • Albenzio M.
      • Corbo M.R.
      • Rehman S.U.
      • Fox P.F.
      • De Angelis M.
      • Corsetti A.
      • Sevi A.
      • Gobbetti M.
      Microbiological and biochemical characteristics of Canestrato Pugliese cheese made from raw milk, or by heating the curd in hot whey.
      reported that heat affected the content of water-soluble N and total N, which were higher in cheese made with raw milk than in cheese made with pasteurized or raw milk (heat treatment of curds at 80°C for 30 s in hot whey). Thus, temperature conditions can affect the amount and specific sequence of bioactive peptides. Changes to proteins are generally related to their functional properties and are favored by the action of enzymes specific to milk. Additionally, the microorganisms present or added during cheese-making may release bioactive compounds (
      • Claeys W.L.
      • Cardoen S.
      • Daube G.
      • De Block J.
      • Dewettinck K.
      • Dierick K.
      • Zutter L.
      • Huyghebaert A.
      • Imberechst H.
      • Thiange P.
      • Vandenplas Y.
      • Herman L.
      Raw or heated cow milk consumption: review of risks and benefits.
      ).
      Proteases and peptidases present in milk (e.g., plasmin, cathepsin D) lead to formation of large and intermediate-sized peptides; subsequently, these peptides are further hydrolyzed by residual coagulant retained in the curd and finally, by enzymes from the cheese starter and the nonstarter microbiota. This set of reactions is known as primary proteolysis. Of the enzymes present in milk, the enzyme that mainly contributes to proteolysis is plasmin. Plasmin is extremely thermostable, and its activity increases after heat treatment, either by inactivation of natural plasmin inhibitors or the activation of plasminogen in milk during heating (
      • Chavan R.S.
      • Chavan S.R.
      • Khedkar C.D.
      • Jana A.H.
      UHT milk processing and effect of plasmin activity on shelf life: A review.
      ). Thus, pasteurization or milk heating during cheese manufacture can enhance the formation of peptides.
      • Moatsou G.
      • Bakopanos C.
      • Katharios D.
      • Katsaros G.
      • Kandarakis I.
      • Taoukis P.
      • Politis I.
      Effect of high-pressure treatment at various temperatures on indigenous proteolytic enzymes and whey protein denaturation.
      found that the activity of plasmin decreased directly related to increased temperature and pressure during the cheese-making process. The combination of both factors (temperature and pressure) on reduction of plasmin activity is desirable because of the effect on cheese yield, proteolysis, and quality milk during storage. In contrast, the activity of another proteolytic enzyme, cathepsin D, is mostly suppressed following pasteurization and whey drainage (
      • McSweeney P.L.H.
      Biochemistry of cheese ripening.
      ).
      • Paul M.
      • Brewster J.D.
      • Van Hekken D.L.
      • Tomasula P.M.
      Measuring the antioxidative activities of Queso Fresco after post-packaging high-pressure processing.
      found that the high pressure and temperature applied during the packaging of fresh cheese affected the antioxidant activity [evaluated by the oxygen radical absorbance capacity (ORAC) method] of water-soluble proteins containing bioactive peptides. The lowest antioxidant activity [10.2 Trolox equivalents (TE)/g of cheese) was for cheese processed at 600 MPa for 20 min at 22°C; meanwhile, for cheese processed at 400 MPa for 10 min at 22°C, the antioxidant activity was 67.6 TE/g. In this sense, the length of processing time and pressure used can affect the antioxidant activity of fresh cheese.
      Another study showed that the application of high hydrostatic pressure to Garrotxa cheese (400 MPa, 5 min, 14°C) affected lipolysis and generated a cheese with lower amounts of free fatty acids. This can be attributed to the resulting decrease of microorganisms or the inactivation of lipolytic enzymes of the secondary microbiota (
      • Saldo J.
      • Fernández A.
      • Sendra E.
      • Butz P.
      • Tauscher B.
      • Guamis B.
      High pressure treatment decelerates the lipolysis in a caprine cheese.
      ).

      ROLE OF RIPENING AND LAB ON THE PRODUCTION OF BIOACTIVE COMPOUNDS

      In the complex microbial niche of cheese, LAB, yeast, and some molds are present. These microbes play an important role in the development of the sensory characteristics of cheese and in the technological aspects of cheese production (
      • Irlinger F.
      • Mounier J.
      Microbial interactions in cheese: Implications for cheese quality and safety.
      ).
      During the cheese-making process, LAB can be added as a starter culture, contributing to the coagulation of caseins (
      • Grattepanche F.
      • Miescher-Schwenninger S.
      • Meile L.
      • Lacroix C.
      Recent developments in cheese cultures with protective and probiotic functionalities.
      ;
      • González L.
      • Sacristán N.
      • Arenas R.
      • Fresno J.M.
      • Eugenia Tornadijo M.
      Enzymatic activity of lactic acid bacteria (with antimicrobial properties) isolated from a traditional Spanish cheese.
      ;
      • Yang E.
      • Fan L.
      • Jiang Y.
      • Doucette C.
      • Fillmore S.
      Antimicrobial activity of bacteriocin-producing lactic acid bacteria isolated from cheeses and yogurts.
      ). On the other hand, at least one group of nonstarter LAB (NSLAB; e.g., lactobacilli, pediococci, enterococci, and Leuconostoc) can also be present naturally in cheese. The main source of NSLAB is raw milk, although other cheese ingredients or equipment can also be a source and therefore enhance their concentration in the final product. The NSLAB grow at a very low rate during the first weeks of ripening but eventually dominate the cheese microbiota after the death phase of the starter culture (
      • Casey M.G.
      • Häni J.P.
      • Gruskovnjak J.
      • Schaeren W.
      • Wechsler D.
      Characterisation of the non-starter lactic acid bacteria (NSLAB) of Gruyere PDO cheese.
      ;
      • Zuljan F.A.
      • Mortera P.
      • Alarcón S.H.
      • Blancato V.S.
      • Espariz M.
      • Magni C.
      Lactic acid bacteria decarboxylation reactions in cheese.
      ). Both groups of LAB are important for the development of the biochemical characteristics of fresh cheese and for cheese ripening. During the ripening process, LAB release bioactive peptides, EPS, vitamins, CLA, GABA, and oligosaccharides (Figure 1; (
      • Beermann C.
      • Hartung J.
      Physiological properties of milk ingredients released by fermentation.
      ).
      Figure thumbnail gr1
      Figure 1The role of lactic acid bacteria during the fermentation or ripening process of cheese. Lactic acid bacteria have been documented as precursors of bioactive compounds, and their action releases peptides, exopolysaccharides, fatty acids, γ-aminobutyric acid (GABA), organic acids, and vitamins. Different mechanisms and factors are involved during the release of bioactive compounds, including enzymes, pH conditions, ripening time, and temperature.

      Bioactive Peptides

      As mentioned above, the release of bioactive peptides has been documented during cheese ripening (
      • Mao X.Y.
      • Ni J.R.
      • Sun W.L.
      • Hao P.P.
      • Fan L.
      Value-added utilization of yak milk casein for the production of angiotensin-I-converting enzyme inhibitory peptides.
      ;
      • Phelan M.
      • Aherne A.
      • FitzGerald R.J.
      • O'Brien N.M.
      Casein-derived bioactive peptides: Biological effects, industrial uses, safety aspects and regulatory status.
      ;
      • Hernández-Ledesma B.
      • del Mar Contreras M.
      • Recio I.
      Antihypertensive peptides: Production, bioavailability and incorporation into foods.
      ). For example, rennet-coagulated cheeses are ripened for periods ranging from 2 wk for Mozzarella, to 2 or more years for Parmigiano-Reggiano and Cheddar cheese. During this time, microbiological and biochemical changes in the curd take place, resulting in characteristic flavors and textures of particular varieties (
      • McSweeney P.L.H.
      Biochemistry of cheese ripening.
      ).
      Cheese ripening is a complex, dynamic system. In this process, the diversity of proteolytic enzymes naturally present in milk and the residual coagulants, as well as the enzymatic metabolism of LAB, play an essential role (
      • Gagnaire V.
      • Mollé D.
      • Herrouin M.
      • Léonil J.
      Peptides identified during Emmental cheese ripening: origin and proteolytic systems involved.
      ) in the final cheese. During ripening, peptides are being constantly released by the action of plasmin and enzymes from LAB; some of these peptides are subsequently hydrolyzed, whereas others accumulate during storage (
      • Ryahanen E.
      • Pihlanto-Leppala A.
      • Pahkala E.
      A new type of ripened, low-fat cheese with bioactive peptides.
      ;
      • Ong L.
      • Henriksson A.
      • Shah N.P.
      Angiotensin converting enzyme-inhibitory activity in Cheddar cheeses made with the addition of probiotic Lactobacillus casei sp.
      ).
      Bioactive peptides that are encrypted or inactivated in the protein matrix can be released by enzymatic hydrolysis (e.g., pepsin, trypsin, and chymotrypsin) during gastrointestinal digestion, or by the action of proteases and peptidases released by LAB (
      • Fitzgerald R.
      • Murray B.A.
      Bioactive peptides and lactic fermentations.
      ). Peptides generally consist of sequences of 3 to 20 AA. Some are resistant to the digestive action of peptidases and are then absorbed and passed through to the bloodstream (
      • Kitts D.D.
      • Weiler K.
      Bioactive proteins and peptides from food sources. Applications of bioprocesses used in isolation and recovery.
      ).
      Three major components are involved in proteolysis by LAB: (1) cell wall-envelope proteinases (CEP) that initiate the degradation of extracellular casein into oligopeptides; (2) peptide transporters that take up peptides into the cell; and (3) intracellular peptidases that degrade peptides into shorter peptides and AA (
      • Liu M.
      • Bayjanov J.R.
      • Renckens B.
      • Nauta A.
      • Siezen R.J.
      The proteolytic system of lactic acid bacteria revisited: A genomic comparison.
      ). Five types of CEP have been characterized, and all have a strong preference for hydrophobic caseins. These caseins contain a large number of Pro residues that prevent the formation of random coils, thereby encouraging the action of CEP on them (
      • Savijoki K.
      • Ingmer H.
      • Varmanen P.
      Proteolytic systems of lactic acid bacteria.
      ). The proteolysis process releases peptides with specific bioactivities, including antimicrobial, antihypertensive, immunomodulatory, analgesic, and antioxidant activities that can positively affect major human body systems (e.g., cardiovascular, digestive, immune, and nervous systems; Table 1) (
      • Hartmann R.
      • Meisel H.
      Food-derived peptides with biological activity: From research to food applications.
      ;
      • Gupta A.
      • Mann B.
      • Kumar R.
      • Sangwan R.B.
      Antioxidant activity of Cheddar cheeses at different stages of ripening.
      ).
      Table 1Bioactive peptides from different types of cheese and their functional effects in vitro
      Type of cheeseSequences of peptidesBioactivityPrincipal findingsReference
      Pecorino Romano, Canestrato Pugliese, Crescenza, Caprino del Piemonte, Caciocavallo, and Mozzarella (Italian)RFVVAPFPE, FVAPFPEVFG, GLSPEVLNENLL, MAIPPKKNQD, YPFTGPIPNAntibacterialWater-soluble fractions showed a large spectrum of inhibition (20–200 μg/mL) toward gram-positive and gram-negative bacteria.
      • Rizzello C.G.
      • Losito I.
      • Gobbetti M.
      • Carbonara T.
      • de Bari M.D.
      • Zambonin P.G.
      Antibacterial activities of peptides from the water-soluble extracts of Italian cheese varieties.
      Cheddar (Australian)
      Not identified.
      Angiotensin converting enzyme (ACE)-inhibitoryACE-inhibitory activity was ripening dependent.
      • Ong L.
      • Shah N.P.
      Influence of probiotic Lactobacillus acidophilus and Lactobacillus helveticus on proteolysis, organic acid profiles, and ACE-inhibitory activity of cheddar cheeses ripened at 4, 8, and 12 °C.
      Cheddar (Indian)AntioxidantACE was ripening dependent. Antiproliferative capacity (AC) ranged from 0 to 16.61 μmol of Trolox/mg of protein.
      • Gupta A.
      • Mann B.
      • Kumar R.
      • Sangwan R.B.
      Antioxidant activity of Cheddar cheeses at different stages of ripening.
      Asiago d'allevo (Italian)PFPE, DKIHPF, FVAPFPE, NVPGEIVE, RELEEL, FVAPFPEVF, VQEPVLGPVRGPFPIIVACE-inhibitoryACE-inhibitory activity was unaffected by ripening time and molecular weight of fractions.
      • Lignitto L.
      • Cavatorta V.
      • Balzan S.
      • Gabai G.
      • Galaverna G.
      • Novelli E.
      • Sforza S.
      • Segato S.
      Angiotensin-converting enzyme inhibitory activity of water-soluble extracts of Asiago d'allevo cheese.
      Commercial Cheddar (Australian)Antioxidant, antimicrobial, and ACE-inhibitoryAntimicrobial, antiproliferative, and ACE-inhibitory activity was variety dependent.
      • Pritchard S.R.
      • Phillips M.
      • Kailasapathy K.
      Identification of bioactive peptides in commercial Cheddar cheese.
      Commercial Montagnard, Pont-l'eveque, Brie, Camembert, Danablue, and Blue (Japanese)AntiproliferativeAC was variety dependent.
      • Yasuda S.
      • Ohkura N.
      • Suzuki K.
      • Yamasaki M.
      • Nishiyama K.
      • Kobayashi H.
      • Kadooka Y.
      • Igoshi K.
      Effects of highly ripened cheese on HL-60 human leukemia cells: Antiproliferative activity and induction of apoptotic DNA damage.
      Fresco (Mexican)YQEPVLGPVRGPFPI, YQEPVLGPVRGPFPIIV, FVAPFPEVFGK, EVLNENLLRF, RPKHPIKHQGLPQEV, RPKHPIKHQGLPQEVLNENLLR, FVAPFPEVFGK, EVLNENLLRF, YQEPVLGPVRGPFAntioxidantAC was affected by processing temperature and pressure.
      • Torres-Llanez M.J.
      • González-Córdova A.F.
      • Hernández-Mendoza A.
      • García H.S.
      • Vallejo-Córdoba B.
      Angiotensin-converting enzyme inhibitory activity in Mexican Fresco cheese.
      Coalho (Brazilian)Antioxidant, zinc-binding, and antimicrobialAC and peptide profile were variety dependent. AC values ranged from 1,895 to 2,221 μM Trolox.
      • Silva R.A.
      • Lima M.S.F.
      • Viana J.B.M.
      • Bezerra V.S.
      • Pimentel M.C.B.
      • Porto A.L.F.
      • Cavalcanti M.T.H.
      • Lima Filho J.L.
      Can artisanal “Coalho” cheese from Northeastern Brazil be used as a functional food?.
      Feta, Roquefort, and Pecorino (Brazilian and Uruguayuan)KEMPFPKYPVE, WMHQPPQPLPPTVMFPPQSVL, MHQPPQPLPPTVMFPPQSVL, HQPPQPLPPTVMFPPQSVL, YQEPVLGPVRGPFPI, QEPVLGPVRGPFPILV, QEPVLGPVRGPFPI, PVLGPVRGPFPI, LGPVRGPFPI, TDAPSFSDIPNPIGSENSGK, DIPNPIGSENSGKTTMPLW, IPNPIGSENSGKIT, NAGPFTPTVNR, YQGPIVLNPWDQVKR, YQGPIVLNPWDQVK, GPIVLNPWDQVKR, VLNPWDQVKRAntioxidant and ACE-inhibitoryAC and ACE-inhibitory activity were variety dependent.
      • Meira S.M.M.
      • Daroit D.J.
      • Helfer V.E.
      • Correa A.P.F.
      • Segalin J.
      • Carro S.
      • Brandelli A.
      Bioactive peptides in water-soluble extracts of ovine cheeses from Southern Brazil and Uruguay.
      Cottage (Mexican)Antioxidant and antilisterialAC was ripening dependent.
      • Abadía-García L.
      • Cardador A.
      • Martin del Campo S.T.
      • Arvízu S.M.
      • Castaño-Tostado E.
      • Regalado-González C.
      • García-Almendarez B.
      • Amaya-Llano S.L.
      Influence of probiotic strains added to Cottage cheese on generation of potentially antioxidant peptides, anti-listerial activity, and survival of probiotic microorganisms in simulated gastrointestinal conditions.
      Parmigiano-Reggiano (Italian)AntioxidantAC was unaffected by ripening time and gastrointestinal digestion.
      • Bottesini C.
      • Paolella S.
      • Lambertini F.
      • Galavera G.
      • Tedeschi T.
      • Dossena A.
      • Marchelli R.
      • Sforza S.
      Antioxidant capacity of water soluble extracts from Parmigiano-Reggiano cheese.
      Burgos-type (Spanish)SDIPNPIGSENSEKTTMPLW, YQQPVLGPRGPFPIIV, ILYQQPVLGPVRGPFPIIVAntioxidantAC and peptide profile were rennet dependent. AC values ranged from 58.9 to 82.2% of 2,2-diphenyl-1-picrylhydrazyl (DPPH) inhibition (12 mg of protein/mL)
      • Timón M.L.
      • Parra V.
      • Otte J.
      • Broncano J.M.
      • Petron M.J.
      Identification of radical scavenging peptides (<3 kDa) from Burgos-type cheese.
      Parmigiano-Reggiano (PR) and Grana Padano (GP) (Italian)ACE-inhibitoryAC (half-maximal concentration) of PR and GP was 16.8 and 10.8 µg of peptides per mL, respectively, and was unaffected by gastrointestinal digestion.
      • Bernabucci U.
      • Catalani E.
      • Basirico L.
      • Morera P.
      • Nardone A.
      In vitro ACE-inhibitory activity and in vivo antihypertensive effects of water-soluble extract by Parmigiano Reggiano and Grana Padano cheeses.
      Stracchino soft (Italian)KEAMAPKH, KVKEAMPKH, RDMPIQH, KAVPYPQR, KAVPYPQR, KTKLTEEEKN, LNEINQF, KITVDDK, RNAVPITPTL, RNAVPITPAntioxidant↓ Cellular oxidative stress
      • Pepe G.
      • Sommella E.
      • Ventre G.
      • Scala M.C.
      • Adesso S.
      • Ostacolo C.
      • Marzocco S.
      • Novellino E.
      • Campiglia P.
      Antioxidant peptides released from gastrointestinal digestion of “Stracchino” soft cheese: characterization, in vitro intestinal protection and bioavailability.
      Fresh goat cheese (Mexican)Antioxidant and ACE-inhibitoryAnalyzed cheeses showed high biological activities with slight differences associated with distinct heat treatments.
      • Hernandez-Galán L.
      • Cardador-Martínez A.
      • López-del-Castillo M.
      • Picque D.
      • Spinnler H.E.
      • Martin del Campo S.T.
      Antioxidant and angiotensin-converting enzyme inhibitory activity in fresh goat cheese prepared without starter culture: A preliminary study.
      1 Not identified.
      Several studies have reported the antioxidant activity of bioactive peptides found in Cheddar (
      • Gupta A.
      • Mann B.
      • Kumar R.
      • Sangwan R.B.
      Antioxidant activity of Cheddar cheeses at different stages of ripening.
      ;
      • Pritchard S.R.
      • Phillips M.
      • Kailasapathy K.
      Identification of bioactive peptides in commercial Cheddar cheese.
      ), Coalho (
      • Silva R.A.
      • Lima M.S.F.
      • Viana J.B.M.
      • Bezerra V.S.
      • Pimentel M.C.B.
      • Porto A.L.F.
      • Cavalcanti M.T.H.
      • Lima Filho J.L.
      Can artisanal “Coalho” cheese from Northeastern Brazil be used as a functional food?.
      ), Fresco (
      • Paul M.
      • Brewster J.D.
      • Van Hekken D.L.
      • Tomasula P.M.
      Measuring the antioxidative activities of Queso Fresco after post-packaging high-pressure processing.
      ), Parmigiano-Reggiano (
      • Bottesini C.
      • Paolella S.
      • Lambertini F.
      • Galavera G.
      • Tedeschi T.
      • Dossena A.
      • Marchelli R.
      • Sforza S.
      Antioxidant capacity of water soluble extracts from Parmigiano-Reggiano cheese.
      ), and cottage cheese (
      • Abadía-García L.
      • Cardador A.
      • Martin del Campo S.T.
      • Arvízu S.M.
      • Castaño-Tostado E.
      • Regalado-González C.
      • García-Almendarez B.
      • Amaya-Llano S.L.
      Influence of probiotic strains added to Cottage cheese on generation of potentially antioxidant peptides, anti-listerial activity, and survival of probiotic microorganisms in simulated gastrointestinal conditions.
      ).
      • Gupta A.
      • Mann B.
      • Kumar R.
      • Sangwan R.B.
      Antioxidant activity of Cheddar cheeses at different stages of ripening.
      evaluated the antioxidant activity of WSE of Cheddar cheese made with and without adjunct cultures at different stages of ripening. The results showed that the antioxidant activity was dependent on the ripening stage. 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity increased for Cheddar cheese manufactured with adjunct cultures and showed the highest activity during the fourth month of ripening (16.61 and 9.76 μmol of TE/mg of protein, for Cheddar cheese made with and without adjunct culture, respectively); the Trolox-equivalent antioxidant capacity (TEAC) showed a steady increase as ripening proceeded and reached a maximum value (9.81 μmol of TE/mg of protein) during the fourth month. The same results were observed for 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, which increased up to the fourth month of ripening. After that, antioxidant activity decreased in the fifth month, indicating that antioxidant peptides at this stage were not resistant to further proteolysis (
      • Gupta A.
      • Mann B.
      • Kumar R.
      • Sangwan R.B.
      Antioxidant activity of Cheddar cheeses at different stages of ripening.
      ;
      • Pritchard S.R.
      • Phillips M.
      • Kailasapathy K.
      Identification of bioactive peptides in commercial Cheddar cheese.
      ).
      The antioxidant capacity of Parmigiano-Reggiano cheese was unaffected by ripening time (7–41 mo). This is likely due to the presence of free AA and only in part to the release of peptides (
      • Bottesini C.
      • Paolella S.
      • Lambertini F.
      • Galavera G.
      • Tedeschi T.
      • Dossena A.
      • Marchelli R.
      • Sforza S.
      Antioxidant capacity of water soluble extracts from Parmigiano-Reggiano cheese.
      ). However, free AA are not effective antioxidants (
      • Elias R.J.
      • Kellerby S.S.
      • Decker E.A.
      Antioxidant activity of proteins and peptides.
      ). The effectiveness of peptides compared with free AA is attributed to the unique chemical and physical properties conferred by their sequences, especially the stability of resultant peptide radicals that do not initiate or propagate oxidative reactions (
      • Samaranayaka A.G.P.
      • Li-Chan E.C.Y.
      Food-derived peptidic antioxidants: A review of their production, assessment, and potential applications.
      ).
      The peptide profiles of Coalho cheese obtained from different towns in Brazil were evaluated for antioxidant (ABTS radical scavenging), zinc-binding, and antimicrobial activities. Results showed that the cheese from Correntes had the highest antioxidant value (91.1%) compared with cheese from other towns: Cachoeirinha (85.9%), Arcoverde (84.2%), Sao Bento do Una (77.9%), Capoeiras (87.8%), and Venturosa (82.8%). Zinc-binding activity is important because cheese intake can enhance the bioavailability of zinc.
      • Silva R.A.
      • Lima M.S.F.
      • Viana J.B.M.
      • Bezerra V.S.
      • Pimentel M.C.B.
      • Porto A.L.F.
      • Cavalcanti M.T.H.
      • Lima Filho J.L.
      Can artisanal “Coalho” cheese from Northeastern Brazil be used as a functional food?.
      showed that Coalho cheese had zinc-binding activity ranging from 61.8% (cheese from Capoeiras) to 75.5% (cheese from Correntes). Meanwhile, antimicrobial activity was effective against Enterococcus faecalis ATCC 6057, Bacillus subtilis ATCC 6633, Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853 for the cheese obtained from Cachoeirinha and Venturosa (
      • Silva R.A.
      • Lima M.S.F.
      • Viana J.B.M.
      • Bezerra V.S.
      • Pimentel M.C.B.
      • Porto A.L.F.
      • Cavalcanti M.T.H.
      • Lima Filho J.L.
      Can artisanal “Coalho” cheese from Northeastern Brazil be used as a functional food?.
      ). The main changes could be attributed to the action of the microbiota, as well as to the making process of each type of cheese, modifying the proteolytic activity and sequence of AA that could be responsible for their activity.
      The antioxidant activity of water-soluble extracts of Feta, Roquefort-type, and Pecorino-type cheese from Brazil and Pecorino Sardo-type and Cerrillano from Uruguay were evaluated in another study (
      • Meira S.M.M.
      • Daroit D.J.
      • Helfer V.E.
      • Correa A.P.F.
      • Segalin J.
      • Carro S.
      • Brandelli A.
      Bioactive peptides in water-soluble extracts of ovine cheeses from Southern Brazil and Uruguay.
      ). The results showed ABTS radical scavenging capacity of 32 to 45% and 87% with respect to control for Feta and Roquefort-type cheeses, respectively. Iron chelating activity was variable, yet Pecorino cheese showed the highest activity. The thiobarbituric acid reactive substances (TBARS) analysis showed similar activities ranging from 25 to 51% among the evaluated cheeses. The DPPH radical scavenging activity was highest for Roquefort-type cheese. Another measure of bioactivity was the ACE inhibitory activity: Feta and Roquefort-type cheeses showed the greatest activity (46 and 80%, respectively). However, none of the water-soluble extracts from the cheese showed antimicrobial activity. Peptides from the Roquefort-type cheese had a sequence of YQGPIVLNPWDQVKR, corresponding to αS2-casein. The peptides released in this cheese coincided with milk peptides shown to have different bioactivities. These results suggest the presence of bioactive peptides with multifunctional activity and different modes of action and highlight the importance of ripening time (
      • Meira S.M.M.
      • Daroit D.J.
      • Helfer V.E.
      • Correa A.P.F.
      • Segalin J.
      • Carro S.
      • Brandelli A.
      Bioactive peptides in water-soluble extracts of ovine cheeses from Southern Brazil and Uruguay.
      ).
      The ACE-inhibitory activity of other cheeses including Mozzarella, Italico (
      • Smacchi E.
      • Gobbetti M.
      Peptides from several Italian cheeses inhibitory to proteolytic enzymes of lactic acid bacteria, Pseudomonas fluorescens ATCC 948 and to the angiotensin I-converting enzyme.
      ), red Cheddar, Camembert (
      • Okamoto A.
      • Hanagata H.
      • Matsumoto E.
      • Kawamura Y.
      • Koizumi Y.
      • Yanagida F.
      Angiotensin-converting enzyme inhibitory activities of various fermented foods.
      ), Gouda, Emmental (
      • Saito T.
      • Nakamura T.
      • Kitazawa H.
      • Kawai Y.
      • Itoh T.
      Isolation and structural analysis of antihypertensive peptides that exist naturally in Gouda cheese.
      ), Manchego, Ronca, and goat cheeses (
      • Gómez-Ruiz J.A.
      • Taborda G.
      • Amigo L.
      • Recio I.
      • Ramos M.
      Identification of ACE-inhibitory peptides in different Spanish cheeses by tandem mass spectrometry.
      ) has also been studied. For example, ACE-inhibitory peptides were released during the cheese-ripening process of young, medium-aged, and mature Gouda (
      • Meisel H.
      • Goepfert A.
      • Günther S.
      ACE-inhibitory activities in milk products.
      ). The sequences of several peptides with bioactivity, mainly VPP and IPP, have also been identified (
      • Sieber R.
      • Butikofer U.
      • Egger C.
      • Portmann R.
      • Walther B.
      • Wechsler D.
      ACE-inhibitory activity and ACE-inhibiting peptides in different cheese varieties.
      ).
      • Pripp A.H.
      • Sorensen R.
      • Stepaniak L.
      • Sorhaug T.
      Relationship between proteolysis and angiotensin-I-converting enzyme inhibition in different cheeses.
      showed a relationship between proteolysis activity and ACE activity in various cheeses, as indicated by an increase in ACE-inhibitory activity during cheese ripening.
      Studies of WSE obtained from Mexican cheeses showed that Fresco cheese had the highest ACE inhibition and the lowest half-maximal inhibitory concentration (IC50) values after 15 d of storage (71.4% and 0.33 mg/mL, respectively;
      • Santos-Espinosa A.
      • González-Córdova A.F.
      • Hernández-Mendoza A.
      • Estrada-Montoya M.C.
      • Vallejo-Cordoba B.
      Angiotensin-converting enzyme inhibitory activity of Mexican Artisanal Cheeses. In: Abstract number 072–05 in IFT Annual Meeting and Expo, Chicago, IL.
      ). Crema de Chiapas cheese displayed the highest antioxidant activity at 15 d of storage when evaluated by ABTS method (
      • Aguilar-Toalá J.E.
      • González-Córdova A.F.
      • Hernández-Mendoza A.
      • Torres-Llanez M.J.
      • Vallejo-Cordoba B.
      Antioxidant activity of bioactive peptides and polyphenols isolated from Mexican Artisanal Cheeses.
      ). Likewise,
      • Aguilar-Toalá J.E.
      • Vallejo-Cordoba B.
      • Hernández-Mendoza A.
      • González-Córdova A.F.
      Antioxidant capacity of water soluble extracts obtained from Queso Crema de Chiapas, an Artisanal Mexican Cheese. Abstract number 023 in IFT Annual Meeting and Expo, Chicago, IL.
      evaluated the antioxidant capacity of WSE fractions with a peptide size of <3 and 3 to 10 kDa from Crema de Chiapas cheese from 3 different regions of Chiapas (north, center, and south) and from Mexico City. Results showed that antioxidant capacity increased significantly (P < 0.05) after 120 d of storage at 4°C, and the fraction with 3–10 kDa peptides had antioxidant capacity 2.5-fold higher than that of the fraction with <3 kDa peptides. Additionally, the antioxidant capacity of both fractions depended on the region, with the southern region having the highest antioxidant activity. In a separate study, antioxidant and ACE-inhibitory activities of acid-soluble N and NPN fractions obtained from Mexican artisanal Cotija cheese showed an increase in these activities with ripening time (
      • Hernández-Galán L.
      • Cardador-Martínez A.
      • Picque D.
      • Spinnler H.E.
      • López-del-Castillo Lozano M.
      • Martín del Campo S.T.
      Angiotensin converting enzyme inhibitors and antioxidant peptides release during ripening of Mexican Cotija hard cheese.
      ).

      GABA

      γ-Aminobutyric acid, a 4-carbon nonprotein AA, is a metabolic product of plants and microorganisms produced by the decarboxylation of glutamic acid (
      • Dhakal R.
      • Bajpai V.K.
      • Baek K.-H.
      Production of GABA (γ-aminobutyric acid) by microorganisms: A review.
      ). Bacteria from the genera Lactobacillus and Lactococcus are reported to produce GABA from fermented foods, with Lactobacillus delbrueckii ssp. bulgaricus, Lactobacillus plantarum, and Lactobacillus paracasei being isolated from cheese (
      • Siragusa S.
      • De Angelis M.
      • Di Cagno R.
      • Rizzello C.G.
      • Coda R.
      • Gobbetti M.
      Synthesis of g-aminobutyric acid by lactic acid bacteria isolated from a variety of Italian cheeses.
      ). The production of GABA is affected by variables such as pH, temperature, cultivation time, and additives in the culture medium. Glutamate decarboxylation occurs in LAB via reaction with the enzyme glutamic acid decarboxylase (GAD), resulting in the stoichiometric release of GABA and the consumption of a proton, thus increasing the alkalinity of the cytosol and the environment (
      • Li H.
      • Qiu T.
      • Huang G.
      • Cao Y.
      Production of gamma-aminobutyric acid by Lactobacillus brevis NCL912 using fed batch fermentation.
      ;
      • Dhakal R.
      • Bajpai V.K.
      • Baek K.-H.
      Production of GABA (γ-aminobutyric acid) by microorganisms: A review.
      ). pH is the principal regulator of GABA synthesis, and the biochemical characteristics of GAD differ between strains. For example, Lb. plantarum DSM19463 synthesizes maximum amounts of GABA at pH 6.0 (
      • Di Cagno R.
      • Mazzacane F.
      • Rizzello C.G.
      • Angelis M.D.E.
      • Giuliani G.
      • Meloni M.
      • Servi B.D.E.
      • Marco G.
      Synthesis of γ-aminobutyric acid (GABA) by Lactobacillus plantarum DSM19463: Functional grape must beverage and dermatological applications.
      ), whereas Lb. paracasei NFRI 7415 produces maximum quantities at pH 5.0 (
      • Kumar S.
      • Punekar N.S.
      • Satyanarayan V.
      • Venkatesh K.V.
      Metabolic fate of glutamate and evaluation of flux through the 4-aminobutyrate (GABA) shunt in Aspergillus niger..
      ) and Lactobacillus brevis GABA 057 at pH 4.2 (
      • Yang S.Y.
      • Lu F.X.
      • Lu Z.X.
      • Bie X.M.
      • Jiao Y.
      • Sun L.J.
      • Yu B.
      Production of gamma-aminobutyric acid by Streptococcus salivarius subsp. thermophilus Y2 under submerged fermentation.
      ). Temperature also affects the thermodynamic equilibrium of the reaction. For example, Lb. brevis NCL912 requires a high cell concentration and an appropriate culture temperature (35°C;
      • Li H.
      • Qiu T.
      • Huang G.
      • Cao Y.
      Production of gamma-aminobutyric acid by Lactobacillus brevis NCL912 using fed batch fermentation.
      ); whereas Lb. plantarum DSM19463 shows peak GABA production between 30 and 35°C (
      • Di Cagno R.
      • Mazzacane F.
      • Rizzello C.G.
      • Angelis M.D.E.
      • Giuliani G.
      • Meloni M.
      • Servi B.D.E.
      • Marco G.
      Synthesis of γ-aminobutyric acid (GABA) by Lactobacillus plantarum DSM19463: Functional grape must beverage and dermatological applications.
      ). In addition, Lb. plantarum DSM and Lb. paracasei NFRI 7415 require 72 and 144 h of fermentation time, respectively, for major production of GABA (
      • Higuchi T.
      • Hayashi H.
      • Abe K.
      Exchange of glutamate and g-aminobutyrate in a Lactobacillus strain.
      ;
      • Di Cagno R.
      • Mazzacane F.
      • Rizzello C.G.
      • Angelis M.D.E.
      • Giuliani G.
      • Meloni M.
      • Servi B.D.E.
      • Marco G.
      Synthesis of γ-aminobutyric acid (GABA) by Lactobacillus plantarum DSM19463: Functional grape must beverage and dermatological applications.
      ). The potential applications of GABA-producing microorganisms during the manufacture of foods such as cheese have been explored at length (
      • Dhakal R.
      • Bajpai V.K.
      • Baek K.-H.
      Production of GABA (γ-aminobutyric acid) by microorganisms: A review.
      ;
      • Lacroix N.
      • St-Gelais D.
      • Champagne C.P.
      • Vuillemard J.C.
      Gamma-aminobutyric acid-producing abilities of lactococcal strains isolated from old-style cheese starters.
      ).
      γ-Aminobutyric acid has several well-characterized physiological functions such as antihypertensive, immunomodulation, antidiuretic, and tranquilizing effects (
      • Inoue K.
      • Shirai T.
      • Ochiai H.
      • Kasaom M.
      • Hayakawa K.
      • Kimura M.
      • Sansawa H.
      Blood-pressure-lowering effect of a novel fermented milk containing gamma-aminobutyric acid (GABA) in mild hypertensives.
      ;
      • Hayakawa K.
      • Kimura M.
      • Kasaha K.
      • Matsumoto K.
      • Sansawa H.
      • Yamori Y.
      Effect of g-aminobutiric acid-enriched dairy product on the blood pressure of spontaneously hypertensive and normotensive Wistar-Kyoto rats.
      ;
      • Shimada M.
      • Hasegawa T.
      • Nishimura C.
      • Kan H.
      • Nakamura T.
      • Matsubayashi T.
      Anti-hypertensive effect of gamma-aminobutyric acid (GABA)-rich Chlorella on high-normal blood pressure and borderline hypertension in placebo-controlled double blind study.
      ;
      • Wang H.K.
      • Dong C.
      • Chen Y.F.
      • Cui L.M.
      • Zhang H.P.
      A new probiotic cheddar cheese with high ACE-Inhibitory activity and g-aminobutyric acid content produced with koumiss-derived Lactobacillus casei Zhang.
      ). Additionally, some studies have shown that GABA can induce the secretion of insulin and therefore help prevent or manage diabetes (
      • Adeghate E.
      • Ponery A.S.
      GABA in the endocrine pancreas: Cellular localization and function in normal and diabetic rats.
      ) and help treat alcoholism (
      • Oh S.H.
      • Oh C.H.
      Brown rice extracts with enhanced levels of GABA stimulate immune cells.
      ) and depression (
      • Okada T.
      • Sugishita T.
      • Murakami T.
      • Murai H.
      • Saikusa T.
      • Horino T.
      • Onoda A.
      • Kajimoto O.
      • Takahashi R.
      • Takahashi T.
      Effect of the defatted rice germ enriched with GABA for sleeplessness, depression, autonomic disorder by oral administration.
      ) by activating specific receptors and promoting lymphocyte proliferation. Intake of GABA can regulate sensations of pain and anxiety and lipid levels in serum (
      • Miura D.
      • Ito Y.
      • Mizukuchi A.
      • Kise M.
      • Aoto H.
      • Yagasaki K.
      Hypercholesterolemic action of pre-germinated brown rice in hepatoma-bearing rats.
      ). Another study linked GABA to an increase in the concentration of growth hormone in plasma and the rate of protein synthesis in the brain (
      • Tujioka K.
      • Ohsumi M.
      • Horie K.
      • Kim M.
      • Hayase K.
      • Yokogoshi H.
      Dietary gamma-aminobutyric acid affects the brain protein synthesis rate in ovariectomized female rats.
      ). In particular, one of the main benefits of GABA in cheese is its ability to induce hypotension in animals (
      • Hayakawa K.
      • Kimura M.
      • Kasaha K.
      • Matsumoto K.
      • Sansawa H.
      • Yamori Y.
      Effect of g-aminobutiric acid-enriched dairy product on the blood pressure of spontaneously hypertensive and normotensive Wistar-Kyoto rats.
      ) and humans (
      • Inoue K.
      • Shirai T.
      • Ochiai H.
      • Kasaom M.
      • Hayakawa K.
      • Kimura M.
      • Sansawa H.
      Blood-pressure-lowering effect of a novel fermented milk containing gamma-aminobutyric acid (GABA) in mild hypertensives.
      ;
      • Shimada M.
      • Hasegawa T.
      • Nishimura C.
      • Kan H.
      • Nakamura T.
      • Matsubayashi T.
      Anti-hypertensive effect of gamma-aminobutyric acid (GABA)-rich Chlorella on high-normal blood pressure and borderline hypertension in placebo-controlled double blind study.
      ).
      The GABA content on 34 types of artisanal Spanish cheese was quantified by HPLC. Results showed GABA concentrations of up to 330 mg/kg, which were not influenced by ripening stage or milk source (
      • Diana M.
      • Rafecas M.
      • Arco C.
      • Quilez J.
      Free amino acid profile of Spanish artisanal cheeses: Importance of gamma-aminobutyric acid (GABA) and ornithine content.
      ). Furthermore, the concentration of GABA in Italian Pecorino Marchigiano and Pecorino Filiano cheeses ripened for 5 mo was 289 and 391 mg/kg, respectively (
      • Siragusa S.
      • De Angelis M.
      • Di Cagno R.
      • Rizzello C.G.
      • Coda R.
      • Gobbetti M.
      Synthesis of g-aminobutyric acid by lactic acid bacteria isolated from a variety of Italian cheeses.
      ). Other studies have demonstrated the presence of GABA in varieties of Gouda, Cheddar, blue, and Edam cheeses, with GABA concentrations of 177, 48, 7.1, and 4.2 μg/g of cheese, respectively (
      • Nomura M.
      • Kimoto H.
      • Someya Y.
      • Furukawa S.
      • Suzuki I.
      Production of γ-aminobutyric acid by cheese starters during cheese ripening.
      ). These findings suggest that variations in total GABA depend on the type of cheese, type of ripening, and the quantity of protein in the raw material used, as well as the presence of native microbiota and the activity of proteolytic enzymes, which are the main factors responsible for AA release (
      • Yvon M.
      • Rijnen L.
      Cheese flavour formation by amino acid metabolism.
      ). Furthermore, the content of GABA in different types of Spanish cheese (mean 330 mg/kg of cheese), given the average daily consumption (21.8 g/person), could mean that these products have a high physiological value for hypertension management (
      • Diana M.
      • Rafecas M.
      • Arco C.
      • Quilez J.
      Free amino acid profile of Spanish artisanal cheeses: Importance of gamma-aminobutyric acid (GABA) and ornithine content.
      ).
      Similarly, ripening conditions can promote an increase in GABA concentration due to glutamate released through casein proteolysis, low pH, and anaerobiosis; this is also dependent on the type of LAB starter used.
      • Lacroix N.
      • St-Gelais D.
      • Champagne C.P.
      • Vuillemard J.C.
      Gamma-aminobutyric acid-producing abilities of lactococcal strains isolated from old-style cheese starters.
      showed that 2 LAB starters, ULAAC-A and ULAAC-H, generated high amounts of GABA in Canadian cheeses.
      Commercial cheeses from France were evaluated to identify GABA, which was detected in 4 of 9 cheeses. The highest concentration of GABA was found in Danish Havarti, with 324 mg/100 g of cheese, whereas Gouda cheese contained 129 mg/100 g of cheese. These results indicate that extensive ripening time and proteolysis of Danish Havarti promoted a greater concentration of free AA and a higher amount of glutamate, whereas, in Gouda and cheese slurry, the concentration of glutamate was minimal, indicating that total conversion to GABA had occurred (
      • Lacroix N.
      • St-Gelais D.
      • Champagne C.P.
      • Vuillemard J.C.
      Gamma-aminobutyric acid-producing abilities of lactococcal strains isolated from old-style cheese starters.
      ).

      CLA

      In cheese, fat content varies between 20 and 35% of dry mass (
      • Rippe J.M.
      Encyclopedia of Lifestyle Medicine and Health.
      ). Of the fat content, approximately 66% is SFA, 30% is MUFA, and 4% is PUFA (
      • López-Expósito I.
      • Amigo L.
      • Recio I.
      A mini-review on health nutritional aspects of cheese with a focus on bioactive peptides.
      ). Fatty acids participate in various biological processes, serving as energy substrates and regulating cells, as well as influencing gene expression, PUFA bioavailability, and fat deposition. In addition, fatty acids may play a role in cancer prevention (
      • Rioux V.
      • Legrand P.
      Saturated fatty acids: Simple molecular structures with complex cellular functions.
      ;
      • Tvrzicka E.
      • Kremmyda L.S.
      • Stankova B.
      • Zak A.
      Fatty acids as biocompounds: their role in human metabolism, health and disease—A review. Part 1: Classification, dietary sources and biological functions.
      ).
      Conjugated linoleic acid refers to a group of isomers of linoleic acid (C18:2) with conjugated double bonds (
      • MacDonald H.B.
      Conjugated linoleic acid and disease prevention: A review of current knowledge.
      ). The main isomers are cis-9,trans-11 CLA, trans-10,cis-12 CLA, and cis-9,cis-12 CLA, but the most biologically active isomer is cis-9,trans-11 (
      • Lin H.
      • Boylston T.D.
      • Chang M.J.
      • Luedecke L.O.
      • Shultz T.D.
      Survey of the conjugated linoleic acid contents of dairy products.
      ;
      • Ham J.S.
      • In Y.M.
      • Jeong S.G.
      • Kim J.G.
      • Lee E.H.
      • Kim H.S.
      • Yoon S.K.
      • Lee B.H.
      Screening of conjugated linoleic acid producing lactic acid bacteria from fecal samples of healthy babies.
      ;
      • van Nieuwenhove C.P.
      • Oliszewski R.
      • Gonzalez S.N.
      • Chaia A.B.P.
      Conjugated linoleic acid conversion by dairy bacteria cultured in MRS broth and buffalo milk.
      ).
      Conjugated linoleic acid is naturally found in milk and is formed as a result of incomplete biohydrogenation of dietary fatty acids in the cow's rumen. Generally, dietary lipids are rapidly hydrolyzed in the rumen, and the resulting free UFA are subjected to biohydrogenation by microorganisms. Consequently, one part is absorbed by the rumen and another in the gastrointestinal tract, thereby incorporating CLA into mammary glands and milk fat (
      • Kelly M.L.
      • Berry J.R.
      • Dwyer D.A.
      • Griinari J.M.
      • Chouinard P.Y.
      • Van Amburgh M.E.
      • Bauman D.E.
      Dietary fatty acid sources affect conjugated linoleic acid concentrations in milk from lactating dairy cows.
      ). Other factors involved in the subsequent formation of CLA in cheeses are the processing conditions, the raw milk composition, and prior fermentation time (
      • Lin H.
      • Boylston T.D.
      • Chang M.J.
      • Luedecke L.O.
      • Shultz T.D.
      Survey of the conjugated linoleic acid contents of dairy products.
      ). Because CLA is formed in the rumen by microorganisms, it has been proposed that other microorganisms may also be capable of producing this fatty acid (
      • Sieber R.
      • Collomb M.
      • Aeschlimann A.
      • Jelen P.
      • Eyer H.
      Impact of microbial cultures on conjugated linoleic acid in dairy products—A review.
      ). Therefore, LAB with the potential to produce CLA in culture medium and milk via linoleate isomerase activity have been evaluated (
      • Jiang J.
      • Bjorck L.
      • Fonden R.
      Production of conjugated linoleic acid by dairy starter cultures.
      ;
      • Sieber R.
      • Collomb M.
      • Aeschlimann A.
      • Jelen P.
      • Eyer H.
      Impact of microbial cultures on conjugated linoleic acid in dairy products—A review.
      ) with the aim of incorporating adjunct cultures into milk to produce dairy products with a higher CLA content (
      • Ham J.S.
      • In Y.M.
      • Jeong S.G.
      • Kim J.G.
      • Lee E.H.
      • Kim H.S.
      • Yoon S.K.
      • Lee B.H.
      Screening of conjugated linoleic acid producing lactic acid bacteria from fecal samples of healthy babies.
      ;
      • van Nieuwenhove C.P.
      • Oliszewski R.
      • Gonzalez S.N.
      • Chaia A.B.P.
      Conjugated linoleic acid conversion by dairy bacteria cultured in MRS broth and buffalo milk.
      ).
      Nonetheless, CLA is naturally present in cheese, partly due to its natural content in milk and because LAB produce CLA via linoleate isomerase activity during milk fermentation; however, the linoleic acid content of milk is low, around 0.1 to 2.5 g/kg of fat (
      • Jenness R.
      Biosynthesis and composition of milk.
      ). The identification of suitable lipid substrates would be necessary to achieve a greater bioconversion of CLA. The exact mechanism of CLA bioconversion remains largely unknown; it is thought that bacteria perform this conversion during detoxification to protect themselves from the antimicrobial activity of free fatty acids (
      • Jiang J.
      • Bjorck L.
      • Fonden R.
      Production of conjugated linoleic acid by dairy starter cultures.
      ). Lactic acid bacteria use hydratase, dehydrogenase, isomerase, and reductase enzymes to catalyze the biohydrogenation of fatty acids (
      • Yang B.
      • Chen H.
      • Gu Z.
      • Tian F.
      • Ross R.P.
      • Staton C.
      • Chen Y.Q.
      • Chen W.
      • Zhang H.
      Synthesis of conjugated linoleic acid by the linoleate isomerase complex in food-derived lactobacilli.
      ). The antioxidant activity of CLA has been proposed as a possible explanation of its anticarcinogenic effect and its role in the decrease of atherosclerosis (
      • Ip C.
      • Chin S.F.
      • Scimeca J.A.
      • Pariza M.W.
      Mammary cancer prevention by conjugated dienoic derivate of linoleic acid.
      ). Additional beneficial effects of CLA include antiadipogenic, antidiabetogenic, and anti-inflammatory properties (
      • Pariza M.W.
      • Park Y.
      • Cook M.E.
      The biologically active isomers of conjugated linoleic acid.
      ;
      • Ryder J.W.
      • Portocarrero C.P.
      • Song X.M.
      • Cui L.
      • Yu M.
      • Combatsiaris T.
      • Galuska D.
      • Bauman D.E.
      • Barbano D.M.
      • Charron M.J.
      • Zierath J.R.
      • Houseknecht K.L.
      Isomer-specific antidiabetic properties of conjugated linoleic acid. Improved glucose tolerance, skeletal muscle insulin action, and UCP-2 gene expression.
      ;
      • Yang M.
      • Cook M.E.
      Dietary conjugated linoleic acid decreased cachexia, macrophage tumor necrosis factor-alpha production, and modifies splenocyte cytokines production.
      ).
      Another important fatty acid in cheese is phytanic acid (C20), which is saturated with 4 methyl branches. This acid has a demonstrated ability to enhance glucose uptake in hepatocytes and may improve glucose homeostasis as well as protect against the development of MetS and type-2 diabetes (
      • Hellgren L.I.
      Phytanic acid—An overlooked bioactive fatty acid in dairy fat?.
      ).

      Organic Acids

      Autolysis of LAB in cheese allows intracellular enzymes involved in cheese ripening to reach their substrates more easily and then release antimicrobial substances such as organic acids, diacetyl, acetoin, hydrogen peroxide, and bacteriocins (
      • Izco J.M.
      • Tormo M.
      • Jiménez-Flores R.
      Rapid simultaneous determination of organic acids, free amino acids, and lactose in cheese by capillary electrophoresis.
      ;
      • Piraino P.
      • Zotta T.
      • Ricciardi A.
      • McSweeney P.L.H.
      • Parente E.
      Acid production, proteolysis, autolytic and inhibitory properties of lactic acid bacteria isolated form pasta filata cheeses: a multivariate screening study.
      ). In this process, citric, orotic, pyruvic, lactic, uric, formic, acetic, propionic, butyric, and hippuric acids have been reportedly released in Ossalano cheese (
      • Zeppa G.
      • Conterno L.
      • Gerbi V.
      Determination of organic acids, sugars, diacetyl, and acetoin in Cheese by high-performance liquid chromatography.
      ), as well as malic acid in Cheddar cheese (
      • Murtaza M.A.
      • Rehman S.U.
      • Anjum F.M.
      • Huma N.
      • Tarar O.M.
      • Mueen-Ud-Din G.
      Organic acid contents of buffalo milk cheddar cheese as influenced by accelerated ripening and sodium salt.
      ).
      These organic acids contribute toward cheese quality and flavor (
      • Buffa M.
      • Guamis B.
      • Saldo J.
      • Trujillo A.J.
      Changes in organic acids during ripening of cheeses made from raw, pasteurized or high-pressure-treated goats milk.
      ). For example, propionic acid is key for the flavor development of Swiss-type cheese and is formed by Propionibacterium spp. through lactate metabolism (
      • Califano A.N.
      • Bevilacqua A.E.
      Multivariate anaysis of the organic acids content of Gouda type cheese during ripening.
      ). Organic acids act as antimicrobial agents capable of bacteriostatic and bactericidal activities, depending on the physiological status of the microorganism and the physicochemical characteristics of the external environment (
      • Ricke S.C.
      Perspectives on the use of organic acids and short chain fatty acids as antimicrobial.
      ). For instance, their acidity prevents the growth of spoilage-causing and pathogenic microorganisms, thereby improving the hygienic quality of cheese. The quantitative determination of organic acids is important for monitoring bacterial growth and sensory quality, as these acids contribute to the final flavor and aroma of cheese (
      • Izco J.M.
      • Tormo M.
      • Jiménez-Flores R.
      Rapid simultaneous determination of organic acids, free amino acids, and lactose in cheese by capillary electrophoresis.
      ).

      Vitamins and Minerals

      Milk and dairy products contain vitamins and minerals in different quantities and represent a significant source of calcium. Semi-hard and hard cheeses contain 6 to 11 g of Ca/kg of cheese. On the other hand, soft cheese has a lower Ca content due to the acidification of the vat milk used in its manufacture, yet the presence of Ca and vitamins varies similarly depending on the cheese variety (
      • Eichholzer M.
      • Camenzid E.
      • Matzke A.
      • Amado R.
      • Ballmer P.E.
      • Beer M.
      • Darioli R.
      • Hasler K.
      • Lüthy J.
      • Moser U.
      • Sieber R.
      • Trabichet C.
      ).
      A greater concentration of fat-soluble vitamins, rather than water-soluble vitamins, is found in cheese because whey is removed during the manufacturing process. The main vitamins present in cheese are riboflavin, vitamin B12, niacin, folate, and vitamin A (
      • López-Expósito I.
      • Amigo L.
      • Recio I.
      A mini-review on health nutritional aspects of cheese with a focus on bioactive peptides.
      ). For instance, 50 g of Cheddar cheese can provide 28 and 32% of the recommended daily intake of vitamin A for men and women, respectively. This is especially important because vitamin A has various biological functions, such as stimulating the immune system, regulating gene expression, and sustaining low-light vision (
      • Russell R.M.
      The vitamin A spectrum: From deficiency to toxicity.
      ).
      In addition to Ca, other important minerals in the cheese matrix are Zn, P, and Mg. Calcium and P are found in greater proportion in cheese than in milk and are approximately 5 times more concentrated in soft cheeses, 8 times more concentrated in semi-hard cheeses, and up to 10 times more concentrated in hard cheeses (
      • de la Fuente M.A.
      • Juárez M.
      Los quesos: Una fuente de nutrientes.
      ). Calcium, along with vitamin D, has the potential to safeguard against osteoporosis and encourage weight loss when combined with a low-calorie diet (
      • Barba G.
      • Russo P.
      Dairy foods, dietary calcium and obesity: A short review of evidence.
      ;
      • Ash A.
      • Wilbey A.
      The nutritional significance of cheese in the UK diet.
      ). One study reported that Ca encourages hypolipidemic mechanisms in the human body via inhibition of the absorption of fat and bile acids and increasing fecal fat excretion and Ca-induced conversion of cholesterol to bile acids (
      • Tholstrup T.
      Dairy products and cardiovascular disease.
      ).

      HEALTH EFFECTS ASSOCIATED WITH CONSUMPTION OF RIPENED CHEESE

      Cheese is a product that is consumed widely around the world. The cheese-making process differs for each cheese type, the type of milk used, and different storage conditions. The metabolites discussed above are released in cheese and can be responsible for different health effects (
      • Kumar V.V.
      • Sharma V.
      • Bector B.S.
      Effect of ripening on total conjugated linoleic acid and its isomers in buffalo Cheddar cheese.
      ). The use of animal and clinical studies indicates that consumption of cheese may contribute to reduced incidence of cardiovascular risk factors and other diseases that are mentioned below.

      Animal Models

      Studies using animal models have been conducted to evaluate the effect of the ripening process on enhancing the beneficial effects of cheese. In one study, different types of cheese ripened for 35 d were administered to diabetic db/db C57BL/J mice, and the effects were evaluated according to glucose tolerance, hepatic lipid content, and blood profiles (P < 0.05). The consumption of cheese ripened for 35 d significantly improved glucose tolerance without affecting insulin secretion, leading to a significant decrease in lipid peroxide markers (TBARS and NADPH-oxidase mRNA expression) in adipose tissues without affecting BW, food intake, or fat mass. In addition, the hepatic lipid content in mice significantly decreased (
      • Geurts L.
      • Everard A.
      • Ruyet P.
      • Delzenne N.M.
      • Cani P.D.
      Ripened dairy products differentially affect hepatic lipid content and adipose tissue oxidative stress markers in obese and type 2 diabetic mice.
      ).
      Cheese consumption has also been reported to reduce the risk of MetS in male Fischer-344 rats. The results of the study showed that serum adiponectin concentration was significantly higher in the cheese group than in the control group, and the concentrations of liver triglycerides and cholesterol were lower (P = 0.016 and P < 0.001, respectively) in the cheese group than in the control group 9 wk after initiation of the experiment. Thus, cheese intake lowered hepatic triglycerides and cholesterol in male rats fed a high-fat diet. The mechanisms of action could be related to the functional peptides produced during the ripening process, which may influence adiponectin concentration (
      • Higurashi S.
      • Ogawa A.
      • Nara T.Y.
      • Kato K.
      • Kodooka Y.
      Cheese consumption prevents fat accumulation in the liver and improve serum lipid parameters in rats fed a high-fat diet.
      ).
      Cheddar cheese aged for 24 mo promoted the production of glycosylated proteins with a molecular weight of 23 kDa derived from αS1- and β-casein. The glycosylated proteins showed resistance to in vitro gastrointestinal digestion and changed the relative abundances of fecal bacteria by increasing the Bacteroidetes:Firmicutes ratio and Bifidobacterium compared with the casein fermented control in obese mice. Furthermore, the metabolites released during fecal fermentation protected the HT-29 and fibroblast CCD-18Co cells from LPS-induced reactive oxygen species (
      • Yuan J.
      • Noratto K.
      • Munske G.
      • Pilla P.
      • Mohanty I.
      • Zapata D.A.
      • Noratto G.
      Potential of glycated proteins produced during aging of cheddar cheese to modulate fecal bacteria from obese mice ex vivo and protect against colon inflammation.
      ).
      Another important characteristic of cheese proteins and peptides is their effect on the inflammatory process and on inflammatory bowel disease. Several factors are involved in the development of the latter disease, such as genetic and environmental aspects, immunological malfunction, and intestinal microbiota (
      • Sartor R.B.
      Mechanisms of disease: Pathogenesis of Crohn's disease and ulcerative colitis.
      ). Studies have demonstrated that the unavailability of the AA Thr, Cys, Ser, and Pro can limit mucin synthesis under conditions of inflammation and that supplementation with these AA increases mucin synthesis, resulting in positive histological changes in cases of colitis induced by dextran sulfate sodium in rats (
      • Faure M.
      • Mettraux C.
      • Moennoz D.
      • Godin J.P.
      • Vuichoud J.
      • Rochat F.
      • Breuille D.
      • Obled C.
      • Corthesy-Thelaz I.
      Specific amino acids increase mucin synthesis and microbiota in dextran sulfate sodium-treated rats.
      ).

      Clinical Trials

      Growing evidence suggests that consumption of cheese may contribute to a reduced incidence of cardiovascular risk factors such as obesity, dyslipidemia, and type-2 diabetes (Table 2;
      • Tholstrup T.
      • Vessby B.
      • Sandstrom B.
      Difference in effect of myristic and stearic acid on plasma HDL cholesterol within 24 h in young men.
      ,
      • Tholstrup T.
      • Høy C.E.
      • Andersen L.N.
      • Christensen R.D.
      • Sandstro¨m B.
      Does fat in milk, butter and cheese affect blood lipids and cholesterol differently?.
      ;
      • Sadeghi M.
      • Khosravi-Boroujeni H.
      • Sarrafzadegan N.
      • Asgary S.
      • Roohafza H.
      • Gharipour M.
      • Sajjadi F.
      • Khalesi S.
      • Rafieian-Kopaei M.
      Cheese consumption in relation to cardiovascular risk factors among Iranian adults-IHHP study.
      ). Research has shown that the balance of gastrointestinal microbiota, in addition to microbiota functions, play an important role in maintaining health and preventing diseases (
      • Marteau P.
      • Seksik P.
      • Jian R.
      Probiotics and intestinal health effects: A clinical perspective.
      ). In this respect, one study evaluated the effect of Camembert cheese intake compared with fermented milk intake on the composition and metabolism of human intestinal microbiota. The study evaluated feces to assess the microbiota of humans and rats in a culture medium via PCR-temporal temperature gradient gel electrophoresis. Intakes of cheese and fermented milk led to similar changes in bacterial metabolism, decreasing azoreductose activity and NH3 concentration and increasing mucolytic activities. Several specific changes were observed. For example, in microbiota-associated, Camembert pasteurized milk group (HMCp) rats, the proportion of ursodeoxycholic resulting from chenodeozycholic epimerization was higher. In microbiota-associated, fermented pasteurized milk group (HMfm) rats, α- and β-galactosidase were higher than in the other groups, and both azoreductases and nitrate reductases were lower. Overall, Camembert intake did not greatly modify the profile or major metabolic activities of the microbiota (
      • Lay C.
      • Sutren M.
      • Lepercq P.
      • Juste C.
      • Rigottier-Gois L.
      • Lhoste E.
      • Lemee R.
      • Ruyet P.L.
      • Doré J.
      • Andrieux C.
      Influence of Camembert consumption on the composition and metabolism of intestinal microbiota: A study in human microbiota-associated rats.
      ).
      Table 2Functional effects of cheese intake in clinical trials
      Type of cheeseDesign/follow-upCheese dosagePopulation profileTime of studyPrincipal findings
      LDL = low density lipoprotein; HDL = high density lipoprotein; TAG = triacylglycerol.
      Reference
      Jarlsberg cheese (Norway)Randomized crossoverControlled diet (20% of energy from cheese)Healthy subjects3 wk↓ Cholesterol and (LDL); no significant difference in HDL, TAG, apo A1, or apoB lipoprotein
      • Biong A.S.
      • Müller H.
      • Seljeflot I.
      • Veirod M.B.
      • Pedersen J.I.
      A comparison of the effects of cheese and butter on serum lipids, haemostatic variables and homocysteine.
      Norway cheeseCross-sectionalCheese intake 0.5–10.5 times/wkHealthy subjects of OsloAssigned number of intake times per weekNegative association with TAG; positive association with HDL
      • Høstmark A.T.
      • Haug A.
      • Tomten S.E.
      • Thelle D.S.
      • Mosdol A.
      Serum HDL cholesterol was positively associated with cheese intake in the Oslo Health Study.
      Diet cheese or butter (Denmark)Randomized, crossoverControlled diet (13% of energy from cheese or butter)Healthy subjects6 wk↓ Serum total, LDL, HDL ↑ Glucose
      • Hjerpsted J.
      • Leedo E.
      • Tholstrup T.
      Cheese intake in large amounts lowers LDL-cholesterol concentrations compared with butter intake of equal fat content.
      Camembert (France)Multicenter, randomized, opened60 g/dModerately hypercholesterolemic subjects5-wk daily consumptionNo change in blood pressure or serum lipids
      • Schlienger J.-L.
      • Paillard F.
      • Lecerf J.M.
      • Romon M.
      • Bonhomme C.
      • Schmit B.
      • Donazzolo Y.
      • Defoort C.
      • Mallmann C.
      • Ruyet P.L.
      • Bresson J.L.
      Effect on blood lipids of two daily servings of Camembert cheese. An intervention trial in mildly hypercholesterolemic subjects.
      Norvegia and Gamalost (Norway)Randomized, single-blinded50 or 80 g/dSubjects with metabolic syndrome8 wkNorvegia: ↓ total cholesterol; ↑ reduction of TAG Gamalost: ↓ significant in total cholesterol
      • Nilsen R.
      • Høstmark A.T.
      • Haug A.
      • Skeie S.
      Effect of a high intake of cheese on cholesterol and metabolic syndrome: results of a randomized trial.
      Gamalost Gouda-type cheese (Norway)Randomized80 g/dBlood pressure8 wkNo difference among cheeses compared with control; Gamalost: ↓ diastolic and systolic blood pressure
      • Nilsen R.
      • Pripp A.H.
      • Høstmark A.T.
      • Haug A.
      • Skeie S.
      Effect of a cheese rich in angiotensin-converting enzyme-inhibiting peptides (Gamalost) and a Gouda-type cheese on blood pressure: results of a randomized trial.
      1 LDL = low density lipoprotein; HDL = high density lipoprotein; TAG = triacylglycerol.
      It is well established that the use of antimicrobial drugs for treating infections may have potentially adverse effects on normal intestinal microflora (
      • Sullivan A.
      • Edlund C.
      • Nord C.
      Effect of antimicrobial agents on the ecological balance of human microflora.
      ); namely, on the development of antimicrobial resistance in bacteria normally present as part of the human microflora and on the overgrowth of pathogens already present in the intestine, such as yeasts and Clostridium difficile (
      • Sullivan A.
      • Edlund C.
      • Nord C.
      Effect of antimicrobial agents on the ecological balance of human microflora.
      ). A clinical pilot trial suggested that the intake of hard-cooked cheese during amoxicillin-clavulanic acid treatment lowered the occurrence of amoxicillin-resistant (Amox) strain in feces. This study consisted of 2 phases separated by 1 yr; during the first phase, the administration of amoxiclav increased the number of Escherichia coli and enterococci. The E. coli and enterococci were evaluated in feces samples and quantitatively by enterococci on Uriselect (Bio-Rad) and Slanetz and Bartley agar, respectively. The percentage of Amox E. coli increased from 0.5 to 32.95% at d 5 and decreased progressively to baseline level (0.5%) at d 12. Instead, the Amox-enterococci increased from 0.001 to 6.75% on d 5 and remained stable at d 8 (2.22%) and d 12 (5.26%), decreasing to baseline level (0.001%) at d 19. In phase 2, the effect of amoxicillin-clavulanic on Amox E. coli increased from a baseline of 1 and 3% to 60% at d 5, 8, 12, and decreased to 3 and 8% until the end of the study. Six volunteers tested positive for Amox-enterococci. The pre-consumption (pre-antibiotic period) of cheese increased the presence of Amox E. coli (P = 0.0013) and in post-consumption (antibiotic posttreatment; P = 0.006) but not during the consumption period (P = 0.609). These results showed that consumption of hard-cooked cheese can decrease the presence of the Amox enterococci in feces (
      • Bertrand X.
      • Dufour V.
      • Millon L.
      • Beuvier E.
      • Gbaguidi-Haore H.
      • Piarroux R.
      • Vuitton D.A.
      • Talon D.
      Effect of cheese consumption on antimicrobial resistance in the intestinal microflora induced by a short course of amoxicillin-clavulanic acid.
      ).
      Hypercholesterolemia has been identified as a major risk for cardiovascular disease that is influenced by saturated fat intake and, as observed in human clinical trials, is associated with a high concentration of low-density lipoprotein (LDL) cholesterol (
      • Gill J.M.
      • Brown J.C.
      • Caslake M.J.
      • Wright D.M.
      • Cooney J.
      • Bedford D.
      • Hughes D.A.
      • Stanley J.C.
      • Packard C.J.
      Effects of dietary monounsaturated fatty acids on lipoprotein concentrations, compositions, and subfraction distributions and on LDL apolipoprotein B kinetics: Dose-dependent effects on LDL.
      ). The atherogenic effect of dairy products with a high level of SFA has been poorly established in clinical studies (
      • Schlienger J.-L.
      • Paillard F.
      • Lecerf J.M.
      • Romon M.
      • Bonhomme C.
      • Schmit B.
      • Donazzolo Y.
      • Defoort C.
      • Mallmann C.
      • Ruyet P.L.
      • Bresson J.L.
      Effect on blood lipids of two daily servings of Camembert cheese. An intervention trial in mildly hypercholesterolemic subjects.
      ). In fact, some cohort studies have reported that a high intake of full-fat dairy products or fermented milk may be associated with a lower risk of hypercholesterolemia (
      • Bonthuis M.
      • Hughes M.C.B.
      • Ibiebele T.I.
      • Green A.C.
      • van der Pols J.C.
      Dairy consumption and patterns of mortality of Australian adults.
      ;
      • Sonestedt E.
      • Wirfa¨lt E.
      • Wallstro P.
      • Gullberg B.
      • Orho-Melander M.
      • Hedblad B.
      Dairy products and its association with incidence of cardiovascular disease: The Malmö diet and cancer cohort.
      ). One study investigated the effect of 2 servings of Camembert cheese on serum lipids in moderately hypercholesterolemic individuals. After consuming 2 daily servings (60 g) of Camembert cheese over a 5-wk period, no changes were observed in blood pressure or serum lipids, suggesting that fermented cheese such as Camembert could be consumed daily without affecting serum lipids or blood pressure (
      • Schlienger J.-L.
      • Paillard F.
      • Lecerf J.M.
      • Romon M.
      • Bonhomme C.
      • Schmit B.
      • Donazzolo Y.
      • Defoort C.
      • Mallmann C.
      • Ruyet P.L.
      • Bresson J.L.
      Effect on blood lipids of two daily servings of Camembert cheese. An intervention trial in mildly hypercholesterolemic subjects.
      ). In another study, a mixture of long-chain SFA in the diet increased plasma cholesterol and LDL cholesterol; thus, replacing SFA with PUFA could be a good approach to prevent coronary heart disease (
      • Mensink R.P.
      • Zock P.L.
      • Kester A.D.
      • Katan M.B.
      Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials.
      ,
      • Jakobsen M.U.
      • O'Reilly E.J.
      • Heitmann B.L.
      • Pereira M.A.
      • Bälter K.
      • Fraser G.E.
      • Goldbourt U.
      • Hallmans G.
      • Knekt P.
      • Liu S.
      • Pietinen P.
      • Spiegelman D.
      • Stevens J.
      • Virtamo J.
      • Willett W.C.
      • Ascherio A.
      Major types of dietary fat and risk of coronary heart disease: A pooled analysis of 11 cohort studies.
      ). Levels of myristic acid of up to 1.8% of total energy were associated with a decrease in LDL cholesterol in murine models, and an increase in high-density lipoprotein (HDL) cholesterol in both animal models and human trials (
      • Tholstrup T.
      • Vessby B.
      • Sandstrom B.
      Difference in effect of myristic and stearic acid on plasma HDL cholesterol within 24 h in young men.
      ,
      • Tholstrup T.
      • Høy C.E.
      • Andersen L.N.
      • Christensen R.D.
      • Sandstro¨m B.
      Does fat in milk, butter and cheese affect blood lipids and cholesterol differently?.
      ).
      The bacteria involved in cheese ripening can potentially release metabolites, such as folic acid (
      • Forssén K.M.
      • Jägerstad M.I.
      • Wigertz K.
      • Witthöft C.M.
      Folates and dairy products: A critical update.
      ). This could affect serum homocysteine levels (
      • Appel L.J.
      • Miller E.R.I.I.I.
      • Jee S.H.
      • Stolzenberg-Solomon R.
      • Lin P.H.
      • Erlinger T.
      • Nadeau M.R.
      • Selhub J.
      Effect of dietary patterns on serum homocysteine: Results of a randomized, controlled feeding study.
      ), which have been identified as another risk factor for chronic heart disease when present at high levels (
      • Wald D.S.
      • Law M.
      • Morris J.K.
      Homocysteine and cardiovascular disease: Evidence on causality from a meta-analysis.
      ). One randomized crossover trial was performed to further investigate the effect of aged cheese compared with butter on serum lipids, lipoproteins, homocysteine, and hemostatic levels, which are risk factors for chronic heart disease. Subjects consumed 1 of 3 diets for 3 wk: cheese, butter + casein, and butter + egg white. Cholesterol levels were significantly lower in individuals fed the cheese diet and in those fed the butter + casein diet (difference between means of cheese and butter + casein diet: −0.27 mmol/L; P = 0.03), although this latter difference was not significant. No significant differences (−0.22 mmol/L, P = 0.06) were found for HDL cholesterol, triacylglycerols, hemostatic, homocysteine, and apo A-1 and apo B lipoprotein levels among the 3 diets. These results show that a diet with heavy cheese consumption may induce lower cholesterol levels than a diet with high butter consumption (
      • Biong A.S.
      • Müller H.
      • Seljeflot I.
      • Veirod M.B.
      • Pedersen J.I.
      A comparison of the effects of cheese and butter on serum lipids, haemostatic variables and homocysteine.
      ).
      An additional study evaluated the effect of an experimental Cheddar cheese enriched with 16 mg of GABA on blood pressure of 23 men (20–65 yr of age) with slightly elevated blood pressure, and considering a placebo-controlled and a double-blind study group. For 12 wk, subjects consumed daily 50 g of the GABA-enriched cheese. Results demonstrated that blood pressure (P = 0.034) and systolic blood pressure (P = 0.048) decreased as a function of intervention time; however, no time by treatment interaction was observed. At the end of the experimental period, blood pressure decreased by 3.5 mmHg and systolic blood pressure by 5.5 mmHg. Furthermore, no significant change in diastolic blood pressure was observed following the consumption of Cheddar cheese with or without GABA enrichment (
      • Pouliot-Mathieu K.
      • Gardner-Fortier C.
      • Lemieux S.
      • St-Gelais S.
      • Champagne C.P.
      • Vuillemard J.C.
      Effect of cheese containing gamma-aminobutyric acid-producing lactic acid bacteria on blood pressure in men.
      ).
      Other studies have proven that consumption of milk and dairy products is associated with a decreased prevalence of MetS, a prediabetic condition characterized by a waist circumference >80 cm for women and >94 cm for men. Furthermore, the population sectors that present with MetS have a higher risk of developing coronary heart disease. Risk factors include high triglyceride, HDL, and cholesterol levels, high fasting blood glucose, and high systolic or diastolic blood pressure (
      • IDF (International Diabetes Federation
      The IDF Consensus Worldwide Definition of the Metabolic Syndrome.
      ). The frequency of cheese intake was inversely related to serum triglycerides and positively related to serum HDL cholesterol concentration (
      • Elwood P.C.
      • Pickering J.E.
      • Fehily A.M.
      Milk and dairy consumption, diabetes and the metabolic syndrome: The Caerphilly prospective study.
      ;
      • Høstmark A.T.
      • Haug A.
      • Tomten S.E.
      • Thelle D.S.
      • Mosdol A.
      Serum HDL cholesterol was positively associated with cheese intake in the Oslo Health Study.
      ). Another study examined the association between the frequency of self-reported cheese intake and an index for estimating the risk of diabetes and cardiovascular disease. The study showed an inverse association between frequency of cheese intake and MetS risk, except in older men (75–76 yr). Furthermore, individuals with a greater number of MetS risk factors consumed cheese at a lower frequency, whereas cheese intake was significantly (P = 0.005 for men and P = 0.001 for women) and inversely related to MetS risk factors, and cheese intake showed an inverse association with body mass index (P = 0.02) (
      • Høstmark A.T.
      • Tomten S.
      The Oslo Health Study: Cheese intake was negatively associated with the metabolic syndrome.
      ). Although other studies have found a positive relationship between cheese consumption and BW, several factors need to be considered, such as study design, the sampled population (age, sex, ethnicity), and lifestyle factors (
      • Beydoun M.A.
      • Gary T.L.
      • Caballero B.H.
      • Lawrence R.S.
      • Cheskin L.J.
      • Wang Y.
      Ethnic differences in dairy and related nutrient consumption among US adults and their association with obesity, central obesity, and the metabolic syndrome.
      ).

      CONCLUSIONS

      Cheese is widely consumed around the world and plays an important role in human nutrition. In recent years, dairy products (cheese in particular) have received negative press over their potential adverse effects on health; nevertheless, consumption of dairy products has also been associated with several health benefits. For example, cheese intake has demonstrated potential in lowering blood pressure and decreasing cardiovascular risk factors (obesity, dyslipidemia, and type 2 diabetes), although the studies are not entirely conclusive. The composition of cheese represents a good matrix for the release of bioactive compounds, which increase during the cheese ripening process by the action of LAB. Several studies have been directed at peptides; however, the presence of compounds such as GABA and CLA are important metabolites also released by LAB, which have shown potential in disease prevention. Other important compounds such as exopolysaccharides, which enhance the rheological properties of cheese, can have antioxidant, antimicrobial, and immunological properties. The identification of cheese bioactive compounds is of primary importance, as is their characterization via metabolomics, separation, and detection techniques. Further in vitro and in vivo studies are necessary to document the health benefits and bioactive effects derived from consumption of fresh and ripened cheese.

      ACKNOWLEDGMENTS

      The authors thank the National Council for Science and Technology (CONACyT) of Mexico for the graduate scholarships provided to L. Santiago-López and J. E. Aguilar-Toalá. This study was supported by the Mexican Council of Science and Technology (CONACYT; México City, Mexico) research project 240338.

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