SCIENTIFIC OPINION. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) 2, 3. European Food Safety Authority (EFSA), Parma, Italy

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1 EFSA Journal 2011;9(2):1981 SCIENTIFIC OPINION Scientific Opinion on the substantiation of a health claim related to Lactobacillus plantarum TENSIA in the semi-hard Edam-type heart cheese of Harmony and maintenance of normal blood pressure pursuant to Article 13(5) of Regulation (EC) No 1924/ EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) 2, 3 European Food Safety Authority (EFSA), Parma, Italy ABSTRACT Following an application from Piimandusühistu E-Piim, submitted pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of Estonia, the Panel on Dietetic Products, Nutrition and Allergies was asked to deliver an opinion on the scientific substantiation of a health claim, based on newly developed scientific evidence and including a request for the protection of proprietary data, related to Lactobacillus plantarum TENSIA and maintenance of normal blood pressure. The food constituent, the strain L. plantarum TENSIA, which is the subject of the health claim, is sufficiently characterised. The Panel considers that the maintenance of normal blood pressure is a beneficial physiological effect. The applicant provided a total of 38 publications as being pertinent to the claim. The Panel notes that none of these publications addressed the effects of L. plantarum TENSIA TM and considers that no conclusions can be drawn from these references for the scientific substantiation of the claim. Four unpublished reports on human intervention studies (identified as proprietary by the applicant) investigating the effects of the L. plantarum TENSIA TM strain on blood pressure were provided. In weighing the evidence, the Panel took into account that the only randomised, placebo-controlled human intervention study provided did not show an effect of consumption of L. plantarum TENSIA TM in Edam-type cheese on blood pressure. The Panel concludes that a cause and effect relationship has not been established between the consumption of L. plantarum TENSIA in the semi-hard Edam-type heart cheese of Harmony and maintenance of normal blood pressure. European Food Safety Authority, 2011 KEY WORDS Lactobacillus plantarum TENSIA, cheese, blood pressure, health claims. 1 On request from the Competent Authority of Estonia following an application by Piimandusühistu E-Piim, Question No EFSA-Q , adopted on 28 January Panel members: Carlo Agostoni, Jean-Louis Bresson, Susan Fairweather-Tait, Albert Flynn, Ines Golly, Hannu Korhonen, Pagona Lagiou, Martinus Løvik, Rosangela Marchelli, Ambroise Martin, Bevan Moseley, Monika Neuhäuser-Berthold, Hildegard Przyrembel, Seppo Salminen, Yolanda Sanz, Sean (J.J.) Strain, Stephan Strobel, Inge Tetens, Daniel Tomé, Hendrik van Loveren and Hans Verhagen. Correspondence: nda@efsa.europa.eu 3 Acknowledgement: The Panel wishes to thank the members of the Working Group on Claims: Carlo Agostoni, Jean-Louis Bresson, Susan Fairweather-Tait, Albert Flynn, Ines Golly, Marina Heinonen, Hannu Korhonen, Martinus Løvik, Ambroise Martin, Hildegard Przyrembel, Seppo Salminen, Yolanda Sanz, Sean (J.J.) Strain, Inge Tetens, Hendrik van Loveren and Hans Verhagen for the preparatory work on this scientific opinion. Suggested citation: EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA); Scientific Opinion on the substantiation of a health claim related to Lactobacillus plantarum TENSIA in the semi-hard Edam-type heart cheese of Harmony and maintenance of normal blood pressure pursuant to Article 13(5) of Regulation (EC) No 1924/2006. EFSA Journal 2011;9(2):1981. [11 pp.]. doi: /j.efsa Available online: European Food Safety Authority, 2011

2 SUMMARY Following an application from Piimandusühistu E-Piim submitted pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of Estonia, the Panel on Dietetic Products, Nutrition and Allergies was asked to deliver an opinion on the scientific substantiation of a health claim related to Lactobacillus plantarum TENSIA and maintenance of normal blood pressure. The scope of the application was proposed to fall under a health claim based on newly developed scientific evidence and including a request for the protection of proprietary data. The food constituent that is the subject of the health claim is L. plantarum TENSIA in the semi-hard Edam-type heart cheese of Harmony. The strain L. plantarum TENSIA (DSM 21380) has been specified using phenotypic and genotypic methods. Data on the conditions of use, specifications, manufacturing process, bioavailability as well as information on stability of the strain were provided. The Panel considers that L. plantarum TENSIA, which is the subject of the health claim, is sufficiently characterised. The claimed effect is helps to maintain the cardio-vascular system/heart health through reduction of blood pressure. The target population as proposed by the applicant is the general population. The Panel notes that the claimed effect relates to the maintenance of normal blood pressure. The Panel considers that the maintenance of normal blood pressure is a beneficial physiological effect. The applicant provided a total of 38 publications as being pertinent to the claim. The Panel notes that none of these publications addressed the effects of L. plantarum TENSIA TM and considers that no conclusions can be drawn from these references for the scientific substantiation of the claim. Four unpublished reports on human intervention studies (identified as proprietary by the applicant) investigating the effects of the strain L. plantarum TENSIA TM on blood pressure were provided. Two of the studies were pilot, non-randomised and sequential interventions. The Panel notes that these studies were uncontrolled and considers that no conclusions can be drawn from these pilot studies for the scientific substantiation of the claim. The third study was an open label human intervention which investigated the acute effects of a single dose of Edam-type cheese comprising L. plantarum TENSIA TM on blood pressure (primary outcome) and arterial stiffness. The Panel considers that no conclusions can be drawn from this acute and uncontrolled study for the scientific substantiation of the claim. The fourth study was a randomised, double-blind, placebo-controlled, cross-over human intervention which investigated the effects of consuming 50 g/day of Edam-type cheese containing L. plantarum TENSIA TM compared to the same amount of cheese without L. plantarum TENSIA TM on blood pressure in healthy volunteers aged 18 to 65 years. The test and control cheeses were consumed daily for three weeks each with a washout period of two weeks in between. A total of 90 subjects were randomised and 83 participants completed the trial. Changes in systolic and diastolic blood pressure were the primary outcomes of the study. No significant differences in systolic or diastolic blood pressure changes were observed between the intervention and control groups during the study. The Panel notes that this study does not show an effect of L. plantarum TENSIA TM on blood pressure. Post-hoc analyses were carried out by dividing the study population according to systolic blood pressure values at baseline. The Panel notes that these post-hoc analyses were not pre-planned and considers that no conclusions can be drawn from these analyses for the scientific substantiation of the claim. EFSA Journal 2011;9(2):1981 2

3 Information on the functional properties (in vitro production of nitric oxide, polyamines, and angiotensin converting enzyme inhibitory peptides) of the strain L. plantarum TENSIA TM were provided by the applicant. The Panel considers that this information does not predict an effect of L. plantarum TENSIA TM on blood pressure in vivo in humans. In weighing the evidence, the Panel took into account that the only randomised, placebo-controlled human intervention study provided did not show an effect of consumption of L. plantarum TENSIA TM in Edam-type cheese on blood pressure. The Panel concludes that a cause and effect relationship has not been established between the consumption of Lactobacillus plantarum TENSIA in the semi-hard Edam-type heart cheese of Harmony and maintenance of normal blood pressure. EFSA Journal 2011;9(2):1981 3

4 TABLE OF CONTENTS Abstract... 1 Summary... 2 Table of contents... 4 Background as provided by the European Commission... 5 Terms of reference as provided by the European Commission... 5 EFSA Disclaimer... 5 Information provided by the applicant... 6 Assessment Characterisation of the food/constituent Relevance of the claimed effect to human health Scientific substantiation of the claimed effect... 7 Conclusions... 9 Documentation provided to EFSA... 9 References... 9 Glossary/Abbreviations EFSA Journal 2011;9(2):1981 4

5 BACKGROUND AS PROVIDED BY THE EUROPEAN COMMISSION Regulation (EC) No 1924/ harmonises the provisions that relate to nutrition and health claims and establishes rules governing the Community authorisation of health claims made on foods. As a rule, health claims are prohibited unless they comply with the general and specific requirements of that Regulation and are authorised in accordance with this Regulation and included in the lists of authorised claims provided for in Articles 13 and 14 thereof. In particular, Article 13(5) of that Regulation lays down provisions for addition of claims (other than those referring to the maintenance of disease risk and to children s development and health), which are based on newly developed scientific evidence or include a request for the protection of proprietary data, to the Community list of permitted claims referred to in Article 13(3). According to Article 18 of that Regulation, an application for inclusion in the Community list of permitted claims referred to in Art 13(3) shall be submitted by the applicant to the national competent authority of a Member State, who will make the application and any supplementary information supplied by the applicant available to the European Food Safety Authority (EFSA). STEPS TAKEN BY EFSA: The application was received on 02/07/2010. The scope of the application was proposed to fall under a health claim based on newly developed scientific evidence and including a request for the protection of proprietary data. The scientific evaluation procedure started on 20/07/2010. On 08/10/2010, the NDA Panel agreed on a list of questions which requests the applicant to supplement additional particulars to accompany the application by 05/11/2010. The applicant submitted the responses to the NDA Panel s list of questions on 05/11/2010. During the meeting on 28/01/2011, the NDA Panel, after having evaluated the overall data submitted, adopted an opinion on the scientific substantiation of a health claim related to. TERMS OF REFERENCE AS PROVIDED BY THE EUROPEAN COMMISSION EFSA is requested to evaluate the scientific data submitted by the applicant in accordance with Article 16(3) of Regulation (EC) No 1924/2006. On the basis of that evaluation, EFSA will issue an opinion on the scientific substantiation of a health claim related to: Lactobacillus plantarum TENSIA and maintenance of normal blood pressure. EFSA DISCLAIMER The present opinion does not constitute, and cannot be construed as, an authorisation to the marketing of Lactobacillus plantarum TENSIA, a positive assessment of its safety, nor a decision on whether Lactobacillus plantarum TENSIA is, or is not, classified as a foodstuff. It should be noted that such an assessment is not foreseen in the framework of Regulation (EC) No 1924/2006. It should also be highlighted that the scope, the proposed wording of the claim and the conditions of use as proposed by the applicant may be subject to changes, pending the outcome of the authorisation procedure foreseen in Article 18(4) of Regulation (EC) No 1924/ European Parliament and Council (2006). Regulation (EC) No 1924/2006 of the European Parliament and of the Council of 20 December 2006 on nutrition and health claims made on foods. Official Journal of the European Union OJ L 404, Corrigendum OJ L 12, , p EFSA Journal 2011;9(2):1981 5

6 INFORMATION PROVIDED BY THE APPLICANT Applicant s name and address: Piimandusühistu E-Piim (Dairy Cooperative E-Piim), Pikk16, Järva-Jaani, 73301, Järvamaa, Estonia. The application includes a request for the protection of proprietary data in accordance with Article 21 of Regulation (EC) No 1924/2006: Mikelsaar et al., 2007, 2008, 2009a, b, unpublished. Food/constituent as stated by the applicant According to the applicant, semi-hard Edam-type Südamejuust (English translation: Heart cheese) of Harmony brand comprising Lactobacillus plantarum TENSIA. Health relationship as claimed by the applicant According to the applicant, blood pressure lowering improves the functions of the cardio-vascular system of human body. Wording of the health claim as proposed by the applicant According to the applicant, regular consumption (at least 3 weeks) of 50 g/day Südamejuust (Heart cheese) of Harmony brand comprising probiotic Lactobacillus plantarum TENSIA helps to maintain the cardio-vascular system/heart health through reduction of blood pressure. /Symbol of heart/. Specific conditions of use as proposed by the applicant According to the applicant, the minimum amount of 5 x 10 8 viable microbial cells in 1 g of semi-hard Edam-type cheese comprising probiotic strain Lactobacillus plantarum TENSIA (DSM 21380) should be present per 50 g daily intake. This quantity could be consumed as a part of a balanced diet. The target population proposed by the applicant is the general population. ASSESSMENT 1. Characterisation of the food/constituent The food constituent that is the subject of the health claim is Lactobacillus plantarum TENSIA in the semi-hard Edam-type heart cheese of Harmony. The bacterial strain L. plantarum TENSIA has been isolated from a faecal sample of a healthy oneyear old Estonian child (Mikelsaar et al., 2002). The strain L. plantarum TENSIA (DSM 21380) species identity as well as strain characterisation have been determined by using phenotypic (carbohydrate fermentation profiles [API 50 CHL], enzymatic activities profile [API ZYM] and short chain fatty acid (SCFA) profile [gas chromatography]) and genotypic (Internal Transcribed Spacer-Polymerase Chain Reaction [ITS- PCR], 16S rrna gene sequencing and sequence analyses, plasmid profiles, and macro-restriction analysis by Pulsed Field Gel Electrophoresis [PFGE], agarose gel electrophoresis image after Random Amplification of Polymorphic DNA by PCR [RAPD-PCR]) methods. Data on the conditions of use, specifications, manufacturing process, bioavailability as well as information on stability of the strain L. plantarum TENSIA in freeze-dried powder are provided in the application. EFSA Journal 2011;9(2):1981 6

7 The deposit of the strain at the German culture collection DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen) under deposit number DSM is indicated in the application. The strain is used in the manufacturing process of a soft Edam-type cheese where the L. plantarum strain TENSIA (10 6 CFU/ml cheese milk) is used as adjunct starter. Detailed specifications of the manufacturing process, stability information (survival and viable stability of the strain), characteristics and composition of the cheese were provided by the applicant. The Panel considers that the food constituent, the strain L. plantarum TENSIA, which is the subject of the health claim, is sufficiently characterised. 2. Relevance of the claimed effect to human health The claimed effect is helps to maintain the cardio-vascular system/heart health through reduction of blood pressure. The target population as proposed by the applicant is the general population. In the context of the scope of the application, which was submitted pursuant to Article 13(5) of the Regulation (EC) No 1924/2006, the Panel notes that the claimed effect relates to the maintenance of normal blood pressure. Blood pressure (BP) is the pressure (force per unit area) exerted by circulating blood on the walls of blood vessels. Elevated blood pressure, by convention above 140 mmhg (systolic) and/or 90 mmhg (diastolic), may compromise the normal arterial and cardiac function. The Panel considers that the maintenance of normal blood pressure is a beneficial physiological effect. 3. Scientific substantiation of the claimed effect The applicant performed a literature search in MEDLINE, PubMed and esp@cenet. Keywords included blood pressure lowering, nitric mono-oxide, polyamines, cardiovascular health, Lactobacillus plantarum, CVD and probiotics, lactobacilli and NO production, milk peptides, ACE inhibitors. The search was limited to publications in English, Russian, and Estonian which were original research articles (peer-reviewed), reviews, consensus documents since 2000, theses, or patent documents describing a relationship between lactobacilli, including L. plantarum, and blood pressure lowering and/or production of polyamines and bioactive milk peptides, and/or describing the blood pressure lowering effect of polyamines and nitric oxide (NO). The Panel notes that the literature search included terms such as L. plantarum and lactobacilli, but not L. plantarum TENSIA TM (DSM 21380) in particular. The applicant provided a total of 38 publications as being pertinent to the claim. These included guidelines, opinions of EFSA, reports, narrative reviews, theses, human studies and ex vivo/in vitro mechanistic studies. The Panel notes that none of these publications addressed the effects of L. plantarum TENSIA TM and considers that no conclusions can be drawn from these references for the scientific substantiation of the claim. Four unpublished reports on human intervention studies (identified as proprietary by the applicant) investigating the effects of the strain L. plantarum TENSIA TM on blood pressure were provided. Two of the studies were pilot, non-randomised, sequential interventions in which 12 healthy adult volunteers (Mikelsaar et al., 2007, unpublished) consumed 50 g/day of Edam-type cheese containing L. plantarum TENSIA TM (viable counts of 5 x 10 8 CFU/g, i.e. daily dose of L. plantarum TENSIA TM : 2.5 x CFU) and 21 elderly healthy subjects (Mikelsaar et al., 2008, unpublished) consumed 150 g/day of Edam-type cheese containing L. plantarum TENSIA TM (viable counts of 10 6 CFU/g, i.e. daily dose of L. plantarum TENSIA TM : 1.5 x 10 8 CFU) for three weeks and then the same amount of EFSA Journal 2011;9(2):1981 7

8 regular Edam-type cheese without L. plantarum TENSIA TM after a two-week washout period. The Panel notes that these studies are uncontrolled for time effects and considers that no conclusions can be drawn from these pilot studies for the scientific substantiation of the claim. The third study provided was an open label, one arm human intervention which investigated the acute effects of a single 150 g dose of Edam-type cheese containing L. plantarum TENSIA TM (viable counts of 2 x 10 7 CFU/g, i.e. L. plantarum TENSIA TM : 3 x 10 9 CFU/150 g cheese) on blood pressure (primary outcome) and arterial stiffness (Mikelsaar et al., 2009a, unpublished). The Panel considers that no conclusions can be drawn from this acute and uncontrolled study for the scientific substantiation of the claim. The fourth study was a randomised, double-blind, placebo-controlled, cross-over human intervention which investigated the effects of consuming 50 g/day of Edam-type cheese containing L. plantarum TENSIA TM (viable counts 2 x 10 8 CFU/g cheese; daily dose of L. plantarum TENSIA TM = 1 x CFU) compared to the same amount of cheese without L. plantarum TENSIA TM on blood pressure in healthy volunteers aged 18 to 65 years (Mikelsaar et al., 2009b, unpublished). The test and control cheeses were consumed daily for three weeks each with a washout period of two weeks in between. A total of 90 subjects were randomised and 83 participants (49 males, 34 females; mean ± SD: 36.6±11.4 years old) completed the trial. Reasons for withdrawal were infection/starting antibiotic therapy (n=3) and unwillingness to proceed (n=4). Three of the subjects were on antihypertensive medications (one on ACE inhibitors, two on beta-blockers). Changes in systolic and diastolic blood pressure were the primary outcomes of the study. Upon a request by EFSA, the applicant assessed the statistical significance of changes in BP between intervention and control during the study. No significant differences in systolic or diastolic blood pressure changes were observed between the intervention and control during the study ( mmhg vs mmhg for systolic BP, P=0.292; and mmhg vs mmhg for diastolic BP, P=0.140, respectively), even when the three subjects under pharmacological treatment for hypertension were excluded from the analysis (P=0.241 and P=0.129 for systolic and diastolic BP, respectively). The Panel notes that this study does not show an effect of L. plantarum TENSIA TM on blood pressure. Post-hoc, non pre-planned subgroup analyses were carried out by dividing the study population according to systolic BP values at baseline according to the classification by the ESC/ESH Guideline (2007): normal BP (systolic BP mmhg; n=38; 27 females), high normal BP (systolic BP mmhg; n=28; 12 females), grade I hypertension (systolic BP mmhg; n=17; 10 females). The Panel notes that these post-hoc analyses were not pre-planned and considers that no conclusions can be drawn from these analyses for the scientific substantiation of the claim. Information on the functional properties of the strain L. plantarum TENSIA TM, i.e. the in vitro production of NO and polyamines such as putrescine and N8 acetylspermidine, was available in two patents provided by the applicant (Songisepp et al. 2009a, b), and the ability of L. plantarum TENSIA TM to produce ACE inhibitory peptides by its proteolytic activity in the cheese environment during maturation were indicated in the application. The Panel considers that this information does not predict an effect of L. plantarum TENSIA TM on blood pressure in vivo in humans. In weighing the evidence, the Panel took into account that the only randomised, placebo-controlled human intervention study provided did not show an effect of consumption of L. plantarum TENSIA TM in Edam-type cheese on blood pressure. The Panel concludes that a cause and effect relationship has not been established between the consumption of Lactobacillus plantarum TENSIA in the semi-hard Edam-type heart cheese of Harmony and maintenance of normal blood pressure. EFSA Journal 2011;9(2):1981 8

9 CONCLUSIONS On the basis of the data presented, the Panel concludes that: The food constituent, the strain Lactobacillus plantarum TENSIA, which is the subject of the health claim, is sufficiently characterised. The claimed effect is helps to maintain the cardio-vascular system/heart health through reduction of blood pressure. The target population as proposed by the applicant is the general population. The Panel notes that the claimed effect relates to the maintenance of normal blood pressure. Maintenance of normal blood pressure is a beneficial physiological effect. A cause and effect relationship has not been established between the consumption of Lactobacillus plantarum TENSIA in the semi-hard Edam-type heart cheese of Harmony and maintenance of normal blood pressure. DOCUMENTATION PROVIDED TO EFSA Health claim application on semi-hard Edam-type Südamejuust (Heart cheese) of Harmony brand comprising Lactobacillus plantarum TENSIA and reduction of blood pressure pursuant to Article 13(5) of Regulation (EC) No 1924/2006 (Claim serial No: 0283_EE). July Submitted by Piimandusühistu E-Piim. REFERENCES ESH-ESC (European Society of Hypertension-European Society of Cardiology), Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Journal of Hypertention, 25, Mikelsaar M, Annuk H, Shchepetova J, Mändar R, Sepp E and Björkstén B, Intestinal lactobacilli of Estonian and Swedish children. Microbiol Ecology in Health and Disease, 14, Mikelsaar M, Hütt P, Rätsep M, Stsepetova J, Smidt I and Pung S, 2007 (study report unpublished, proprietary data). Effect of the cheese comprising Lactobacillus plantarum TENSIA on blood indices and intestinal microflora of healthy volunteers. Mikelsaar M, Kals J, Sergejev M, Sepp E, Zagura M, Salum E, Kolk H, Hütt P, Rätsep M, Stsepetova J, Smidt I, Pung S, Jõgi E, Kullisaar T and Zilmer K, 2008 (study report unpublished, proprietary data). Effect of probiotic cheese on blood indices and intestinal microflora of healthy elderly volunteers. Mikelsaar M, Kals J, Sergejev M, Zagura M, Salum E, Hütt P, Rätsep M, Stsepetova J, Smidt I and Pung S, 2009a (study report unpublished, proprietary data). Effect of probiotic cheese on blood indices and intestinal microflora of healthy volunteers and elderly subjects. Mikelsaar M, Hütt P, Rätsep M, Stsepetova J, Smidt I, Shkut E and Pung S, 2009b (study report unpublished, proprietary data). Effect of probiotic cheese on blood indices and intestinal microflora of healthy volunteers and elderly subjects. Songisepp E, Mikelsaar M, Rätsep M, Zilmer M, Hütt P, Utt M, Zilmer K, Üksti J and Kõljalg S, 2009a. Isolated microorganism strain Lactobacillus plantarum Tensia DSM as antimicrobial and antihypertensive probiotic, food product and composition comprising said microorganism and use of said microorganism for preparation of antihypertensive medicine and method for suppressing pathogens and non-starter lactobacilli in food product, International patent application WO EFSA Journal 2011;9(2):1981 9

10 Songisepp E, Mikelsaar M, Rätsep M, Zilmer M, Hütt P, Utt M, Zilmer K, Üksti J and Kõljalg S, 2009b. Isoleeritud mikroorganismi tüvi Lactobacillus plantarum Tensia DSM kui antimikroobne ning vererõhku alandav probiootik, seda sisaldav toiduaine ja kompositsioon ning mikroorganismi kasutamine vererõhku langetava ravimi valmistamiseks ning meetod toiduaines mittestarter-laktobatsillide toime allasurumiseks. Estonian patent application No EE EFSA Journal 2011;9(2):

11 GLOSSARY/ABBREVIATIONS ACE Angiotensin Converting Enzyme BP CFU DSMZ ITS-PCR NO PFGE RAPD-PCR SCFA Blood Pressure Colony-forming Unit Deutsche Sammlung von Mikroorganismen und Zellkulturen Internal Transcribed Spacer-Polymerase Chain Reaction Nitric Oxide Pulsed Field Gel Electrophoresis Random Amplification of Polymorphic DNA-Polymerase Chain Reaction Short Chain Fatty Acid EFSA Journal 2011;9(2):