Standardized Perilla frutescens extract improves acute postprandial meal-induced Gastrointestinal discomfort: Randomized control trial

Standardized Perilla frutescens extract improves acute postprandial meal-induced Gastrointestinal discomfort: Randomized control trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Standardized Perilla frutescens extract improves acute postprandial meal-induced Gastrointestinal discomfort: Randomized control trial Jananee Muralidharan, Cindy Romain, Kohei Homma, Christiane Schön, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6886069/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Gastrointestinal (GI) discomforts affect a large population all over the world. Acute symptom relief without side effects is an attractive option. Perilla frutescens is an herb rich in phytochemicals that is traditionally used for anti-inflammatory and anti-allergenic effects. In this acute study we elucidate the effects of Benegut®, a proprietary Perilla frutescens extract, on relief of postprandial GI discomfort on 30 (22 women, 8 men) healthy participants in the age group of ≥ 25 and ≤ 70 years. Participants were included in the study if they obtained an overall GI discomfort score of 5 out of 10 on a VAS questionnaire post a high caloric meal on the screening visit. Participants attended two other visits where they either consumed 300 mg of Benegut® or placebo after the same high caloric meal as the screening. During these visits subjects rated their discomfort symptoms at defined time points (0, 5, 15, 30, 45, 60 and 90 min). We observed that iAUC 0− 90 min overall GI discomfort significantly improved in the Benegut® group (3073 ± 1255) compared to placebo (3742 ± 1611) and screening (4286 ± 1131). Bloating, burping and feeling of fullness significantly improved with Perilla frutescens supplementation compared to screening. Overall Benegut® provided an acute symptom relief for GI discomfort post high caloric meal consumption. Clinical trial Gov registration number: NCT05603416 GI discomfort phenolic compounds bloating burping Perilla frutescens Benegut® human study Figures Figure 1 Figure 2 INTRODUCTION Gastrointestinal (GI) discomfort affects a wide range of population and impairs quality of life. GI discomfort symptoms are recurrent in nature and are characterized by heartburn/epigastric pain, postprandial fullness, bloating and burping( 1 ). Generally, these symptoms are also accompanied by nausea and abdominal cramps/spasms. This cluster of symptoms without an underlying pathophysiology is known as functional GI disorders. GI symptoms are predominantly meal-related symptoms as they get aggravated after meal consumption( 2 ). The prevalence of bloating based on population studies are estimated between 16–30%( 3 ). Physiological factors such as excess acid secretion, delayed gastric emptying, visceral hypersensitivity, disordered communication between gut-brain, as well as psychological factors such as stress and depression are involved in the development of GI disorders. GI discomforts are widely reported in patients with undiagnosed Helicobacter pylori gastritis or in subjects with irritable bowel syndrome( 4 ). Due to the multifactorial nature of this condition, monotherapy might not be apt for all patients. Thus, symptom relief is regarded as the primary treatment option in these cases. Proton pump inhibitors (PPI) are widely used as first line therapy for GI discomfort. However long-term use of PPI poses health risks( 5 ). Traditional and natural ingredients offer an interesting option for the management of GI discomforts in primary intervention. Products derived from plant sources such as Iberogast, motilitone has been widely used for the treatment of GI discomforts ( 6 ). Perilla frutescens L Britton is an annual aromatic herbaceous plant that belongs to the species of Perilla in the mint family Lamiaceae. In China, cultivated taxa of perilla are divided into five varieties: var. frutescens, var. arguta, var. crispa, var. auriculato-dentata and var. acuta. The edible parts of the plant are the leaves, stems and the seeds that have been used whole in Asian cooking (sauces, soups, as spices) or as extracts for medicinal reason depending on the variety. The leaves of Perilla frutescens L. Britton contain many phytochemical compounds that can be classified either as hydrophilic (phenolic acids, flavonoids, anthocyanins) or hydrophobic (lipophilic) ( 7 ). The flavonoids include vicenin-2 (apigenin-6,8-di-C-glycoside) and rosmarinic acid. Preclinical studies have shown the antioxidant ability of Perilla leaf extracts and inhibitory effects on producing proinflammatory cytokines ( 8 , 9 ). Although predominant of the effects of Perilla extracts are from in vivo or in vitro studies, few human clinical studies have shown proven therapeutic effects such as antiallergic, antioxidant, prokinetic and anti-aging related cognitive effects ( 10 – 13 ). Furthermore, Perilla leaf extract and its patented component Vicenin-2 has shown to display antispasmodic effect which could potentially aid in relieving gastrointestinal discomfort. This hypothesis was further tested in a pilot trial. Benegut® the standardized Perilla leaf extract, displayed chronic beneficial effects on GI discomfort relief in a human pilot clinical trial. In this scope, a proprietary standardized extract of Perilla frutescens (L.) Britton, Benegut® with a phytochemical composition of phenolic acids, mainly rosmarinic acid and a flavonoid fraction was investigated. The characterisation of the product has been published earlier( 14 ). Benegut® has previously displayed chronic beneficial effects on GI discomfort relief in a human pilot clinical trial and has also displayed antispasmodic effects in an in vitro mechanistic study. This study aims to determine whether Benegut® can alleviate overall GI discomfort in a post-meal acute set up. Secondary outcomes include evaluating changes in individual GI discomfort symptoms postprandially after a high caloric meal. METHODS AND MATERIALS Study population Healthy volunteers (male and female) in the age of ≥ 25 and ≤ 70 years and BMI of 19–30 kg/m2 without clinically diagnosed diseases with relevant effect on gastrointestinal system were included in the study. After informed consent, subjects were screened for their eligibility to take part in the study. Exclusion criteria included subjects who were diagnosed for any medical condition or under prescription medications for digestive symptoms. Further exclusion criteria are mentioned in the supplementary information. Lifestyle, nutritional and sporting habits were assessed during screening. Subjects were instructed to keep their normal nutritional, sporting and lifestyle habits. The clinical study was performed at the study site of BioTeSys GmbH in Esslingen, Germany. The protocol was approved by the Institutional Review Board (IRB) of Landesärztekammer Baden-Württemberg (Ethical committee number: F-2022-093). Study was conducted in accordance with Good Clinical Practice and was registered in clinicaltrials.gov.in (NCT05603416, https://clinicaltrials.gov/study/NCT05603416 ) registered on October 21, 2022. Study product and study design Study product was composed of Filler sorbitol (ad 100%), Benegut® (15.0%, 300 mg per portion), aroma (1.5%), release agent magnesium salts of fatty acids (0.16%), sweetener steviol glycosides (0.15%). Benegut®, a proprietary extract of Perilla frutescens (Amino Up Co., Ltd., Japan), is standardized on a special flavonoid fraction, on vicenin 2 and on rosmarinic acid, determined by HPLC ( 14 ). Placebo contained maltodextrin with the same excipients as the study product. Both the products were provided as direct dissolve preparation in sticks and ingested orally directly after end of high caloric meal as single dose. The study was performed as a double blind, randomized, placebo-controlled cross-over design with at least a 7-day washout phase between visits. Study was conducted between November 2022 to March 2023. Participants were stratified according to gender and were randomly allocated to the sequence of placebo followed by test product (or) test product followed by placebo. The randomization list was allocated with Randlist. This was a double blinding were the blinding was removed after the last patient out. After the screening/baseline visit, the consumption of the test meal was repeated twice in combination of intake of Benegut® (supplement) or placebo. During the screening phase a high caloric meal was served, to determine their individual portion causing GI discomfort. Briefly, they consumed cheeseburger, coleslaw, tortilla chips/nachos/tacos with cheese dip and salsa dip, ketchup/mayonnaise, chocolate muffin and lemonade, until the defined GI discomfort level was reached. As previous meal could have a carryover impact on GI complaints, an easy to digest light meal was first provided in the lunch. The time of this last meal prior to the high caloric meal was also standardized with 5 hours. Subjects were adivsed to eat as much as they can and then rate their overall GI discomfort. Only subjects with minimum overall GI discomfort of 5 on a visual analog scale (VAS, 0-100mm) were enrolled. Only subjects experiencing such a cut-off value after the meal have been included. The amount of food consumed during the “overeating dinner” at screening visit was standardized for visit 1 and visit 2. The screening visit was considered as the baseline level of each participant as this involved symptom registration without placebo or the product. The study products were ingested directly after the meal. The assessment of GI symptoms was done over a period of 90 min after intake of study products, during which subjects stayed under calm relaxing conditions. During this time, subjects were rating their overall GI-discomfort on a VAS at defined time points (0, 5, 15, 30, 45, 60 and 90 min). Additionally, the nature and severity of selected symptoms (feeling of fullness, burping, bloating, heartburn, rumbling, passage of gas, GI discomfort/cramps/pains, nausea, urge to defecate.) were assessed at the specified time points with a 6-point Likert scale. Participants also answered the questionnaire 10–15 minutes before the beginning of meal ingestion (-15 min). Questionnaire evaluating the bowel movement were also recorded at each visit. Safety at each visit was ensured by recording any adverse events in accordance with ICH/GCP. Sample size Based on the previous clinical study( 14 ) a subjective alleviation of symptoms was reported in women for bloating and abdominal discomfort with − 0.57 ± 0.63 and during placebo intervention of -0.19 ± 0.53. Based on these data applying a matched pairs test approach and consideration of an alpha level of 0.05 and power of 0.8, an effect size of 0.65 was estimated for the a priori sample size determination using G*power 3.1.9.2. Based on the following input details - two tailed, effect size d = 0.65, alpha error problem: α = 0.05, actual power: 80%, correlation between groups: 0.5 - a sample size of n = 21 subjects were estimated. As women are predominantly affected by gastrointestinal complaints (Guarner et al. 2008; Kim & Kim 2018), it was decided to perform the study with approximately 3:1 of women and men, respectively (n = 22 women and n = 8 men; total n = 30). Statistical analysis All the values are reported as mean and standard deviation. For the incremental AUC, baseline corrected (score prior to meal start) symptom scores were used. Differences amongst groups were evaluated with linear mixed model that accounts for repeated measures. Statistics were performed in R software (4.1.2). All randomized participants were included in the analysis. RESULTS Population characteristics Study participant flow diagram is represented in Fig. 1 . Baseline clinical characteristics are provided in Table 1 . 30 participants (22 women and 8 men) with an average of 47.6 (SD 11.1) years and BMI of 25.2 (SD 3.3) Kg/m 2 participated and completed the study. Average calories consumed from the high calorific meal was 1551 Kcal (95% CI 1346–1756). Portion size was individually defined by subjects during the baseline visit. There were no significant differences in bowel movements during the three visits (data not shown). Table 1 Baseline clinical characteristics of the study participants Characteristic Men Women Age (years) 46.4 (16.6) 48.1 (14.4) BMI (Kg/m 2 ) 25.8 (2.3) 24.9 (3.7) Blood pressure (mm Hg, Systolic/Diastolic) 126.3 (16.3)/ 80.0 (10.7) Tolerability and safety Tolerability and safety were assessed by asking and recording all reported adverse events. Two adverse events were noted on the study days, which were already present when the subjects arrived to the study site. None of the adverse events were related to the study products. Overall GI discomfort Participants reported a similar lower levels of GI discomfort before the start (pre-test) of the high caloric meal in all the three visits. Overall GI was assessed on a VAS and the incremental area under the curve (iAUC) was calculated for overall GI discomfort from 0 to 90 min post intake of the study products. The primary endpoint iAUC 0 − 90 min for overall GI-discomfort (Table 2 ) was significantly decreased after intake of supplement (3073 ± 1255) in comparison to intake of placebo (3742 ± 1611) (p = 0.0061) with 66.7% of subjects having lower iAUC 0 − 90 min overall GI discomfort after intake of supplement in comparison to placebo. The maximum symptom score observed (denoted by Cmax) also reduced in supplement and placebo in comparison to baseline visit. When leaving the study site after 90 min, the overall GI discomfort was not returned to the baseline conditions. Table 2 Incremental AUC (0-90min) of overall GI discomfort and individual symptoms with maxium symptom score (Cmax) and time at which maximum symptom score occured (Tmax) Groups No. of participants with symptom iAUC Cmax Tmax Overall GI Symptoms Benegut 30 3073 ± 1255 *a 49 ± 18* 23 ± 28* Placebo 30 3742 ± 1611 56 ± 21b 28 ± 27 Screening 30 4286 ± 1131 65 ± 10 39 ± 37 Feeling of Fullness Benegut 30 198 ± 95 * 3 ± 2* 7 ± 18 Placebo 30 230 ± 107 4 ± 2 6 ± 18 Screening 30 277 ± 99 4 ± 2 16 ± 25 Passage of gas Benegut 26 101 ± 86 2 ± 2* 30 ± 26 Placebo 28 108 ± 104 2 ± 2 30 ± 27 Screening 29 134 ± 100 3 ± 2 41 ± 32 Bloating Benegut 30 177 ± 113 * 3 ± 2 19 ± 27 Placebo 30 206 ± 119 4 ± 2 18 ± 25 Screening 30 241 ± 125 4 ± 2 24 ± 32 Abdominal Pain and cramps Benegut 24 86 ± 95 2 ± 2 10 ± 21* Placebo 23 96 ± 119 2 ± 2 16 ± 25 Screening 26 128 ± 101 3 ± 2 25 ± 29 Rumbling in stomach Benegut 26 92 ± 104 2 ± 2 20 ± 27 Placebo 26 94 ± 110 2 ± 2 29 ± 33 Screening 30 104 ± 123 2 ± 2 28 ± 31 Burping Benegut 30 130 ± 86 * 3 ± 2 20 ± 28 Placebo 28 174 ± 110 3 ± 2 15 ± 26 Screening 30 177 ± 101 3 ± 2 12 ± 24 Heart Burn Benegut 15 28 ± 54 1 ± 1 10 ± 21 Placebo 13 15 ± 62 1 ± 1b 12 ± 25 Screening 15 39 ± 78 1 ± 2 19 ± 32 Nausea Benegut 18 45 ± 68 * 1 ± 2* 10 ± 22 Placebo 15 58 ± 77 2 ± 2 11 ± 23 Screening 18 85 ± 106 2 ± 2 17 ± 31 Urge to defecate Benegut 19 62 ± 93 2 ± 2 21 ± 29 Placebo 17 70 ± 106 2 ± 2 27 ± 36 Screening 23 90 ± 87 2 ± 2 36 ± 38 * significant differences between Benegut and Screening; a significant differences between Benegut and Placebo; b significant differences between Placebo and Screening Individual GI discomfort symptoms Nine individual GI symptoms were measured during three visits. Similar to overall GI discomfort, iAUC 0 − 90 min was calculated for each of the symptom. Feeling of fullness, bloating and burping were the three main prevalent symptoms. Heart burn, nausea and urge to defecate were the less prevalent symptoms. The iAUC 0 − 90 min of feeling of fullness, bloating, burping and nausea significantly reduced in the supplement group compared to the baseline visit (Table 1 ). Even though there were no statistical significance in other symptoms, supplement had a lower iAUC 0 − 90 min compared to screening and placebo. The number of participants experiencing each symptom at each visit is given in Table 1 . Additionally, we also evaluated the differences between symptoms at the end of study (90th minute) represented as Fig. 2 . While iAUC gave the overall symptom experience, the evaluation of symptoms at end of postprandial period showed if the participants attained symptom relief at the end of the observation. We noticed that abdominal pain and cramps, bloating were the two symptoms that were significantly different from placebo and baseline at 90th minute. DISCUSSION Upper GI discomfort is common after a high caloric meal. Previous studies have shown that high caloric meal consumption can significantly induce bloating, feeling of fullness and nausea( 15 , 16 ). We observed a similar trend in our study where during all the three visits, feeling of fullness, bloating and burping were the main symptoms noted. With supplementation of Perilla frutescens extract we noted that these individual symptoms improved in comparison to baseline and overall postprandial GI discomfort was improved in comparison to baseline and placebo. The polyphenolic mixture of rosmarinic acid and the flavonoid fraction in Perilla frutescens extract are expected to contribute to the alleviation of the symptoms that were observed in this study. Predominant of the studies in the area of symptom relief for GI discomforts are based on probiotics and postbiotics. Although these solutions have shown promising results, these studies involve a chronic treatment period. Thus, there is a need for product development for acute symptom relief. Perilla frutescens extract, in a previous clinical trial, has displayed GI discomfort relief effects on a chronic set up. Thus, the current study strengthens the previous one by offering proof on acute symptom relief. The aetiology of GI discomfort is multifactorial. We suggest that during chronic consumption of Perilla frutescens extract, the effect might be mediated via changes in gut microbiota and improvement of barrier function. Intestinal barrier dysfunction leading to increased infiltration of mast cells have been noted in cases of functional dyspepsia ( 17 ). Mast cells lead to proinflammatory cytokine release causing an acute inflammation potentially interfering with enteric nerve functions and increased visceral sensitivity ( 18 ). Interestingly, Perilla frutescens extract has shown to improve the intestinal barrier function measured with trans epithelial electrical resistance in cell culture model( 19 ). Rosmarinic acid and apigenin components of Perilla frutescens extract has demonstrated beneficial gut barrier function in several preclinical models( 20 , 21 ). In dextran sulphate sodium induced colitis mice, apigenin has demonstrated to enhance the expressions of important gut barrier markers such as ZO-1, occludin, claudin-1, and claudin-3( 22 ). Whilst chronic effects are potentially modified via gut microbiota and intestinal barrier, acute effects might be mitigated by altering visceral sensitivity, smooth muscle contractions and post prandial gut hormones. Visceral sensitivity affected by acute inflammation, gut hormones and nutrients modulate the communication of nociceptive information from GI tract to the brain( 1 ). This leads to improper gastric emptying and therefore bloating. Post prandial state involves regulation of various hormones some of which are suggested to be altered in subjects with gastrointestinal disorders. Subjects with functional dyspepsia have been noted to have higher plasma cholecystokin (CCK) and lower ghrelin compared to healthy controls( 16 ). Interestingly apigenin found in seeds of Perilla frutescens has shown to inhibit food intake by acting on gut hormones( 23 ). Symptoms such as spasms and pain are induced by smooth muscle contractions in stomach and upper GI tract which are influenced by various pathways such release of acetylcholine, excess influx of calcium ions etc. Inhibition of these pathways could offer antispasmodic effect. Interestingly, rosmarinic acid and vicenin-2 have displayed inhibition of acetylcholine receptors in rat ileum, thus acting as anti-spasmodic agents( 24 ). Rosmarinic acid from Perilla frutescens extract has also shown attenuation of atropine- and dopamine-induced inhibition of gastric emptying and gastrointestinal motility in animal model( 25 ). Excess entry of calcium ions from extracellular fluid incites smooth muscle contractions. Cucumis melo seeds, which are rich in flavonoids, such as apigenin, luteolin, quercetin and rutin, has displayed antispasmodic, antiperistalsis actions by blocking calcium ion channels thus reducing calcium influx into smooth muscle cells. We expect a similar mode of action from the supplement, which needs to be evaluated in future mechanistic studies. Studies focusing on treatment for GI discomfort and functional GI disorders are prone to placebo effects. Thus, also in the Placebo group overall GI was lower in compariso to screening, but not significant. As the study was powered and designed to evaluate the primary outcome, we did not see significance against placebo in iAUC of certain individual symptoms (burping, bloating and feeling of fullness). The key study limitation is that the study design involved evaluation of product intake after a high caloric meal, hence the discomfort relief cannot be generalized to normo-caloric situations. Future studies focusing on the triggers of GI discomforts and potential modes of action by Perilla frutescens extract would allow us to focus on individual symptoms as well. Overall, we conclude that Benegut® offers postprandial acute symptomatic relief for overall GI discomfort. Abbreviations GI Gastrointestinal, AUC area under curve, VAS visual analogue scale, CCK Cholecystokin Declarations Ethics approval: The protocol was approved by the Institutional Review Board (IRB) of Landesärztekammer Baden-Württemberg (Ethical committee number: F-2022-093). The study was conducted ethically, in accordance with the Declaration of Helsinki, and informed consent was obtained from all participants. Consent for publication: Corresponding author and all authors provide their consent for consideration to publish this manuscript. Acknowledgements: Not applicable Author contributions Conceptualiation: SBW; Investigation CS, SBW; Methodology: CS, SBW; Data analysis: JM, CR; Data interpretation:JM, CR, KH, JC; Supervision: CR, JC, SBW, KH; Writing and review of draft: JM, CR, JC, SBW, KH Availability of data and materials The data presented in this study are available upon reasonable request from the corresponding author, due to privacy restriction. Funding and conflict of interests Biotesys (CRO) was paid by Amino Up and Vital Solutions (now a part of Fytexia Group) to perform and report the scientific work that formed the basis of this publication. C.R., J.M. and J.C are employed by Fytexia; KH is employed by AminoUP and SBW is employed by Vital Solutions. Fytexia is involved in the research and development, and marketing and sales of (poly)phenol extract-based ingredients for food and nutraceutical industries and supported the study. Amino UP is the producer of the raw ingredient Perilla frutescens extract. Therefore, Fytexia, Vital Solutions and Amino UP has a commercial interest in this publication. Vital Solutions approved the final trial protocol prior to its implementation but was not involved in the study implementation and data collection. References Ford AC, Mahadeva S, Carbone MF, Lacy BE, Talley NJ. Functional dyspepsia. The Lancet [Internet]. 2020 Nov 21;396(10263):1689–702. 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Apigenin isolated from the seeds of perilla frutescens britton var crispa (Benth.) inhibits food intake in C57BL/6J mice. Arch Pharm Res [Internet]. 2010 Dec 30 [cited 2023 Nov 14];33(11):1741–6. Available from: https://link.springer.com/article/10.1007/s12272-010-1105-5 Verspohl EJ, Fujii H, Homma K, Buchwald-Werner S. Testing of Perilla frutescens extract and Vicenin 2 for their antispasmodic effect. Phytomedicine. 2013 Mar 15;20(5):427–31. Kimura Y, Taniguchi M. Effects of Perilla frutescens var. crispa herb extract, the essential oil perillaldehyde, and the caffeetannin rosmarinic acid on gastric emptying and gastrointestinal motility in mice. Traditional & Kampo Medicine [Internet]. 2021 Dec 1 [cited 2023 Nov 14];8(3):194–203. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/tkm2.1296 Additional Declarations Competing interest reported. Biotesys (CRO) was paid by Amino Up and Vital Solutions (now a part of Fytexia Group) to perform and report the scientific work that formed the basis of this publication. C.R., J.M. and J.C are employed by Fytexia; KH is employed by AminoUP and SBW is employed by Vital Solutions. Fytexia is involved in the research and development, and marketing and sales of (poly)phenol extract-based ingredients for food and nutraceutical industries and supported the study. Amino UP is the producer of the raw ingredient Perilla frutescens extract. Therefore, Fytexia, Vital Solutions and Amino UP has a commercial interest in this publication. Vital Solutions approved the final trial protocol prior to its implementation but was not involved in the study implementation and data collection. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6886069","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":505531423,"identity":"f4f0bb29-1107-416b-a0d5-62d3b3e1ae9a","order_by":0,"name":"Jananee Muralidharan","email":"","orcid":"","institution":"Fytexia - ZAE","correspondingAuthor":false,"prefix":"","firstName":"Jananee","middleName":"","lastName":"Muralidharan","suffix":""},{"id":505531424,"identity":"716dc99b-2c34-4fbc-8876-90770c424ce5","order_by":1,"name":"Cindy Romain","email":"","orcid":"","institution":"Fytexia - ZAE","correspondingAuthor":false,"prefix":"","firstName":"Cindy","middleName":"","lastName":"Romain","suffix":""},{"id":505531425,"identity":"5aaa8191-1e11-41f4-9aa4-5a8df7f56184","order_by":2,"name":"Kohei Homma","email":"","orcid":"","institution":"Amino Up Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Kohei","middleName":"","lastName":"Homma","suffix":""},{"id":505531426,"identity":"f9bf9d4a-0039-4a8c-9b38-e854da0c759b","order_by":3,"name":"Christiane Schön","email":"","orcid":"","institution":"BioTeSys GmbH","correspondingAuthor":false,"prefix":"","firstName":"Christiane","middleName":"","lastName":"Schön","suffix":""},{"id":505531427,"identity":"1d0eb7dd-fa75-4f40-9381-d61c62b695e7","order_by":4,"name":"Julien Cases","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0UlEQVRIiWNgGAWjYBACxgYwZcMPphJI0JIm2cBGrBYoOAzRQhRgbj/8+MOHP+clDO43H5N4UMMgzy92gIDDetLMJGe23ZYwOMaWbJBwjMFw5mwCzmOcwWDGzNtwu87gGI/hgwQ2hgSD2wS1sH/+/OfPOaAt/B8OJPwjSguPgTQD2wGgFh7GB4ltxGjpySmT7G1LlpA8lmZskNgnQdgvhu3HN3/48cdOgu/w4WeSP77ZyPNLE9LSAGUoHABTEviVg4A8nNGAR9UoGAWjYBSMbAAACoJEaggeGzMAAAAASUVORK5CYII=","orcid":"","institution":"Fytexia - ZAE","correspondingAuthor":true,"prefix":"","firstName":"Julien","middleName":"","lastName":"Cases","suffix":""},{"id":505531428,"identity":"9262ae78-24e2-4cc4-8442-f26c5b8b05c6","order_by":5,"name":"Sybille Buchwald-Werner","email":"","orcid":"","institution":"Vital Solutions GmbH","correspondingAuthor":false,"prefix":"","firstName":"Sybille","middleName":"","lastName":"Buchwald-Werner","suffix":""}],"badges":[],"createdAt":"2025-06-13 08:08:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6886069/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6886069/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90465590,"identity":"aa0be599-b3d9-46aa-9fb7-70b411355d62","added_by":"auto","created_at":"2025-09-03 05:31:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":25393,"visible":true,"origin":"","legend":"\u003cp\u003eParticipant flow diagram\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6886069/v1/246ef3547ea461f0e0d90adb.png"},{"id":90466843,"identity":"80dcba78-1e95-4e8c-a36b-7f68860617ac","added_by":"auto","created_at":"2025-09-03 05:38:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":101380,"visible":true,"origin":"","legend":"\u003cp\u003eCurves representing the VAS score of symptoms at each time point represented by mean and SE for each group 1) Feeling of fullness 2) Bloating 3) Passage of gas 4) Abdominal pain and cramps 5) Rumbling in stomach 6) Burping 7) Heart burn 8) Nausea 9) Urge to defecate\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6886069/v1/e2c9ef25bda97533c121d1b8.png"},{"id":102397354,"identity":"5de22b37-c9c3-4347-b88d-651307f9ed3c","added_by":"auto","created_at":"2026-02-11 10:16:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":821186,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6886069/v1/8710e1fb-9622-4e57-bcdb-98cc1a2384d1.pdf"}],"financialInterests":"Competing interest reported. Biotesys (CRO) was paid by Amino Up and Vital Solutions (now a part of Fytexia Group) to perform and report the scientific work that formed the basis of this publication. C.R., J.M. and J.C are employed by Fytexia; KH is employed by AminoUP and SBW is employed by Vital Solutions. Fytexia is involved in the research and development, and marketing and sales of (poly)phenol extract-based ingredients for food and nutraceutical industries and supported the study. Amino UP is the producer of the raw ingredient Perilla frutescens extract. Therefore, Fytexia, Vital Solutions and Amino UP has a commercial interest in this publication. Vital Solutions approved the final trial protocol prior to its implementation but was not involved in the study implementation and data collection.","formattedTitle":"Standardized Perilla frutescens extract improves acute postprandial meal-induced Gastrointestinal discomfort: Randomized control trial","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eGastrointestinal (GI) discomfort affects a wide range of population and impairs quality of life. GI discomfort symptoms are recurrent in nature and are characterized by heartburn/epigastric pain, postprandial fullness, bloating and burping(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Generally, these symptoms are also accompanied by nausea and abdominal cramps/spasms. This cluster of symptoms without an underlying pathophysiology is known as functional GI disorders. GI symptoms are predominantly meal-related symptoms as they get aggravated after meal consumption(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The prevalence of bloating based on population studies are estimated between 16–30%(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePhysiological factors such as excess acid secretion, delayed gastric emptying, visceral hypersensitivity, disordered communication between gut-brain, as well as psychological factors such as stress and depression are involved in the development of GI disorders. GI discomforts are widely reported in patients with undiagnosed Helicobacter pylori gastritis or in subjects with irritable bowel syndrome(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Due to the multifactorial nature of this condition, monotherapy might not be apt for all patients. Thus, symptom relief is regarded as the primary treatment option in these cases. Proton pump inhibitors (PPI) are widely used as first line therapy for GI discomfort. However long-term use of PPI poses health risks(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Traditional and natural ingredients offer an interesting option for the management of GI discomforts in primary intervention. Products derived from plant sources such as Iberogast, motilitone has been widely used for the treatment of GI discomforts (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Perilla frutescens L Britton is an annual aromatic herbaceous plant that belongs to the species of \u003cem\u003ePerilla\u003c/em\u003e in the mint family Lamiaceae. In China, cultivated taxa of perilla are divided into five varieties: var. frutescens, var. arguta, var. crispa, var. auriculato-dentata and var. acuta. The edible parts of the plant are the leaves, stems and the seeds that have been used whole in Asian cooking (sauces, soups, as spices) or as extracts for medicinal reason depending on the variety. The leaves of Perilla frutescens L. Britton contain many phytochemical compounds that can be classified either as hydrophilic (phenolic acids, flavonoids, anthocyanins) or hydrophobic (lipophilic) (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). The flavonoids include vicenin-2 (apigenin-6,8-di-C-glycoside) and rosmarinic acid. Preclinical studies have shown the antioxidant ability of Perilla leaf extracts and inhibitory effects on producing proinflammatory cytokines (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Although predominant of the effects of Perilla extracts are from in vivo or in vitro studies, few human clinical studies have shown proven therapeutic effects such as antiallergic, antioxidant, prokinetic and anti-aging related cognitive effects (\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e–\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Furthermore, Perilla leaf extract and its patented component Vicenin-2 has shown to display antispasmodic effect which could potentially aid in relieving gastrointestinal discomfort. This hypothesis was further tested in a pilot trial. Benegut® the standardized Perilla leaf extract, displayed chronic beneficial effects on GI discomfort relief in a human pilot clinical trial.\u003c/p\u003e\u003cp\u003eIn this scope, a proprietary standardized extract of \u003cem\u003ePerilla frutescens\u003c/em\u003e (L.) Britton, Benegut® with a phytochemical composition of phenolic acids, mainly rosmarinic acid and a flavonoid fraction was investigated. The characterisation of the product has been published earlier(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Benegut® has previously displayed chronic beneficial effects on GI discomfort relief in a human pilot clinical trial and has also displayed antispasmodic effects in an \u003cem\u003ein vitro\u003c/em\u003e mechanistic study. This study aims to determine whether Benegut® can alleviate overall GI discomfort in a post-meal acute set up. Secondary outcomes include evaluating changes in individual GI discomfort symptoms postprandially after a high caloric meal.\u003c/p\u003e"},{"header":"METHODS AND MATERIALS","content":"\u003cp\u003e\u003cb\u003eStudy population\u003c/b\u003e\u003c/p\u003e\u003cp\u003eHealthy volunteers (male and female) in the age of ≥ 25 and ≤ 70 years and BMI of 19–30 kg/m2 without clinically diagnosed diseases with relevant effect on gastrointestinal system were included in the study. After informed consent, subjects were screened for their eligibility to take part in the study. Exclusion criteria included subjects who were diagnosed for any medical condition or under prescription medications for digestive symptoms. Further exclusion criteria are mentioned in the supplementary information. Lifestyle, nutritional and sporting habits were assessed during screening. Subjects were instructed to keep their normal nutritional, sporting and lifestyle habits. The clinical study was performed at the study site of BioTeSys GmbH in Esslingen, Germany. The protocol was approved by the Institutional Review Board (IRB) of Landesärztekammer Baden-Württemberg (Ethical committee number: F-2022-093). Study was conducted in accordance with Good Clinical Practice and was registered in clinicaltrials.gov.in (NCT05603416, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://clinicaltrials.gov/study/NCT05603416\u003c/span\u003e\u003cspan address=\"https://clinicaltrials.gov/study/NCT05603416\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) registered on October 21, 2022.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStudy product and study design\u003c/b\u003e\u003c/p\u003e\u003cp\u003eStudy product was composed of Filler sorbitol (ad 100%), Benegut® (15.0%, 300 mg per portion), aroma (1.5%), release agent magnesium salts of fatty acids (0.16%), sweetener steviol glycosides (0.15%). Benegut®, a proprietary extract of \u003cem\u003ePerilla frutescens\u003c/em\u003e (Amino Up Co., Ltd., Japan), is standardized on a special flavonoid fraction, on vicenin 2 and on rosmarinic acid, determined by HPLC (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Placebo contained maltodextrin with the same excipients as the study product. Both the products were provided as direct dissolve preparation in sticks and ingested orally directly after end of high caloric meal as single dose.\u003c/p\u003e\u003cp\u003eThe study was performed as a double blind, randomized, placebo-controlled cross-over design with at least a 7-day washout phase between visits. Study was conducted between November 2022 to March 2023. Participants were stratified according to gender and were randomly allocated to the sequence of placebo followed by test product (or) test product followed by placebo. The randomization list was allocated with Randlist. This was a double blinding were the blinding was removed after the last patient out. After the screening/baseline visit, the consumption of the test meal was repeated twice in combination of intake of Benegut® (supplement) or placebo. During the screening phase a high caloric meal was served, to determine their individual portion causing GI discomfort. Briefly, they consumed cheeseburger, coleslaw, tortilla chips/nachos/tacos with cheese dip and salsa dip, ketchup/mayonnaise, chocolate muffin and lemonade, until the defined GI discomfort level was reached. As previous meal could have a carryover impact on GI complaints, an easy to digest light meal was first provided in the lunch. The time of this last meal prior to the high caloric meal was also standardized with 5 hours. Subjects were adivsed to eat as much as they can and then rate their overall GI discomfort. Only subjects with minimum overall GI discomfort of 5 on a visual analog scale (VAS, 0-100mm) were enrolled. Only subjects experiencing such a cut-off value after the meal have been included. The amount of food consumed during the “overeating dinner” at screening visit was standardized for visit 1 and visit 2. The screening visit was considered as the baseline level of each participant as this involved symptom registration without placebo or the product.\u003c/p\u003e\u003cp\u003eThe study products were ingested directly after the meal. The assessment of GI symptoms was done over a period of 90 min after intake of study products, during which subjects stayed under calm relaxing conditions. During this time, subjects were rating their overall GI-discomfort on a VAS at defined time points (0, 5, 15, 30, 45, 60 and 90 min). Additionally, the nature and severity of selected symptoms (feeling of fullness, burping, bloating, heartburn, rumbling, passage of gas, GI discomfort/cramps/pains, nausea, urge to defecate.) were assessed at the specified time points with a 6-point Likert scale. Participants also answered the questionnaire 10–15 minutes before the beginning of meal ingestion (-15 min). Questionnaire evaluating the bowel movement were also recorded at each visit. Safety at each visit was ensured by recording any adverse events in accordance with ICH/GCP.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSample size\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBased on the previous clinical study(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) a subjective alleviation of symptoms was reported in women for bloating and abdominal discomfort with − 0.57 ± 0.63 and during placebo intervention of -0.19 ± 0.53. Based on these data applying a matched pairs test approach and consideration of an alpha level of 0.05 and power of 0.8, an effect size of 0.65 was estimated for the a priori sample size determination using G*power 3.1.9.2. Based on the following input details - two tailed, effect size d = 0.65, alpha error problem: α = 0.05, actual power: 80%, correlation between groups: 0.5 - a sample size of n = 21 subjects were estimated. As women are predominantly affected by gastrointestinal complaints (Guarner et al. 2008; Kim \u0026amp; Kim 2018), it was decided to perform the study with approximately 3:1 of women and men, respectively (n = 22 women and n = 8 men; total n = 30).\u003c/p\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eAll the values are reported as mean and standard deviation. For the incremental AUC, baseline corrected (score prior to meal start) symptom scores were used. Differences amongst groups were evaluated with linear mixed model that accounts for repeated measures. Statistics were performed in R software (4.1.2). All randomized participants were included in the analysis.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cb\u003ePopulation characteristics\u003c/b\u003e\u003c/p\u003e\u003cp\u003eStudy participant flow diagram is represented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Baseline clinical characteristics are provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. 30 participants (22 women and 8 men) with an average of 47.6 (SD 11.1) years and BMI of 25.2 (SD 3.3) Kg/m\u003csup\u003e2\u003c/sup\u003e participated and completed the study. Average calories consumed from the high calorific meal was 1551 Kcal (95% CI 1346\u0026ndash;1756). Portion size was individually defined by subjects during the baseline visit. There were no significant differences in bowel movements during the three visits (data not shown).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline clinical characteristics of the study participants\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMen\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eWomen\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e46.4 (16.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e48.1 (14.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI (Kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25.8 (2.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24.9 (3.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood pressure (mm Hg, Systolic/Diastolic)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003e126.3 (16.3)/ 80.0 (10.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eTolerability and safety\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTolerability and safety were assessed by asking and recording all reported adverse events. Two adverse events were noted on the study days, which were already present when the subjects arrived to the study site. None of the adverse events were related to the study products.\u003c/p\u003e\u003cp\u003e\u003cb\u003eOverall GI discomfort\u003c/b\u003e\u003c/p\u003e\u003cp\u003eParticipants reported a similar lower levels of GI discomfort before the start (pre-test) of the high caloric meal in all the three visits. Overall GI was assessed on a VAS and the incremental area under the curve (iAUC) was calculated for overall GI discomfort from 0 to 90 min post intake of the study products. The primary endpoint iAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;90 min\u003c/sub\u003e for overall GI-discomfort (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) was significantly decreased after intake of supplement (3073\u0026thinsp;\u0026plusmn;\u0026thinsp;1255) in comparison to intake of placebo (3742\u0026thinsp;\u0026plusmn;\u0026thinsp;1611) (p\u0026thinsp;=\u0026thinsp;0.0061) with 66.7% of subjects having lower iAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;90 min\u003c/sub\u003e overall GI discomfort after intake of supplement in comparison to placebo. The maximum symptom score observed (denoted by Cmax) also reduced in supplement and placebo in comparison to baseline visit. When leaving the study site after 90 min, the overall GI discomfort was not returned to the baseline conditions.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eIncremental AUC (0-90min) of overall GI discomfort and individual symptoms with maxium symptom score (Cmax) and time at which maximum symptom score occured (Tmax)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGroups\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo. of participants with symptom\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eiAUC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCmax\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTmax\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eOverall GI Symptoms\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBenegut\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e3073\u0026thinsp;\u0026plusmn;\u0026thinsp;1255 *a\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e49\u0026thinsp;\u0026plusmn;\u0026thinsp;18*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e23\u0026thinsp;\u0026plusmn;\u0026thinsp;28*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3742\u0026thinsp;\u0026plusmn;\u0026thinsp;1611\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e56\u0026thinsp;\u0026plusmn;\u0026thinsp;21b\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e28\u0026thinsp;\u0026plusmn;\u0026thinsp;27\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eScreening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4286\u0026thinsp;\u0026plusmn;\u0026thinsp;1131\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e65\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e39\u0026thinsp;\u0026plusmn;\u0026thinsp;37\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eFeeling of Fullness\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBenegut\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e198\u0026thinsp;\u0026plusmn;\u0026thinsp;95 *\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e3\u0026thinsp;\u0026plusmn;\u0026thinsp;2*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7\u0026thinsp;\u0026plusmn;\u0026thinsp;18\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e230\u0026thinsp;\u0026plusmn;\u0026thinsp;107\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6\u0026thinsp;\u0026plusmn;\u0026thinsp;18\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eScreening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e277\u0026thinsp;\u0026plusmn;\u0026thinsp;99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e16\u0026thinsp;\u0026plusmn;\u0026thinsp;25\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003ePassage of gas\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBenegut\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e101\u0026thinsp;\u0026plusmn;\u0026thinsp;86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e2\u0026thinsp;\u0026plusmn;\u0026thinsp;2*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e30\u0026thinsp;\u0026plusmn;\u0026thinsp;26\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e108\u0026thinsp;\u0026plusmn;\u0026thinsp;104\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e30\u0026thinsp;\u0026plusmn;\u0026thinsp;27\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eScreening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e134\u0026thinsp;\u0026plusmn;\u0026thinsp;100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e41\u0026thinsp;\u0026plusmn;\u0026thinsp;32\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eBloating\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBenegut\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e177\u0026thinsp;\u0026plusmn;\u0026thinsp;113 *\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e19\u0026thinsp;\u0026plusmn;\u0026thinsp;27\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e206\u0026thinsp;\u0026plusmn;\u0026thinsp;119\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e18\u0026thinsp;\u0026plusmn;\u0026thinsp;25\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eScreening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e241\u0026thinsp;\u0026plusmn;\u0026thinsp;125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e24\u0026thinsp;\u0026plusmn;\u0026thinsp;32\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eAbdominal Pain and cramps\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBenegut\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e86\u0026thinsp;\u0026plusmn;\u0026thinsp;95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e10\u0026thinsp;\u0026plusmn;\u0026thinsp;21*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e96\u0026thinsp;\u0026plusmn;\u0026thinsp;119\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e16\u0026thinsp;\u0026plusmn;\u0026thinsp;25\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eScreening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e128\u0026thinsp;\u0026plusmn;\u0026thinsp;101\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e25\u0026thinsp;\u0026plusmn;\u0026thinsp;29\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eRumbling in stomach\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBenegut\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e92\u0026thinsp;\u0026plusmn;\u0026thinsp;104\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20\u0026thinsp;\u0026plusmn;\u0026thinsp;27\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e94\u0026thinsp;\u0026plusmn;\u0026thinsp;110\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e29\u0026thinsp;\u0026plusmn;\u0026thinsp;33\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eScreening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e104\u0026thinsp;\u0026plusmn;\u0026thinsp;123\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e28\u0026thinsp;\u0026plusmn;\u0026thinsp;31\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eBurping\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBenegut\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e130\u0026thinsp;\u0026plusmn;\u0026thinsp;86 *\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20\u0026thinsp;\u0026plusmn;\u0026thinsp;28\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e174\u0026thinsp;\u0026plusmn;\u0026thinsp;110\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e15\u0026thinsp;\u0026plusmn;\u0026thinsp;26\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eScreening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e177\u0026thinsp;\u0026plusmn;\u0026thinsp;101\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12\u0026thinsp;\u0026plusmn;\u0026thinsp;24\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eHeart Burn\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBenegut\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28\u0026thinsp;\u0026plusmn;\u0026thinsp;54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e10\u0026thinsp;\u0026plusmn;\u0026thinsp;21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15\u0026thinsp;\u0026plusmn;\u0026thinsp;62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e1\u0026thinsp;\u0026plusmn;\u0026thinsp;1b\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12\u0026thinsp;\u0026plusmn;\u0026thinsp;25\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eScreening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e39\u0026thinsp;\u0026plusmn;\u0026thinsp;78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e19\u0026thinsp;\u0026plusmn;\u0026thinsp;32\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eNausea\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBenegut\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e45\u0026thinsp;\u0026plusmn;\u0026thinsp;68 *\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e1\u0026thinsp;\u0026plusmn;\u0026thinsp;2*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e10\u0026thinsp;\u0026plusmn;\u0026thinsp;22\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e58\u0026thinsp;\u0026plusmn;\u0026thinsp;77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e11\u0026thinsp;\u0026plusmn;\u0026thinsp;23\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eScreening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e85\u0026thinsp;\u0026plusmn;\u0026thinsp;106\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e17\u0026thinsp;\u0026plusmn;\u0026thinsp;31\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eUrge to defecate\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBenegut\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e62\u0026thinsp;\u0026plusmn;\u0026thinsp;93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e21\u0026thinsp;\u0026plusmn;\u0026thinsp;29\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e70\u0026thinsp;\u0026plusmn;\u0026thinsp;106\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e27\u0026thinsp;\u0026plusmn;\u0026thinsp;36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eScreening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e90\u0026thinsp;\u0026plusmn;\u0026thinsp;87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36\u0026thinsp;\u0026plusmn;\u0026thinsp;38\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e*\u003c/sup\u003e significant differences between Benegut and Screening; \u003csup\u003ea\u003c/sup\u003e significant differences between Benegut and Placebo; \u003csup\u003eb\u003c/sup\u003e significant differences between Placebo and Screening\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eIndividual GI discomfort symptoms\u003c/b\u003e\u003c/p\u003e\u003cp\u003eNine individual GI symptoms were measured during three visits. Similar to overall GI discomfort, iAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;90 min\u003c/sub\u003e was calculated for each of the symptom. Feeling of fullness, bloating and burping were the three main prevalent symptoms. Heart burn, nausea and urge to defecate were the less prevalent symptoms. The iAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;90 min\u003c/sub\u003e of feeling of fullness, bloating, burping and nausea significantly reduced in the supplement group compared to the baseline visit (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Even though there were no statistical significance in other symptoms, supplement had a lower iAUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;90 min\u003c/sub\u003e compared to screening and placebo. The number of participants experiencing each symptom at each visit is given in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eAdditionally, we also evaluated the differences between symptoms at the end of study (90th minute) represented as Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. While iAUC gave the overall symptom experience, the evaluation of symptoms at end of postprandial period showed if the participants attained symptom relief at the end of the observation. We noticed that abdominal pain and cramps, bloating were the two symptoms that were significantly different from placebo and baseline at 90th minute.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eUpper GI discomfort is common after a high caloric meal. Previous studies have shown that high caloric meal consumption can significantly induce bloating, feeling of fullness and nausea(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). We observed a similar trend in our study where during all the three visits, feeling of fullness, bloating and burping were the main symptoms noted. With supplementation of \u003cem\u003ePerilla frutescens\u003c/em\u003e extract we noted that these individual symptoms improved in comparison to baseline and overall postprandial GI discomfort was improved in comparison to baseline and placebo. The polyphenolic mixture of rosmarinic acid and the flavonoid fraction in \u003cem\u003ePerilla frutescens\u003c/em\u003e extract are expected to contribute to the alleviation of the symptoms that were observed in this study.\u003c/p\u003e\u003cp\u003ePredominant of the studies in the area of symptom relief for GI discomforts are based on probiotics and postbiotics. Although these solutions have shown promising results, these studies involve a chronic treatment period. Thus, there is a need for product development for acute symptom relief. \u003cem\u003ePerilla frutescens\u003c/em\u003e extract, in a previous clinical trial, has displayed GI discomfort relief effects on a chronic set up. Thus, the current study strengthens the previous one by offering proof on acute symptom relief. The aetiology of GI discomfort is multifactorial. We suggest that during chronic consumption of \u003cem\u003ePerilla frutescens\u003c/em\u003e extract, the effect might be mediated via changes in gut microbiota and improvement of barrier function. Intestinal barrier dysfunction leading to increased infiltration of mast cells have been noted in cases of functional dyspepsia (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Mast cells lead to proinflammatory cytokine release causing an acute inflammation potentially interfering with enteric nerve functions and increased visceral sensitivity (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Interestingly, \u003cem\u003ePerilla frutescens\u003c/em\u003e extract has shown to improve the intestinal barrier function measured with trans epithelial electrical resistance in cell culture model(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Rosmarinic acid and apigenin components of \u003cem\u003ePerilla frutescens\u003c/em\u003e extract has demonstrated beneficial gut barrier function in several preclinical models(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). In dextran sulphate sodium induced colitis mice, apigenin has demonstrated to enhance the expressions of important gut barrier markers such as ZO-1, occludin, claudin-1, and claudin-3(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eWhilst chronic effects are potentially modified via gut microbiota and intestinal barrier, acute effects might be mitigated by altering visceral sensitivity, smooth muscle contractions and post prandial gut hormones. Visceral sensitivity affected by acute inflammation, gut hormones and nutrients modulate the communication of nociceptive information from GI tract to the brain(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). This leads to improper gastric emptying and therefore bloating. Post prandial state involves regulation of various hormones some of which are suggested to be altered in subjects with gastrointestinal disorders. Subjects with functional dyspepsia have been noted to have higher plasma cholecystokin (CCK) and lower ghrelin compared to healthy controls(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Interestingly apigenin found in seeds of \u003cem\u003ePerilla frutescens\u003c/em\u003e has shown to inhibit food intake by acting on gut hormones(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eSymptoms such as spasms and pain are induced by smooth muscle contractions in stomach and upper GI tract which are influenced by various pathways such release of acetylcholine, excess influx of calcium ions etc. Inhibition of these pathways could offer antispasmodic effect. Interestingly, rosmarinic acid and vicenin-2 have displayed inhibition of acetylcholine receptors in rat ileum, thus acting as anti-spasmodic agents(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Rosmarinic acid from \u003cem\u003ePerilla frutescens\u003c/em\u003e extract has also shown attenuation of atropine- and dopamine-induced inhibition of gastric emptying and gastrointestinal motility in animal model(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Excess entry of calcium ions from extracellular fluid incites smooth muscle contractions. Cucumis melo seeds, which are rich in flavonoids, such as apigenin, luteolin, quercetin and rutin, has displayed antispasmodic, antiperistalsis actions by blocking calcium ion channels thus reducing calcium influx into smooth muscle cells. We expect a similar mode of action from the supplement, which needs to be evaluated in future mechanistic studies.\u003c/p\u003e\u003cp\u003eStudies focusing on treatment for GI discomfort and functional GI disorders are prone to placebo effects. Thus, also in the Placebo group overall GI was lower in compariso to screening, but not significant. As the study was powered and designed to evaluate the primary outcome, we did not see significance against placebo in iAUC of certain individual symptoms (burping, bloating and feeling of fullness). The key study limitation is that the study design involved evaluation of product intake after a high caloric meal, hence the discomfort relief cannot be generalized to normo-caloric situations. Future studies focusing on the triggers of GI discomforts and potential modes of action by \u003cem\u003ePerilla frutescens\u003c/em\u003e extract would allow us to focus on individual symptoms as well. Overall, we conclude that Benegut\u0026reg; offers postprandial acute symptomatic relief for overall GI discomfort.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eGI Gastrointestinal, AUC area under curve, VAS visual analogue scale, CCK Cholecystokin\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval:\u0026nbsp;\u003c/strong\u003eThe protocol was approved by the Institutional Review Board (IRB) of Landes\u0026auml;rztekammer Baden-W\u0026uuml;rttemberg (Ethical committee number: F-2022-093).\u0026nbsp;The study was conducted ethically, in accordance with the Declaration of Helsinki, and informed consent was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eCorresponding author and all authors provide their consent for consideration to publish this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualiation: SBW; Investigation CS, SBW; Methodology: CS, SBW; Data analysis: JM, CR; Data interpretation:JM, CR, KH, JC; Supervision: CR, JC, SBW, KH; Writing and review of draft: JM, CR, JC, SBW, KH\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data presented in this study are available upon reasonable request from the corresponding author, due to privacy restriction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding and conflict of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBiotesys (CRO) was paid by Amino Up and Vital Solutions (now a part of Fytexia Group) to perform and report the scientific work that formed the basis of this publication. C.R., J.M. and J.C are employed by Fytexia; KH is employed by AminoUP and SBW is employed by Vital Solutions. Fytexia is involved in the research and development, and marketing and sales of (poly)phenol extract-based ingredients for food and nutraceutical industries and supported the study. Amino UP is the producer of the raw ingredient Perilla frutescens extract. Therefore, Fytexia, Vital Solutions and Amino UP has a commercial interest in this publication. Vital Solutions approved the final trial protocol prior to its implementation but was not involved in the study implementation and data collection.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFord AC, Mahadeva S, Carbone MF, Lacy BE, Talley NJ. Functional dyspepsia. The Lancet [Internet]. 2020 Nov 21;396(10263):1689\u0026ndash;702. 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Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/tkm2.1296\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"GI discomfort, phenolic compounds, bloating, burping, Perilla frutescens, Benegut®, human study","lastPublishedDoi":"10.21203/rs.3.rs-6886069/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6886069/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGastrointestinal (GI) discomforts affect a large population all over the world. Acute symptom relief without side effects is an attractive option. \u003cem\u003ePerilla frutescens\u003c/em\u003e is an herb rich in phytochemicals that is traditionally used for anti-inflammatory and anti-allergenic effects. In this acute study we elucidate the effects of Benegut\u0026reg;, a proprietary \u003cem\u003ePerilla frutescens\u003c/em\u003e extract, on relief of postprandial GI discomfort on 30 (22 women, 8 men) healthy participants in the age group of \u0026ge;\u0026thinsp;25 and \u0026le;\u0026thinsp;70 years. Participants were included in the study if they obtained an overall GI discomfort score of 5 out of 10 on a VAS questionnaire post a high caloric meal on the screening visit. Participants attended two other visits where they either consumed 300 mg of Benegut\u0026reg; or placebo after the same high caloric meal as the screening. During these visits subjects rated their discomfort symptoms at defined time points (0, 5, 15, 30, 45, 60 and 90 min). We observed that iAUC\u003csub\u003e0\u0026minus;\u0026thinsp;90 min\u003c/sub\u003e overall GI discomfort significantly improved in the Benegut\u0026reg; group (3073\u0026thinsp;\u0026plusmn;\u0026thinsp;1255) compared to placebo (3742\u0026thinsp;\u0026plusmn;\u0026thinsp;1611) and screening (4286\u0026thinsp;\u0026plusmn;\u0026thinsp;1131). Bloating, burping and feeling of fullness significantly improved with \u003cem\u003ePerilla frutescens\u003c/em\u003e supplementation compared to screening. Overall Benegut\u0026reg; provided an acute symptom relief for GI discomfort post high caloric meal consumption.\u003c/p\u003e\u003cp\u003eClinical trial Gov registration number: NCT05603416\u003c/p\u003e","manuscriptTitle":"Standardized Perilla frutescens extract improves acute postprandial meal-induced Gastrointestinal discomfort: Randomized control trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-03 05:12:57","doi":"10.21203/rs.3.rs-6886069/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"148b374a-bef9-4e71-a8bf-a59fb3a927fb","owner":[],"postedDate":"September 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-05T13:57:34+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-03 05:12:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6886069","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6886069","identity":"rs-6886069","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}