| Study ID | |
| RefID (DistillerSR) | 3789 |
| Reference (authors, year, title, other info) | Tetzloff, W., Dauchy, F., Medimagh, S., Carr, D. and Bär, A. (1996). Tolerance to subchronic, high‐dose ingestion of erythritol in human volunteers. Regulatory Toxicology and Pharmacology, 24(2), 286–295. https://doi.org/10.1006/rtph.1996.0110 |
| Source (published/unpublished) | Published |
| Study design | |
| Study type | HCT ‐ Two‐way crossover study |
| Type of blinding | Double‐blinded |
| Duration of the study and length of follow‐up | 7 days erythritol and 7 days sucrose |
| Subjects | |
| Number of participants in the study | 12 participants |
| Number of exposed/non‐exposed subjects or number of cases/controls (if applicable) | 12 exposed |
| Sex (male/female) | Males |
| Age (mean or range as reported) | Range: 22–46 |
| Geography (country) | Not reported |
| Ethnicity | Not reported |
| Confounders and other variables as reported | Not reported |
| Special health condition of participants | Healthy |
| Inclusion and exclusion criteria in the study | Not reported |
| Other information | |
| Intervention/exposure | |
| Test material | Erythritol |
| Description of the intervention and estimated dietary exposure |
The 14‐day protocol comprised two treatment periods with administration of erythritol and sucrose for 7 days each. Six randomly selected subjects received erythritol in the first and sucrose in the second week; for the other six subjects the sequence of the treatments was reversed. The subjects were not informed about their dosing sequence Each treatment period started on a Saturday morning and ended on a Friday evening. In order to adapt the subjects to the treatments, the test compounds were provided at a dose of 0.3 g/kg bw on Saturdays and 0.6 g/kg bw on Sundays (adaptation period). Exposure to the full dose of 1 g/kg bw began on Monday morning and ended on Friday evening (test period) The total daily dose of 1 g/kg bw of erythritol or sucrose was consumed in five portions. At breakfast (8A M), about 20% of the total daily dose was consumed, at coffee break (10:30 AM) about 10%, at lunch (12:30 AM) about 30%, during afternoons (12:30 AM–7 PM) about 20%, and at dinner (7 PM) about 20%. In practice, fixed amounts of the test compounds were given with test foods at each meal except for dinner at which time the test compounds were dosed individually so as to reach the nominal dose level of 1 g/kg bw per day for each subject. The test substances were given with yogurt (breakfast, dinner), cookies (breakfast, morning coffee), soft drink (lunch) and chocolate (afternoon) Subjects were asked to abstain from alcohol intake during the adaptation period. During the test periods, no alcoholic beverages were consumed. Beverages, such as mineral water and fruit juice, were allowed ad libitum but the consumption of coffee or tea was limited to four cups per day |
| Co‐exposure description (if applicable) | Not applicable |
| Endpoint measured, measurement time points and methods |
During the 2‐day adaptation periods, each participant recorded their food and beverage consumption on daily report sheets. During the 5‐day test periods, food and beverage intake was recorded On each day of the two test periods, body weight and pressure, and sitting blood pressure were measured. Each subject was interviewed about their subjective perception of general well‐being, satisfaction with the offered test foods, feelings of hunger and thirst, desire for sweet or salty foods, and subjective perception of regularity, consistency and quantity of stool, frequency and quantity of urine, gastrointestinal intolerance and other side effects For determination of the urinary electrolytes, enzymes, proteins, urea and creatinine, the urines were thawed at room temperature, vortexed and centrifuged (3000 rpm, 20 min, 47C). The supernatants were then analysed for sodium, potassium, chloride, calcium, phosphate, citrate, gamma‐glutamyl transferase (GGT), N‐acetyl glucosaminidase (NAG), b2‐microglobulin (b2M), urea and creatinine. Although GGT was analysed, the data are not reported For determination of erythritol, the urine samples were thawed, vortexed and filtered through a 0.45‐μm filter; 1,3‐butanediol was added as an internal standard. HPLC was performed on a Shodex Ionpack colum KC 811 (0.8 × 300 mm) at 75°C using 1.8 mM H2SO4 as an eluant (sample volume, 5 μL; flow rate, 1 mL/min) Erythritol and 1,3‐butanediol were detected in the effluent by measurement of the refractive index (Waters RI‐Detector R401) |
| Were sub‐groups analyses predefined? (yes/no, including justification) | Not applicable |
| Results | |
| Findings reported by the study author/s |
During the two test periods (i.e. Days 3–7 of each treatment period), the mean body weights varied only slightly. A treatment‐related difference was not observed. All blood pressure values were within the normal physiological range. Statistical analysis of the data did not reveal treatment‐related effect During the erythritol test period, erythritol was detected in the urine of all subjects on all days. The value on any of the 48 subject‐days was 38.4 g/day corresponding to 54.3% of the nominal ingested dose. On average of all subject‐days, the erythritol excretion was 62.4 g/day, corresponding to about 78.0% of the nominal ingested dose. Since erythritol absorption is estimated at about 80%–90% from other studies, this value documents good compliance with the test regimes of the present subjects Urine production was increased during the erythritol period by about 7% (difference not statistically significant, p = 0.08) Urinary osmolality and the hourly urinary output of osmotically active solutes were significantly increased during the erythritol test period. The observed increase of 576 mOsm/24 h corresponds well to the expected increase calculated from the erythritol range The urinary output of creatinine, urea, Na+, K+, Cl‐, Pi and citrate was not influenced by erythritol treatment. Only calcium was significantly increased during the erythritol treatment (p < 0.04). However, in absolute terms, this increase was small (4%). The urinary NAG‐, beta2M‐ and albumin outputs were significantly increased during the erythritol test period. However, these increases, which were significant also after normalisation for creatinine excretion, were numerically small and all values remained well within the physiological range The participants reported that the frequency of their faeces did not differ between the treatments however the appearance was judged slightly more often as being ‘softer than usual’ during the erythritol treatment than during the sucrose treatment (14/60 vs. 8/60 observations). On the other hand, the quantity of stool was more often rated as ‘less than usual’ during the erythritol treatment than the sucrose treatment period (13/60 vs. 5/60) Gastrointestinal side effects such as flatulence, bloated feeling and sensation of fullness were reported by six subjects on a total of 10 occasions during the erythritol test period and 13 occasions during the sucrose test period |
| Statistical analysis | |
| Statistical methods (including power analyses, multiple comparison, potential sources of bias, adjustment for confounders, test for interactions) |
The data on body weight, systolic and diastolic blood pressure, and fluid intake were analysed by repeated measures analysis of variance (ANOVA) (Wiener, 1977). For each of these parameters, 120 observations (i.e. 2 treatments × 5 observation days × 12 subjects) were available for statistical analysis. From the data on urinary electrolyte, enzyme, protein, urea and creatinine concentrations (i.e. mmol/L, U/L, μg/L), the respective hourly outputs (i.e. mmol/h, U/h, μg/h) as well as excretions relative to that of creatinine (i.e. mmol/mmol creatinine, U/mmol creatinine) were calculated. From the data on hourly outputs and excretions relative to that of creatinine, as well as from the data on pH, osmolality and conductivity, 24 h means were then calculated for each subject and each treatment day. For calculating these means it was taken into account that the overnight sample represented a period three times longer (9 h) than the samples collected during the daytime (3 h each). The urine flow was expressed in ml/hr for each sampling interval, and time‐weighed 24 h means were calculated as well. For calculating the 24 h means of the different parameters, the urine produced between 10 PM of Day 3 (i.e. urine collected at 7 AM of Day 4) and 10 PM of Day 4 (i.e. urine collected at 10 PM of Day 4) was considered to represent the first full 24 h cycle. In this way, four complete 24 h cycles were available for evaluation for each of the two treatment periods For the statistical assessment of treatment‐related differences of urinary parameters, a repeated measures ANOVA was applied to the 24 h mean values (2 treatments × 12 subjects × 4 24 h periods = 96 observations for each parameter). Since one of the assumptions of ANOVA is that the residuals from the model are approximately normally distributed, the normality (Shapiro–Wilk test), skewness and kurtosis of the data were examined. Where the conditions for ANOVA were not fulfilled, inverse scores of ranks were calculated and the repeated measures ANOVA was applied to these transformed values For descriptive analysis, the hourly outputs of urine, NAG, beta2M and erythritol and the excretion of osmotically active solutes (mOsm/litre; mOsm/h) were depicted graphically for each test period (i.e. excretion profiles from 7 AM of Day 3 to 10 PM of Day 7) |
| Further information | |
| Study ID | |
| RefID (DistillerSR) | 3788 |
| Reference (authors, year, title, other info) | Oku & Okazaki, 1996. Laxative threshold of sugar alcohol erythritol in human subjects. Nutrition Research, 16(4), 577–589. https://doi.org/10.1016/0271‐5317(96)00036‐X |
| Source (published/unpublished) | Published |
| Study design | |
| Study type | HCT |
| Type of blinding | Not reported |
| Duration of the study and length of follow‐up | 1 day per test material |
| Subjects | |
| Number of participants in the study | 38 participants |
| Number of exposed/non‐exposed subjects or number of cases/controls (if applicable) | 38 exposed |
| Sex (male/female) | 14 Males workers and 24 Females students |
| Age (mean or range as reported) |
M: 45.3 ± 2.6 F: 21.7 ± 4.4 |
| Geography (country) | Japan |
| Ethnicity | Not reported |
| Confounders and other variables as reported | Not reported |
| Special health condition of participants | Healthy |
| Inclusion and exclusion criteria in the study | Not reported |
| Other information | |
| Intervention/exposure | |
| Test material | Erythritol |
| Description of the intervention and estimated dietary exposure |
One, two or three cups of jelly containing erythritol (25 g in a cup) were given to a half of the male and female subjects, and 1, 1.5 or 2.5 cups of jelly were fed to the other half of the subjects to produce a detailed distribute of values of g of erythritol/kg of bw. The jelly (about 85 g) containing 25 g of erythritol, sorbitol or sucrose was administered in order from the smallest to the largest amount and stopped at the dose level that caused diarrhoea or at the maximum dose level used in the study. Sorbitol which readily induces diarrhoea was used as a positive control, and sucrose which does not produce diarrhoea was used as a negative control On the day prior to administration, the ingestion of foods and beverages containing other sugar substitutes which might affect diarrhoea were avoided On the day of administration, the jelly containing the test substance was given with water, if needed, 2–3 h after lunch or breakfast and subjects were permitted to take any foods except for wine and other fermented foods containing erythritol or sorbitol which they were asked to avoid for about 2 h after test substance intake Only a half (sorbitol 12.5 g) or 1 (sorbitol 25 g) cup of jelly containing sorbitol was given to all subjects. The dose level was lower than that of erythritol because it readily causes diarrhoea. The dose level of jelly containing sucrose was the same as the level of erythritol that caused diarrhoea The order of ingestion of test substances was erythritol, sorbitol and sucrose. When the ingestion of test substance did not cause diarrhoea, the next ingestion of test substance was carried out on the following day or the day after next day. When the ingestion of test substance caused diarrhoea, the next ingestion of test substance was carried out after abdominal symptoms associated with the ingestion of the test substance disappeared Who ingested the jelly containing erythritol were also administered a palatable solution containing the same amount of erythritol to compare the effect of two different forms and no significant difference was observed. The diarrhoeal symptoms were self‐reported |
| Co‐exposure description (if applicable) | Not applicable |
| Endpoint measured, measurement time points and methods | A questionnaire on diarrhoea included classification of stool shape, i.e. very hard (ball shape like rabbit stool), hard, normal (banana shape), soft (pastelet), very soft (muddy) and watery. For the macroscopic classification of the stool, pictures of stool shape meeting the criteria for classification were handed to each subject to standardise their judgement of faecal condition. The detection of muddy or watery stool was defined as diarrhoea. A question on abdominal symptoms asked about upper and lower abdominal pain, vomiting, nausea, thirst, flatus, gurgle, borborygmus and tenesmus |
| Were sub‐groups analyses predefined? (yes/no, including justification) | Not applicable |
| Results | |
| Findings reported by the study author/s |
When female subjects (n = 24 h) ingested 25 g of erythritol (0.34–0.64 g/kg bw), no one experienced watery or muddy faeces. With the ingestion of 37.5 or 50 g of erythritol (0.63–1.16 g/kg bw), 12.5% of subjects had watery or muddy faeces and about 50% of subjects had normal faeces. The ingestion of 62.5 or 75 g of erythritol (1.04–1.74 g/kg bw) caused watery or muddy faeces in 14 out of 21 subjects (66.7%). One subject experienced constipation. On the other hand, no male subjects (n = 14) experienced watery or muddy faeces with the ingestion of 25 g of erythritol (0.33–0.44 g/kg bw). With the ingestion of 37.5 g or 50 g of erythritol (0.53–0.88 g/kg bw), 21.4% of subjects had watery or muddy faeces, and more than 50% of subjects had normal faeces. With the ingestion of 62.5 or 75 g of erythritol (O‐83‐1.32 g/kg bw), 4 out of 11 subjects (36.4%) experienced watery or muddy faeces. Only one of 24 female subjects showed muddy faeces with the ingestion of 12.5 g of sorbitol (0.17–0.32 g/kg bw) and 13 out of 23 subjects (56.5%) had watery or muddy faeces with the ingestion of 25 g of sorbitol (0.42–0.58 g/kg bw). For male subjects (n = 14), the ingestion of 12.5 g of sorbitol (O‐17‐0.22 g/kg bw), 6 out of 14 subjects (42.8%) experienced watery or muddy faeces and the ingestion of 25 g of sorbitol (O‐33‐0.44 g/kg bw) caused muddy faeces in one out of eight male subjects (12.5%) The laxative threshold of erythritol was estimated as 0.80 g/kg bw for females and 0.66 g/kg bw for males, respectively. The effective dose (ED) 50 was 1.58 g/kg bw for the female group and 1.07 g/kg bw for the male group The results suggest that female subjects are more resistant than male subjects to diarrhoea caused by a high ingestion of erythritol and that the diarrhoeal effect of sorbitol is stronger than that of erythritol. |
| Statistical analysis | |
| Statistical methods (including power analyses, multiple comparison, potential sources of bias, adjustment for confounders, test for interactions) | The minimum dose level per kg body weight (g/kg) which first caused diarrhoea, was calculated for each subject, and the values obtained were plotted from lowest to highest. Thus, the cumulative incidence of dose–response diarrhoea was obtained. From the minimum dose level which induced diarrhoea and the cumulative incidence of diarrhoea, a regression equation was made, and the maximum permissible dose level which did not cause diarrhoea was calculated. The side‐effect symptoms of erythritol, sorbitol and sucrose were compared using the Wilcoxon signed‐rank test |
| Further information | |
| Study ID | |
| RefID (DistillerSR) | 4301 |
| Reference (authors, year, title, other info) | Nikken Chemicals Co. Ltd., Japan. (1992a). Study on the Maximum No‐Effect Level of Erythritol Using Transient Diarrhoeal Action as Index. |
| Source (published/unpublished) | Unpublished |
| Study design | |
| Study type | HCT – Dose escalation cross over trial – Not randomised |
| Type of blinding | Not blinded |
| Duration of the study and length of follow‐up | 1 day per test material |
| Subjects | |
| Number of participants in the study | 12 |
| Number of exposed/non‐exposed subjects or number of cases/controls (if applicable) | 12 |
| Sex (male/female) | Eight males and four females |
| Age (mean or range as reported) |
M: 39.0 ± 11.5 F: 25.3 ± 15.1 |
| Geography (country) | Not reported |
| Ethnicity | Not reported |
| Confounders and other variables as reported | Not reported |
| Special health condition of participants | Healthy |
| Inclusion and exclusion criteria in the study | Healthy adults without liver or kidney disorders |
| Other information | Three out of twelve subjects dropped out from the sugar group because of the pain due to the extreme sweetness of large amounts of sugar, and 3 of 12 subjects dropped out from the sorbitol group because of sorbitol |
| Intervention/exposure | |
| Test material | Erythritol |
| Description of the intervention and estimated dietary exposure |
The study substances were dissolved as sweetener in coffee, tea or warm water (150–180 mL). Ingested amount: Erythritol 30, 40 and 50 g Sorbitol 10g Sugar 60 g On the day before ingestion, the subjects avoided foods and drinks likely to cause diarrhoea, as listed in the questionnaire, and ingested the study substances on a day when they felt in good physical condition. Ingestion was completed within 10 min. The study substances were ingested in the order of sugar, erythritol and sorbitol and if diarrhoeal symptoms were noted, the next study substance was ingested after an interval of 3–4 days, when the abdominal condition had stabilised. The erythritol dose increased stepwise every 1–2 days and when diarrhoeal symptoms were noted, ingestion of the next higher dose was discontinued. The subjects were observed without any restrictions on ingested foods and liquids, based on their normal eating habits |
| Co‐exposure description (if applicable) | Not applicable |
| Endpoint measured, measurement time points and methods | A survey by questionnaire was conducted before ingestion of the test substance on items such as age, body weight, normal gastrointestinal condition, evacuation pattern, favourite foods, evacuation and foods eaten on the day before ingestion. The time of ingestion was more than 2 h after meals on a day when the subjects felt in good physical condition, and abdominal condition (abdominal pain, feeling of enlarged abdomen and gas), presence and time of occurrence of diarrhoeal symptoms, frequency of diarrhoeal stools and condition of stool (round, banana‐ shaped, semi‐ soft, muddy, watery stools) were investigated |
| Were sub‐groups analyses predefined? (yes/no, including justification) | Not applicable |
| Results | |
| Findings reported by the study author/s |
The median ED50 of erythritol inducing diarrhoea was estimated to be 0.83 g/kg bw for the males and at 1.30 g/kg bw for the females. The NOEL estimated was at 0.55 g/kg for the males and at 0.76 g/kg for the females, with the females showing higher tolerance than the males In cases of abnormal physical condition (abdominal anomalies, diarrhoea symptoms) due to ingestion of the maximum dose of erythritol (50 g) the anomalies occurred within 3 h after ingestion, and diarrhoeal symptoms (muddy to watery stools) were noted one to three times. There were no further complaints after these abdominal and diarrhoeal symptoms had normalised within 24 h, and they are thus attributed to transient action Other than abdominal symptoms due to erythritol ingestion, strange sensation in the throat (feeling of irritation, thirst) was noted in 1 of 12 subjects receiving 30 g, in 2 subjects receiving 40 g and in 1 subject receiving 50 g. This is attributed to osmotic pressure induced by the high‐concentration liquid, resulting from the low molecular weight of erythritol. The symptom was promptly eliminated by drinking water. Temporary headache after ingestion was observed in one subject each of the 30 and 50 g dose groups, but it was attributed to mental factors and subsequently disappeared |
| Statistical analysis | |
| Statistical methods (including power analyses, multiple comparison, potential sources of bias, adjustment for confounders, test for interactions) | Not reported |
| Further information | |
| No diarrhoea at all was noted in nine subjects of the sugar ingestion group, but diarrhoea was observed in three out of nine subjects in the 10 g sorbitol ingestion group (incidence: 33%) | |
| Study ID | |
| RefID (DistillerSR) | 4302 |
| Reference (authors, year, title, other info) | Mitsubishi Kasei Corporation, Food Business Department, 1992. Study concerning transient diarrhoea induced by Erythritol. |
| Source (published/unpublished) | Unpublished |
| Study design | |
| Study type | HCT – Dose escalation cross over trial – Not randomised |
| Type of blinding | Not described |
| Duration of the study and length of follow‐up | 1 day per test material |
| Subjects | |
| Number of participants in the study | Six participants |
| Number of exposed/non‐exposed subjects or number of cases/controls (if applicable) | Six exposed |
| Sex (male/female) | Males |
| Age (mean or range as reported) | 26–46 years old |
| Geography (country) | Not reported |
| Ethnicity | Not reported |
| Confounders and other variables as reported | Not reported |
| Special health condition of participants | Healthy |
| Inclusion and exclusion criteria in the study | Not reported |
| Other information | |
| Intervention/exposure | |
| Test material | Erythritol |
| Description of the intervention and estimated dietary exposure |
A prescribed amount of the test substance was mixed in about 180 mL of water or weak coffee to prepare solution for ingestion. The method of ingestion was as follows: The test substance was mixed in water or weak coffee and taken within 10 min from the initiation of ingestion Ingestion of the test substance was performed in the order of sucrose, erythritol and sorbitol Amount ingested: Erythritol: 30 g, 40 g, 50 g, 60 g Sorbitol: 10 g Sucrose: 60 g When diarrhoea was observed, ingestion of the next test substance was performed after 3–4 days of, recovery period to assure stable abdominal condition The dose of erythritol was increased step by step to reach 60 g. If diarrhoea was observed at any dose of erythritol higher doses were not given to the subject. For 24 h after the ingestion, there was no special limitation on the meals and water consumption of the subjects |
| Co‐exposure description (if applicable) | Not applicable |
| Endpoint measured, measurement time points and methods | Before the ingestion of the test substance, age, body weight, ordinary condition of the gastrointestinal system, condition of evacuation, luxury materials, condition of evacuation on the day before ingestion and contents of meal were asked in questionnaire. Questionnaire was also made on the abdominal condition until 24 h after the ingestion, diarrhoea or not, onset time of and times of diarrhoea if occurred and appearance of the stool |
| Were sub‐groups analyses predefined? (yes/no, including justification) | Not applicable |
| Results | |
| Findings reported by the study author/s |
Diarrhoea was not induced in any subject by the ingestion of 30 g of erythritol. By the ingestion of 60 g of erythritol, all subjects were considered to show diarrhoea. NOEL of erythritol making diarrhoea was estimated to be 0.51 g/kg bw (30 g/person). The abnormal physical signs induced by the bulk ingestion of erythritol were as follows: about 3 h or earlier after the ingestion, abdominal pain and/or growling occurred. Then, one to three times of diarrhetic symptoms (muddy to watery stool) occurred. These abdominal and/or diarrhetic symptoms recovered to normal within 24 h. Other than the abdominal symptoms, thirst and headache were observed after the ingestion of erythritol |
| Statistical analysis | |
| Statistical methods (including power analyses, multiple comparison, potential sources of bias, adjustment for confounders, test for interactions) | Not reported |
| Further information | |
| All the subjects complained of the pain of high sweetness due to the bulk consumption of erythritol and sucrose. However, there was no dropout case | |
| Study ID | |
| RefID (DistillerSR) | 4300 |
| Reference (authors, year, title, other info) | Nikken Chemicals Co. Ltd., Japan. (1992b). The effect of continuous injection of erythritol with laxative action serving as index. |
| Source (published/unpublished) | Unpublished |
| Study design | |
| Study type | HCT |
| Type of blinding | Not blinded |
| Duration of the study and length of follow‐up | Twice a day for 5 days continuously |
| Subjects | |
| Number of participants in the study | 10 participants |
| Number of exposed/non‐exposed subjects or number of cases/controls (if applicable) | 10 exposed |
| Sex (male/female) | Eight Males and two Females |
| Age (mean or range as reported) |
M: 46 (average) F: 55.5 (average) |
| Geography (country) | Not reported |
| Ethnicity | Not reported |
| Confounders and other variables as reported | Not reported |
| Special health condition of participants | Healthy |
| Inclusion and exclusion criteria in the study | Not reported |
| Other information | |
| Intervention/exposure | |
| Test material | Erythritol |
| Description of the intervention and estimated dietary exposure |
Erythritol, dissolved in 1 cup (150–180 mL) of cold water (5–10°C), was orally ingested in single 20g doses twice a day (40 g/day), 2–3 h after meals (breakfast, lunch) and was subsequently continuously ingested in the same manner for a total of 5 days. On the day before the start of ingestion, the subjects avoided foods and drinks likely to cause diarrhoea, as listed in the questionnaire, and started ingesting the test substance on a day where they felt in good physical condition The subjects ingested the prepared erythritol solution over a period of 10 min at least 2 h after meals. Subsequent ingestion was discontinued in the subject who experienced diarrhoea during the trial During the study, the subjects were observed without any restrictions on food and liquids, under conditions of normal food and normal daily activities |
| Co‐exposure description (if applicable) | Not applicable |
| Endpoint measured, measurement time points and methods | The subjects were asked by questionnaire before ingestion of the test substance about their age, body weight, normal gastrointestinal condition, evacuation pattern, favourite foods, and evacuation and foods eaten on the day before ingestion and after ingestion about their abdominal condition (abdominal pain, feeling of enlarged abdomen, gas, etc.), the presence, time of occurrence and frequency of diarrhoeal symptoms, and evacuation |
| Were sub‐groups analyses predefined? (yes/no, including justification) | Not applicable |
| Results | |
| Findings reported by the study author/s |
At an erythritol intake of 40 g/day, no laxative action such as diarrhoea was noted in nine subjects. No cumulative effect due to continuous erythritol ingestion was observed Three of the 10 subjects noted single reoccurrence of a feeling of enlarged abdomen on days 2 and 3 of ingestion, but since there was no subsequent worsening and no recurrence of this feeling of enlargement abdomen after subsequent erythritol ingestion, the symptoms are not attributed to erythritol but to effects on the physical condition due to other factors. No other symptoms were observed Meanwhile, laxative action was noted in 1 case on day 2 of ingestion, but since this subject had a disposition toward frequent diarrhoea, reported laxative action even when ingesting 10 g of sorbitol (the maximal ineffective dose), and felt a strange sensation after ingestion, he is considered a mentally susceptible type, who is hypersensitive to sugar alcohol |
| Statistical analysis | |
| Statistical methods (including power analyses, multiple comparison, potential sources of bias, adjustment for confounders, test for interactions) | Not described |
| Further information | |
| Study ID | |
| RefID (DistillerSR) | 3859 |
| Reference (authors, year, title, other info) | Meyer‐Gerspach, A.C., Wingrove, J.O., Beglinger, C., Rehfeld, J.F., Le Roux, C.W., Peterli, R., Dupont, P., O'Daly, O., Van Oudenhove, L. and Wölnerhanssen, B.K. (2021). Erythritol and xylitol differentially impact brain networks involved in appetite regulation in healthy volunteers. Nutritional Neuroscience, 25(11), 2344–2358. https://doi.org/10.1080/1028415x.2021.1965787 |
| Source (published/unpublished) | Published |
| Study design | |
| Study type | HCT – Cross‐over trial – Randomised – Placebo‐controlled |
| Type of blinding | Double‐blind |
| Duration of the study and length of follow‐up | 1 day per test material |
| Subjects | |
| Number of participants in the study | 23 participants |
| Number of exposed/non‐exposed subjects or number of cases/controls (if applicable) | 20 exposed |
| Sex (male/female) | 10 Males and 10 Females |
| Age (mean or range as reported) | 21–45 |
| Geography (country) | Switzerland |
| Ethnicity | Not reported |
| Confounders and other variables as reported | Not reported |
| Special health condition of participants | Healthy |
| Inclusion and exclusion criteria in the study | Exclusion criteria were smoking, substance abuse, regular intake of medications, medical or psychiatric illness, any MRI contraindication (e.g. claustrophobia, non‐removable metal devices) and any abnormalities detected upon laboratory screening |
| Other information | |
| Intervention/exposure | |
| Test material | Erythritol |
| Description of the intervention and estimated dietary exposure |
On the evening before each study day, subjects consumed a restricted simple carbohydrate standard dinner before 08:00 pm and fasted from 12:00 am (midnight) until the study visit, which started at 08:00 am on four separate occasions, at least 3 days apart. On arrival, a polyvinyl feeding tube was inserted into the stomach. The rationale for intragastric administration of the test substances was to bypass oro‐sensory cues to provide information on the isolated post‐oral effects At t = 0 min, subjects received an ig load of one of the following test solutions, freshly prepared each morning, over 2 min: (i) 75 g glucose in 300 mL tap water (Haenseler AG, Herisau, Switzerland), (ii) 50 g xylitol in 300 mL tap water (Mithana GmbH, Zimmerwald, Switzerland), (iii) 75 g erythritol in 300 mL tap water (Mithana GmbH, Zimmerwald, Switzerland), (iv) 300 mL tap water (placebo) |
| Co‐exposure description (if applicable) | Not applicable |
| Endpoint measured, measurement time points and methods |
An intravenous catheter was inserted into an antecubital vein for blood sample collection at specific time intervals (t = −15, −5, +15 and + 60 min) for determination of plasma CCK, PYY, insulin and glucose concentrations At 6 and 21 min after administration, resting blood oxygenation level‐dependent (rBOLD) (for 5 min) followed by resting cerebral blood flow (rCBF) (for 4 min) data were acquired, respectively Appetite‐related sensations (hunger, prospective food consumption, satiety and fullness) were assessed by visual analog scales (VAS) after each blood sample collection During the study day, the volunteers were asked to report gastrointestinal symptoms such as nausea, bloating and diarrhoea |
| Were sub‐groups analyses predefined? (yes/no, including justification) | Not applicable |
| Results | |
| Findings reported by the study author/s |
– Xylitol, but not erythritol, increased rCBF in the hypothalamus, whereas glucose had the opposite effect. – Graph analysis of resting functional connectivity revealed a complex pattern of similarities and differences in brain network properties following xylitol, erythritol and glucose. – Erythritol and xylitol induced a rise in CCK and PYY. – Erythritol had no and xylitol only minimal effects on glucose and insulin. – The administration of 50g of xylitol led to bloating and diarrhoea in 40% of all subjects (8 out of 20), and 75 g of erythritol had the same side effects in 16.6% of all subjects (3 out of 20; xylitol vs. erythritol p = 0.16). Despite diarrhoea (which usually stopped after one to two bowel movements), no study session had to be terminated prematurely. |
| Statistical analysis | |
| Statistical methods (including power analyses, multiple comparison, potential sources of bias, adjustment for confounders, test for interactions) |
A two‐tailed p‐value < 0.05 was considered significant To analyse the time course of the subjective and endocrine responses to the different infusions, marginal linear mixed model analyses were performed ‐ one for each dependent variable. The optimal variance–covariance structure was chosen based on the observed variance–covariance matrix and the best fit indicated by the lowest value of Akaike's Information Criterion (AIC). If the assumption of normally distributed residuals was violated (based on a significant p‐value of the Shapiro–Wilk test), box‐cox transformations on the dependent variables were used to normalise the residual distribution. Observed untransformed values will be shown on graphs to facilitate interpretation and comparison with previous results The treatment‐by‐time interaction effect (testing the difference between the four treatments between the three time points) are the effects of interest. To follow‐up on the latter effect and test specific hypotheses on the difference in the change from pre‐infusion baseline at each of the two post‐infusion time points between the four treatments, planned contrast analyses were performed using paired Student's t‐tests, with step‐down Bonferroni (Holm) correction for multiple testing. Specifically, were compared the change from pre‐infusion baseline at each of the two post‐infusion timepoints between treatments. Further, was tested whether this change from pre‐infusion baseline at each of the two post‐infusion time points was significantly different from zero in each treatment separately by planned contrast analyses using one‐sample Student's t‐tests, with step‐down Bonferroni (Holm) correction for multiple testing. Similar models and contrasts were used to analyse the brain data. Finally, to explore putative relationships between the differences in hormone response and brain response to the different sweet substances, were used Spearman's rank non‐parametric correlations |
| Further information | |
| 23 volunteers were recruited, but 2 did not meet the eligibility criteria, and one did not tolerate the nasogastric tube. This person's data was excluded from analysis and replaced by a new participant, giving a final total of 20 participants | |
| Study ID | |
| RefID (DistillerSR) | 3850 |
| Reference (authors, year, title, other info) | Wölnerhanssen, B. K., Drewe, J., Verbeure, W., le Roux, C. W., Dellatorre‐Teixeira, L., Rehfeld, J. F., Holst, J. J., Hartmann, B., Tack, J., Peterli, R., Beglinger, C., & Meyer‐Gerspach, A. C. (2021). Gastric emptying of solutions containing the natural sweetener erythritol and effects on gut hormone secretion in humans: A pilot dose‐ranging study. Diabetes Obesity Metabolism, 23(6), 1311–1321. https://doi.org/10.1111/dom.14342 |
| Source (published/unpublished) | Published |
| Study design | |
| Study type | HCT – Cross‐over trial – Randomised – Placebo‐controlled |
| Type of blinding | Double‐blinded |
| Duration of the study and length of follow‐up | 1 day per test material |
| Subjects | |
| Number of participants in the study | 12 participants |
| Number of exposed/non‐exposed subjects or number of cases/controls (if applicable) | 12 exposed |
| Sex (male/female) | Seven Males and five Females |
| Age (mean or range as reported) | 18–40 |
| Geography (country) | Switzerland |
| Ethnicity | Not reported |
| Confounders and other variables as reported | Not reported |
| Special health condition of participants | Healthy |
| Inclusion and exclusion criteria in the study | The exclusion criteria included substance and alcohol abuse, regular intake of medications (except for oral contraceptives), acute infections, chronic medical illness or illnesses affecting the GI system, a history of food allergies, dietary restrictions or pre‐existing consumption of erythritol on a regular basis |
| Other information | |
| Intervention/exposure | |
| Test material | Erythritol |
| Description of the intervention and estimated dietary exposure | On four separate occasions, at least 3 days apart and after a 10‐h overnight fast, after taking fasting blood (t = −10 and − 1 min) and breath samples (t = −10 min), as well as assessing appetite‐related perceptions and GI symptoms, participants received one of the following test solutions (at t = 0 min) directly into the stomach by use of a nasogastric feeding tube over 2 min: 10, 25 or 50 g erythritol +50 mg of 13C‐sodium acetate dissolved in 300 mL tap water or 300 mL tap water +50 mg of 13C‐sodium acetate (placebo). The active treatments were given in a completely randomised order |
| Co‐exposure description (if applicable) | Not applicable |
| Endpoint measured, measurement time points and methods | Following administration of the test solution blood samples (after 15, 30, 45, 60, 90, 120 and 180 min for analysis of plasma CCK, aGLP‐1, PYY, GIP, motilin, glucose, insulin and glucagon), and breath samples (after 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210 and 240 min for analysis of gastric emptying) were taken. Appetite‐related sensations were assessed immediately after each blood collection; participants were asked to rate GI symptoms at 30, 60, 90, 120, 150, 180 and 240 min after administration of the test solutions. Extra blood samples were taken during the visit, with the highest erythritol load (50 g) for analysis of serum total cholesterol, high‐ and low‐density lipoprotein (HDL and LDL, respectively), triglyceride and uric acid concentrations. Blood samples were collected on ice into tubes and analysed using enzyme‐ or radioimmunoassay. Gastric emptying was determined using a 13C‐sodium acetate breath test: test solutions were labelled with 50 mg of 13C‐sodium acetate, an isotope that is absorbed readily in the proximal small intestine then transported to the liver where it is metabolised to 13CO2, which is then exhaled rapidly and can therefore be used as an indirect marker of gastric emptying. Validated visual analog scales were used to rate the appetite‐related sensations (hunger, prospective food consumption, satiety and fullness) |
| Were sub‐groups analyses predefined? (yes/no, including justification) | Not applicable |
| Results | |
| Findings reported by the study author/s |
A dose‐dependent stimulation of CCK, aGLP‐1 and PYY, and slowing of GE: there was an overall statistically significant difference for 10 and 50g of erythritol versus placebo comparing the iAUCs for 0–60 min and for the iAUCs for 0–180 min Emptying of erythritol‐containing solutions from the stomach was slower compared with placebo No effect on blood glucose, insulin, motilin, glucagon or glucose‐dependent insulinotropic polypeptide No effect on blood lipids and uric acid No abdominal pain, nausea or vomiting |
| Statistical analysis | |
| Statistical methods (including power analyses, multiple comparison, potential sources of bias, adjustment for confounders, test for interactions) | Descriptive statistics were used for demographic variables such as age, weight, height and BMI. For hormone and glucose profiles, gastric emptying and appetite‐related sensations, incremental values were used to calculate the incremental area under the curve (iAUC) by the trapezoidal rule. Isolated missing values (because of technical problems or being below the detection limit) were replaced by the treatment group median to enable calculation of the iAUC. The maximum and minimum deviations from baseline – iCmax and iCmin, respectively – were determined using baseline‐corrected data. For iAUC calculations, in addition to the total time interval of 180 min, an interval of 60 min is reported because in some variables (CCK and GLP‐1) the main effect was observed during this time period. Linear mixed effects modelling was applied to describe differences between the different treatments (placebo, 10, 25 and 50 g). In the case of significant overall treatment effects, pairwise post hoc within‐subject comparisons were performed using a Šidak multicomparison test. In addition, for the variables of interest (e.g. iAUCs of 0–60 min for CCK, aGLP‐1 and PYY), the minimum detectable differences were estimated on the basis of the observed data in the current study by a simulation with power analysis and sample size 2020 software (NCSS, LLC, Kaysville, UT, USA) using 1000 iterations per run. The order of treatments was evaluated as a covariate. To explore putative relationships between different gut hormone responses (e.g. CCK, PYY and aGLP‐1) and gastric emptying of the different treatments, the integrated responses (iAUC 0–60 min) were correlated on an individual basis by linear matrix correlation. The goodness of this correlation was expressed by Pearson's correlation coefficient, R. All statistical analysis was performed using SPSS statistics for windows version 25.0 (IBM, Armonk, NY, USA) |
| Further information | |
| All the subjects tolerated the study well, and there were no adverse events during the period of the study. Five subjects did not receive placebo treatment and, therefore, complete data for seven (placebo) to 12 participants (all erythritol doses) were available for analysis | |
| Study ID | |
| RefID (DistillerSR) | 3759 |
| Reference (authors, year, title, other info) | Wölnerhanssen, B. K., Cajacob, L., Keller, N., Doody, A., Rehfeld, J. F., Drewe, J., Peterli, R., Beglinger, C., & Meyer‐Gerspach, A. C. (2016). Gut hormone secretion, gastric emptying, and glycemic responses to erythritol and xylitol in lean and obese subjects. American Journal of Physiology‐Endocrinology and Metabolism, 310, E1053–E1061. https://doi.org/10.1152/ajpendo.00037.2016 |
| Source (published/unpublished) | Published |
| Study design | |
| Study type | HCT – single‐centre, randomised, placebo‐controlled, cross‐over study |
| Type of blinding | Double‐blinded |
| Duration of the study and length of follow‐up | 1 day per test material |
| Subjects | |
| Number of participants in the study | 20 participants |
| Number of exposed/non‐exposed subjects or number of cases/controls (if applicable) | 20 exposed |
| Sex (male/female) |
Five males and five females in the lean group; Five males and five females in the obese group |
| Age (mean or range as reported) |
24.6 ± 0.2 years old in the lean group; 27.2 ± 2.8 years old in the obese group |
| Geography (country) | Switzerland |
| Ethnicity | Not reported |
| Confounders and other variables as reported | Not reported |
| Special health condition of participants | Lean or obese |
| Inclusion and exclusion criteria in the study |
Inclusion criteria: in general good health, 18–50 years old and BMI < 18 and > 25 kg/m2 in the lean group and > 30 kg/m2 in the obese group Exclusion criteria: smoking, substance abuse, regular intake of medications, psychiatric or medical illness, and any abnormalities detected by physical examination or laboratory screening. None of the subjects had a history of GI disorders, food allergies or dietary restrictions |
| Other information | |
| Intervention/exposure | |
| Test material | Erythritol (Mithana, Switzerland) |
| Description of the intervention and estimated dietary exposure | On the day prior to each study day, subjects consumed a restricted, simple‐carbohydrate standard dinner before 20:00 h and then fasted from midnight. On the study day, subjects were admitted to the test centre and an antecubital catheter was inserted into a forearm vein for blood collection. Subjects swallowed a polyvinyl feeding tube (external diameter 8 French) that was placed through an anaesthetised nostril. Study days were identical in design, except for the different test solutions administered: 75 g erythritol dissolved in 300 mL of tap water or 75 g glucose dissolved in 300 mL of tap water (positive control) or 300 mL of tap water alone (negative control). The washout period was not stated |
| Co‐exposure description (if applicable) | Not applicable |
| Endpoint measured, measurement time points and methods |
Plasma glucose, insulin, active GLP‐1, CCK, gastric emptying and subjective feelings of satiation Intragastric infusions were freshly prepared each morning of the study day and were at room temperature when administered. After recording two fasting blood samples (t = –10 and –1 min) and a fasting breath sample (t = –1 min), subjects received the test solution via the feeding tube within 2 min (t = 0–2 min). Blood samples were then taken at regular intervals (15, 30, 45, 60, 90, 120 and 180 min) on ice into tubes containing EDTA (6 μmol/L), a protease inhibitor cocktail (Complete®, EDTA‐free, 1 tablet/50 mL of blood; Roche, Mannheim, Germany) and a dipeptidylpeptidase IV inhibitor (10 μL/mL; Millipore, St. Charles, MO, USA). Tubes were centrifuged at 3000 rpm for 10 min at 4°C, and plasma samples were stored at –70°C until analysis of plasma glucose, insulin, active GLP‐1 and CCK was performed Plasma glucose concentration was measured by a glucose oxidase method (Rothen Medizinische Laboratorien, Basel, Switzerland). Plasma insulin was measured using a commercial electrochemiluminescence immunoassay (Cobas/Roche Diagnostics, Mannheim, Germany). Plasma active GLP‐1 was measured with a commercial ELISA kit (Millipore, St. Charles, MO, USA). Plasma CCK concentrations were measured with a sensitive radioimmunoassay using a highly specific antiserum (No. 92128) Test solutions were labelled with 50 mg 13C‐sodium acetate for determination of gastric emptying. End‐expiratory breath samples were taken at fixed time intervals (15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 210 and 240 min) after instillation of the test solution. The subject's vital signs (blood pressure and heart rate) were measured before and after each study intervention. Appetite perceptions (feelings of hunger, satiety, fullness and prospective food consumption) were assessed by VAS The 13C exhalation was determined by nondispersive infrared spectroscopy using an isotope ratio mass spectrophotometer (IRIS; Wagner Analysen Technik, Bremen, Germany) and expressed as the relative difference from the universal reference standard (carbon from Pee Dee Belemnite limestone). 13C enrichment was defined as the difference between preprandial 13C exhalation and postprandial 13C exhalation at defined time points, over basal. ∆ values were converted into atom percent excess and then into percent of administered dose of 13C excreted per h (CO2 production of the subjects was used, assumed to be 300 mmol/h multiplied by the body surface area as calculated by the weight height formula of Haycock et al. (1978) a |
| Were sub‐groups analyses predefined? (yes/no, including justification) | Not applicable |
| Results | |
| Findings reported by the study author/s |
Erythritol administration led to a marked increase in CCK and GLP‐1, whereas insulin and plasma glucose were not affected. Erythritol also induced a significant retardation in gastric emptying compared to placebo. Subjective feelings of appetite were not significantly different after erythritol intake compared with placebo Limitations of the study included: high acute doses, greater than those likely to be encountered in a real‐life scenario, that did not permit the investigation of potential adaptive processes |
| Statistical analysis | |
| Statistical methods (including power analyses, multiple comparison, potential sources of bias, adjustment for confounders, test for interactions) |
Hormone and glucose profiles were analysed by AUC from baseline values. The Shapiro–Wilk test was used to test parameters for normality. General linear model repeated measures ANOVA was applied to describe differences between lean subjects and obese participants in the different treatment groups, where obesity status was used as between‐subject factor in this analysis. Pairwise post hoc within‐subject comparisons were done with the Šidak multi‐comparison test and between‐subject comparisons by univariate ANOVA. All statistical analysis was done using the statistical software package SPSS for Windows, version 23.0 (SPSS, Chicago, IL., USA). Prevalence of diarrhoea associated with intake was compared by use of Fisher's exact test The sample size was reported to have been chosen based on practical considerations rather than statistical estimation, though the authors considered that a sample size of 8–12 subjects would likely allow the detection of large differences in parameters (50%) between the treatment groups |
| Further information | |
|
Subjects were also administered a test solution containing 50 g xylitol dissolved in tap water (300 mL) Subjects were instructed to abstain from alcohol, caffeine, black and green tea, coke, chocolate and strenuous exercise for 24 h before each treatment and, also to abstain from sprouts, broccoli and grapefruit for the study duration | |
Haycock, G. B., Schwartz, G. J., & Wisotsky, D. H. (1978). Geometric Method for Measuring Body Surface Area: A Height‐weight Formula validated in Infants, Children, and Adults. Journal of Pediatry, 93, 62–66.