A low FODMAP diet plus traditional dietary advice versus a low-carbohydrate diet versus pharmacological treatment in irritable bowel syndrome (CARIBS): a single-centre, single-blind, randomised controlled trial.

BACKGROUND: Dietary advice and medical treatments are recommended to patients with irritable bowel syndrome (IBS). Studies have not yet compared the efficacy of dietary treatment with pharmacological treatment targeting the predominant IBS symptom. We therefore aimed to compare the effects of two restrictive dietary treatment options versus optimised medical treatment in people with IBS. METHODS: This single-centre, single-blind, randomised controlled trial was conducted in a specialised outpatient clinic at the Sahlgrenska University Hospital, Gothenburg, Sweden. Participants (aged ≥18 years) with moderate-to-severe IBS (Rome IV; IBS Severity Scoring System [IBS-SSS] ≥175) and no other serious diseases or food allergies were randomly assigned (1:1:1) by web-based randomisation to receive a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) plus traditional IBS dietary advice recommended by the UK National Institute for Health and Care Excellence (hereafter the LFTD diet), a fibre-optimised diet low in total carbohydrates and high in protein and fat (hereafter the low-carbohydrate diet), or optimised medical treatment based on predominant IBS symptom. Participants were masked to the names of the diets, but the pharmacological treatment was open-label. The intervention lasted 4 weeks, after which time participants in the dietary interventions were unmasked to their diets and encouraged to continue during 6 months' follow-up, participants in the LFTD group were instructed on how to reintroduce FODMAPs, and participants receiving pharmacological treatment were offered diet counselling and to continue with their medication. The primary endpoint was the proportion of participants who responded to the 4-week intervention, defined as a reduction of 50 or more in IBS-SSS relative to baseline, and was analysed per modified intention-to-treat (ie, all participants who started the intervention). Safety was analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02970591, and is complete. FINDINGS: Between Jan 24, 2017, and Sept 2, 2021, 1104 participants were assessed for eligibility and 304 were randomly assigned. Ten participants did not receive their intervention after randomisation and thus 294 participants were included in the modified intention-to-treat population (96 assigned to the LFTD diet, 97 to the low-carbohydrate diet, and 101 to optimised medical treatment). 241 (82%) of 294 participants were women and 53 (18%) were men and the mean age was 38 (SD 13). After 4 weeks, 73 (76%) of 96 participants in the LFTD diet group, 69 (71%) of 97 participants in the low-carbohydrate diet group, and 59 (58%) of 101 participants in the optimised medical treatment group had a reduction of 50 or more in IBS-SSS compared with baseline, with a significant difference between the groups (p=0·023). 91 (95%) of 96 participants completed 4 weeks in the LFTD group, 92 (95%) of 97 completed 4 weeks in the low-carbohydrate group, and 91 (90%) of 101 completed 4 weeks in the optimised medical treatment group. Two individuals in each of the intervention groups stated that adverse events were the reason for discontinuing the 4-week intervention. Five (5%) of 91 participants in the optimised medical treatment group stopped treatment prematurely due to side-effects. No serious adverse events or treatment-related deaths occurred. INTERPRETATION: Two 4-week dietary interventions and optimised medical treatment reduced the severity of IBS symptoms, with a larger effect size in the diet groups. Dietary interventions might be considered as an initial treatment for patients with IBS. Research is needed to enable personalised treatment strategies. FUNDING: The Healthcare Board Region Västra Götaland, the Swedish Research Council, the Swedish Research Council for Health, Working Life and Welfare, AFA Insurance, grants from the Swedish state, the Wilhelm and Martina Lundgren Science Foundation, Skandia, the Dietary Science Foundation, and the Nanna Swartz Foundation.

Coffee, Alcohol, and Artificial Sweeteners Have Temporal Associations with Gastrointestinal Symptoms.

BACKGROUND: Various dietary strategies for managing irritable bowel syndrome (IBS) target mechanisms such as brain-gut interactions, osmotic actions, microbial gas production, and local immune activity. These pathophysiological mechanisms are diverse, making it unclear which foods trigger IBS symptoms for a substantial proportion of patients. AIM: To identify associations between foods and gastrointestinal symptoms. METHODS: From the mySymptoms smartphone app, we collected anonymized diaries of food intake and symptoms (abdominal pain, diarrhea, bloating, and gas). We selected diaries that were at least 3 weeks long. The diaries were analyzed for food-symptom associations using a proprietary algorithm. As the participants were anonymous, we conducted an app-wide user survey to identify IBS diagnoses according to Rome IV criteria. RESULTS: A total of 9,710 food symptom diaries that met the quality criteria were collected. Of the survey respondents, 70% had IBS according to Rome IV criteria. Generally, strong associations existed for caffeinated coffee (diarrhea, 1-2 h postprandial), alcoholic beverages (multiple symptoms, 4-72 h postprandial), and artificial sweeteners (multiple symptoms, 24-72 h postprandial). Histamine-rich food intake was associated with abdominal pain and diarrhea. Some associations are in line with existing literature, whilst the absence of an enriched FODMAP-symptom association contrasts with current knowledge. CONCLUSIONS: Coffee, alcohol, and artificial sweeteners were associated with GI symptoms in this large IBS-predominant sample. Symptom onset is often within 2 h postprandial, but some foods were associated with a delayed response, possibly an important consideration in implementing dietary recommendations. Clinical trials must test the causality of the demonstrated food-symptom associations.

Effects on Serum Hormone Concentrations after a Dietary Phytoestrogen Intervention in Patients with Prostate Cancer: A Randomized Controlled Trial.

Phytoestrogens have been suggested to have an anti-proliferative role in prostate cancer, potentially by acting through estrogen receptor beta (ERß) and modulating several hormones. We primarily aimed to investigate the effect of a phytoestrogen intervention on hormone concentrations in blood depending on the ERß genotype. Patients with low and intermediate-risk prostate cancer, scheduled for radical prostatectomy, were randomized to an intervention group provided with soybeans and flaxseeds (∼200 mg phytoestrogens/d) added to their diet until their surgery, or a control group that was not provided with any food items. Both groups received official dietary recommendations. Blood samples were collected at baseline and endpoint and blood concentrations of different hormones and phytoestrogens were analyzed. The phytoestrogen-rich diet did not affect serum concentrations of testosterone, insulin-like growth factor 1, or sex hormone-binding globulin (SHBG). However, we found a trend of decreased risk of increased serum concentration of estradiol in the intervention group compared to the control group but only in a specific genotype of ERß (p = 0.058). In conclusion, a high daily intake of phytoestrogen-rich foods has no major effect on hormone concentrations but may lower the concentration of estradiol in patients with prostate cancer with a specific genetic upset of ERß.

The effect of a phytoestrogen intervention and impact of genetic factors on tumor proliferation markers among Swedish patients with prostate cancer: study protocol for the randomized controlled PRODICA trial.

BACKGROUND: A high intake of phytoestrogens, found in soy, rye, and seeds, is associated with a reduced risk of a prostate cancer diagnosis. Previously, we found that the overall decreased risk of prostate cancer diagnosis in males with a high intake of phytoestrogens was strongly modified by a nucleotide sequence variant in the estrogen receptor-beta (ERß) gene. However, we do not know if phytoestrogens can inhibit the growth of prostate cancer in males with established diseases. If there is an inhibition or a delay, there is reason to believe that different variants of the ERß gene will modify the effect. Therefore, we designed an intervention study to investigate the effect of the addition of foods high in phytoestrogens and their interaction with the ERß genotype on prostate tumor proliferation in patients with prostate cancer. METHOD: The PRODICA trial is a randomized ongoing intervention study in patients with low- and intermediate-risk prostate cancer with a Gleason score < 8, prostate-specific antigen (PSA) < 20, and scheduled for radical prostatectomy. The study is conducted at Sahlgrenska University Hospital in Gothenburg, Sweden. The intervention consists of a daily intake of soybeans and flaxseeds (~ 200 mg of phytoestrogens) until the surgery, approximately 6 weeks. The aim is to recruit 200 participants. The primary outcome is the difference in the proliferation marker Ki-67 between the intervention and the control groups. The genotype of ERß will be investigated as an effect-modifying factor. Secondary outcomes include, e.g., concentrations of PSA and steroid hormones in the blood. DISCUSSION: The results of the PRODICA trial will contribute important information on the relevance of increasing the intake of phytoestrogens in patients with prostate cancer who want to make dietary changes to improve the prognosis of their cancer. If genetic factors turn out to influence the effect of the intervention diet, dietary advice can be given to patients who most likely benefit from it. Dietary interventions are cost-effective, non-invasive, and result in few mild side effects. Lastly, the project will provide basic pathophysiological insights which could be relevant to the development of treatment strategies for patients with prostate cancer. CLINICALTRIALS: gov NCT02759380. Registered on 3 May 2016.

Low FODMAP diet reduces gastrointestinal symptoms in irritable bowel syndrome and clinical response could be predicted by symptom severity: A randomized crossover trial.

BACKGROUND & AIMS: Fermentable oligo-, di-, monosaccharides and polyols (FODMAPs) can provoke symptoms in patients with irritable bowel syndrome (IBS). We aimed to compare the effects of diets with low vs. moderate FODMAP content on gastrointestinal (GI) symptoms and bowel habits, and to identify possible predictors of clinical response to a low FODMAP diet and FODMAP sensitivity in IBS. METHODS: Adult participants with IBS (Rome IV criteria, n = 29) were included and adhered to two 7-day diet periods, with either low (4 g/day) or moderate (23 g/day) amounts of FODMAPs, in this randomized, double-blind, crossover study. The periods were separated by a wash-out period (≥14 days). IBS-Severity Scoring System (IBS-SSS) and a stool diary (Bristol Stool Form) were completed before and after the diet periods. At baseline, severity of GI symptoms and gut microbial fermentation were assessed (every 15 min, 4 h) during the Lactulose Nutrient Challenge Test (LNCT). Clinical response and FODMAP sensitivity were defined by reduction after low FODMAP period, and increase after moderate FODMAP period in IBS-SSS (≥50 points), respectively. RESULTS: Severity of GI symptoms (P = 0.04), stool consistency (P = 0.01), and stool frequency (P = 0.01) differed between the interventions, with reduced overall GI symptom severity, abdominal pain intensity and frequency, bowel habits dissatisfaction, and daily life interference (P < 0.05 for all), as well as more firm (P = 0.03) and less frequent (P < 0.01) stools after low FODMAP intervention, but not after moderate FODMAP intervention. A third (34%) responded clinically to the low FODMAP diet, and the response could be predicted by higher IBS-SSS at baseline (P = 0.02). Although modest associations between FODMAP sensitivity (22%) and GI symptoms during LNCT were observed, no independent predictors could be identified. CONCLUSIONS: A diet low in FODMAPs reduces GI symptoms and affects bowel habits in IBS, compared with a moderate FODMAP diet. Assessment of IBS severity before the intervention may be used to predict clinical response to a low FODMAP diet. Trial registry (http://www. CLINICALTRIALS: gov): Registered under Clinical Trial number NCT05182593.

Predictors of Symptom-Specific Treatment Response to Dietary Interventions in Irritable Bowel Syndrome.

(1) Background: Predictors of dietary treatment response in irritable bowel syndrome (IBS) remain understudied. We aimed to investigate predictors of symptom improvement during the low FODMAP and the traditional IBS diet for four weeks. (2) Methods: Baseline measures included faecal Dysbiosis Index, food diaries with daily energy and FODMAP intake, non-gastrointestinal (GI) somatic symptoms, GI-specific anxiety, and psychological distress. Outcomes were bloating, constipation, diarrhea, and pain symptom scores treated as continuous variables in linear mixed models. (3) Results: We included 33 and 34 patients on the low FODMAP and traditional IBS diet, respectively. Less severe dysbiosis and higher energy intake predicted better pain response to both diets. Less severe dysbiosis also predicted better constipation response to both diets. More severe psychological distress predicted worse bloating response to both diets. For the different outcomes, several differential predictors were identified, indicating that baseline factors could predict better improvement in one treatment arm, but worse improvement in the other treatment arm. (4) Conclusions: Psychological, nutritional, and microbial factors predict symptom improvement when following the low FODMAP and traditional IBS diet. Findings may help individualize dietary treatment in IBS.

The Role of Carbohydrates in Irritable Bowel Syndrome: Protocol for a Randomized Controlled Trial Comparing Three Different Treatment Options.

BACKGROUND: Although it is widely acknowledged that food intake can worsen symptoms in patients with irritable bowel syndrome (IBS), there is a lack of efficient treatments that can apply to all patients and subtypes of IBS. As IBS can manifest in different ways, it is likely that the most successful treatment option will differ among patients; therefore, this large, randomized controlled trial comparing 3 different treatment options for patients with IBS is highly warranted. OBJECTIVE: This study aims to conduct a randomized controlled trial to evaluate the effectiveness of 3 different treatment options for patients with IBS. METHODS: A total of 300 patients with IBS will be randomized (1:1:1) to receive one of the following three treatment options: a diet with low total carbohydrate content; a diet combining low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols and traditional dietary advice in IBS; and optimized medical treatment. The study will comprise a 10-day screening period, 28 days of intervention, and a 6-month follow-up for patients receiving dietary treatment. Questionnaires assessing both gastrointestinal and extraintestinal symptoms will be used as end points, as well as metabolomics, microbiota profiling, and immunological markers. Furthermore, qualitative methods will be used to evaluate the patients' experiences regarding diet treatments. RESULTS: Recruitment for this study began in January 2017. By May 2021, of the proposed 300 participants, 270 (90%) had been randomized, and 244 (81.3%) participants had finished the 4-week intervention. The study is still in progress, and the results are expected to be published in 2022. CONCLUSIONS: By collecting a wide range of data before, during, and after treatment in a large group of patients with IBS and diverse bowel habits, we will gain new insights into the predictors of response to treatment. That information can, in the future, be used to personalize treatment for the patient, based on the individual's phenotype and IBS symptoms. In addition, the long-term effects of 2 different dietary treatments will be evaluated regarding their impact on gut microbiota and clinical laboratory tests and to ensure that they are safe, effective, and applicable for patients with IBS. TRIAL REGISTRATION: ClinicalTrials.gov NCT02970591; https://clinicaltrials.gov/ct2/show/NCT02970591. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31413.

Changes in serum and urinary metabolomic profile after a dietary intervention in patients with irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a multi-faceted gastrointestinal disorder where food intake often triggers symptoms. Metabolomics may provide mechanistical insights to why responses to dietary modifications are diverse. OBJECTIVE: This study aimed to identify metabolite patterns related to dietary intake in patients with IBS, and to identify metabolites driving the separation between responders and non-responders to treatment. METHODS: Participants were randomized to a low fermentable oligo-, di-, monosaccharide and polyol (FODMAP) diet (LFD) or traditional IBS diet (TID) for four weeks. Fasting serum and urine samples pre- and post-intervention were analyzed using 1H nuclear magnetic resonance (NMR) metabolomics. Response to treatment was defined as a reduction in IBS severity scoring system (IBS-SSS) ≥50. RESULTS: Twenty-five individuals in the LFD (13 responders) and 28 in the TID (14 responders) were included in these post hoc analyses. In endpoint samples, significant decreases in polyols and glucose were seen in the LFD. Post-intervention samples revealed that LFD responders had significantly increased levels of 2-hydroxybuturate and decreased levels of glucose and pantothenic acid compared to non-responders. For the TID, only weak multivariate models were identified and a larger diversity in metabolite response compared to the LFD were noted. CONCLUSIONS: In this study, metabolite patterns between individuals who responded well to an LFD compared to non-responders could be distinguished. This provides new hypotheses for mechanistic actions related to response to dietary modifications, but the results need to be validated in larger cohorts. CLINICAL TRIAL REGISTRATION: This trial was registered at www.clinicaltrials.gov, registry number NCT02107625.

Habitual FODMAP Intake in Relation to Symptom Severity and Pattern in Patients with Irritable Bowel Syndrome.

Restricting intake of FODMAPs (Fermentable Oligo-, Di-, Monosaccharides and Polyols) is used as treatment for irritable bowel syndrome (IBS). However, whether habitual FODMAP consumption correlates to symptom severity, and if this relationship differs among IBS subtypes, is unclear. The aim was to study the relationship between habitual FODMAP intake and symptom severity. A total of 189 patients with IBS-IBS with constipation (IBS-C) n = 44 (22.3%), IBS with diarrhea (IBS-D) n = 54 (27.4%), mixed IBS (IBS-M) n = 46 (23.4%) and unsubtyped IBS (IBS-U) n = 46 (23.4%)-recorded food intake during four days. Symptom severity was measured with the IBS severity scoring system (IBS-SSS). For FODMAP intake, a lower lactose intake was noted among women with IBS-D, p = 0.009. In women, there was a statistically significant relationship between energy-adjusted FODMAP intake and IBS-SSS (r = 0.21, p = 0.003). This was mainly driven by the subtype IBS-U, where excess fructose intake accounted for 19.9% of explained variance in IBS-SSS (p = 0.007). This study demonstrates small differences in FODMAP intake among IBS patients with different subtypes. Association between IBS symptoms and FODMAP intake was most prominent in unsubtyped IBS. However, patients who are intolerant to certain FODMAPs may already have reduced their FODMAP intake, and this warrants future cohort or experimental studies to uncover.

Within- and Between-Subject Variation in Dietary Intake of Fermentable Oligo-, Di-, Monosaccharides, and Polyols Among Patients with Irritable Bowel Syndrome.

BACKGROUND: A diet low in fermentable carbohydrates, fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs) is a promising treatment option for patients with irritable bowel syndrome (IBS). In order to correctly estimate and study the intake of FODMAPs, information about within- and between-subject variations in intakes is needed, but is currently lacking. OBJECTIVES: The aim was to characterize the variation in FODMAP intake among patients with IBS and to calculate how many days of observations are required to capture absolute intakes as well as to rank individuals. METHODS: Food intake was recorded during 4 consecutive days, and intakes of energy and FODMAPs were calculated. The coefficient of variation within subjects (CVw), coefficient of variation between subjects (CVb), number of days required to estimate an individual's intake, and number of observations required to correctly rank individuals into quartiles of consumption were calculated. RESULTS: Diet records were provided from 151 women and 46 men with IBS. The reported mean energy intake was 2039 ± 502 kcal among women and 2385 ± 573 kcal among men, and the median FODMAP intakes were 18.7 g (range 3.7-73.4) and 22.8 g (range 3.6-165.7), respectively. The ratio of CVw/CVb for total FODMAP intake was 0.83 for women and 0.67 for men, and below 1 for all FODMAPs. To capture intake of FODMAPs at the individual level, 19 d of observations are required. Ranking individuals within a group would require 2-6 d of observations. CONCLUSION: There is more variation between subjects than within subjects regarding FODMAP intake. To correctly estimate an individual's absolute intake of FODMAPs, the number of days of diet records required exceeds what is reasonable for a participant to accomplish. However, ranking individuals into quartiles of FODMAP consumption can be achieved using a 4-d food record. This trial was registered at www.clinicaltrials.gov as NCT02107625 and NCT01252550.

New alkylresorcinol metabolites in spot urine as biomarkers of whole grain wheat and rye intake in a Swedish middle-aged population.

BACKGROUND/OBJECTIVES: Studies on the health effects of whole grains typically use self-reported intakes which are prone to large measurement errors. Dietary biomarkers that can provide an objective measure of intake are needed. New alkylresorcinol (AR) metabolites (3,5-dihydroxycinnamic acid (DHCA), 2-(3,5-dihydroxybenzamido)acetic acid (DHBA-glycine) and 5-(3,5-dihydroxyphenyl) pentanoic acid (DHPPTA)) in 24 h urine samples have been suggested as biomarkers for whole grain (WG) wheat and rye intake but remain to be evaluated in spot urine samples. SUBJECTS/METHODS: The reproducibility of the new AR metabolites (DHCA, DHBA-glycine and DHPPTA) was investigated in 4 repeated samples over a period of 2 wk in spot urine from 40 Swedish men and women enroled in the SCAPIS-study, after adjustment of creatinine. Metabolite concentrations were correlated with total whole grain intake estimated during the same period. RESULTS: The medium-term reproducibility determined for DHCA, DHPPTA and DHBA-glycine varied from moderate to excellent (intra-class correlation coefficient = 0.35-0.67). Moreover, DHCA and DHBA-glycine were independently associated with self-reported total WG intake (ß = 0.18, P = 0.08 and ß = 0.18, P = 0.02, respectively) and all metabolites except for DHPPA were higher among women. CONCLUSIONS: This study supports the idea of using AR metabolites in one or several spot urine samples as biomarkers of whole grain intake. These findings need to be confirmed in different populations.

Validity of a web-based dietary questionnaire designed especially to measure the intake of phyto-oestrogens.

A diet questionnaire (DQ) designed to assess habitual diet and phyto-oestrogen intake was developed. This study aimed to examine the validity of the DQ in men, with and without having prostate cancer. The DQ was validated against alkylresorcinol metabolites measured in urine as objective biomarkers of whole grain wheat and rye (WG) intake, and a 4-d estimated food record (FR) was used for relative comparison. Participants (n 61) completed both methods and provided spot urine samples. We found a statistically significant correlation between the DQ and FR for reported whole grain intake and isoflavonoids, as well as for intake of macronutrients, except protein. The correlation coefficient between the two methods was on average r 0·30, lowest for lignans (r -0·11) and highest for alcohol (r 0·65). Reported energy intake was lower in the DQ compared with FR (8523 v. 9249 kJ (2037 v. 2211 kcal), respectively; P = 0·014). Bland-Altman plots showed an acceptable agreement; most cases were within the limits (95 % CI) of agreement on reported energy intake, as well as intake of macronutrients, except protein (which was underestimated in the DQ compared with the FR). The correlation of alkylresorcinol with WG intake was statistically significant in the DQ (r 0·31, P = 0·015), but not in the FR (r 0·18, P = 0·12) and the weighted κ was 0·29 and 0·11, respectively. In conclusion, the results showed that the DQ have a reasonable validity for measuring WG intake and most nutrients, and, after some adjustments regarding protein intake assessment have been made, the DQ will be a promising tool.

Comparison of a web-based food record tool and a food-frequency questionnaire and objective validation using the doubly labelled water technique in a Swedish middle-aged population.

Two web-based dietary assessment tools have been developed for use in large-scale studies: the Riksmaten method (4-d food record) and MiniMeal-Q (food-frequency method). The aim of the present study was to examine the ability of these methods to capture energy intake against objectively measured total energy expenditure (TEE) with the doubly labelled water technique (TEEDLW), and to compare reported energy and macronutrient intake. This study was conducted within the pilot study of the Swedish CArdioPulmonary bioImage Study (SCAPIS), which included 1111 randomly selected men and women aged 50-64 years from the Gothenburg general population. Of these, 200 were enrolled in the SCAPIS diet substudy. TEEDLW was measured in a subsample (n 40). Compared with TEEDLW, both methods underestimated energy intake: -2·5 (sd  2·9) MJ with the Riksmaten method; -2·3 (sd 3·6) MJ with MiniMeal-Q. Mean reporting accuracy was 80 and 82 %, respectively. The correlation between reported energy intake and TEEDLW was r 0·4 for the Riksmaten method (P < 0·05) and r 0·28 (non-significant) for MiniMeal-Q. Women reported similar average intake of energy and macronutrients in both methods whereas men reported higher intakes with the Riksmaten method. Energy-adjusted correlations ranged from 0·14 (polyunsaturated fat) to 0·77 (alcohol). Bland-Altman plots showed acceptable agreement for energy and energy-adjusted protein and carbohydrate intake, whereas the agreement for fat intake was poorer. According to energy intake data, both methods displayed similar precision on energy intake reporting. However, MiniMeal-Q was less successful in ranking individuals than the Riksmaten method. The development of methods to achieve limited under-reporting is a major challenge for future research.