A low FODMAP diet plus traditional dietary advice versus a low-carbohydrate diet versus pharmacological treatment in irritable bowel syndrome (CARBIS): 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.

Development of celiac-safe foods: prevention of transglutaminase 2 (TG2) deamidation of gluten in healthy non-celiac volunteers.

In celiac disease, intestinal transglutaminase (TG2) produces immunogenic peptides by deamidation of gluten proteins. These products drive the celiac immune response. We have previously identified an interaction between gliadin and a food additive, E304i, which prevents gliadin processing (both deamidation and transamidation) by TG2, in vitro. In this study, we investigated if E304i could prevent TG2 processing of gluten in flours and if the effect was evident after simulated gastrointestinal digestion. We also confirmed the outcome in vivo in a human cross-over intervention study in healthy non-celiac participants. TG2 transamidation experiments (in vitro) of digested wheat and rye flours supplemented with E304i at 30 mg/g indicated full prevention of TG2 processing. In the intervention study, participant serum levels of deamidated gliadin peptides (dGDPs) increased after the intake of reference wheat rolls (80 g per day for a week; 41% ± 4% compared to washout), while the intake of the intervention E304i/zinc sulfate wheat rolls generated a modest response (80 g per day for a week; 8 ± 10% of control). The difference between the groups (32.8 ± 15.6%) was significant (p = 0.00003, n = 9), confirming that E304i /zinc addition to wheat rolls prevented TG2 deamidation of gluten. In conclusion, this study shows that E304i /zinc addition to wheat rolls prevents TG2 deamidation of gluten in non-celiac participants. Clinical trial registration: clinicaltrials.gov, identifier (NCT06005376).

Structural enrichment for laboratory mice: exploring the effects of novelty and complexity.

Providing structural enrichment is a widespread refinement method for laboratory rodents and other animals in captivity. So far, animal welfare research has mostly focused on the effect of increased complexity either by accumulating or combining different enrichment items. However, increasing complexity is not the only possibility to refine housing conditions. Another refinement option is to increase novelty by regularly exchanging known enrichment items with new ones. In the present study, we used pair-housed non-breeding female C57BL/6J and DBA/2N mice to investigate the effect of novelty when applying structural enrichment. We used a double cage system, in which one cage served as home cage and the other as extra cage. While the home cage was furnished in the same way for all mice, in the extra cage we either provided only space with no additional enrichment items (space), a fixed set of enrichment items (complexity), or a changing set of enrichment items (novelty). Over 5 weeks, we assessed spontaneous behaviors, body weight, and extra cage usage as indicators of welfare and preference. Our main results showed that mice with access to structurally enriched extra cages (complexity and novelty) spent more time in their extra cages and complexity mice had lower latencies to enter their extra cages than mice with access to the extra cages without any structural enrichment (space). This indicates that the mice preferred the structurally enriched extra cages over the structurally non-enriched space cages. We found only one statistically significant difference between the novelty and complexity condition: during week 3, novelty mice spent more time in their extra cages than complexity mice. Although we did not detect any other significant differences between the novelty and complexity condition in the present study, more research is required to further explore the potential benefits of novelty beyond complexity.

Transcriptional profiles in the mouse amygdala after a cognitive judgment bias test largely depend on the genotype.

Background: The amygdala is crucial for emotional cognitive processing. Affective or emotional states can bias cognitive processes, including attention, memory, and decision-making. This can result in optimistic or pessimistic behaviors that are partially driven by the activation of the amygdala. The resulting emotional cognitive bias is a common feature of anxiety and mood disorders, both of which are interactively influenced by genetic and environmental factors. It is also known that emotional cognitive biases can be influenced by environmental factors. However, little is known about the effects of genetics and/or gene-environment interactions on emotional cognitive biases. We investigated the effects of the genetic background and environmental enrichment on the transcriptional profiles of the mouse amygdala following a well-established cognitive bias test. Methods: Twenty-four female C57BL/6J and B6D2F1N mice were housed either in standard (control) conditions or in an enriched environment. After appropriate training, the cognitive bias test was performed on 19 mice that satisfactorily completed the training scheme to assess their responses to ambiguous cues. This allowed us to calculate an "optimism score" for each mouse. Subsequently, we dissected the anterior and posterior portions of the amygdala to perform RNA-sequencing for differential expression and other statistical analyses. Results: In general, we found only minor changes in the amygdala's transcriptome associated with the levels of optimism in our mice. In contrast, we observed wide molecular effects of the genetic background in both housing environments. The C57BL/6J animals showed more transcriptional changes in response to enriched environments than the B6D2F1N mice. We also generally found more dysregulated genes in the posterior than in the anterior portion of the amygdala. Gene set overrepresentation analyses consistently implicated cellular metabolic responses and immune processes in the differences observed between mouse strains, while processes favoring neurogenesis and neurotransmission were implicated in the responses to environmental enrichment. In a correlation analysis, lipid metabolism in the anterior amygdala was suggested to influence the levels of optimism. Conclusions: Our observations underscore the importance of selecting appropriate animal models when performing molecular studies of affective conditions or emotional states, and suggest an important role of immune and stress responses in the genetic component of emotion regulation.

Once an optimist, always an optimist? Studying cognitive judgment bias in mice.

Individuals differ in the way they judge ambiguous information: some individuals interpret ambiguous information in a more optimistic, and others in a more pessimistic way. Over the past two decades, such "optimistic" and "pessimistic" cognitive judgment biases (CJBs) have been utilized in animal welfare science as indicators of animals' emotional states. However, empirical studies on their ecological and evolutionary relevance are still lacking. We, therefore, aimed at transferring the concept of "optimism" and "pessimism" to behavioral ecology and investigated the role of genetic and environmental factors in modulating CJB in mice. In addition, we assessed the temporal stability of individual differences in CJB. We show that the chosen genotypes (C57BL/6J and B6D2F1N) and environments ("scarce" and "complex") did not have a statistically significant influence on the responses in the CJB test. By contrast, they influenced anxiety-like behavior with C57BL/6J mice and mice from the "complex" environment displaying less anxiety-like behavior than B6D2F1N mice and mice from the "scarce" environment. As the selected genotypes and environments did not explain the existing differences in CJB, future studies might investigate the impact of other genotypes and environmental conditions on CJB, and additionally, elucidate the role of other potential causes like endocrine profiles and epigenetic modifications. Furthermore, we show that individual differences in CJB were repeatable over a period of seven weeks, suggesting that CJB represents a temporally stable trait in laboratory mice. Therefore, we encourage the further study of CJB within an animal personality framework.

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.

Aloe barbadensis Mill. extract improves symptoms in IBS patients with diarrhoea: post hoc analysis of two randomized double-blind controlled studies.

BACKGROUND: Aloe barbadensis Mill. (Aloe) extract was found to be well-tolerated, safe and showed beneficial effects in subsets of irritable bowel syndrome (IBS) patients in two randomized, double-blind, controlled studies. However, the individual studies were underpowered to perform subgroup analyses. We therefore determined the effect of Aloe extract in IBS subgroups in a post hoc analysis combining the results from the two studies. METHODS: Data from the two controlled studies comparing Aloe and control treatment taken orally for 4 weeks, were pooled. Both studies included IBS patients fulfilling the ROME III criteria and IBS Symptom Severity Score (IBS-SSS) was assessed. We analysed the effect of Aloe extract on IBS symptom severity and the proportion of responders (IBS-SSS reduction ⩾ 50) in IBS subgroups. RESULTS: In total, 213 IBS patients were included in the post hoc subgroup analyses. A reduction in overall symptom severity, primarily driven by effect on pain severity and frequency, comparing baseline versus end of treatment, was recorded in IBS patients with diarrhoea (IBS-D) receiving Aloe (n = 38, p < 0.001) but not control treatment (n = 33, p = 0.33), with difference between the treatment groups (p = 0.01). Moreover, the frequency of responders was higher in IBS-D patients receiving Aloe (n = 22, 58%) compared to control treatment (n = 10, 30%) (p = 0.02). The effect of Aloe extract treatment on IBS symptom severity was not superior to control treatment in the other IBS subtypes. CONCLUSION: Aloe extract improves symptom severity in IBS-D patients and can be regarded as a safe and effective treatment option for this patient group.

A randomized double-blind placebo-controlled crossover pilot study: Acute effects of the enzyme α-galactosidase on gastrointestinal symptoms in irritable bowel syndrome patients.

BACKGROUND: Postprandial symptoms presumably related to intestinal gas production are common in patients with irritable bowel syndrome (IBS). The aim of the study was to assess if oral α-galactosidase is superior to placebo in reducing gastrointestinal (GI) symptoms and intestinal gas production after ingestion of carbohydrate-rich meals in adult patients with IBS. METHODS: We studied the effect of 1200 GaIU/meal α-galactosidase (Nogasin® ) or placebo capsules on GI symptoms in patients with IBS after three standardized, meals high in oligosaccharides, in a randomized, double-blind, crossover study. The intensity of eight GI symptoms was rated, and breath hydrogen and methane were measured every 30 min during 7.5 h. The severity of GI symptoms the following morning was assessed and compared with baseline. S KEY RESULTS: Twenty adult patients with IBS (19 females), mean age 49 years (range 22-75 years), were included. All test meals were well tolerated but induced a gradual increase in GI symptom severity. Neither GI symptom ratings over time, nor hydrogen and methane concentrations differed between the days with α-galactosidase or placebo. The severity of abdominal pain and bloating was lower the following morning, but with no differences between α-galactosidase and placebo. CONCLUSIONS & INFERENCES: The use of α-galactosidase together with meals high in oligosaccharides was in this pilot study not superior to placebo in reducing postprandial GI symptoms or the concentration of hydrogen and methane in expired air in IBS.

Randomized clinical trial: Effects of Aloe barbadensis Mill. extract on symptoms, fecal microbiota and fecal metabolite profiles in patients with irritable bowel syndrome.

BACKGROUND: Aloe barbadensis Mill. (Aloe) with potential prebiotic effects has been suggested to reduce symptoms in patients with irritable bowel syndrome (IBS). We therefore aimed to determine the effects of an Aloe extract on symptoms of IBS, and evaluate whether effects may be mediated by fecal microbiota and metabolites in a randomized, double-blind, controlled trial. METHODS: Patient with IBS diagnosed according to the ROME III criteria (all subtypes), received Aloe or control treatment (inulin) for 4 weeks. IBS Symptom Severity Score (IBS-SSS) was assessed, and fecal samples collected before and at end of treatment. Fecal microbiota composition and metabolomic profile were determined. KEY RESULTS: In total, 160 IBS patients completed the study. The overall severity of IBS symptoms was reduced in both Aloe and control treatment groups (P < .001, both groups, comparing baseline vs end of treatment), without difference between groups (P = .62). The frequency of responders (IBS-SSS reduction ≥ 50) did not differ between Aloe treatment (n = 33, 39%) and control (n = 34, 45%) (P = .49). However, fecal microbiota and metabolite profiles differed between Aloe, but not control treatment responders and non-responders both before and after treatment. CONCLUSION: In a mixed group of IBS patients, Aloe was not superior to control treatment, although it showed potential to reduce IBS symptom severity in subsets of IBS patients which could be predicted by fecal microbiota and metabolite profiles. ClinicalTrials.gov no: NCT01400048.

Adherence to diet low in fermentable carbohydrates and traditional diet for irritable bowel syndrome.

OBJECTIVES: Dietary interventions in irritable bowel syndrome (IBS) include a traditional IBS diet following the guidelines from the National Institute for Health and Clinical Excellence and a diet low in fermentable oligo-, di-, monosaccharides and polyols (FODMAPs). The aim of this study was to evaluate the adherence to these diets, food groups difficult to replace, and dietary determinants of symptom improvement. METHODS: Sixty-six patients with IBS were randomized to a 4-wk low FODMAP or traditional IBS diet. Participants completed 4-d diet diaries before and during the intervention and reported symptoms on the IBS severity scoring system. We described adherence to the diets on the food group and product level and investigated the association between adherence and symptom improvement. RESULTS: Adherence to the low FODMAP diet was good and consistent: All participants had a comparable shift in the diet's principal components compatible with the guidelines. Most high FODMAP products were well replaced with low FODMAP equivalents. However, total energy intake fell by 25%, mainly owing to a 69% decreased intake of snacks (P < 0.001). The traditional IBS diet did not shift the diet's principal components, and despite the guidelines, consumption of coffee and alcoholic beverages remained rather high (>50% of baseline). Total energy intake fell by 11% (P = 0.15). For both diets, there was a trend toward an association between adherence and symptom improvement (P < 0.10). CONCLUSION: In both the low FODMAP and traditional IBS diet, certain food groups were difficult to replace. Because adherence may predict symptom improvement, close dietary guidance might enhance the efficacy of both diets.

Multivariate modelling of faecal bacterial profiles of patients with IBS predicts responsiveness to a diet low in FODMAPs.

OBJECTIVE: The effects of dietary interventions on gut bacteria are ambiguous. Following a previous intervention study, we aimed to determine how differing diets impact gut bacteria and if bacterial profiles predict intervention response. DESIGN: Sixty-seven patients with IBS were randomised to traditional IBS (n=34) or low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) (n=33) diets for 4 weeks. Food intake was recorded for 4 days during screening and intervention. Faecal samples and IBS Symptom Severity Score (IBS-SSS) reports were collected before (baseline) and after intervention. A faecal microbiota dysbiosis test (GA-map Dysbiosis Test) evaluated bacterial composition. Per protocol analysis was performed on 61 patients from whom microbiome data were available. RESULTS: Responders (reduced IBS-SSS by ≥50) to low FODMAP, but not traditional, dietary intervention were discriminated from non-responders before and after intervention based on faecal bacterial profiles. Bacterial abundance tended to be higher in non-responders to a low FODMAP diet compared with responders before and after intervention. A low FODMAP intervention was associated with an increase in Dysbiosis Index (DI) scores in 42% of patients; while decreased DI scores were recorded in 33% of patients following a traditional IBS diet. Non-responders to a low FODMAP diet, but not a traditional IBS diet had higher DI scores than responders at baseline. Finally, while a traditional IBS diet was not associated with significant reduction of investigated bacteria, a low FODMAP diet was associated with reduced Bifidobacterium and Actinobacteria in patients, correlating with lactose consumption. CONCLUSIONS: A low FODMAP, but not a traditional IBS diet may have significant impact on faecal bacteria. Responsiveness to a low FODMAP diet intervention may be predicted by faecal bacterial profiles. TRIAL REGISTRATION NUMBER: NCT02107625.

Divergence of developmental trajectories is triggered interactively by early social and ecological experience in a cooperative breeder.

Cooperative breeders feature the highest level of social complexity among vertebrates. Environmental constraints foster the evolution of this form of social organization, selecting for both well-developed social and ecological competences. Cooperative breeders pursue one of two alternative social trajectories: delaying reproduction to care for the offspring of dominant breeders or dispersing early to breed independently. It is yet unclear which ecological and social triggers determine the choice between these alternatives and whether diverging developmental trajectories exist in cooperative vertebrates predisposing them to dispersal or philopatry. Here we experimentally reared juveniles of cooperatively breeding cichlid fish by varying the social environment and simulated predation threat in a two-by-two factorial long-term experiment. First, we show that individuals develop specialized behavioral competences, originating already in the early postnatal phase. Second, these specializations predisposed individuals to pursue different developmental trajectories and either to disperse early or to extend philopatry in adulthood. Thus, our results contrast with the proposition that social specializations in early ontogeny should be restricted to eusocial species. Importantly, social and ecological triggers were both required for the generation of divergent life histories. Our results thus confirm recent predictions from theoretical models that organisms should combine relevant information from different environmental cues to develop integrated phenotypes.

Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: a randomized controlled trial.

BACKGROUND & AIMS: A diet with reduced content of fermentable short-chain carbohydrates (fermentable oligo-, di-, monosaccharides, and polyols [FODMAPs]) has been reported to be effective in the treatment of patients with irritable bowel syndrome (IBS). However, there is no evidence of its superiority to traditional dietary advice for these patients. We compared the effects of a diet low in FODMAPs with traditional dietary advice in a randomized controlled trial of patients with IBS. METHODS: We performed a multi-center, parallel, single-blind study of 75 patients who met Rome III criteria for IBS and were enrolled at gastroenterology outpatient clinics in Sweden. Subjects were randomly assigned to groups that ate specific diets for 4 weeks-a diet low in FODMAPs (n = 38) or a diet frequently recommended for patients with IBS (ie, a regular meal pattern; avoidance of large meals; and reduced intake of fat, insoluble fibers, caffeine, and gas-producing foods, such as beans, cabbage, and onions), with greater emphasis on how and when to eat rather than on what foods to ingest (n = 37). Symptom severity was assessed using the IBS Symptom Severity Scale, and patients completed a 4-day food diary before and at the end of the intervention. RESULTS: A total of 67 patients completed the dietary intervention (33 completed the diet low in FODMAPs, 34 completed the traditional IBS diet). The severity of IBS symptoms was reduced in both groups during the intervention (P < .0001 in both groups before vs at the end of the 4-week diet), without a significant difference between the groups (P = .62). At the end of the 4-week diet period, 19 patients (50%) in the low-FODMAP group had reductions in IBS severity scores ≥50 compared with baseline vs 17 patients (46%) in the traditional IBS diet group (P = .72). Food diaries demonstrated good adherence to the dietary advice. CONCLUSIONS: A diet low in FODMAPs reduces IBS symptoms as well as traditional IBS dietary advice. Combining elements from these 2 strategies might further reduce symptoms of IBS. ClinicalTrials.gov ID NCT02107625.

Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life.

OBJECTIVES: Despite the fact that food and diet are central issues, that concern patients with irritable bowel syndrome (IBS), the current understanding about the association between the intake of certain foods/food groups and the gastrointestinal (GI) symptom pattern, psychological symptoms, and quality of life is poor. The aim of this study was to determine which food groups and specific food items IBS patients report causing GI symptoms, and to investigate the association with GI and psychological symptoms and quality of life. METHODS: We included 197 IBS patients (mean age 35 (18-72) years; 142 female subjects) who completed a food questionnaire in which they specified symptoms from 56 different food items or food groups relevant to food intolerance/allergy. The patients also completed questionnaires to assess depression and general anxiety (Hospital Anxiety and Depression), GI-specific anxiety (Visceral Sensitivity Index), IBS symptoms (IBS-Severity Scoring System), somatic symptoms (Patient Health Questionnaire-15), and quality of life (Irritable Bowel Syndrome Quality of Life Questionnaire). RESULTS: In all, 84% of the studied population reported symptoms related to at least one of the food items surveyed. Symptoms related to intake of food items with incompletely absorbed carbohydrates were noted in 138 (70%) patients; the most common were dairy products (49%), beans/lentils (36%), apple (28%), flour (24%), and plum (23%). Of these, 58% experienced GI symptoms from foods rich in biogenic amines, such as wine/beer (31%), salami (22%), and cheese (20%). Histamine-releasing foods, such as milk (43%), wine/beer (31%), and pork (21%), were also considered causes of symptoms in IBS patients. GI symptoms were also frequently reported after intake of fried and fatty foods (52%). With increasing IBS symptom severity, patients reported more food items responsible for their GI symptoms (P=0.004), and this was also found in patients with more severe somatic symptoms (P<0.0001). Women tended to report more food items causing symptoms than men (P=0.06). A high number of food items causing GI symptoms was also associated with reduced quality of life and this was significant for the following domains: sleep (r=-0.25; P=0.001), energy (r=-0.21; P=0.005), food (r=-0.29; P<0.001), social functioning (r=-0.23; P=0.001), and physical status (r=-0.16; P<0.05). However, the number of food items reported to provoke GI symptoms was unrelated to body mass index, age, IBS subtype, anxiety, depression, or GI-specific anxiety. CONCLUSIONS: The majority of IBS patients believe that certain food items are important triggers of their GI symptoms. This is especially true for foods containing carbohydrates and fat, and also may be relevant for histamine-releasing food items and foods rich in biogenic amines. Self-reported food intolerance is associated with high symptom burden and reduced quality of life.