Wide-scale profiling technologies including metabolomics broaden the possibility of novel discoveries related to the pathogenesis of type 2 diabetes (T2D). By applying non-targeted metabolomics approach, we investigated here whether serum metabolite profile predicts T2D in a well-characterized study population with impaired glucose tolerance by examining two groups of individuals who took part in the Finnish Diabetes Prevention Study (DPS); those who either early developed T2D (n = 96) or did not convert to T2D within the 15-year follow-up (n = 104). Several novel metabolites were associated with lower likelihood of developing T2D, including indole and lipid related metabolites. Higher indolepropionic acid was associated with reduced likelihood of T2D in the DPS. Interestingly, in those who remained free of T2D, indolepropionic acid and various lipid species were associated with better insulin secretion and sensitivity, respectively. Furthermore, these metabolites were negatively correlated with low-grade inflammation. We replicated the association between indolepropionic acid and T2D risk in one Finnish and one Swedish population. We suggest that indolepropionic acid, a gut microbiota-produced metabolite, is a potential biomarker for the development of T2D that may mediate its protective effect by preservation of β-cell function. Novel lipid metabolites associated with T2D may exert their effects partly through enhancing insulin sensitivity.

Background Irritable bowel syndrome (IBS) has been associated with diets rich in fermentable oligo-, di-, monosaccharides and polyols (FODMAPs), and gluten. Most previous studies have been single-blind and have focused on elimination of FODMAPs or provocation with single FODMAPs. The effect of gluten is unclear, large trials isolating the effect of gluten from that of FODMAPs are needed. Objective The aims of this study were to ensure high intakes of a wide range of FODMAPs, gluten, or placebo, and to evaluate the effects on IBS symptoms using the IBS severity scoring system (IBS-SSS). Methods The study was carried out with a double-blind, placebo-controlled, randomized three-way crossover design in a clinical facility in Uppsala in September 2018—June 2019. In all, 110 participants fulfilling the IBS Rome IV criteria, with moderate to severe IBS, were randomized; 103 (90 female, 13 male) completed the trial. Throughout, IBS participants maintained a diet with minimal FODMAP content and no gluten. Participants were block-randomized to one-week interventions with FODMAPs (50 g/day), gluten (17.3 g/day), or placebo, separated by one week washout. All participants who completed at least one intervention were included in the intention-to-treat analysis. Results In participants with IBS (n = 103), FODMAPs caused higher IBS-SSS scores (mean 240 [95% CI 222, 257]) than placebo (198 [180, 215]; 0.00056) or gluten (208 [190, 226]; P = 0.013); no differences were found between the placebo and gluten groups (P = 1.0). There were large inter-individual differences in IBS-SSS scores associated with treatment. No adverse events were reported. Conclusion In participants with IBS, FODMAPs had a modest effect on typical IBS symptoms, whereas gluten had no effect. The large inter-individual differences in responses to the interventions warrant further detailed studies to identify possible underlying causes and enable individual prediction of responses. Trial registration www.ClinicalTrials.gov (NCT03653689).

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INTRODUCTION: Altered bowel habits constitute a criterion of irritable bowel syndrome (IBS), with the Bristol Stool Form Scale (BSFS) as the recommended tool for assessment of fecal consistency. However, BSFS is devoid of a comprehensive objective evaluation in subjects with IBS. Therefore, we aimed to evaluate the concordance between subjective reporting of BSFS and objective stool water content in subjects with IBS. Furthermore, we evaluated whether intake of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) or gluten would affect stool water content. METHODS:Data from a previous crossover trial in IBS with 1-week provocations of FODMAPs, gluten, or placebo were subanalyzed. After each intervention, fecal consistency was subjectively assessed using the BSFS and stool samples were collected. The stool water content was analyzed, where £68.5% water content was classified as hard stool, while ‡78% was classified as diarrhea. RESULTS:BSFS correlated to stool water content (r 5 0.36, P < 0.0001). The BSFS score increased in parallel with increasing water content, but with considerable overlap between BSFS scores. Stool water content differed between the BSFS categories 1-2, 3-5, and 6-7 (hard, normal, and loose, respectively) (P < 0.0001). For BSFS categories 1-2, 77% had water content £68.5%, whereas for BSFS categories 6-7, 52% had water content ‡78%. There was no difference in stool water content after consumption of FODMAPs, gluten, or placebo (P 5 0.94).

Objectives Irritable bowel syndrome (IBS) symptoms have been associated with fermentable oligo-, di-, monosaccharides and polyols (FODMAPs) as well as gluten. We aimed to evaluate the effects of provocations with diets rich in such components on IBS symptoms. We further aimed to study effects of FODMAPs and gluten on microbiota and if the microbiota composition was related to the severity of IBS symptoms. Methods A double-blind, placebo-controlled, randomised three-way crossover design (n = 110) was conducted. From run-in and throughout the study, IBS subjects maintained a diet with minimal FODMAP content and no gluten. Participants were block-randomised to one-week interventions with FODMAPs (50 g/day), gluten (17.3 g/day) or placebo, separated by one week of wash-out. Fecal samples were collected after each study week and analyzed for gut microbiota composition by sequencing of 16S rRNA gene amplicons. IBS symptoms were monitored by the IBS severity scoring system (IBS-SSS). Results In subjects with moderate to severe IBS (n = 103), FODMAPs caused higher total IBS-SSS (mean [SE] = 240 [9]) than placebo (208 [9]; p = 0.00056) or gluten (198 [9]; p = 0.013), but with no difference between gluten and placebo (p = 1.0). Relative abundance of Anaerostipes, Bifidobacterium and Faecalibacterium were higher after FODMAP compared to placebo. We found no difference in gut microbiota composition between gluten and placebo and no significant correlations between genera and severity of IBS-SSS. Conclusions In subjects with IBS, FODMAPs had an adverse but modest effect on typical IBS symptoms, whereas gluten had no effect. The microbiota composition was affected by the FODMAP but not the gluten intervention, in comparison to placebo. None of these differences were correlated to the severity of symptoms reflected in IBS-SSS, suggesting no apparent link between gut microbiota composition and IBS symptoms following intervention. Funding Sources Formas and the Swedish Research Council.