Effects of FODMAPs and gluten on irritable bowel syndrome- from self-reported symptoms to molecular profiling

Irritable bowel syndrome (IBS) is a complex disorder of gut-brain interactions. The diagnosis of IBS is based on subjective reporting of abdominal pain and altered bowel habits in the absence of any clinical alterations of the gut or other pathological conditions. Dietary regimens for symptom management include a low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) diet and a gluten-free diet. However, scientific evidence supporting these dietary recommendations for managing IBS symptoms is weak: trials have been non-blinded and underpowered. While mechanistic understanding and objective markers of response remain scarce. Therefore, the aim of this thesis was to conduct a large double-blind study to investigate the effect of FODMAPs and gluten on symptomatic and molecular data including 16S rRNA analysis of the gut microbiota and metabolomics analyses, both at a group and subgroup (differential response) level. The resulting data served also to assess the accuracy of the Bristol Stool Form Scale (BSFS) used in IBS subtype diagnosis, and thus overcome the lack of objective evaluation of IBS symptoms.Trial data revealed that gluten caused no symptoms and FODMAPs triggered only modest symptoms of IBS, albeit with large inter-individual differences. Subjective reporting according to the BSFS conformed only modestly with stool water content in IBS, warranting caution towards IBS subtyping. FODMAPs increased saccharolytic microbial genera, phenolic-derived metabolites and 3-indolepropionate, but decreased bile acids. The genera Agathobacter, Anaerostipes, Fusicatenibacter, and Bifidobacterium correlated with increased plasma concentrations of phenolic-derived metabolites and 3-indolepropionate, i.e, metabolites related to decreased risk of incident type 2 diabetes and inflammation. Indeed, among FODMAP-related metabolites, only weak correlations to IBS symptoms were detected, as in the case of 3-indolepropionate to abdominal pain and interference with quality of life, warranting further investigation. Gluten displayed a modest effect on metabolites involved in lipid metabolism, including carnitine derivates, an acyl-CoA derivate, a medium-chain fatty acid, and an unknown lipid, but with no interpretable link to health.No molecular markers of a differential response were found, despite a comprehensive exploration with multiple analytical approaches. This could be explained by the absence of baseline variables, such as other omics layers or psychological factors, that could have determined the difference. In summary, the results indicate that gluten does not cause IBS symptoms. Moreover, the minor effect of FODMAPs on IBS symptoms must be weighed against their potential beneficial health effects. While the complexity of IBS likely explains the absence of molecular evidence for differential responses, such data analytical approach has potential where clear benefits of dietary interventions exist. Finally, the use of BSFS should include training for self-assessment, as a tool for subtyping IBS

Alkylresorcinoler som biomarkör för fullkornsintag av råg och vete i den finska förebyggande diabetesstudien

Type 2 diabetes (T2D) is a public health problem of great concern. Globally it is increasing and it generates a huge economic burden to society and problems for the individuals. Whole grain has shown to have a protective role against T2D in epide-miological studies and underlying mechanisms are poorly understood, but de-creased energy intake, higher insulin sensitivity and improved glucose tolerance have been suggested and partly confirmed in studies. Alkylresorcinols (AR) are phenolic lipids found in different homologs only in the outer parts of wheat and rye among commonly consumed foods. It is used as a biomarker of whole grain for rye and wheat intake. The Finnish Diabetes Prevention Study (DPS) started in 1993 with the purpose to evaluate if an intensive diet- and exercise program could pre-vent or delay T2D in persons with impaired glucose tolerance (IGT). The aim of this study was to investigate if there was a difference in whole grain cereal intake among non-diabetics and people who developed diabetes under a period of 8 years. A fraction of the subjects in the (DPS) was studied. The aim was also to investigate differences in whole grain intake between participants who got lifestyle intervention and those who did not. Plasma AR was measured and used as a proxy of whole grain rye and wheat intake. Quality control samples were included in each batch to ensure adequate precision. AR were extracted with diethyl ether and further cleaned up with solid phase extraction (SPE). AR were made more volatile through derivat-isation with trifluoroacetic anhydride (TFAA) and analyzed with gas chromatog-raphy-mass spectrometry (GC-MS). The coefficient of variation (CV) within batch-es were ≤ 9% and between batches ≤ 15% except of one homolog, C25. No signifi-cant difference was found in total AR concentration between the lifestyle interven-tion and control groups or between subjects who developed diabetes during follow up and non-diabetic controls. Even if there was no difference in plasma AR be-tween the lifestyle intervention- and control groups there was a significant differ-ence in fiber intake (p=0.001). The Finnish population consumes large amounts of whole grain in the form of rye bread. When the subjects were advised to raise their consumption of dietary fiber during the lifestyle intervention, it is likely they did this with other foods than rye and wheat sources. The main findings of this study were a positive correlation between the AR C17/C21 ratio and time to T2D diagno-sis (p=0.027) and the fact that the AR C17/C21 ratio was higher within non-diabetics than diabetics (p=0.025). This indicates that individuals with a high intake of whole grain rye develop T2D later than those with a low intake, or does not de-velop it at all, i.e. that whole grain rye is protective. This should be confirmed with more sophisticated analysis of data in the present study but that is out of scope for this study.Typ 2-diabetes är ett stort folkhälsoproblem. Prevalensen ökar globalt och genererar en stor ekonomisk kostnad för samhälle och lidande för individen. Det har i epide-miologiska studier visat sig att fullkorn skyddar mot typ 2-diabetes. Mekanismerna bakom fullkorns positiva inverkan är inte kartlagda men reducerat energiintag, ökad insulinkänslighet och ökad glukostolerans är faktorer som har föreslagits och delvis bekräftats i studier. Alkylresorsinoler (AR) är fenoliska lipider vilka endast finns i de yttersta skikten av råg och vete bland vanliga livsmedel. AR används idag som biomarkör av fullkornsintag av råg och vete. En finsk studie i förebyggande av diabetes, The Finnish Diabetes Prevention Study (DPS), startade 1993 med syfte att utvärdera ett intensivt diet- och träningsprogram för personer med nedsatt glukosto-lerans. Syftet med den här studien var att undersöka om det fanns en skillnad i full-kornsintag mellan de som inte utvecklat- och de som utvecklat typ 2 diabetes under en åtta års period. Studien gjordes på en del av deltagarna i DPS. Syftet var också att undersöka fullkornsintaget hos de som fick livsstils intervention och de som inte fick det. Fullkornsprodukterna råg och vete mättes genom AR i plasma. Kontroll-prover användes för att säkerställa precision. AR extraherades med dietyl eter och renades med fast-fas-extraktion. AR gjordes mer flyktiga med derivatisering av trifluoracetylacetat och analyserades med gas kromatografi-mass spektrometri (GC-MS). CV värdet av kontrollproverna inom batcherna var ≤ 9% och mellan batcherna ≤ 15% med undantag av homolog C25. Det var ingen signifikant skillnad mellan totala AR och interventionsgrupperna eller mellan totala AR och de som utvecklade diabetes och de som inte gjorde det. Även om det inte fanns en skillnad mellan AR intag och interventionsgrupperna fanns det en signifikant skillnad i fiberintag (p=0.001). Den finska populationen konsumerar mycket fullkorn och den största delen utgörs av rågbröd. När deltagarna fick rådet att öka sitt fiberintag gjordes det troligtvis genom andra källor än via råg- och vete produkter. De viktigaste fynden i denna studie är det positiva förhållandet mellan AR kvoten C17/C21 och tiden till att utveckla typ 2-diabetes (p=0.027) och den högre kvoten av C17/C21 hos icke diabetiker än diabetiker (p=0.025). Detta indikerar att individer med ett högt intag av fullkornsråg senare utvecklar typ 2 diabetes än de med ett lågt intag samt att en högre fullkornskonsumtion av råg kan förebygga en utveckling av diabetes typ 2. Resultaten bör bekräftas med mer avancerade analysmetoder men det ligger utanför detta kandidatarbete

Analys av vitamin B6 innehåll i bruna bönor från Öland : påverkan av sorter, odlingsår, odlingsområde och typ av gödsel

Legumes are nutritious and contribute to a sustainable food production system. In Sweden, brown beans (Phaseolus vulgaris L) are cultivated on Öland. Vitamin B6 is one of many nutrients found in brown beans and it works as a coenzyme in the metabolism in the human body. Vitamin B6 consist of pyridoxal (PL), pyridoxine (PN) and pyridoxamine (PM) and their phosphorylated forms PL-5-phosphate, PN-5-phosphate and PM-5-phosphate. Pyridoxine is in plants glycosylated (pyridoxine-5--D-glucoside) to 5-80 percent and this form has a reduced bioavailability in hu-mans. The aim of this study was to determine the content of vitamin B6 in brown beans from Öland and to find factors which influence the content. Consideration was taken to the factors cultivars, year of cultivation, geographical areas, and dif-ferent types of fertilizer. The total-, free-, glycosylated vitamin B6 as well as the water content were determined. In total 25 samples were analysed with HPLC with fluorescence detector. The content of vitamin B6 in brown beans was 0.32 0.02 mg/100g and on average 49 percent was glycosylated. There was no difference in the content of vitamin B6 between cultivars, geographical areas or types of fertiliz-er, but there was a difference between years. Vitamin B6 was higher 2008 com-pared to 2009. Glycosylated vitamin B6 was higher 2008 and 2010 compared to 2009 meanwhile there was no significant difference in free PN (all vitamers except glycosylated PN). The meteorological weather conditions were less beneficial for the beans 2008 and 2010 compared to 2009. Thereby, during less beneficial mete-orological weather conditions, the content of vitamin B6 increased by increased content of glycosylated pyridoxine. The water content was significantly higher in Katja compared to Karin, indicating on better water holding capacity (WHC). For Katja, there was a significant difference between years and water content. The chemical composition between cultivars and in cultivars between years (affected by weather) must be elucidated for an explanation of the difference in WHC.Baljväxter har ett högt näringsvärde och bidrar till en hållbar livsmedelsproduktion. I Sverige odlas bruna bönor (Phaseolus vulgaris L) på Öland. Vitamin B6 är ett av många näringsämnen i bruna bönor och det fungerar som ett koenzym i metabol-ismen i kroppen. Vitamin B6 består av pyridoxal (PL), pyridoxin (PN) och pyridox-amin (PM) och deras fosforylerade former PL-5-fosfat, PN-5-fosfat och PM-5-fosfat. Pyridoxin är i olika mängd glykosylerat i växter (pyridoxin-5--D-glukosid). Sett till totalhalten av vitamin B6 är 5-80 procent glykosylerat i växter. Syftet med studien var att bestämma innehållet av vitamin B6 i bruna bönor från Öland och hitta fak-torer som kan påverka innehållet. Faktorer som inkluderades var sort (Karin och Katja), odlingsår (2008-2010), geografiskt område för odling (Borgholm, Färjesta-den, Mörbylånga, Kastlösa, Degerhamn) och typ av gödsel (konst- eller naturgöd-sel). Den totala, fria och glykosylerade halten av vitamin B6 bestämdes. Även vat-tenhalten analyserades. Totalt analyserades 25 prover med HPLC med flourescens som detektor. Bruna bönor innehöll 0.32 0.02 mg/100g vitamin B6 och 49 procent var glykosylerat. Det fanns ingen skillnad i innehåll av vitamin B6 mellan sorter, od-lingsområde och typ av gödsel. Det fanns en signifikant skillnad mellan år för total halt av vitamin B6 respektive glykolyserat pyridoxin men det var ingen signifikant skillnad mellan år för fritt vitamin B6 (alla vitamerer förutom glykosylerat PN). Total halt av vitamin B6 var högre 2008 jämfört med 2009. Glykosyserat PN var högre 2008 och 2010 jämfört med 2009. Väderförhållandena (nederbörd och tempera-tur) var mindre gynnsamma 2008 och 2010 jämfört med 2009. Därav dras slutsat-sen att under mindre gynnsamma odlingsförhållanden ökar vitamin B6. Vattenhalten var högre i Katja än Karin vilket visar på en bättre vattenhållande kapacitet. Den kemiska sammansättningen måste kartläggas för att förklara skillnaden. Katja hade en högre vattenhalt 2009 jämfört med 2008 och 2010. Skillnaden beror troligtvis på att väderförhållanden påverkat den kemiska sammansättningen

An inverse association between plasma benzoxazinoid metabolites and PSA after rye intake in men with prostate cancer revealed with a new method

Prostate cancer (PC) is a common cancer among men, and preventive strategies are warranted. Benzoxazinoids (BXs) in rye have shown potential against PC in vitro but human studies are lacking. The aim was to establish a quantitative method for analysis of BXs and investigate their plasma levels after a whole grain/bran rye vs refined wheat intervention, as well as exploring their association with PSA, in men with PC. A quantitative method for analysis of 22 BXs, including novel metabolites identified by mass spectrometry and NMR, was established, and applied to plasma samples from a randomized crossover study where patients with indolent PC (n = 17) consumed 485 g whole grain rye/rye bran or fiber supplemented refined wheat daily for 6 wk. Most BXs were significantly higher in plasma after rye (0.3-19.4 nmol/L in plasma) vs. refined wheat (0.05-2.9 nmol/L) intake. HBOA-glc, 2-HHPAA, HBOA-glcA, 2-HPAA-glcA were inversely correlated to PSA in plasma (p < 0.04). To conclude, BXs in plasma, including metabolites not previously analyzed, were quantified. BX metabolites were significantly higher after rye vs refined wheat consumption. Four BX-related metabolites were inversely associated with PSA, which merits further investigation

Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study

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 alpha-cell function. Novel lipid metabolites associated with T2D may exert their effects partly through enhancing insulin sensitivity.Peer reviewe

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Vägen till egen försörjning - vad hjälpte? : En kvalitativ intervjustudie med deltagare i en arbetsmarknadsinsats.

2019-06-05</p

Vägen till egen försörjning - vad hjälpte? : En kvalitativ intervjustudie med deltagare i en arbetsmarknadsinsats.

2019-06-05</p

Effects of FODMAPs and Gluten on Gut Microbiota and Their Association with the Metabolome in Irritable Bowel Syndrome: A Double-Blind, Randomized, Cross-Over Intervention Study

Background: A mechanistic understanding of the effects of dietary treatment in irritable bowel syndrome (IBS) is lacking. Our aim was therefore to investigate how fermentable oligo- di-, monosaccharides, and polyols (FODMAPs) and gluten affected gut microbiota and circulating metabolite profiles, as well as to investigate potential links between gut microbiota, metabolites, and IBS symptoms. Methods: We used data from a double-blind, randomized, crossover study with week-long provocations of FODMAPs, gluten, and placebo in participants with IBS. To study the effects of the provocations on fecal microbiota, fecal and plasma short-chain fatty acids, the untargeted plasma metabolome, and IBS symptoms, we used Random Forest, linear mixed model and Spearman correlation analysis. Results: FODMAPs increased fecal saccharolytic bacteria, plasma phenolic-derived metabolites, 3-indolepropionate, and decreased isobutyrate and bile acids. Gluten decreased fecal isovalerate and altered carnitine derivatives, CoA, and fatty acids in plasma. For FODMAPs, modest correlations were observed between microbiota and phenolic-derived metabolites and 3-indolepropionate, previously associated with improved metabolic health, and reduced inflammation. Correlations between molecular data and IBS symptoms were weak. Conclusions: FODMAPs, but not gluten, altered microbiota composition and correlated with phenolic-derived metabolites and 3-indolepropionate, with only weak associations with IBS symptoms. Thus, the minor effect of FODMAPs on IBS symptoms must be weighed against the effect on microbiota and metabolites related to positive health factors