Dietary fat and bile acids in the pathogenesis of gut barrier dysfunction

Gut barrier function is impaired in several disorders such as inflammatory bowel diseases, diabetes and steatohepatitis. It is suspected that this is related to increased permeability to bacterial endotoxins from the lumen through the gut epithelium. Recent studies have shown a link between high-fat diet and endotoxemia, but the underlying mechanisms are unknown. One possible explanation is the contribution of other luminal substances, such as bile acids. Fat ingestion induces bile flow to the duodenum to facilitate the absorption of fat. At high concentrations, bile acids especially very hydrophobic bile acids are cytotoxic. The aim of this study was to investigate whether dietary fat or obesity causes barrier dysfunction, and whether bile acids play a role in its pathogenesis. The role of bile acid hydrophobicity in their capability of inducing barrier dysfunction was given special attention. The effects of dietary fat and obesity on gut barrier function were investigated in the diet induced obesity and ob/ob -mouse models. Fecal bile acids were quantified and profiles calculated from these mice. The effects of bile acids on intestinal permeability were studied in an in vivo feeding trial with deoxycholic acid and in vitro in an Ussing chamber. In vitro, tissue preparations were incubated with deoxycholic acid and/or ursodeoxycholic acid - two bile acids greatly different in their hydrophobicity. Gut barrier function was impaired by a high-saturated fat diet in mice, but not in genetically obese mice that were fed normal low-fat chow. Barrier dysfunction by dietary fat was especially prominent in jejunum and colon - no significant difference was seen in the permeability of duodenum or ileum. Fecal bile acid hydrophobicity was increased only by dietary fat, not by genetic obesity, and was positively correlated with intestinal permeability. Deoxycholic acid alone increased gut permeability both in vivo and in vitro. The effect was more evident in colonic than jejunal tissue preparations, and the mechanism seemed not to be inflammation-dependent. Barrier impairment was reduced by the hydrophilic ursodeoxycholic acid, which was also reflected as improved tissue morphology. Deoxycholic acid -induced barrier dysfunction seemed to be aggravated by translocated lipopolysaccharides. The present results suggest that dietary fat, but not obesity itself, impairs gut barrier function. The data imply that luminal bile acids are one mechanism for barrier impairment, with hydrophobic bile acids initiating tissue disruption and lipopolysaccharides likely playing the role of a second hit.Tuore väitöstutkimus osoittaa, että rasvainen ruokavalio vaurioittaa suoliston limakalvoestettä. Suoliston limakalvoeste on suolen sisäosan pintakerros, joka estää suolistomikrobien pääsyn verenkiertoon. Mikrobien läpipääsy on yhdistetty muun muassa lihavuuteen, diabetekseen ja rasvamaksaan, sillä mikrobit aiheuttavat elimistössä tulehdusreaktion. Väitöstutkimuksessa havaittiin, että rasvaista ruokavaliota syöneiden hiirten limakalvoeste heikkeni suhteessa vähärasvaista ruokaa saaneisiin. Limakalvoesteen häiriöiden syynä on aiemmin pidetty suolistomikrobiston koostumuksen muutoksia. Väitöstutkimus kuitenkin osoittaa, että syy voi löytyä myös suoliston sisällön sappihappojen rakenteellisista muutoksista, kun hiiret syövät runsaasti rasvaa. Suoliston limakalvoesteen toimintaa ja ulosteen sappihappoja tutkittiin kokeellisessa mallissa, jossa hiiret lihovat, kun niiden ruokavalio sisältää paljon tyydyttynyttä rasvaa. Erilaisten sappihapporakenteiden vaikutusta limakalvoesteeseen tutkittiin myös suolistosta otetuilla koepaloilla. Työ osoittaa, että runsaasti rasvaa sisältävä ruokavalio lisää sellaisten sappihappojen määrää, jotka vaurioittavat suoliston limakalvoestettä. Vastaavasti limakalvoestettä ylläpitävien sappihappojen määrä oli vähentynyt ravinnon rasvaisuuden seurauksena. Näitä muutoksia ei tapahtunut geneettisen lihavuuden mallissa, jossa hiiret lihovat ilman runsasrasvaista ruokavaliota. Vaurio näyttää siis olevan yksinomaan seurausta ruokavalion rasvaisuudesta, ei lihavuudesta. Lihavuuden yhteydestä suoliston limakalvoesteen häiriöön on viime aikoina kohistu tiedemaailmassa. Väitöstyö osoittaa, että limakalvoeste ei vaurioidu lihavuuden, vaan siihen mahdollisesti liittyvän rasvaisen ruokavalion takia. Väitöstyössä on myös keksitty uusi selitys sille, miksi rasvainen ruokavalio vaurioittaa suoliston limakalvoestettä. Jatkossa on syytä selvittää, miten suolistomikrobisto muokkaa sappihappojen rakenteita, kun limakalvoesteen häiriö kehittyy

High-fat-induced intestinal permeability dysfunction associated with altered fecal bile acids

Peer reviewe

The majority of type 2 diabetic patients in Finnish primary care are at very high risk of cardiovascular events : A cross-sectional chart review study (STONE HF)

Publisher Copyright: © 2021 The AuthorsAims: To characterize clinical profiles, prevalence of chronic kidney disease (CKD), and treatment patterns in type 2 diabetes (T2D) and heart failure (HF) patients in Finnish primary care. Methods: A total of 1385 patients (1196 with T2D, 50 with HF, and 139 with T2D and HF) in 60 Finnish primary care centers were recruited to this cross-sectional study. Data on demographic and clinical characteristics, laboratory measurements, and medications were collected retrospectively from medical records. T2D patients were classified according to their risk of cardiovascular (CV) events as very high-risk (62%) and other patients (38%). Results: Of the T2D patients, 10% (139/1335) had a diagnosis of HF and 42% (457/1090) had stage 3–5 CKD and/or albuminuria based on laboratory measurement. Of the HF patients, 74% (139/189) had T2D and 78% (114/146) had stage 3–5 CKD and/or albuminuria. Metformin was the most frequently used medication in both very high-risk patients (74%) and other patients (86%). SGLT2 inhibitors and/or GLP-1 analogues were used by 37% of very high-risk patients compared to 42% in other patients. Conclusions: The majority of T2D patients in Finnish primary care are at very high risk of cardiovascular events. However, the implementation of treatments with proven cardioprotective effects in very high-risk patients is currently suboptimal.Peer reviewe

Tyypin 2 diabeteksen hoitosuunnitelmissa ja hoidon kohdentamisessa on parantamisen varaa

Lähtökohdat : Tyypin 2 diabeteksen hoidon keskeisiä tavoitteita ovat taudin etenemisen hidastaminen ja hyvä elämänlaatu. Hoidon tueksi tehdään hoitosuunnitelma, joka auttaa toimenpiteiden kohdentamisessa potilaan tarpeiden mukaan. Hoitosuunnitelman toteutumista Suomessa ei ole tutkittu. Menetelmät :Tässä kyselytutkimuksessa kerättiin tietoa tyypin 2 diabetesta sairastavien lääkityksestä, liitännäissairauksista, hoitosuunnitelmasta ja hoidon tavoitteiden sisäistämisestä. Osallistujiksi pyydettiin diabeteslääkityksenään muuta kuin pelkästään insuliinia käyttäneitä avoapteekkien asiakkaita. Tulokset : Kyselyyn vastasi 1 067 diabetespotilasta. Heistä 70 % oli osallistunut hoitonsa suunnitteluun, 63 % koki saaneensa hoitosuunnitelmasta tukea, mutta vain 35 % kertoi saaneensa suunnitelman kirjallisena. Hyödyt toteutuivat pienillä paikkakunnilla useammin kuin suurilla. Kirjallinen suunnitelma oli yhteydessä hoitotavoitteiden parempaan ymmärtämiseen. Sydän- ja verisuoni tautiriski ei vaikuttanut käyntitiheyteen (53–55 % vastaanotolla alle 6 kk aiemmin). Vain puolet riskipotilaista käytti uusia ennusteeseen vaikuttavia diabeteslääkkeitä. Päätelmät : Diabeteksen kirjallista hoitosuunnitelmaa käytetään riittämättömästi. Resurssien ja hoidon parempi kohdentaminen potilaan tarpeiden mukaan olisi sekä kansanterveydellisesti että kansantaloudellisesti järkevää.Peer reviewe

The majority of type 2 diabetic patients in Finnish primary care are at very high risk of cardiovascular events: A cross-sectional chart review study (STONE HF).

AimsTo characterize clinical profiles, prevalence of chronic kidney disease (CKD), and treatment patterns in type 2 diabetes (T2D) and heart failure (HF) patients in Finnish primary care.MethodsA total of 1385 patients (1196 with T2D, 50 with HF, and 139 with T2D and HF) in 60 Finnish primary care centers were recruited to this cross-sectional study. Data on demographic and clinical characteristics, laboratory measurements, and medications were collected retrospectively from medical records. T2D patients were classified according to their risk of cardiovascular (CV) events as very high-risk (62%) and other patients (38%).ResultsOf the T2D patients, 10% (139/1335) had a diagnosis of HF and 42% (457/1090) had stage 3-5 CKD and/or albuminuria based on laboratory measurement. Of the HF patients, 74% (139/189) had T2D and 78% (114/146) had stage 3-5 CKD and/or albuminuria. Metformin was the most frequently used medication in both very high-risk patients (74%) and other patients (86%). SGLT2 inhibitors and/or GLP-1 analogues were used by 37% of very high-risk patients compared to 42% in other patients.ConclusionsThe majority of T2D patients in Finnish primary care are at very high risk of cardiovascular events. However, the implementation of treatments with proven cardioprotective effects in very high-risk patients is currently suboptimal.</p

Probiotic With or Without Fiber Controls Body Fat Mass, Associated With Serum Zonulin, in Overweight and Obese Adults—Randomized Controlled Trial

Abstract The gut microbiota is interlinked with obesity, but direct evidence of effects of its modulation on body fat mass is still scarce. We investigated the possible effects of Bifidobacterium animalis ssp. lactis 420 (B420) and the dietary fiber Litesse® Ultra polydextrose (LU) on body fat mass and other obesity-related parameters. 225 healthy volunteers (healthy, BMI 28–34.9) were randomized into four groups (1:1:1:1), using a computer-generated sequence, for 6months of double-blind, parallel treatment: 1) Placebo, microcrystalline cellulose, 12g/d; 2) LU, 12g/d; 3) B420, 1010CFU/d in microcrystalline cellulose, 12g/d; 4) LU+B420, 12g+1010CFU/d. Body composition was monitored with dual-energy X-ray absorptiometry, and the primary outcome was relative change in body fat mass, comparing treatment groups to Placebo. Other outcomes included anthropometric measurements, food intake and blood and fecal biomarkers. The study was registered in Clinicaltrials.gov (NCT01978691). There were marked differences in the results of the Intention-To-Treat (ITT; n=209) and Per Protocol (PP; n=134) study populations. The PP analysis included only those participants who completed the intervention with >80% product compliance and no antibiotic use. In addition, three participants were excluded from DXA analyses for PP due to a long delay between the end of intervention and the last DXA measurement. There were no significant differences between groups in body fat mass in the ITT population. However, LU+B420 and B420 seemed to improve weight management in the PP population. For relative change in body fat mass, LU+B420 showed a−4.5% (−1.4kg, P=0.02, N=37) difference to the Placebo group, whereas LU (+0.3%, P=1.00, N=35) and B420 (−3.0%, P=0.28, N=24) alone had no effect (overall ANOVA P=0.095, Placebo N=35). A post-hoc factorial analysis was significant for B420 (−4.0%, P=0.002 vs. Placebo). Changes in fat mass were most pronounced in the abdominal region, and were reflected by similar changes in waist circumference. B420 and LU+B420 also significantly reduced energy intake compared to Placebo. Changes in blood zonulin levels and hsCRP were associated with corresponding changes in trunk fat mass in the LU+B420 group and in the overall population. There were no differences between groups in the incidence of adverse events. This clinical trial demonstrates that a probiotic product with or without dietary fiber controls body fat mass. B420 and LU+B420 also reduced waist circumference and food intake, whereas LU alone had no effect on the measured outcomes.Peer reviewe

The Gut Microbiota Regulates Intestinal CD4 T Cells Expressing RORγt and Controls Metabolic Disease

SummaryA high-fat diet (HFD) induces metabolic disease and low-grade metabolic inflammation in response to changes in the intestinal microbiota through as-yet-unknown mechanisms. Here, we show that a HFD-derived ileum microbiota is responsible for a decrease in Th17 cells of the lamina propria in axenic colonized mice. The HFD also changed the expression profiles of intestinal antigen-presenting cells and their ability to generate Th17 cells in vitro. Consistent with these data, the metabolic phenotype was mimicked in RORγt-deficient mice, which lack IL17 and IL22 function, and in the adoptive transfer experiment of T cells from RORγt-deficient mice into Rag1-deficient mice. We conclude that the microbiota of the ileum regulates Th17 cell homeostasis in the small intestine and determines the outcome of metabolic disease

Probiotic With or Without Fiber Controls Body Fat Mass, Associated With Serum Zonulin, in Overweight and Obese Adults-Randomized Contolled Trial

DiscussionThis clinical trial demonstrates that a probiotic product with or without dietary fiber controls body fat mass. B420 and LU + B420 also reduced waist circumference and food intake, whereas LU alone had no effect on the measured outcomes.</p

Up-regulation of endothelin type B receptors in the human internal mammary artery in culture is dependent on protein kinase C and mitogen-activated kinase signaling pathways

<p>Abstract</p> <p>Background</p> <p>Up-regulation of vascular endothelin type B (ET_B) receptors is implicated in the pathogenesis of cardiovascular disease. Culture of intact arteries has been shown to induce similar receptor alterations and has therefore been suggested as a suitable method for, <it>ex vivo</it>, in detail delineation of the regulation of endothelin receptors. We hypothesize that mitogen-activated kinases (MAPK) and protein kinase C (PKC) are involved in the regulation of endothelin ET_Breceptors in human internal mammary arteries.</p> <p>Methods</p> <p>Human internal mammary arteries were obtained during coronary artery bypass graft surgery and were studied before and after 24 hours of organ culture, using <it>in vitro </it>pharmacology, real time PCR and Western blot techniques. Sarafotoxin 6c and endothelin-1 were used to examine the endothelin ET_Aand ET_Breceptor effects, respectively. The involvement of PKC and MAPK in the endothelin receptor regulation was examined by culture in the presence of antagonists.</p> <p>Results</p> <p>The endohtelin-1-induced contraction (after endothelin ET_Breceptor desensitization) and the endothelin ET_Areceptor mRNA expression levels were not altered by culture. The sarafotoxin 6c contraction, endothelin ET_Breceptor protein and mRNA expression levels were increased after organ culture. This increase was antagonized by; (1) PKC inhibitors (10 μM bisindolylmaleimide I and 10 μM Ro-32-0432), and (2) inhibitors of the p38, extracellular signal related kinases 1 and 2 (ERK1/2) and C-jun terminal kinase (JNK) MAPK pathways (10 μM SB203580, 10 μM PD98059 and 10 μM SP600125, respectively).</p> <p>Conclusion</p> <p>In conclusion, PKC and MAPK seem to be involved in the up-regulation of endothelin ET_Breceptor expression in human internal mammary arteries. Inhibiting these intracellular signal transduction pathways may provide a future therapeutic target for hindering the development of vascular endothelin ET_Breceptor changes in cardiovascular disease.</p