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more authorsAbstractIt is well established that gluten-free diet reduces the incidence of type 1 diabetes mellitus (T1D) in non-obese diabetic (NOD) mice, though the mechanism is not known. However, regulatory T cells (Treg) are likely to play an important role. Also, it is known that dietary gluten induces an intestinal increase in the bacterium Lactococcus garvieae, but the importance of this phenomenon for T1D development is doubtful. Our hypothesis is that gluten is responsible for mediating its effect on T1D through the influence on Treg development independent of gluten-induced Lactococci. Four groups of female NOD and BALB/c mice of 3 week old were fed either a gluten-free diet or a standard diet. Lactococcus garvieae or saline water was administered per oral to one of each dietary group. Spleen and Peyer's patches were sampled from BALB/c mice for flow cytometric monitoring of IL-10 and Treg. NOD mice were diagnosed diabetic with blood glucose level &12 mmol/l. Dietary gluten significantly decreased the occurrence of Tregs by 10-15% (P & 0.05) in mice compared with those fed a standard diet. These results and the diabetes incidence were independent of the gluten-induced bacterial factor Lactococci. The prevalence of Treg was 5- to 10-fold more abundant in the Peyer's patches than in the spleen (P & 0.001). In conclusion, dietary gluten has a significant negative quantitative impact on the generation of Treg in mice, independent of gluten-induced Lactococcus garvieae, and Treg are far more abundant in Peyer's patches than in the spleen.Discover the world's research12+ million members100+ million publications700k+ research projects
Dietary Gluten Reduces the Number of IntestinalRegulatory T Cells in MiceM. Ejsing-Duun*, J. Josephsen?, B. Aasted*, K. Buschardà & A. K. Hansen*IntroductionType 1 diabetes (T1D) mellitus is an organ-specific auto-immune disease in which insulin-producing pancreaticb-cells are selectively destroyed. This destruction is medi-ated by the action of adaptive effector CD4+and CD8+T cells, so-called T-helper cells type 1 (Th1) [1]. Yet theexact etiology of the diseas e is unknown but it seems tobe multifactorial. A high inciden ce of T1D has beendescribed, especially in the Western World [1–3].Genetic predisposition is of importance for the develop-ment of T1D, although it is not the triggering factor [1,4]. Several environmental and nutritional agents thatmight act as triggers in the pathogenesis have beendescribed [1, 5, 6]. Dietary gluten is one such nutritionalagent, which contains proteins with considerable anti-genic properties to which intolerance is very frequent,and it is already well established that gluten is highlydiabetogenic in rodents [7–10]. Gluten feeding inT1D-prone NOD mice in addition to increasing the inci-dence of T1D dramatically increases the number ofGram-positive microaerophilic bacteria in the gut andthe intestinal flora of diabetic NOD mice [9], as well asof diabetic BB rats [11 ]. On this background, it may behypothesized that these bacteria induce too clean an envi-ronment in the gut by preventing the propagation ofmore antigenic bacteria to stimulate early life generationof regulatory T cells (Treg) first described by Sackaguchiet al. [12], which encompass an essential factor in regulat-ing the homeostasis of a healthy immune system, as theymaintain the oral tolerance, which leads the immune sys-tem into a more innate rather than an adaptive reactionwhen coping with the broad range of intestinal bacteria[13]. They do this by mediating the inhibitory cytokines,such as IL-10 and TGF-b, sustaining the Th1 / Th2 bal-ance against self-tissue and commonly occurring antigens[14]. This could be actions toward dietar y antigens suchas gluten, or in the case of autoimmune diseases toward*Department of Veterinary Pathobiology,Faculty of Life Sciences, University ofCopenhagen, Frederiksberg C, D?Department of Food Science, Faculty of LifeSciences, University of Copenhagen,Frederiksberg C, D andàBartholin Institute, Rigshospitalet,Copenhagen, DenmarkReceived 8 October 2007; Accepted in revisedform 19 February 2008Correspondence to: Prof. A. K. Hansen, D.V.M,Dr. Vet.Sci., Department of VeterinaryPathobiology, Faculty of Life Sciences,University of Copenhagen, Dyrlaegevej 88, DK-1870 Frederiksberg C, Denmark. E-mail:akh@life.ku.dkAbstractIt is well established that gluten-free diet reduces the incidence of type 1 dia-betes mellitus (T1D) in non-obese diabetic (NOD) mice, though the mecha-nism is not known. However, regulatory T cells (Treg) are likely to play animportant role. Also, it is known that dietary gluten induces an intestinalincrease in the bacteri um Lactococcus garvieae, but the importance of this phe-nomenon for T1D development is doubtful. Our hypothesis is that gluten isresponsible for mediating its effect on T1D through the influence on Tregdevelopment independent of gluten-induced Lactococci. Four groups of femaleNOD and BALB / c mice of 3 week old were fed either a gluten-free diet or astandard diet. Lactococcus garvieae or saline water was administered per oral toone of each dietary group. Spleen and Peyer ’s patches we re sampled fromBALB / c mice for flow cytometric monitoring of IL-10 and Treg. NOD micewere diagnosed diabetic with blood glucose level &12 mmol / l. Dietary glutensignificantly decreased the occurrence of Tregs by 10–15% (P & 0.05) in micecompared with those fed a standard diet. These results and the diabetes inci-dence were independent of the gluten-induced bacterial factor Lactococci. Theprevalence of Treg was 5- to 10-fold more abundant in the Peyer’s patchesthan in the spleen (P & 0.001). In conclusion, dietary gluten has a significantnegative quantitative impact on the generation of Treg in mice, independentof gluten-induced Lactococcus garvieae, and Treg are far more abundant inPeyer’s patches than in the spleen.BASIC IMMUNOLOGY doi: 10.1111/j.08.02104.x..................................................................................................................................................................? 2008 The AuthorsJournal compilation ? 2008 Blackwell Publishing Ltd. Scandinavian Journal of Immunology 67, 553–559553
self-tissue like pancreatic b-cells, as is the case in T1D.Thus, the primary immunoregulation seems to be supe-rior, and is not only related to the imbalance betweenTh1 and Th2, but rather lies in the balance between reg-ulatory T cells and effecter T cells [3, 15–17]. Tregcounts have been demonstrated to be lower in peripheralblood in T1D patients compared with controls [18].Proper Treg induction is thus thought to be crucial inorder to suppress unwanted immunological actions , sincefailure in this respect leads to susceptibility towardsautoimmune and atopic diseases [19, 20]. Functional defi-cits of Treg influence T1D development in humans [21].Strongly antigenic bacteria may, when they appear laterin life, be hypothesized to stimulate the action of Th1cells in the lack of Treg. Calcinaro et al. found thatrepeated antigenic stimulation in the presence of highlevels of IL-10 contributed to the generation of Treg[22]. Treg specifically express Foxp3 [23, 24]. Foxp3encodes Forkhead box P3, the transcription factor Scurfin[25], and its role in regulating the development of regu-latory T-cells was first described by Hori et al. (2003 ;[26]). To date Foxp3 is probably the best marker fordetecting Treg [24].In a previous study, we demonstrated that the domi-nant bacterial species in gluten-fed mice were Lactococcusspp. [9], which therefore seems to be a good startingpoint for studying the existence of an indirect gut micro-biological link between gluten and intestinal immunol-ogy. Gram-positive bacteria have been shown to bestrong inducers of Th1-mediated cytokines such as IL-12,INF-c and TNF-a [27], although Lactococci are notknown to be very antigenic.Thus, the aim of this study was to show whethergluten has any impact on the generation of Treg andwhether this effect is directly or more indirectly medi-ated through the gluten-induced Gram-positive bacte-ria. The hypothesis was that gluten is responsible formediating this effect through the influence on Tregdevelopment independent of gluten-induced Lactococci.For this purpose, we used both the NOD mouse, as aspontaneously diabetic strain to test the diabetes inci-dence study, and the BALB / c mouse known to have astrong cellular immune response to test the generationof Treg.Materials and methodsExperimental design. 32 BALB / cJBomTac and 72NOD / BomTac mice (Taconic, Ry, Denmark), bothfemale strains, were bought at the age of 3 weeks. Thetwo strains will subsequently be referred to as BALB / cand NOD, respectively . One substudy aimed at register-ing the incidence of type 1 diabetes (T1D) using NODmice and another substudy aimed at registering theamount of Treg using BALB / c mice.Each substudy consisted of four groups treated by thefollowing regime: gluten-free diet and bacteria inocu- gluten-free diet
standard diet and bacteria standard diet control. After 1 week of accli-matization, all mice were treated per oral (p.o.), witheither 300 ll bacterial mixture or 0.9% saline waterevery Monday, Wednesday and Friday, for a period of8 weeks.NOD mice and BALB / c mice were housed in 16 cagesin groups of 9 and 4, respectively with free access to foodand water. Temperature was maintained at 21 ?C andlight was automatically switched off from 6 pm to 6 am,and the air was changed 10–12 times per 24 h.Sixteen BALB / c mice and 36 NOD mice were fed astandard 1434 Altromin rodent diet (Brogaarden,Denmark), while the other 16 BALB / c mice and 36 NODmice were fed a gluten-free modified 1434 Altromin diet(Brogaarden). A com position of the diet is given in ref. 7.Following 8 weeks of oral treatment, the NOD micewere given a 2-week resting period before initiation ofblood glucose measurem ent. Blood from the tail vein wassampled once a week and tested for glucose (FreeStyleMini, Hermedico A / S, Copenhagen, Denmark). Whenthe blood glucose level was equal to or above 12 mmol / l,mice were considered diabetic and euthanized.Following 8 weeks of oral dosing, 16 of the 32BALB / c mice were euthanized. Four days later theremaining 16 mice were euthanized. Eu thanasia was car-ried out on two subsequent days due to the time spentfor preparation of samples. Spleen and Peyer ’s patcheswere sampled and stored in saline on ice until cells wereprepared for FACS analysis as described below.Preparation of inoculum with Lactococcus garvieae. Themost prevalent microaerophilic Gram-positive bacteriaisolated in the previous study from the caecal content ofmice given a gluten-containing diet [8] was chosen as theGram-positive factor for our study also. This strain wasin this study identified by PCR amplificatio n of the 16sregion. A subsequent sequence analysis revealed this bac-terium to be a Lactococcus garvieae. Microsco pic examina-tion of the bacterium further verified it to be an ovallyshaped coccus. On the basis of a literature search on thenumber of colony-forming units (cfu) in different probi-otic mixtures, it was decided to prepare a L. garvieae mix-ture containing 108cfu / ml. The bacterium was stored at)80 ?C in saline-containing 10% glycerol. A tube-containing GM17 media was inoculated with the strain,and stored at 30 ?C for 24 h. Cfu was checked at dilu-tions 10)5–10)8on GM17 agar plates. Then 10 ml ofovernight culture and 10 ml glucose was added to 1 l ofGM17 media for exponential growth for 6 h. The con-tent was spun down (10 min at 4000 g), and supernatantdiscarded and pellet resuspended in 500 ml 0.9% saline-containing 10% glycerol. The viability was checkedbefore and after storage at )80 ?C (all reagents and554Dietary Gluten Reduces the Number of Intestinal Treg in Mice M. Ejsing-Duun et al...................................................................................................................................................................? 2008 The AuthorsJournal compilation ? 2008 Blackwell Publishing Ltd. Scandinavian Journal of Immunology 67, 553–559
materials were delivered by Department of Food Science,University of Copenhagen, Frederiksberg, Denmark).Fifty-two mice were orally treated with L. garvieae. Our10)6stock suspension contained 333 cfu / ml. Fortymicrolitre of stock suspension was diluted in 260 llof0.9% saline to get 108cfu / ml, and each mouse wasdosed 300 ll p.o. The last 52 mice were controls andwere given 300 ll 0.9% saline p.o.FACS analys is. For flowcytometric monitoring of IL-10-positive cells and the presence of regulatory T-cells,anti-mouse IL-10 (PE conjugated, MCA1302PE), and ratanti-mouse CD4 (FITC conjugated, MCA1107F) wereboth purchased from AbD Serotec (Oxford, UK). Anti-mouse / rat Foxp3 (PE conjugated, 12-5773), werepurchased from eBioscienceTM(San Diego, CA, USA).Single-cell spleen cells from 32 BALB / c mice (see Exper-imental design under the heading Materials and methodsfor details) were prepared in PBSA by squeezing thespleen manually against a stainless steel mesh, and singlecell Peyer’s patch cells from the same mice were preparedin a Medimachine (DAKO A / S, Glostrup, Denmark).Extracellular and intracellular staining procedures wereperformed as published previously [28].Statistics. Cumulative diabetes incidence was calcu-lated using the Kaplan–Meier estimation. Statistical sig-nificance was evaluated by the log-rank test. Calculatingthe strength in diabetes incidence between the fourgroups a v2-test was used. ANOVA was used forcomparing the parameters IL-10 and Foxp3 betweenindividual groups. Multifactorial ANOVA was used toinclude both gluten and bacteria as a factor in thecomparisons.ResultsFeeding mice a gluten-free diet significantly reduced thediabetes incidence (P & 0.05). The bacteria-inoculatedgluten-free group had an incidence of 58%, while thegluten-free saline inoculated group had an incidence of56% compared with 71% and 78%, respectively, in theirstandard fed counterparts. The difference in the cumula-tive incidence between the gluten-free fed groups and thestandard fed groups at the end of the study were 56%and 74%, respectively (P & 0.05) (Fig. 1). There was nodifference in the cumulative incidence between the bacte-ria and saline inoculated controls, at all (Fig. 2).In the Peyer ’s patches, the mice fed a glut en-contain-ing diet had a decreased level of Treg as expressed byFoxp3 (P & 0.05) (Fig. 3) as the bacteria-inoculated glu-ten fed mice had a ratio of 21.7%, while the bacteria-inoculated gluten-free fed mice had a ratio of 34.5%.The ratio was 24.8% and 41.7%, respectively, for thecontrol mice inoculated with saline. In the spleen, therewere no such differences no matter which diet the micewere fed (Fig. 3). There were no statistically significantdifferences between the four groups in respect to the levelof IL-10 neither in spleen nor in Peyer’s patches (Fig. 4).The number of Treg was significantly higher in thePeyer’s patches, in which the Foxp3 ratios range d from21.7% to 41.7%, compared with the spleen, in whichthe Foxp3 ratios ranged from 4.2% to 5.4% (P & 0.001).The number of IL-10-producing cells was also observedto be significantly higher in the Peyer’s patches, in whichIL-10 ratios ranged from 22.2% to 26.4%, comparedwith the spleen, in which IL 10 ratios ranged from 3.3%to 4.5% (P & 0.001) (Fig. 4). Lactococcus garvieae was notobserved to have any effect on the occurrence on Treg ineither Peyer’s patches or spleen (Fig. 3). Also no signifi-cant effect was seen on IL-10 (Fig. 4). As an example,scatter plots on which these data are based are demon-strated in Fig. 5.–Gluten vs. + Gluten0 10 20 30 40 50 60 70 80 40 101 115 129 150 164 206 Days Cumulative diabetes incidence–GLU +GLU * Figure 1 Cumulative incidence of type 1 diabetes in non-obese diabeticmice between groups orally fed a gluten-containing (+GLU) versusgroups fed a gluten-free diet ()GLU), treated with saline or bacteria.Diabetes incidence was significantly higher in groups fed a gluten-containing standard diet *P & 0.05.0 10 20 30 40 50 60 70 80 0 40 101 115 129 150 164 206 Days Cumulative diabetes incidence –BACT –Bacteria vs. + Bacteria+BACT Figure 2 Cumulative incidence of type 1 diabetes in non-obese diabeticmice between groups orally treated with saline ()BACT) versus thegroups orally inoculated with Lactococcus garvieae (+BACT), fed standardor gluten-free diet. No significant differences in diabetes incidence wereobserved.M. Ejsing-Duun et al. Dietary Gluten Reduces the Number of Intestinal Treg in Mice 555..................................................................................................................................................................? 2008 The AuthorsJournal compilation ? 2008 Blackwell Publishing Ltd. Scandinavian Journal of Immunology 67, 553–559
DiscussionA gluten-containing diet significantly reduced the num-ber of Treg in BALB / c mice. This observation maypartly explain why elimination of gluten in the dietreduces the incidence of diabetes in rodents, as the pres-ence of Treg to suppress Th1 effector cells reactivetowards pancreatic self b-cells is critical to avoidthe pathogenesis in genetically predi sposed individuals[18–21]. Gluten feeding propagates microaerophilic bac-teria [9], in this study represented by L. garvieae, butthis does not seem to influence the immunology,although there were slightly more Treg in the Peyer’spatches of the non-inoculated compared with the inocu-lated gluten-free group. However, it cannot be ruled outthat such micro aerophilic bacteria might have a negativeimpact on Treg generation. In 1989 Strachan launchedthe hygiene hypothesis to explain the increase in the inci-dence of allergic diseases as due to better hygiene andliving standards [ 17 ]. That microbial contact early inlife is needed to drive the immunological development[16, 27, 29] has later been extended to comprise auto-immune disorders as well [16], indicating that especiallythe lack of farming-related bacterial species should ren-der our immune system less compatible towards fre-quently occurring and potentially antigenic triggers [3,15, 17]. Disturbance in the fine-tuned interplay betweenthe innate immune system, the adaptiv e immune systemand the intestine as the physical protective barrier mightprovoke an imbalance in this system [14, 27]. Treatmentwith fusidic acid, a Gram-positive oriented antibiotic,reduces the incidence of T1D in rodents [30–34], and sodoes treatment with more broad-spectred sulphamethox-azole and trimethoprim [11]. It is unclear, how this pro-cess is evoked, but an increased generation of Treg inanimals lacking a Gram-positive flora after antibiotictreatment in early life may be due to increased contactto the Gram-negative flora. It is also known that neona-tal antibiotic treatment may skew the Th1 immuneresponse towards a Th2 profile, an effect which can bereduced by supplementation of Gram-positive, microaer-ophilic bacteria [35]. Also, Mycobacteria are consideredimportant for the gener ation of Treg [15], and treatm entwith Mycobacterium avium in NOD mice reduces theincidence of T1D [36]. Probiotic treatment may also behypothesized to reduce T1D incidence due to preventionof later contact to the more antigenic Gram-negativeflora, as oral feeding with Lactobacillus casei in NODmice [37 ] and Lactobacillus GG in streptozotocin-induceddiabetic rats [38] prevented T1D, but the effect asinducing or protecting is probably very much linked tothe treatment age. In our study, neither of these effectswere observed and the difference in T1D incidencebetween gluten-free Lactococ ci-inoculated mice and thegluten-free fed control mice was only 2%. Previousstudies do not show that gluten-fed mice have fewerGram-negative or anaerobic bacteria in their gut [9 ],and we therefore hypot hesized that gluten exerts itsimpact on the immune system in a more direct waywithout linking through the gut microbiology. This issupported by the fact that NOD mice fed a cereal-baseddiet express higher levels of Th1, interferon-gamma(IFN-gamma), tumour necrosis factor (TNF-alpha) andinducible NO synthase mRNA compared with mice fedFoxp3 positive cells010203040506070Glu–/Lact+ Glu–/Lact– Glu+/Lact+ Glu+/Lact–% staining of CD4SpleenPeyers patchesaaebfbcceddfFigure 3 Percentage of Foxp3-producing cells from spleen and Peyer’spatches of 32 BALB / c mice. The level of Foxp3 was significantly higherin the Peyer’s patches than in the spleen (P & 0.001), indicated by thebars marked a, b, c and d and those given the same letter being signifi-cantly different. The groups were given the following treatment:gluten-free diet and saline
gluten-free diet and gluten-containing diet and
gluten-containing diet and salinewater. The level of Foxp3 was significantly higher in the Peyer’s patchesof mice fed a gluten-free diet compared with mice fed a standard diet(P & 0.05), indicated by the bars marked with the letters e and f andthose given the same letter being significantly different.IL-10 positive cells 0 5 10 15 20 25 30 35 40 45 50 Glu–/Lact+ Glu–/Lact– Glu+/Lact+ Glu+/Lact– % staining of CD4Spleen Peyers patches a a b c b d c d Figure 4 Percentage of CD4 and IL-10-positive cells from spleen andPeyer’s patches of 32 BALB / c mice. The level of IL-10 producing cellswas significantly higher in the Peyer’s patches than in the spleen. Barswith the letters a, b, c and d are significantly different (P & 0.001). Thegroups were given the following treatment: gluten-free diet and saline gluten-free diet and
gluten-containing diet and bacte- gluten-containing diet and saline water.556 Dietary Gluten Reduces the Number of Intestinal Treg in Mice M. Ejsing-Duun et al...................................................................................................................................................................? 2008 The AuthorsJournal compilation ? 2008 Blackwell Publishing Ltd. Scandinavian Journal of Immunology 67, 553–559
a semi-purified soy-protein-based diet [39]. Furthermore,human T1D patients show an impaired intestinal barrierfunction that may be a contributing factor in the patho-genesis [40]. Propagation of microaerophilic bacteria,such as L. garvieae , is expectable in gluten-consumingNOD mice due to their ability to hydrolyse gluten [41,42], so in the gluten fed groups already having numer-ous of these bacteria in their gut, it is not reasonable toassume that further inoculation would have had anyimpact on T1D incidence. Thus, L. garvieae did notinfluence the developing immune system in our study,even when given at this critical time early in life, andtherefore these Lactococci did not influence diabetesincidence.The Th2-derived parameter IL-10 was influenced byneither gluten nor Lactococci. IL-10 expression may beassociated with different types of T cells, like Tr1 whichis another subset of regulatory T cells strongly repre-sented in the gut. Tr1 expresses increased levels of IL-10[18, 43], whereas Foxp3 expression is not seen in this celltype [43]. This might be a reason why a reduced IL-10level is not observed in spite of less Treg being present,which would have been expectable as a direct effect ofgluten. Also IL-10 and TGF-b are closely related inimmunosuppressive actions, and an imbalance betweenthe two, i.e. more IL-10 generation than TGF-b orotherwise, might pose negative consequences [18].Inafuture experiment, monitoring the two together could beinteresting.The T1D incidence score in the groups on gluten-free diet was relatively high in all groups, comparedwith previous observations [7, 9]. This increase in inci-dence score might very well have to do with the treat-ment regime. NOD mice are easily stressed and it isexpectable that more mice in all groups would becomediabetic as a cause of inoculation, which is a stressfulprocedure.A significant difference between the number of Tregin spleen and Peyer’s patches was observed. The increasedTreg number in Peyer ’s patches indicates that they havea very important niche in the peripheral gut, where newencounters with antigens are very critical. In this respect,it seems natural that Treg are more numerous in Peyer’spatches as it is in the gut that antigens to cross theintestinal barrier are to be processed and exert theireffect, and thus it is an area where essential antigenicsurveillance is taking place. The spleen represents asystemic division and it is interesting that Treg are notas frequent here.In conclusion, this study demonstrates that dietarygluten reduces the generation of Treg in mice, indepen-dent of the gluten-induced bacteria Lactococcus garvieae.CD4 / FoxP3
CD4 / IL-10 SpleenPeyerpatchesFigure 5 Scatter plots from the data obtained by FACS procedure for spleen and Peyer’s patches. The spleen is represented by the two upper plotsand the Peyer’s patches in the two lower plots, where percent IL-10 (right) or Foxp3 (left) staining of CD4 are indicated.M. Ejsing-Duun et al. Dietary Gluten Reduces the Number of Intestinal Treg in Mice 557..................................................................................................................................................................? 2008 The AuthorsJournal compilation ? 2008 Blackwell Publishing Ltd. Scandinavian Journal of Immunology 67, 553–559
Quantitatively Treg are observed more abundant inPeyer’s patches than in the spleen.AcknowledgmentsWe wish to thank all staff who helped with the experi-mental preparations, in particular Senior LaboratoryTechnician Basheer Aideh (Faculty of Life Science,Department of Food Science, University of Copenhagen),for helping with the bacterial preparations. Also thanksto the Animal Technicians and PhD student Gitte BachChristensen (Faculty of Life Science, Department of Vet-erinary Pathobiology, University of Copenhagen) forhelping taking care of the animals and measuring bloodglucose levels.References1 Tisch R, McDevitt H. Insulin-dependent diabetes mellitus. Cell–7.2 Bach JF. Mechanisms of disease: The effect of infections on suscepti-bility to autoimmune and allergic diseases. N Engl J Med–20.3 Vercelli D. Mechanisms of the hygiene hypothesis – molecular andotherwise. Curr Opin Immunol –7.4 Knip M, Veijola W, Virtanen SM et al. Environmental triggers anddeterminants of type 1 diabetes. 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&Whereas it is clear that a gluten-free diet benefits patients with coeliac disease and possibly the pre-diabetic state of type 1 diabetes (T1D) [13], the effects of a gluten-free diet on other types of diseases, such as atherosclerosis, is largely unknown. In both mice [14] and humans [15] it has been shown that dietary gluten reduces the abundance of bacteria capable of stimulating the immune system, which in animal models have been shown to increase the risk of development of inflammatory disease, such as type 1 diabetes (T1D) [16]. In the gut, both dietary gluten and GM-derived particles have been suggested to interact with TLRs causing a pro-inflammatory innate immune response [6,7,17– 19] . &ABSTRACT: The importance of the gut microbiota (GM) in disease development has recently received increased attention, and numerous approaches have been made to better understand this important interplay. For example, metabolites derived from the GM have been shown to promote atherosclerosis, the underlying cause of cardiovascular disease (CVD), and to increase CVD risk factors. Popular interest in the role of the intestine in a variety of disease states has now resulted in a significant proportion of individuals without coeliac disease switching to gluten-free diets. The effect of gluten-free diets on atherosclerosis and cardiovascular risk factors is largely unknown. We therefore investigated the effect of a gluten-free high-fat cholesterol-rich diet, as compared to the same diet in which the gluten peptide gliadin had been added back, on atherosclerosis and several cardiovascular risk factors in apolipoprotein E-deficient (Apoe-/-) mice. The gluten-free diet transiently altered GM composition in these mice, as compared to the gliadin-supplemented diet, but did not alter body weights, glucose tolerance, insulin levels, plasma lipids, or atherosclerosis. In parallel, other Apoe-/- mice fed the same diets were treated with ampicillin, a broad-spectrum antibiotic known to affect GM composition. Ampicillin-treatment had a marked and sustained effect on GM composition, as expected. Furthermore, although ampicillin-treated mice were slightly heavier than controls, ampicillin-treatment transiently improved glucose tolerance both in the absence or presence of gliadin, reduced plasma LDL and VLDL cholesterol levels, and reduced aortic atherosclerotic lesion area. These results demonstrate that a gluten-free diet does not seem to have beneficial effects on atherosclerosis or several CVD risk factors in this mouse model, but that sustained alteration of GM composition with a broad-spectrum antibiotic has beneficial effects on CVD risk factors and atherosclerosis. These findings support the concept that altering the microbiota might provide novel treatment strategies for CVD. Full-text · Article · Jan 2016 +10 more authors ...&For instance, serum levels and mucosal expression of anti-transglutaminase antibodies are not gluten-dependent [31]. In NOD mice, dietary gluten alters the composition of their gut microbiome [32], intestinal regulatory T cells [33], as well as their natural killer cell cytotoxicity [34, 35]. The significance of these findings in NOD mice to the human situation needs further investigation. &ABSTRACT: Non allergy-non-celiac wheat sensitivity (NCWS) has become a common and often overrated diagnosis. Skepticism mainly relates to patients with prominent intestinal symptoms in the absence of general or intestinal signs of inflammation. There is consensus that the major wheat sensitivities, celiac disease and wheat allergy, have to be ruled out which may be difficult for wheat allergy. The non-inflammatory intolerances to carbohydrates, mainly lactose and FODMAPs (fermentable oligi-, di-, monosaccharides and polyols), which cause bloating or diarrhoea, can usually be excluded clinically or by simple tests. Recent studies and experimental data strongly indicate that NCWS exists in a substantial proportion of the population, that it is an innate immune reaction to wheat and that patients often present with extraintestinal symptoms, such as worsening of an underlying inflammatory disease in clear association with wheat consumption. Wheat amylase-trypsin inhibitors (ATIs) have been identified as the most likely triggers of NCWS. They are highly protease resistant and activate the toll-like receptor 4 (TLR4) complex in monocytes, macrophages and dendritic cells of the intestinal mucosa. Non-gluten containing cereals or staples display no or little TLR4 stimulating activity. Wheat ATIs are a family of up to 17 similar proteins of molecular weights around 15 kD and represent 2-4% of the wheat protein. With oral ingestion they costimulate antigen presenting cells and promote T cell activation in celiac disease, but also in other immune-mediated diseases within and outside the GI tract.
Copyright (C) 2015. Published by Elsevier Ltd. Full-text · Article · May 2015 &For instance, serum levels and mucosal expression of anti-transglutaminase antibodies are not gluten-dependent [31]. In NOD mice, dietary gluten alters the composition of their gut microbiome [32], intestinal regulatory T cells [33], as well as their natural killer cell cytotoxicity [34,35] . The significance of these findings in NOD mice to the human situation needs further investigation. &ABSTRACT: Non-celiac gluten sensitivity is an undefined syndrome with gastrointestinal and extra-intestinal manifestations triggered by gluten in patients without celiac disease and wheat allergy. The pathogenesis involves immune-mediated mechanisms requiring further research. Symptoms disappear in a few hours or days after gluten withdrawal and recur rapidly after gluten ingestion. Besides gluten, other wheat proteins as well as fermentable oligo-, di-, mono-saccharides and polyols (FODMAPs) may contribute to this syndrome. This syndrome occurs mainly in young women, being rare in children. Its prevalence ranges from 0.6% to 6%, based on primary or tertiary care center estimates. No biomarker is available, but half of patients tests positive for IgG anti-gliadin antibodies, which disappear quickly after gluten-free diet together with symptoms. Also, genetic markers are still undefined. Although currently limited to a research setting, double-blind, placebo-controlled, cross-over trial strategy is recommended to confirm the diagnosis. Treatment is based on dietary restriction with special care to nutrient intake.
Copyright (C) 2015 Elsevier Ltd. All rights reserved. Full-text · Article · May 2015 +2 more authors ... Full-text · Article · Apr 2017 +8 more authors ...Article · Apr 2017 +7 more authors ...Article · Apr 2017 +7 more authors ...Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.This publication is from a journal that may support self archiving.Last Updated: 24 Jan 17
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