A Low FODMAP Diet Reduces Symptoms in Treated Celiac Patients With Ongoing Symptoms-A Randomized Controlled Trial.

BACKGROUND & AIMS: A gluten-free diet usually leads to mucosal remission in celiac disease, but persistent symptoms are common. A low fermentable oligo-, di-, monosaccharides and polyols (FODMAP) diet is an established treatment for irritable bowel syndrome (IBS). We have assessed the efficacy of a moderately low FODMAP diet on persistent symptoms in treated celiac patients. METHODS: A randomized controlled trial was performed from 2018 to 2019 in 70 adults with biopsy-proven celiac disease. Inclusion criteria were as follows: persistent gastrointestinal symptoms defined by a Gastrointestinal Symptom Rating Scale (GSRS)-IBS version score of 30 or higher, gluten-free diet adherence for 12 months or longer, and serologic and mucosal remission. Participants were randomized to a low FODMAP-gluten-free diet (intervention) or usual gluten-free diet (control). The GSRS-IBS score was recorded at baseline and at weeks 1 to 4, and the Celiac Symptom Index at baseline and at week 4. Statistics included marginal models for repeated data and analyses of covariance. RESULTS: We included 34 participants in the intervention group and 36 in the control group. Time development of GSRS-IBS total scores differed significantly between the groups (Pinteraction < .001), evident after 1 week (mean difference in intervention vs control, -8.2; 95% CI, -11.5 to -5.0) and persisting through week 4 (mean difference in intervention vs control, -10.8; 95% CI, -14.8 to -6.8). Moreover, significantly lower scores were found for the dimensions of pain, bloating, diarrhea, and satiety (Pinteraction ≤ .04), but not constipation (Pinteraction = .43). FODMAP intake during the intervention was moderately low (mean, 8.1 g/d; 95% CI, 6.7-9.3 g/d). The Celiac Symptom Index was significantly lower in the intervention group at week 4 (mean difference, -5.8; 95% CI, -9.6 to -2.0). CONCLUSIONS: A short-term moderately low FODMAP diet significantly reduced gastrointestinal symptoms and increased celiac disease-specific health, and should be considered for the management of persistent symptoms in celiac disease. CLINICALTRIALS: gov: NCT03678935.

Pathogenic T Cells in Celiac Disease Change Phenotype on Gluten Challenge: Implications for T-Cell-Directed Therapies.

Gluten-specific CD4+ T cells being drivers of celiac disease (CeD) are obvious targets for immunotherapy. Little is known about how cell markers harnessed for T-cell-directed therapy can change with time and upon activation in CeD and other autoimmune conditions. In-depth characterization of gluten-specific CD4+ T cells and CeD-associated (CD38+ and CD103+ ) CD8+ and γδ+ T cells in blood of treated CeD patients undergoing a 3 day gluten challenge is reported. The phenotypic profile of gluten-specific cells changes profoundly with gluten exposure and the cells adopt the profile of gluten-specific cells in untreated disease (CD147+ , CD70+ , programmed cell death protein 1 (PD-1)+ , inducible T-cell costimulator (ICOS)+ , CD28+ , CD95+ , CD38+ , and CD161+ ), yet with some markers being unique for day 6 cells (C-X-C chemokine receptor type 6 (CXCR6), CD132, and CD147) and with integrin α4ß7, C-C motif chemokine receptor 9 (CCR9), and CXCR3 being expressed stably at baseline and day 6. Among gluten-specific CD4+ T cells, 52% are CXCR5+ at baseline, perhaps indicative of germinal-center reactions, while on day 6 all are CXCR5- . Strikingly, the phenotypic profile of gluten-specific CD4+ T cells on day 6 largely overlaps with that of CeD-associated (CD38+ and CD103+ ) CD8+ and γδ+ T cells. The antigen-induced shift in phenotype of CD4+ T cells being shared with other disease-associated T cells is relevant for development of T-cell-directed therapies.

Circulating CD103+ γδ and CD8+ T cells are clonally shared with tissue-resident intraepithelial lymphocytes in celiac disease.

Gut intraepithelial γδ and CD8+ αß T lymphocytes have been connected to celiac disease (CeD) pathogenesis. Based on the previous observation that activated (CD38+), gut-homing (CD103+) γδ and CD8+ αß T cells increase in blood upon oral gluten challenge, we wanted to shed light on the pathogenic involvement of these T cells by examining the clonal relationship between cells of blood and gut during gluten exposure. Of 20 gluten-challenged CeD patients, 8 and 10 had increase in (CD38+CD103+) γδ and CD8+ αß T cells, respectively, while 16 had increase in gluten-specific CD4+ T cells. We obtained γδ and αß TCR sequences of >2500 single cells from blood and gut of 5 patients, before and during challenge. We observed extensive sharing between blood and gut γδ and CD8+ αß T-cell clonotypes even prior to gluten challenge. In subjects with challenge-induced surge of γδ and/or CD8+ αß T cells, as larger populations of cells analyzed, we observed more expanded clonotypes and clonal sharing, yet no discernible TCR similarities between expanded and/or shared clonotypes. Thus, CD4+ T cells appear to drive expansion of clonally diverse γδ or CD8+ αß T-cell clonotypes that may not be specific for the gluten antigen.

CD38 expression on gluten-specific T cells is a robust marker of gluten re-exposure in coeliac disease.

Background: Increasing efforts are being put into new treatment options for coeliac disease (CeD), a chronic disorder of the small intestine induced by gluten. Interleukin-2 (IL-2) and gluten-specific CD4 + T cells increase in the blood after four hours and six days, respectively, following a gluten challenge in CeD patients. These responses are unique to CeD and are not seen in controls. We aimed to evaluate different markers reflecting a recall response to gluten exposure that may be used to monitor therapy. Methods: CeD patients on a gluten-free diet underwent a one- (n = 6) or three-day (n = 7) oral gluten challenges. We collected blood samples at several time points between baseline and day 8, and monitored gluten-specific CD4 + T cells for their frequency and CD38 expression using HLA-DQ:gluten tetramers. We assessed the IL-2 concentration in plasma four hours after the first gluten intake. Results: The frequency of gut-homing, tetramer-binding, CD4 + effector memory T (tetramer + ß7 + TEM) cells and the IL-2 concentration measured shortly after the first dose of gluten increased significantly after the one- and three-day gluten challenges, but large interindividual differences were exhibited. The frequency of tetramer + ß7 + TEM plateaued between days 6 and 8 and was lower after the one-day challenge. We observed a consistent increase in CD38 expression on tetramer + ß7 + TEM cells and did not find a significant difference between the one- and three-day challenges. Conclusions: The optimal time points for monitoring therapy response in CeD after a three-day oral gluten challenge is four hours for plasma IL-2 or six to eight days for the frequency of tetramer + ß7 + TEM cells, but both these parameters involved large interindividual differences. In contrast, CD38 expression on tetramer + ß7 + TEM cells increased uniformly and irrespectively of the length of gluten challenge, suggesting that this parameter is more suited for monitoring drug efficacy in clinical trials for CeD.

Distinct phenotype of CD4+ T cells driving celiac disease identified in multiple autoimmune conditions.

Combining HLA-DQ-gluten tetramers with mass cytometry and RNA sequencing analysis, we find that gluten-specific CD4+ T cells in the blood and intestines of patients with celiac disease display a surprisingly rare phenotype. Cells with this phenotype are also elevated in patients with systemic sclerosis and systemic lupus erythematosus, suggesting a way to characterize CD4+ T cells specific for disease-driving antigens in multiple autoimmune conditions.