Corrigendum: Characterization of the "gut microbiota-immunity axis" and microbial lipid metabolites in atrophic and potential celiac disease.

[This corrects the article DOI: 10.3389/fmicb.2022.886008.].

Diagnostic delay in adult coeliac disease: An Italian multicentre study.

BACKGROUND: There are few data regarding the diagnostic delay and its predisposing factors in coeliac disease (CD). AIMS: To investigate the overall, the patient-dependant, and the physician-dependant diagnostic delays in CD. METHODS: CD adult patients were retrospectively enroled at 19 Italian CD outpatient clinics (2011-2021). Overall, patient-dependant, and physician-dependant diagnostic delays were assessed. Extreme diagnostic, i.e., lying above the third quartile of our population, was also analysed. Multivariable regression models for factors affecting the delay were fitted. RESULTS: Overall, 2362 CD patients (median age at diagnosis 38 years, IQR 27-46; M:F ratio=1:3) were included. The median overall diagnostic delay was 8 months (IQR 5-14), while patient- and physician-dependant delays were 3 (IQR 2-6) and 4 (IQR 2-6) months, respectively. Previous misdiagnosis was associated with greater physician-dependant (1.076, p = 0.005) and overall (0.659, p = 0.001) diagnostic delays. Neurological symptoms (odds ratio 2.311, p = 0.005) and a previous misdiagnosis (coefficient 9.807, p = 0.000) were associated with a greater extreme physician-dependant delay. Gastrointestinal symptoms (OR 1.880, p = 0.004), neurological symptoms (OR 2.313, p = 0.042), and previous misdiagnosis (OR 4.265, p = 0.000) were associated with increased extreme overall diagnostic delay. CONCLUSION: We identified some factors that hamper CD diagnosis. A proper screening strategy for CD should be implemented.

Evaluation and comparison of short chain fatty acids composition in gut diseases.

BACKGROUND: An altered (dysbiosis) and unhealthy status of the gut microbiota is usually responsible for a reduction of short chain fatty acids (SCFAs) concentration. SCFAs obtained from the carbohydrate fermentation processes are crucial in maintaining gut homeostasis and their determination in stool samples could provide a faster, reliable and cheaper method to highlight the presence of an intestinal dysbiosis and a biomarker for various gut diseases. We hypothesize that different intestinal diseases, such as celiac disease (CD), adenomatous polyposis (AP) and colorectal cancer (CRC) could display a particular fecal SCFAs' signature. AIM: To compare the fecal SCFAs' profiles of CD, AP, CRC patients and healthy controls, using the same analytical method. METHODS: In this cross-sectional study, we defined and compared the SCFAs' concentration in fecal samples of 9 AP, 16 CD, 19 CRC patients and 16 healthy controls (HC). The SCFAs' analysis were performed using a gas-chromatography coupled with mass spectrometry method. Data analysis was carried out using Wilcoxon rank-sum test to assess pairwise differences of SCFAs' profiles, partial least squares-discriminate analysis (PLS-DA) to determine the status membership based on distinct SCFAs' profiles, and Dirichlet regression to determine factors influencing concentration levels of SCFAs. RESULTS: We have not observed any difference in the SCFAs' amount and composition between CD and healthy control. On the contrary, the total amount of SCFAs was significantly lower in CRC patients compared to HC (P = 0.044) and CD (P = 0.005). Moreover, the SCFAs' percentage composition was different in CRC and AP compared to HC. In detail, HC displayed higher percentage of acetic acid (P value = 1.3 × 10-6) and a lower amount of butyric (P value = 0.02192), isobutyric (P value = 7.4 × 10-5), isovaleric (P value = 0.00012) and valeric (P value = 0.00014) acids compared to CRC patients. AP showed a lower abundance of acetic acid (P value = 0.00062) and higher percentages of propionic (P value = 0.00433) and isovaleric (P value = 0.00433) acids compared to HC. Moreover, AP showed higher levels of propionic acid (P value = 0.03251) and a lower level of isobutyric acid (P value = 0.00427) in comparison to CRC. The PLS-DA model demonstrated a significant separation of CRC and AP groups from HC, although some degree of overlap was observed between CRC and AP. CONCLUSION: Analysis of fecal SCFAs shows the potential to provide a non-invasive means of diagnosis to detect patients with CRC and AP, while CD patients cannot be discriminated from healthy subjects.

Metabolic Signature of Primary Biliary Cholangitis and Its Comparison with Celiac Disease.

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by ongoing inflammatory destruction of the interlobular bile ducts, eventually leading to chronic cholestasis and biliary cirrhosis. This study primarily aims to define the metabolomic signature of PBC after comparison with healthy controls (HC). Second, it aims to evaluate the possible metabolic association between PBC and celiac disease (CD), an immune-mediated disorder frequently associated with PBC. Serum and urine samples from 20 PBC, 21 CD, and 19 sex-matched HC subjects were collected. 1H nuclear magnetic resonance (NMR) spectra for all samples were acquired, and multivariate statistics were used to evaluate the differences among the three groups and to provide information about the involved metabolites. The classification accuracies to discriminate PBC and HC groups were 78.9-84.6% for serum and 76.9% for urine. In comparison to HC, PBC patient sera were characterized by altered levels ( p value <0.05) of pyruvate, citrate, glutamate, glutamine, serine, tyrosine, phenylalanine, and lactate. PBC patient urine showed lower levels ( p value <0.05) of trigonelline and hippurate with respect to HC. Furthermore, the NMR metabolomic fingerprint was able to cluster PBC with respect to CD patients, and the classification accuracies in the discriminations between these groups were 81.9-91.7% for serum and 77.7% for urine. Our results show that PBC displays a unique metabolomic fingerprint, which led to speculation about an impaired energy metabolism, probably associated with an altered gut microbiota. PBC and CD showed two distinct metabolic fingerprints. These data could provide clues for the comprehension of the PBC pathogenetic mechanisms and the detection of novel therapeutic targets.

Female Patients with Dermatitis Herpetiformis Show a Reduced Diagnostic Delay and Have Higher Sensitivity Rates at Autoantibody Testing for Celiac Disease.

OBJECTIVE: Our objective was to characterize the demographic information, clinical features, and laboratory data of patients with dermatitis herpetiformis (DH). METHODS: In this multicentre cross-sectional study, consecutive patients with a new diagnosis of DH that referred to nine different Italian centers between 2011 and 2016 were characterized assessing demographic, clinical and laboratory findings, and evaluating gender and age differences across selected variables. RESULTS: A total of 151 patients were included. Among them, 81 (53.6%) were males and 70 (46.4%) were females, with a male to female ratio of 1.2 : 1. The median age at the time of diagnosis was 41 years (range 0-85). Males had a significant longer diagnostic delay if compared to females (9 vs. 3 months, respectively; p = 0.01). Direct immunofluorescence was positive in 94.7% of the patients, while duodenal biopsy showed partial to total villous atrophy in 70.1% of patients. All the females resulted positive to at least one of the antibodies tested, while a total of 12 male patients (10.5%) tested negative to celiac-specific antibodies. Female patients had a high rate (14.1%) of autoimmune thyroiditis. CONCLUSIONS: Our study confirmed some of the most relevant data regarding DH that have been previously reported in the literature. In addition, we found a reduced diagnostic delay in females with respect to males, possibly related to the higher sensitivity of serologic testing in females with DH compared to males. Finally, we demonstrated that intestinal involvement could be severe in patients with DH and that females should be tested for thyroiditis.

Human leukocyte antigen DQ2/DQ8 positivity in women with history of stillbirth.

PROBLEM: The aim of this study was to investigate the prevalence of human leukocyte antigens (HLA) DQ2 and DQ8 haplotypes, two common polymorphisms associate with celiac disease (CD), in women with previous stillbirth, but not affected by CD. METHOD OF STUDY: Women with history of unexplained term stillbirth referred to our Center for High-Risk Pregnancies for a preconception counseling, and women with previous uncomplicated pregnancies, were enrolled as cases and controls. Celiac women were excluded from the study. Genetic tests for HLA DQ2/DQ8 were performed, and patients' data were compared. RESULTS: The population included 56 women with a previous term stillbirth and 379 women with history of uncomplicated pregnancies. The prevalence of HLA-DQ2 or DQ8 positivity was significantly higher in cases than in controls (50% vs 29.5%) (P = 0.0031). Women with HLA DQ8 genotype have a significantly higher risk of stillbirth (OR: 2.84 CI: 1.1840-6.817) and in case of DQ2 genotype the OR for stillbirth was even higher (OR: 4.46 CI: 2.408-8.270). In the stillbirth group, SGA neonates were significantly more frequent in those with HLA-DQ2/DQ8 haplotypes than in those resulted negative to genetic testing (85.7% vs 42 .8%, P = 0.004). CONCLUSION: In women with history of term stillbirth, a significantly higher prevalence of HLA DQ2/DQ8 haplotypes has been found compared to women with previous uneventful pregnancies. In addition, HLA DQ2/DQ8 positivity was significantly associated with suboptimal fetal growth in intrauterine fetal death cases, as shown by an increased prevalence of SGA babies.

Regulatory T cells as well as IL-10 are reduced in the skin of patients with dermatitis herpetiformis.

BACKGROUND: Dermatitis herpetiformis (DH) and celiac disease (CD) are considered as autoimmune diseases that share a defined trigger (gluten) and a common genetic background (HLA-DQ2/DQ8). However, the pathogenesis of DH is not fully understood and no data are available about the immune regulation in such a disease. OBJECTIVE: The aim of this study was to assess if alterations in the pattern of the immune response and, in particular, impairments of regulatory T (Tregs) cells may contribute to the phenotypic differences between DH and CD. METHODS: We investigated the presence of Tregs cell markers, in the skin, the duodenum and the blood of patients with DH by immunohistochemistry, confocal microscopy and flow cytometry. As controls, we included patients with bullous pemphigoid, patients with CD without skin lesions, as well as healthy subjects (HS). RESULTS: In the skin of DH patient, we found a significantly lower proportion of FOXP3(+) Tregs and IL-10(+) cells than in HS (p < 0.001 for both cell populations). In duodenal samples, no differences where found in the proportion of Tregs between patients with DH and patients with CD without skin manifestations. Finally, the frequency of CD25(bright)FOXP3(+) cells within the CD4(+) subset was significantly reduced in CD patients either with or without DH with respect to HS (p = 0.029 and p = 0.017, respectively). CONCLUSIONS: Our findings suggested that a reduction of Tregs may play a major role in the skin, leading to a defective suppressive function and thus to the development of the lesions. By contrast, no differences could be detected about Tregs between patients with DH and patients with CD in the duodenum, suggesting that the mechanisms of the intestinal damage are similar in both diseases.