Mână de mână cu Boala Celiacă (BC)

Proiectul CD SKILLS PP13 a Universității de Stat de Medicină și Farmacie “Nicolae Testemițanu” din Republica Moldova și permisă spre traducere din limba engleză cu suportul tehnic al echipei de implementare: Tatiana Raba, Olesea Nicu, Anton Pivtora

Influence of probiotic Bifidobacterium breve BR03 administration on the level of pro-inflammatory and anti-inflammatory cytokines and short-chain fatty acids in children with celiac disease

Celiakija je imunsko posredovana sistemska bolezen, ki je posledica uživanja glutena. Edini do sedaj učinkovit način zdravljenja je brezglutenska dieta (BGD), dosledno izvajanje le-te pa predstavlja težavo za mnoge osebe s celiakijo. Pri nekaterih osebah kljub strogi BGD simptomi bolezni vztrajajo in pri 40¬¬–50 % je vnetje še vedno prisotno. V več študijah je bilo ugotovljeno, da imajo osebe s celiakijo neravnovesno črevesno mikrobioto (povečan delež gramnegativnih bakterij in zmanjšan delež bifidobakterij), ki ima pomembno vlogo v patogenezi bolezni. Tudi po uvedbi BGD imajo te osebe še vedno zmanjšan delež bifidobakterij. Določene vrste Bifidobacterium breve so v in vitro študijah delovale protivnetno. Cilj doktorske disertacije je bil ugotoviti vpliv 3-mesečnega jemanja Bifidobacterium breve BR03 in B632 (v nadaljevanju probiotik) na provnetni citokin dejavnik tumorske nekroze alfa (TNF-α), protivnetni citokin interlevkin 10 (IL-10) v serumu in na raven kratkoverižnih maščobnih kislin (KVMK) v blatu pri otrocih s celiakijo na BGD. V raziskavo smo vključili 10 otrok z na novo odkrito aktivno celiakijo, 49 otrok s celiakijo na BGD in 18 zdravih otrok. Otroke s celiakijo na BGD smo randomizirali v dve skupini. Prva skupina je 3 mesece prejemala probiotik, druga skupina pa placebo. Meritve citokinov TNF-α in IL-10 so potekale po navodilih proizvajalca z metodo kemiluminiscence na aparatu Immulite One. Iz vzorcev blata smo s pomočjo visokozmogljivostne tekočinske kromatografije analizirali ocetno, propionsko, masleno in mlečno kislino. Fermentacijski indeks ([ocetna kislina] – ([propionska kislina] + [n-maslena kislina]) / [skupne KVMK]) smo uporabili za prikaz vnetnega količnika KVMK. Pri otrocih s celiakijo na BGD je prišlo po jemanju probiotika do značilnega znižanja TNF-α. Ob kontroli, 3 mesece po koncu jemanja probiotika, se je raven TNF-α ponovno značilno dvignila. Vrednosti IL-10 so bile pri večini otrok pod ravnjo kvantifiacije. Otroci z aktivno celiakijo so imeli značilno višje začetne vrednosti ocetne in propionske kisline v blatu v primerjavi z zdravimi otroki. Otroci s celiakijo na BGD so imeli značilno več propionske kisline v primerjavi z zdravimi otroki. Vrednosti mlečne kisline so bile pri večini otrok pod ravnjo kvantifikacije. Po jemanju probiotika ni prišlo do značilnih sprememb vrednosti KVMK v blatu. Fermentacijski indeks (FI) se je 3 mesece po koncu uživanju probiotika še značilno znižal, kar nakazuje zmanjšanje vnetja na ravni črevesja. Z raziskavo smo dokazali, da sta izbrana probiotična seva Bifidobacterium breve BR03 in B632 delovala protivnetno, saj so se po jemanju le-teh vrednosti TNF-α v serumu značilno znižale in nakazano se je znižal FI, ki ponazarja aktivnost kroničnega, s črevesno floro povezanega vnetja.Celiac disease (CD) is an immune-mediated disorder triggered by ingestion of gluten. Gluten-free diet (GFD) has so far proved to be the only effective treatment. Many patients with CD have problems with full compliance to GFD. Symptoms persist in some patients despite strict GFD and in 40¬¬–50 % of them inflammation is still present. Increasing evidence suggests that persons with CD have gut microbiota dysbiosis (increased number of Gram negative bacteria and decreased number of bifidobacteria), which play an important role in the disease pathogenesis. Even after a long-term treatment with GFD patients have a decreased number of bifidobacteria. Some strains of Bifidobacterium breve have shown in vitro anti-inflammatory effect on the gut level. The aim of doctoral dissertation was to investigate the influence of three months administration of Bifidobacterium breve BR03 and B632 (afterwards probiotic) on the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α), anti-inflammatory cytokine interleukin 10 (IL-10) in serum and on the level of short chain fatty acids (SCFA) in faeces of children with celiac disease on GFD. Clinical study was conducted on 10 children with newly diagnosed active CD, 49 children with CD on GFD and 18 healthy children. Children with CD on GFD were randomized in two groups. The first group received probiotic for three months and the second group was administered placebo. Measurements of cytokines TNF-α and IL-10 was performed according to the manufacturer’s instructions with chemiluminescent immunometric assay in Immulite One. Faecal samples were analyzed for acetic, propionic, butyric and lactic acid with high performance liquid chromatography. Fermentation index ([acetic acid] – ([propionic acid] + [n-butyric acid]) / [total SCFAs]) was used for the assessment of inflammatory status in the gut of patients. TNF-α levels were significantly decreased in children with CD on GFD after receiving probiotics for three months. At checkup, three months after the end of intervention with probiotics, TNF-α significantly increased again. IL-10 levels were below the detection level in most of the children. Children with an active CD had significantly higher baseline levels of acetic and propionic acid in faeces compared to healthy children. Children with CD on GFD had significantly higher baseline levels of propionic acid in faeces compared to the healthy children. Lactic acid levels were below detection level in most of the children. After probiotic administration there was no significant differences in individual SCFA levels in faeces. However, faecal fermentation index was significantly decreased three months after the end of probiotic intervention, suggesting a decrease of inflammation on the gut level. Our study has shown that selected B. breve strains have an anti-inflammatory effect. After administration of the probiotic, TNF-α levels in serum as well as faecal FI decreased, which represents chronical, gut microbiota-mediated inflammation

Organization and function of gut microflora

Črevesna mikrobiota je sestavljena iz 10-100 trilijonov mikrobov s presnovno dejavnostjo, enako nekakemu organu v organu in igra ključno vlogo v vzdrževanju črevesne homeostaze. Sestava črevesne flore se spreminja vzdolž prebavne cevi. Dejavniki, ki vplivajo na kolonizacijo črevesne flore novorojenčkov, so način poroda, vrsta hranjenja dojenčkov, bolezen in nedonošenost. Prehrana igra prevladujočo vlogo glede na ostale okoljske dejavnike. Namen članka je predstaviti dosedanje znanje s področja organiziranosti in vloge črevesne flore.The human intestinal microbiota is composed of 10 to 100 trillion microbes whose metabolic activity equals to a virtual organ within an organ. Gut microflora have a crucial role in the maintenance of intestinal homeostasis. The composition of gut microflora is changing along the gastrointestinal tract. Factors that affect colonization of newborn’s gut microbiota are delivery mode, type of feeding, illness and prematurity. Our diet has a dominant role in shaping the microbial composition of the gut over other inviromental factors. The aim of this article is to introduce up-to-date knowledge of the organization and function of gut microflora

Safety beyond Sight: Handheld Metal Detectors as Diagnostic Allies in the Management of Children Suspected to have Ingested Foreign Bodies

Background. Foreign body (FB) ingestion remains a common cause of pediatric emergency department referrals, and the gold standard for detection is whole-digestive-tract radiographic examination. Our study explores whether handheld metal detectors (HHMD) can effectively identify the presence and location of ingested metal objects, potentially reducing the need for additional radiographic examination. Methods. We collected medical data from children with suspected metal FB ingestion who were referred to our emergency department (October 2017–March 2023), focusing on object type and correlating metal detector findings with radiographic images. Results. Data from 43 children (39.5% female; mean age: 4 y) referred to our emergency department were analyzed. Coins (32.6%), button batteries (18.6%), and hairpins (11.6%) were the most common ingested objects. Metal detectors detected the presence of FBs in 81.4% of cases (sensitivity: 89.7%; specificity: 100%). Radiographs, taken for 40 children, showed that the most common locations were the stomach (37%) and intestine (33%). The metal detector signals matched the radiography results in 69.8% of cases. According to HHMD, 34.9% of objects were accessible via endoscopy, contrasting with 51.2% via radiography (p < 0.05). Conclusion. While the findings obtained using handheld metal detectors often correlate well with radiograph findings in detecting metal FBs, for an important number of children, this confirmation is lacking, especially when determining the exact location of an object

Diagnostic Delays in Children with Coeliac Disease in the Central European Region

OBJECTIVES: Coeliac disease (CD) is a systemic autoimmune disorder affecting about 1% of the population. Many patients remain undiagnosed or are diagnosed with substantial delay. We assessed diagnostic delays in symptomatic CD children in Central Europe (CE). METHODS: Paediatric gastroenterologists in five CE countries retrospectively reported data of their patients diagnosed in 2016. Age at first CD related symptom(s), first visit to paediatric gastroenterologist and confirmed diagnosis were used to determine diagnostic delays. RESULTS: Data from 393 children (65% female, median age 7 years, range 7m-18.5y) from Croatia, Hungary, Germany, Italy and Slovenia were analysed. Median duration from first symptom(s) to visit to paediatric gastroenterologist was 5 months (range 0-10y; preschool 4m, school-aged 5m), and further duration until final diagnosis was 1 month (range 0-5y) with significant regional differences (p\u200a<\u200a0.001). Median diagnostic delay was 6 months (range 0-10y; preschool 5m, school-aged 7m). Type of clinical presentation had little, however significant effect on delays. Reduced body mass in delays longer than 3 years compared to delays shorter than 1 year was found (z-score -0.93 vs -0.39, p\u200a<\u200a0.05). CONCLUSIONS: Time from first symptoms to CD diagnosis in children in five CE countries is slightly shorter compared to few other small paediatric studies, and significantly shorter than reported for adults. Nevertheless, delays of more than 3 years in 6.6% of children are worrisome. Raising awareness about the variable symptoms and implementation of reliable diagnostic tools will further reduce diagnostic delays

Clinical intervention using Bifidobacterium strains in celiac disease children reveals novel microbial modulators of TNF-\u3b1 and short-chain fatty acids

Background & aims: Celiac disease (CD) is an immune-mediated systemic disease, caused by ingestion of gluten in genetically predisposed individuals. Gut microbiota dysbiosis might play a significant role in pathogenesis of chronic enteropathies and its modulation can be used as an intervention strategy in CD as well. In this study, we aimed to identify correlations between fecal microbiota, serum tumor necrosis factor alpha (TNF-\u3b1) and fecal short-chain fatty acids (SCFAs) in healthy children and children with CD after administration of probiotic Bifidobacterium breve BR03 and B632. Methods: A double-blind placebo-controlled study enrolled 40 children with CD (CD) and 16 healthy children (HC). CD children were randomly allocated into two groups, of which 20 belonged to the placebo (PL) group and 20 to the Probiotic (PR) group. The PR group received a probiotic formulation containing a mixture of 2 strains, B. breve BR03 (DSM 16604) and B. breve B632 (DSM 24706) in 1:1 ratio for 3 months. Subsequently, for statistical analysis, blood and fecal samples from CD children (on enrolment - T0 and after 3 months, at the end of intervention with probiotic/placebo - T1) and HC children were used. The HC group was sampled only once (T0). Results: Verrucomicrobia, Parcubacteria and some yet unknown phyla of Bacteria and Archaea may be involved in the disease, indicated by a strong correlation to TNF-\u3b1. Likewise, Proteobacteria strongly correlated with fecal SCFAs concentration. The effect of probiotic administration has disclosed a negative correlation between Verrucomicrobia, some unknown phyla of Bacteria, Synergistetes, Euryarchaeota and some SCFAs, turning them into an important target in microbiome restoration process. Synergistetes and Euryarchaeota may have a role in the anti-inflammatory process in healthy human gut. Conclusions: Our results highlight new phyla, which may have an important relation to disease-related parameters, CD itself and health

Clinical Presentation in Children With Coeliac Disease in Central Europe

Objectives: During the past decades, there has been a shift in the clinical presentation of coeliac disease (CD) to nonclassical, oligosymptomatic, and asymptomatic forms. We assessed clinical presentation of CD in children and adolescents in Central Europe. Methods: Paediatric gastroenterologists in 5 countries retrospectively reported data of their patients diagnosed with CD. Clinical presentation was analyzed and the differences among very young (<3 years) and older children and adolescents were studied. Results: Data from 653 children and adolescents (median age 7 years 2 months; 63.9% girls) from Croatia, Germany, Hungary, Italy, and Slovenia were available for the analysis. One fifth (N = 134) of all children were asymptomatic. In symptomatic children, the most common leading symptom was abdominal pain (33.3%), followed by growth retardation (13.7%) and diarrhoea (13.3%). The majority of symptomatic children (47.6%; N = 247) were polysymptomatic. Abdominal pain was the most common symptom in polysymptomatic (66.4%) as well as in monosymptomatic children (29.7%). Comparing clinical presentation of CD in very young children (younger than 3 years) with older children (3 years or older), we found that symptoms and signs of malabsorption were significantly more common in younger (P < 0.001), whereas abdominal pain and asymptomatic presentation were more common in older children and adolescents (both P < 0.001). Conclusion: In children with CD, abdominal pain has become the most common symptom. However, in younger children, symptoms of malabsorption are still seen frequently. This raises a question about the underlying mechanism of observed change in clinical presentation in favour of nonclassical presentation and asymptomatic disease at certain age

The Knowledge About Celiac Disease Among Healthcare Professionals and Patients in Central Europe

OBJECTIVES: Celiac disease (CD) remains undiagnosed for a long time in many adult and pediatric patients. We assessed the knowledge about CD among healthcare professionals (HCPs) and CD patients in Central Europe (CE). METHODS: HCPs and CD patients from 5 CE countries were asked to complete the web-based questionnaire about CD. The questions were divided into subsections on epidemiology, clinical presentation, diagnostics, treatment, and follow-up. Achieved scores of different specialists managing patients with CD were compared and regional differences in patients' knowledge were analyzed. RESULTS: Questionnaire was completed by 1381 HCPs and 2262 CD patients or their caregivers from Croatia, Hungary, Germany, Italy, and Slovenia. Mean score achieved by HCPs was 50.9%, and by CD patients 56.4%. Pediatric gastroenterologists scored the highest (69.4%; P < 0.001). There were significant differences in knowledge of patients from different CE regions with German participants scoring the highest (58.3%). Members of CD societies scored higher compared with nonmembers (mean score 58% vs 53.2%; P < 0.001) and patients diagnosed less than 5 years ago scored higher compared with those diagnosed more than 10 years ago (mean score 57.3% vs 54.6%; P < 0.001). CONCLUSIONS: The knowledge about CD among HCPs and CD patients is not satisfactory. Further awareness-raising and learning activities are needed to improve HCPs' knowledge and to minimize the number of unrecognized patients and unnecessary diagnostic delays. Patients should be better informed about their disease to reach higher compliance with the gluten-free diet

Management of coeliac disease patients after the confirmation of diagnosis in Central Europe

Background Recently published paediatric guidelines for diagnosing coeliac disease do not include recommendations on the follow-up of coeliac disease patients. Goal The aim of this study was to assess the management practices and experience of coeliac disease patients with their follow-up appointments in Central Europe. Study Gastroenterologists and coeliac disease patients in five Central European countries were asked to complete the webbased questionnaire focusing on coeliac disease management practices. Results Answers from 147 gastroenterologists and 2041 coeliac disease patients were available for the analysis. More than half of the gastroenterologists (58.5%) schedule the first follow-up visit within 3 months after the diagnosis. At follow-up, tissue transglutaminase antibodies are checked in almost all patients (95.9%). Approximately two-thirds (60.7%) of gastroenterologists refer all of their patients to the dietitian at diagnosis. Similarly, 42.8% of coeliac disease patients reported that they had not been appointed to a dietitian. Almost one-third of coeliac disease patients (30.8%) reported that they had no follow-up appointments with gastroenterologist at all. Conclusions Follow-up of coeliac disease patients is suboptimal in Central Europe. Many patients are not followed regularly. A lot of patients are not referred to a dietitian. The recommendations on the optimal follow-up of coeliac disease patients are needed in order to improve patient care

Management of Helicobacter pylori infection in paediatric patients in Europe: results from the EuroPedHp Registry

Purpose: The EuroPedHp-registry aims to monitor guideline-conform management, antibiotic resistance, and eradication success of 2-week triple therapy tailored to antibiotic susceptibility (TTT) in Helicobacter pylori-infected children. Methods: From 2017 to 2020, 30 centres from 17 European countries reported anonymized demographic, clinical, antibiotic susceptibility, treatment, and follow-up data. Multivariable logistic regression identified factors associated with treatment failure. Results: Of 1605 patients, 873 had follow-up data (53.2% female, median age 13.0 years, 7.5% with ulcer), thereof 741 (85%) treatment naïve (group A) and 132 (15%) after failed therapy (group B). Resistance to metronidazole was present in 21% (A: 17.7%, B: 40.2%), clarithromycin in 28.8% (A: 25%, B: 51.4%), and both in 7.1% (A: 3.8%, B: 26.5%). The majority received 2-week tailored triple therapy combining proton pump inhibitor (PPI), amoxicillin with clarithromycin (PAC) or metronidazole (PAM). Dosing was lower than recommended for PPI (A: 49%, B: 41%) and amoxicillin (A: 6%, B: 56%). In treatment naïve patients, eradication reached 90% (n = 503, 95% CI 87–93%) and 93% in compliant children (n = 447, 95% CI 90–95%). Tailored triple therapy cured 59% patients after failed therapy (n = 69, 95% CI 48–71%). Treatment failure was associated with PAM in single clarithromycin resistance (OR = 2.47, 95% CI 1.10–5.53), with PAC in single metronidazole resistance (OR = 3.44, 95% CI 1.47–8.08), and with low compliance (OR = 5.89, 95% CI 2.49–13.95). Conclusions: Guideline-conform 2-weeks therapy with PPI, amoxicillin, clarithromycin or metronidazole tailored to antibiotic susceptibility achieves primary eradication of ≥ 90%. Higher failure rates in single-resistant strains despite tailored treatment indicate missed resistance by sampling error.SCOPUS: ar.jinfo:eu-repo/semantics/publishe