{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T18:43:36Z","timestamp":1789065816215,"version":"build-2803163510"},"reference-count":49,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T00:00:00Z","timestamp":1745452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background: Probiotics alter gut microbiota and have beneficial effects on immune homeostasis. The role of probiotics in diabetes has been shown in some studies. Interleukin (IL)-21 and IL-22 have been implicated in the pathogenesis of type 1 diabetes mellitus (T1DM). Objectives: This study aimed to assess the effect of oral supplementation with probiotics on glycemic control and IL-21 and IL-22 levels in pediatric patients with T1DM. Methods: This randomized controlled trial was registered in ClinicalTrials (NCT04579341) and included 70 children and adolescents with T1DM. They were randomly assigned into two groups to receive either an oral probiotic tablet containing 0.5 mg Lactobacillus acidophilus once daily or a matching placebo. Both groups were followed up for 6 months with assessment of fasting blood glucose (FBG), lipids, hemoglobin A1c (HbA1c), and IL-21 and IL-22 levels. Results: Baseline clinical characteristics and laboratory parameters were similar between both groups (p &gt; 0.05). After six months, probiotic supplementation for the intervention group resulted in significant decreases in FBG, HbA1c, total cholesterol, and IL-21 levels, while IL-22 was increased compared with baseline levels (p &lt; 0.001) and compared with the placebo group (p &lt; 0.001). No adverse reactions were reported. Baseline IL-21 was positively correlated to FBG, HbA1c, and total cholesterol while there were negative correlations between these variables and IL-22 levels. Conclusions: Probiotic supplementation improved glucose homeostasis and glycemic control, possibly through their immunomodulatory effects on cytokines IL-21 and IL-22. Thus, probiotics could be a safe adjuvant therapy to intensive insulin in pediatric patients with T1DM.<\/jats:p>","DOI":"10.3390\/metabo15050288","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T04:04:50Z","timestamp":1745467490000},"page":"288","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Probiotic Supplementation Improves Glucose Homeostasis and Modulates Interleukin (IL)-21 and IL-22 Levels in Pediatric Patients with Type 1 Diabetes: A Randomized Placebo-Controlled Trial"],"prefix":"10.3390","volume":"15","author":[{"given":"Amira Abdel Moneam","family":"Adly","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo 11591, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1162-0171","authenticated-orcid":false,"given":"Eman Abdel Rahman","family":"Ismail","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo 11591, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahasen Mohamed","family":"Abd-Elgawad","sequence":"additional","affiliation":[{"name":"General Practitioner, Ministry of Health, Cairo 11591, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6507-8835","authenticated-orcid":false,"given":"Nouran Yousef","family":"Salah","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo 11591, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.gtc.2012.08.008","article-title":"Fecal microbiota transplantation: Techniques, applications, and issues","volume":"41","author":"Borody","year":"2012","journal-title":"Gastroenterol. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nature11550","article-title":"Diversity, stability and resilience of the human gut microbiota","volume":"489","author":"Lozupone","year":"2012","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/nature13564","article-title":"Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes","volume":"514","author":"Wang","year":"2014","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1136\/gutjnl-2014-308514","article-title":"Does the microbiota play a role in the pathogenesis of autoimmune diseases?","volume":"64","author":"McLean","year":"2015","journal-title":"Gut"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/nrendo.2015.218","article-title":"The role of the intestinal microbiota in type 1 diabetes mellitus","volume":"12","author":"Knip","year":"2016","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.nut.2011.08.013","article-title":"Probiotic yogurt improves antioxidant status in type 2 diabetic patients","volume":"28","author":"Ejtahed","year":"2012","journal-title":"Nutrition"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4745","DOI":"10.3390\/ijerph110504745","article-title":"Microorganisms with claimed probiotic properties: An overview of recent literature","volume":"11","author":"Fijan","year":"2014","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Liu, Y., Alookaran, J.J., and Rhoads, J.M. (2018). Probiotics in autoimmune and inflammatory disorders. Nutrients, 10.","DOI":"10.20944\/preprints201809.0397.v1"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1128\/AEM.06983-11","article-title":"Differential targeting of the E-cadherin\/\u03b2-catenin complex by Gram-positive probiotic lactobacilli improves epithelial barrier function","volume":"78","author":"Hummel","year":"2012","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_10","first-page":"7","article-title":"Immunomodulatory effects of probiotics on cytokine profiles","volume":"18","author":"Azad","year":"2018","journal-title":"BioMed Res. Int."},{"key":"ref_11","first-page":"104","article-title":"Role of probiotics in diabetes: A review of their rationale and efficacy","volume":"5","author":"Shah","year":"2017","journal-title":"Diabetes"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3676","DOI":"10.1016\/j.jmb.2015.10.013","article-title":"Pathogen resistance mediated by IL-22 signaling at the epithelial\u2013microbiota interface","volume":"427","author":"Schreiber","year":"2015","journal-title":"J. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1038\/nm.3705","article-title":"Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress","volume":"20","author":"Hasnain","year":"2014","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4527","DOI":"10.1038\/s41467-024-48320-2","article-title":"Pancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis","volume":"15","author":"Sajiir","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.2337\/db08-0882","article-title":"Interleukin-21 is required for the development of type 1 diabetes in NOD mice","volume":"58","author":"Sutherland","year":"2009","journal-title":"Diabetes"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1100\/tsw.2007.275","article-title":"Biological functions of interleukin-21 and its role in inflammation","volume":"7","author":"Pelletier","year":"2007","journal-title":"Sci. World J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1007\/s00125-015-3509-8","article-title":"IL-21 production by CD4+ effector T cells and frequency of circulating follicular helper T cells are increased in type 1 diabetes patients","volume":"58","author":"Ferreira","year":"2015","journal-title":"Diabetologia"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Schroderus, A.M., Poorbaugh, J., McElyea, S., Beasley, S., Zhang, L., N\u00e4nt\u00f6-Salonen, K., Rintam\u00e4ki, R., Pihlajam\u00e4ki, J., Knip, M., and Veijola, R. (2023). Evaluation of plasma IL-21 as a potential biomarker for type 1 diabetes progression. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1157265"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/mi.2014.134","article-title":"Interleukin (IL)-21 promotes intestinal IgA response to microbiota","volume":"8","author":"Cao","year":"2015","journal-title":"Mucosal Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"726","DOI":"10.7326\/0003-4819-152-11-201006010-00232","article-title":"CONSORT 2010 statement: Updated guidelines for reporting parallel group randomized trials","volume":"152","author":"Schulz","year":"2010","journal-title":"Ann. Intern. Med."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"American Diabetes Association (2020). 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2020. Diabetes Care, 43, S14\u2013S31.","DOI":"10.2337\/dc20-S002"},{"key":"ref_22","first-page":"228","article-title":"Effect of Probiotic Fermented Milk (Kefir) on Glycemic Control and Lipid Profile In Type 2 Diabetic Patients: A Randomized Double-Blind Placebo-Controlled Clinical Trial","volume":"44","author":"Ostadrahimi","year":"2015","journal-title":"Iran. J. Public. Health"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1111\/pedi.13442","article-title":"ISPAD Clinical Practice Consensus Guidelines 2022: Insulin treatment in children and adolescents with diabetes","volume":"23","author":"Cengiz","year":"2022","journal-title":"Pediatr. Diabetes"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e20171904","DOI":"10.1542\/peds.2017-1904","article-title":"Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents","volume":"140","author":"Flynn","year":"2017","journal-title":"Pediatrics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/j.1524-4733.2007.00213.x","article-title":"Medication compliance and persistence: Terminology and definitions","volume":"11","author":"Cramer","year":"2008","journal-title":"Value Health"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1080\/07853890.2016.1222449","article-title":"Is there a role for gut microbiota in type 1 diabetes pathogenesis?","volume":"49","author":"Bibbo","year":"2017","journal-title":"Ann. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.jaut.2014.03.005","article-title":"Long term effect of gut microbiota transfer on diabetes development","volume":"53","author":"Peng","year":"2014","journal-title":"J. Autoimmun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.clnu.2015.11.011","article-title":"Clinical application of probiotics in type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled study","volume":"36","author":"Tonucci","year":"2017","journal-title":"Clin. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1172\/JCI60530","article-title":"Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice","volume":"122","author":"Takiishi","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2876","DOI":"10.2337\/db13-1236","article-title":"Oral delivery of glutamic acid decarboxylase (GAD)-65 and IL10 by Lactococcus lactis reverses diabetes in recent-onset NOD mice","volume":"63","author":"Robert","year":"2014","journal-title":"Diabetes"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Sato, J., Kanazawa, A., Azuma, K., Ikeda, F., Goto, H., Komiya, K., Kanno, R., Tamura, Y., Asahara, T., and Takahashi, T. (2017). Probiotic reduces bacterial translocation in type 2 diabetes mellitus: A randomised controlled study. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-12535-9"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1111\/j.1365-2672.2009.04350.x","article-title":"Effect of Lactobacillus gasseri BNR17 on blood glucose levels and body weight in a mouse model of type 2 diabetes","volume":"107","author":"Yun","year":"2009","journal-title":"J. Appl. Microbiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/1476-511X-11-29","article-title":"Effect of the consumption of a new symbiotic shake on glycemia and cholesterol levels in elderly people with type 2 diabetes mellitus","volume":"11","author":"Moroti","year":"2012","journal-title":"Lipids Health Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1016\/j.lfs.2006.06.038","article-title":"Effects of the probiotic strain Lactobacillus johnsonii strain La1 on autonomic nerves and blood glucose in rats","volume":"79","author":"Yamano","year":"2006","journal-title":"Life Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1007\/s00125-005-1831-2","article-title":"Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse","volume":"48","author":"Calcinaro","year":"2005","journal-title":"Diabetologia"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7569431","DOI":"10.1155\/2016\/7569431","article-title":"Oral probiotic VSL#3 prevents autoimmune diabetes by modulating microbiota and promoting indoleamine 2,3-dioxygenase-enriched tolerogenic intestinal environment","volume":"2016","author":"Dolpady","year":"2016","journal-title":"J. Diabetes Res."},{"key":"ref_37","first-page":"2963","article-title":"Oral administration of Lactobacillus acidophilus restores nitric oxide level in diabetic rats","volume":"3","author":"Harisa","year":"2009","journal-title":"Aust. J. Basic. Appl. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"96","DOI":"10.3164\/jcbn.11-07","article-title":"Antidiabetic effects of lactic acid bacteria in normal and type 2 diabetic mice","volume":"51","author":"Honda","year":"2012","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.bbrc.2012.12.121","article-title":"Lactobacillus rhamnosus GG improves insulin sensitivity and reduces adiposity in high-fat diet-fed mice through enhancement of adiponectin production","volume":"431","author":"Kim","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/BF03191026","article-title":"Probiotic treatment reduces blood glucose levels and increases systemic absorption of gliclazide in diabetic rats","volume":"33","author":"Butt","year":"2008","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"813","DOI":"10.2337\/diacare.27.3.813","article-title":"Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes","volume":"27","author":"Pickup","year":"2004","journal-title":"Diabetes Care"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2374","DOI":"10.1007\/s00125-007-0791-0","article-title":"Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia","volume":"50","author":"Cani","year":"2007","journal-title":"Diabetologia"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Chiu, Y.H., Lu, Y.C., Ou, C.C., Lin, S.L., Tsai, C.C., Huang, C.T., and Lin, M.Y. (2013). Lactobacillus plantarum MYL26 induces endotoxin tolerance phenotype in Caco-2 cells. BMC Microbiol., 13.","DOI":"10.1186\/1471-2180-13-190"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Datta, S., and Sarvetnick, N.E. (2008). IL-21 limits peripheral lymphocyte numbers through T cell homeostatic mechanisms. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003118"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"14028","DOI":"10.1073\/pnas.0804358105","article-title":"IL-21 signaling is critical for the development of type I diabetes in the NOD mouse","volume":"105","author":"Spolski","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1530\/JME-17-0182","article-title":"Interleukin-22 reverses human islet dysfunction and apoptosis triggered by hyperglycemia and LIGHT","volume":"60","author":"Abadpour","year":"2018","journal-title":"J. Mol. Endocrinol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.numecd.2011.04.008","article-title":"Influence of consumption of probiotics on the plasma lipid profile: A meta-analysis of randomised controlled trials","volume":"21","author":"Guo","year":"2011","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_48","first-page":"38","article-title":"Effect of probiotics on lipid profile, glycemic control, insulin action, oxidative stress, and inflammatory markers in patients with type 2 diabetes: A clinical trial","volume":"38","author":"Mazloom","year":"2013","journal-title":"Iran. J. Med. Sci."},{"key":"ref_49","first-page":"1","article-title":"Probiotics as complementary therapy for hypercholesterolemia","volume":"1","author":"Sudha","year":"2009","journal-title":"Biol. Med."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/5\/288\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:20:27Z","timestamp":1760030427000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/5\/288"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,24]]},"references-count":49,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["metabo15050288"],"URL":"https:\/\/doi.org\/10.3390\/metabo15050288","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,24]]}}}