{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T11:07:29Z","timestamp":1777633649702,"version":"3.51.4"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Berotralstat, the first oral plasma kallikrein inhibitor approved for hereditary angioedema (HAE) prophylaxis, may be associated with gastrointestinal (GI) side effects, particularly during the first three months of therapy. Probiotics have been shown to reduce GI disturbances in several conditions. This pilot study described GI tolerability in patients receiving initiation-phase probiotic co-administration alongside berotralstat and explored whether this supportive strategy merits further controlled evaluation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>We analyzed 25 adolescents and adults with HAE treated with berotralstat across six Italian centers (December 2023-November 2025). All patients received probiotics during the early treatment phase. Demographic and clinical data, side effects, and monthly HAE attack rates were collected. Severity of complaints was graded using the Common Terminology Criteria for Adverse Events (CTCAE).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Participants were 60% females, and the mean age for the cohort was 45 years (range 12-82). The most common probiotics were\n                      <jats:italic>\n                        Lacteol\n                        <jats:sup>\u00ae<\/jats:sup>\n                      <\/jats:italic>\n                      ,\n                      <jats:italic>\n                        Codex\n                        <jats:sup>\u00ae<\/jats:sup>\n                      <\/jats:italic>\n                      , and\n                      <jats:italic>\n                        Lactoflorene Plus\n                        <jats:sup>\u00ae<\/jats:sup>\n                      <\/jats:italic>\n                      . GI complaints occurred in 5\/25 patients (20%); only 3\/25 (12%) experienced GI side effects while receiving probiotics. 2\/25 GI complaints occurred after probiotic discontinuation. No serious side effects were reported. Mean monthly attack rate decreased from 2.6 to 0.8 attacks per month, ~3.3-fold reduction from baseline.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Probiotic co-administration during early berotralstat therapy was accompanied by a low incidence of GI side effects, while clinical effectiveness was maintained. These preliminary findings support further controlled studies to validate probiotics as a supportive strategy for improving the tolerability of berotralstat.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1790199","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T04:45:36Z","timestamp":1777437936000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Probiotic supplementation to mitigate berotralstat gastrointestinal side effects: a multicenter case series from the ITACA network"],"prefix":"10.3389","volume":"17","author":[{"given":"Antonio","family":"Gidaro","sequence":"first","affiliation":[{"name":"Internal Medicine, L. Sacco Hospital, Azienda Socio Sanitaria Territoriale (ASST) Fbf-Sacco","place":["Milan, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Domenica","family":"Guarino","sequence":"additional","affiliation":[{"name":"Allergy Unit, Hospital of Civitanova Marche","place":["Civitanova Marche, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Arcoleo","sequence":"additional","affiliation":[{"name":"Azienda Ospedaliera (AO) \u201cOspedali Riuniti Villa Sofia-Cervello\u201d-Presidio Ospedaliero Cervello","place":["Palermo, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donatella","family":"Bignardi","sequence":"additional","affiliation":[{"name":"Department Allergy Unit, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Policlinico San Martino","place":["Genova, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristian","family":"D\u2019Antonio","sequence":"additional","affiliation":[{"name":"Allergy Unit, Santissima (SS) Trinita Borgomanero Hospital, Azienda Sanitaria Locale Novara (ASL NO)","place":["Novara, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa","family":"Brussino","sequence":"additional","affiliation":[{"name":"Allergy and Immunology Unit, Department of Medical Science, University of Turin, Mauriziano Hospital","place":["Turin, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pietro","family":"Accardo","sequence":"additional","affiliation":[{"name":"Azienda Ospedaliera (AO) \u201cOspedali Riuniti Villa Sofia-Cervello\u201d-Presidio Ospedaliero Cervello","place":["Palermo, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefania","family":"Nicola","sequence":"additional","affiliation":[{"name":"Allergy and Immunology Unit, Department of Medical Science, University of Turin, Mauriziano Hospital","place":["Turin, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Pucci","sequence":"additional","affiliation":[{"name":"Allergy Unit, Hospital of Civitanova Marche","place":["Civitanova Marche, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam","family":"Cognigni","sequence":"additional","affiliation":[{"name":"Allergy Unit, Hospital of Civitanova Marche","place":["Civitanova Marche, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Popescu Janu","sequence":"additional","affiliation":[{"name":"Internal Medicine, L. Sacco Hospital, Azienda Socio Sanitaria Territoriale (ASST) Fbf-Sacco","place":["Milan, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Cogliati","sequence":"additional","affiliation":[{"name":"Internal Medicine, L. Sacco Hospital, Azienda Socio Sanitaria Territoriale (ASST) Fbf-Sacco","place":["Milan, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuele","family":"Bizzi","sequence":"additional","affiliation":[{"name":"Internal Medicine, Vita-Salute University San Raffaele","place":["Milan, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mauro","family":"Cancian","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University Hospital of Padua","place":["Padua, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1186\/s13023-022-02360-3","article-title":"The symptom experience of hereditary angioedema (HAE) patients beyond HAE attacks: literature review and clinician interviews","volume":"17","author":"Jean-Baptiste","year":"2022","journal-title":"Orphanet J Rare Dis"},{"key":"B2","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.jaci.2024.03.024","article-title":"Definition, acronyms, nomenclature, and classification of angioedema (DANCE): AAAAI, ACAAI, ACARE, and APAAACI DANCE consensus","volume":"154","author":"Reshef","year":"2024","journal-title":"J Allergy Clin Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1159\/000543321","article-title":"Worldwide prevalence of hereditary angioedema: a systematic review and meta-analysis","volume":"186","author":"Fisch","year":"2025","journal-title":"Int Arch Allergy Immunol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"5879","DOI":"10.1007\/s12325-025-03382-6","article-title":"Therapeutic advances in hereditary angioedema: a focus on present and future options","volume":"42","author":"Uminski","year":"2025","journal-title":"Adv Ther"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1159\/000514973","article-title":"Prophylactic treatment in hereditary angioedema is associated with reduced anxiety in patients in Leipzig, Germany","volume":"182","author":"Zarnowski","year":"2021","journal-title":"Int Arch Allergy Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/all.15214","article-title":"The international WAO\/EAACI guideline for the management of hereditary angioedema\u2014the 2021 revision and update","volume":"77","author":"Maurer","year":"2022","journal-title":"Allergy"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2023.12.046","article-title":"Comorbidities in angioedema due to C1-inhibitor deficiency: an Italian survey","volume":"12","author":"Zanichelli","year":"2024","journal-title":"J Allergy Clin Immunol: In Pract"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1080\/1744666X.2023.2150611","article-title":"A review of berotralstat for the treatment of hereditary angioedema","volume":"19","author":"Farkas","year":"2023","journal-title":"Expert Rev Clin Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.jaci.2020.10.015","article-title":"Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: a randomized, double-blind, placebo-controlled phase 3 trial","volume":"148","author":"Zuraw","year":"2021","journal-title":"J Allergy Clin Immunol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1016\/j.jaip.2023.12.019","article-title":"Once-daily oral berotralstat for long-term prophylaxis of hereditary angioedema: the open-label extension of the APeX-2 randomized trial","volume":"12","author":"Kiani-Alikhan","year":"2024","journal-title":"J Allergy Clin Immunol: In Pract"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/clt2.12035","article-title":"Long\u2010term safety and effectiveness of berotralstat for hereditary angioedema: the open\u2010label APeX\u2010S study","volume":"11","author":"Farkas","year":"2021","journal-title":"Clin Trans All"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.anai.2025.07.012","article-title":"Oral berotralstat for hereditary angioedema prophylaxis in patients aged 2 to <12 years","volume":"135","author":"Bernatoniene","year":"2025","journal-title":"Ann Allergy Asthma Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3390\/medicina61111897","article-title":"Hereditary angioedema prophylaxis therapy: berotralstat and lanadelumab safety profile","volume":"61","author":"Donadoni","year":"2025","journal-title":"Medicina"},{"key":"B14","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.anai.2025.06.004","article-title":"Long-term safety and efficacy of once-daily berotralstat in patients with hereditary angioedema","volume":"135","author":"Farkas","year":"2025","journal-title":"Ann Allergy Asthma Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/all.15641","article-title":"Berotralstat for the prophylaxis of hereditary angioedema\u2014real\u2010world evidence data from the United Kingdom","volume":"78","author":"Ahuja","year":"2023","journal-title":"Allergy"},{"key":"B16","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/j.anai.2022.01.021","article-title":"Gut microbiome alterations in hereditary angioedema","volume":"128","author":"Cao","year":"2022","journal-title":"Ann Allergy Asthma Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.waojou.2022.100694","article-title":"Throat microbiota alterations in patients with hereditary angioedema","volume":"15","author":"Wang","year":"2022","journal-title":"World Allergy Organ J"},{"key":"B18","article-title":"Probiotics for gastrointestinal conditions: a summary of the evidence","volume":"96","author":"Wilkins","year":"2017","journal-title":"Am Fam Physician"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1959","DOI":"10.1001\/jama.2012.3507","article-title":"Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis","volume":"307","author":"Newberry","year":"2012","journal-title":"JAMA"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1080\/01635581.2023.2267779","article-title":"Effects of probiotics on chemotherapy-induced diarrhea","volume":"75","author":"Thet","year":"2023","journal-title":"Nutr Cancer"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2023.110806","article-title":"Effects of combined treatment of probiotics and metformin in management of type 2 diabetes: a systematic review and meta-analysis","volume":"202","author":"Memon","year":"2023","journal-title":"Diabetes Res Clin Pract"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1080\/00031305.1978.10479236","article-title":"Variations of box plots","volume":"32","author":"Mcgill","year":"1978","journal-title":"Am Stat"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/all.70086","article-title":"National audit of long\u2010term real\u2010world outcomes of berotralstat use in UK patients with hereditary angioedema","author":"Elbashir","year":"2025","journal-title":"Allergy"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2025.1634990","article-title":"Efficacy and safety of probiotics as a complementary treatment for urticaria: a systematic review and meta-analysis","volume":"16","author":"Tan","year":"2025","journal-title":"Front Microbiol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1790199\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T04:45:48Z","timestamp":1777437948000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1790199\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,29]]},"references-count":24,"alternative-id":["10.3389\/fimmu.2026.1790199"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1790199","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,29]]},"article-number":"1790199"}}