{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:10:39Z","timestamp":1791418239606,"version":"4.3.3"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"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. Pharmacol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Live combined <jats:italic>Bacillus subtilis<\/jats:italic> and <jats:italic>Enterococcus faecium<\/jats:italic> (LCBE) provides favorable clinical benefits in patients with constipation, although a comprehensive evaluation is lacking. This meta-analysis aimed to thoroughly evaluate the efficacy and safety of LCBE in patients with constipation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Randomized controlled trials (RCTs) assessing the efficacy or safety of LCBE in patients with constipation, published before September 2025, were comprehensively searched for in Wan Fang, China National Knowledge Infrastructure, China Science and Technology Journal Database, Web of Science, Cochrane Library, and PubMed. Efficacy and safety outcomes were extracted.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 32 studies were included, containing 1,565 patients receiving LCBE and control treatment (experimental group) and 1,490 patients receiving control treatment alone (control group). The experimental group showed a higher total effective rate [odds ratio (OR) (95% confidence interval (CI)) = 5.789 (4.598\u20137.288); <jats:italic>p<\/jats:italic> &amp;lt; 0.001], Bristol Stool Scale score [standardized mean difference (SMD) (95% CI) = 2.532 (1.274\u20133.790); <jats:italic>p<\/jats:italic> &amp;lt; 0.001], defecation frequency per week [SMD (95% CI) = 1.937 (1.252\u20132.623); <jats:italic>p<\/jats:italic> &amp;lt; 0.001], and defecation rate within 24\u00a0h [OR (95% CI) = 2.545 (1.377\u20134.705); <jats:italic>p<\/jats:italic> = 0.003] than the control group. The defecation difficulty score tended to decrease in the experimental group relative to that in the control group, although this did not reach statistical significance [SMD (95% CI) = \u22121.924 (\u22123.947 to 0.099); <jats:italic>p<\/jats:italic> = 0.062]. There was no difference in the total adverse reaction rate between groups [OR (95% CI) = 0.703 (0.414\u20131.191); <jats:italic>p<\/jats:italic> = 0.190]. Subgroup analyses suggested that LCBE was effective, regardless of dosage form or treatment course. All studies were of moderate-to-high quality.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>LCBE demonstrates a favorable efficacy and good tolerability in patients with constipation. This meta-analysis provides supportive evidence for its clinical application in the management of constipation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1688544","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T08:07:16Z","timestamp":1760515636000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Efficacy and safety of live combined Bacillus subtilis and Enterococcus faecium in patients with constipation: a meta-analysis of randomized controlled trials"],"prefix":"10.3389","volume":"16","author":[{"given":"Wenwen","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangcai","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1080\/17474124.2020.1708718","article-title":"An approach to the diagnosis and management of Rome IV functional disorders of chronic constipation","volume":"14","author":"Aziz","year":"2020","journal-title":"Expert Rev. Gastroenterology and Hepatology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"277","DOI":"10.23736\/s2724-5985.22.03335-6","article-title":"Chronic constipation: from pathophysiology to management","volume":"69","author":"Barbara","year":"2023","journal-title":"Minerva Gastroenterol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.1053\/j.gastro.2019.12.034","article-title":"Mechanisms, evaluation, and management of chronic constipation","volume":"158","author":"Bharucha","year":"2020","journal-title":"Gastroenterology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"247","DOI":"10.2174\/1389450124666221209123541","article-title":"Potential targets in constipation research: a review","volume":"24","author":"Bisht","year":"2023","journal-title":"Curr. Drug Targets"},{"key":"B5","doi-asserted-by":"publisher","first-page":"625","DOI":"10.13381\/j.cnki.cjm.2012.07.022","article-title":"Clinical efficacy of lactulose combined with medilac-s in the treatment of functional constipation","volume":"24","author":"Cao","year":"2012","journal-title":"Chin. J. Microecology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"6022","DOI":"10.3390\/ijms25116022","article-title":"Effects of probiotics on gut microbiota: an overview","volume":"25","author":"Chandrasekaran","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"154","DOI":"10.14163\/j.cnki.11-5547\/r.2014.05.187","article-title":"Effect of lactulose oral solution combined with mommy on the treatment of intractable constipation in children","volume":"9","author":"Chen","year":"2014","journal-title":"China Pract. Med."},{"key":"B8","first-page":"618","article-title":"Efficacy of live combined bacillus subtilis and bacillus subtilis granules in the treatment of functional constipation in children","volume":"28","author":"Chen","year":"2013","journal-title":"Chin. J. Pract. Pediatr."},{"key":"B9","doi-asserted-by":"publisher","first-page":"4628","DOI":"10.3969\/j.issn.1001-4411.2007.32.066","article-title":"Clinical observation of live combined Bacillus subtilis and Enterococcus faecium granules in the treatment of functional constipation in infants","volume":"22","author":"Cheng","year":"2007","journal-title":"Maternal Child Health Care China"},{"key":"B10","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3969\/j.issn.1671-332X.2011.06.005","article-title":"The therapeutic effects of Medilac-S combined with lactulose on chronic functional constipation","volume":"11","author":"Deng","year":"2011","journal-title":"Mod. Hosp."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1007\/s12603-023-2028-4","article-title":"Efficacy and safety of probiotics in geriatric patients with constipation: systematic review and meta-analysis","volume":"27","author":"Deng","year":"2023","journal-title":"J. Nutr. health and aging"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1999","DOI":"10.1007\/s00394-024-03410-1","article-title":"Network meta-analysis of probiotics, prebiotics, and synbiotics for the treatment of chronic constipation in adults","volume":"63","author":"Deng","year":"2024","journal-title":"Eur. J. Nutr."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.3945\/ajcn.114.089151","article-title":"The effect of probiotics on functional constipation in adults: a systematic review and meta-analysis of randomized controlled trials","volume":"100","author":"Dimidi","year":"2014","journal-title":"Am. J. Clin. Nutr."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e074557","DOI":"10.1136\/bmjopen-2023-074557","article-title":"Efficacy in bowel movement and change of gut microbiota on adult functional constipation patients treated with probiotics-containing products: a systematic review and meta-analysis","volume":"14","author":"Ding","year":"2024","journal-title":"BMJ open"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1438778","DOI":"10.3389\/fmicb.2024.1438778","article-title":"Causal relationship between gut microbiota and constipation: a bidirectional Mendelian randomization study","volume":"15","author":"Feng","year":"2024","journal-title":"Front. Microbiol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"507","DOI":"10.3969\/j.issn.1671-4695.2013.07.011","article-title":"The therapeutic effect of living Bacillus subtilis and Enterococcus faecium combined with lactulose in treatment of chronic functional constipation","volume":"12","author":"Fu","year":"2013","journal-title":"J. Clin. Exp. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"878","DOI":"10.3969\/J.issn.1004-7115.2014.07.014","article-title":"Therapeutic effects of Medilac-S combined with Lactulose on chronic functional constipation","volume":"35","author":"Ge","year":"2014","journal-title":"J. Taishan Med. Coll."},{"key":"B18","doi-asserted-by":"publisher","first-page":"128","DOI":"10.16662\/j.cnki.1674-0742.2017.26.128","article-title":"Efficacy of testa Triticum tricum purif combined with medilac-S in the treatment of adult constipation","volume":"36","author":"Guo","year":"2017","journal-title":"China Foreign Med. Treat."},{"key":"B19","doi-asserted-by":"publisher","first-page":"104","DOI":"10.15887\/j.cnki.13-1389\/r.2020.31.048","article-title":"Clinical effect of lactulose oral solution combined with live combined bacillus subtilis and bacillus subtilis in the treatment of functional constipation in children","volume":"13","author":"He","year":"2020","journal-title":"Chin. J. Clin. Ration. Drug Use"},{"key":"B20","doi-asserted-by":"publisher","first-page":"153","DOI":"10.3389\/fcimb.2017.00153","article-title":"Positive effect of probiotics on constipation in children: a systematic review and meta-analysis of six randomized controlled trials","volume":"7","author":"Huang","year":"2017","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"B21","first-page":"14","article-title":"The therapeutic effects of medilac-SIVith liuwei-anxiao on chronic functional constipation","volume":"12","author":"Huang","year":"2014","journal-title":"Guide China Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"fnad118","DOI":"10.1093\/femsle\/fnad118","article-title":"Enterococcus faecium R-026 combined with Bacillus subtilis R-179 alleviate hypercholesterolemia and modulate the gut microbiota in C57BL\/6 mice","volume":"370","author":"Huang","year":"2023","journal-title":"FEMS Microbiol. Lett."},{"key":"B23","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1080\/07388551.2024.2336531","article-title":"How do probiotics alleviate constipation? A narrative review of mechanisms","volume":"45","author":"Huang","year":"2025","journal-title":"Crit. Rev. Biotechnol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1159\/000540912","article-title":"Evidence-based clinical guidelines for chronic constipation 2023","volume":"106","author":"Ihara","year":"2025","journal-title":"Digestion"},{"key":"B25","first-page":"413","article-title":"The effects of probiotics on symptoms of irritable bowel syndrome","volume":"47","author":"Kim","year":"2006","journal-title":"Korean J. gastroenterology Taehan Sohwagi Hakhoe chi"},{"key":"B26","doi-asserted-by":"publisher","first-page":"92","DOI":"10.3969\/j.issn.1672-2159.2015.02.004","article-title":"The effect of Medilac-s combined with lactulose in the treatment of adult functional constipation","volume":"20","author":"Kong","year":"2015","journal-title":"Mod. Dig. and Intervention"},{"key":"B27","doi-asserted-by":"publisher","first-page":"316","DOI":"10.11569\/wcjd.v24.i2.316","article-title":"Therapeutic effects of lactulose in combination with live combined Bacillus subtilis and Enterococcus faecium enteric-coated Capsuless in elderly patients with chronic functional constipation","volume":"24","author":"Liang","year":"2016","journal-title":"World Chin. J. Dig."},{"key":"B28","doi-asserted-by":"publisher","first-page":"176","DOI":"10.3969\/j.issn.1002-1256.2019.02.019","article-title":"The short-term and long-term efficacy of live combined Bacillus subtilis and bacillus subtilis combined with lactulose in the treatment of functional constipation in children","volume":"40","author":"Liang","year":"2019","journal-title":"J. Qiqihar Univ. Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"34","DOI":"10.7704\/kjhugr.2022.0051","article-title":"Probiotic supplementation for treatment of Helicobacter pylori infection: a double-blind randomized clinical trial","volume":"23","author":"Lim","year":"2023","journal-title":"Korean J. helicobacter Up. Gastrointest. Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"111","DOI":"10.3969\/j.issn.1006-2238.2013.02.007","article-title":"Effects of Medilac-S combined with Lactulose on treating functional constipation in geriatrics","volume":"48","author":"Liu","year":"2013","journal-title":"Jiangxi Med. J."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.13241\/j.cnki.pmb.2021.08.005","article-title":"Characterization and genome analysis of Enterococcus faecium and Bacillus subtilis","volume":"21","author":"Liu","year":"2021","journal-title":"Prog. Mod. Biomedcine"},{"key":"B32","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1186\/s12876-025-03774-6","article-title":"Clinical practice guidelines for the diagnosis of constipation-predominant irritable bowel syndrome and functional constipation in adults: a scoping review","volume":"25","author":"Luo","year":"2025","journal-title":"BMC Gastroenterol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"103","DOI":"10.3969\/j.issn.2095-3097.2017.02.010","article-title":"Effect of live combined b.subtilis and e.faecium enteric-coated Capsuless combined with mosapride on functional constipation and analysis of clinical observation in personnel undertaking long voyage","volume":"6","author":"Lv","year":"2017","journal-title":"Transl. Med. J."},{"key":"B34","doi-asserted-by":"publisher","first-page":"10","DOI":"10.3760\/cma.j.issn.1674-4756.2013.10.005","article-title":"Effect of Medilac-S combined with macrogol 4000 powder on chronic functional constipation","volume":"40","author":"Ma","year":"2013","journal-title":"Chin. J. Pract. Med."},{"key":"B35","article-title":"Clinical efficacy of mommy love in the treatment of children with functional constipation","author":"Mao","year":"2013","journal-title":"Seek Med. Ask Medicine"},{"key":"B36","doi-asserted-by":"publisher","first-page":"61","DOI":"10.3969\/j.issn.1009-4393.2014.33.044","article-title":"Clinical treatment of functional constipation in children","volume":"20","author":"Peng","year":"2014","journal-title":"Contemp. Med."},{"key":"B37","first-page":"118","article-title":"Efficacy of lactulose oral solution combined with live combined Bacillus subtilis and bacillus subtilis granules in the treatment of functional constipation in infants","volume":"14","author":"Peng","year":"2016","journal-title":"Contemp. Med. Forum"},{"key":"B38","doi-asserted-by":"publisher","first-page":"2367","DOI":"10.3969\/j.issn.1001-8174.2018.15.008","article-title":"Effects of live combined Bacillus subtilis and Bacillus subtilis enteric-coated Capsuless and lactitol on senile constipation","volume":"29","author":"Qi","year":"2018","journal-title":"Mod. Diagnosis Treat."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1753","DOI":"10.14309\/ajg.0000000000001945","article-title":"Recognizing and defining occasional constipation: expert consensus recommendations","volume":"117","author":"Rao","year":"2022","journal-title":"Am. J. gastroenterology"},{"key":"B40","doi-asserted-by":"publisher","first-page":"778","DOI":"10.3390\/nu16060778","article-title":"Prebiotics and probiotics for gastrointestinal disorders","volume":"16","author":"Rau","year":"2024","journal-title":"Nutrients"},{"key":"B41","first-page":"299","article-title":"Chronic constipation in adults","volume":"106","author":"Sadler","year":"2022","journal-title":"Am. Fam. Physician"},{"key":"B42","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/164_2016_111","article-title":"Constipation: pathophysiology and current therapeutic approaches","volume":"239","author":"Sharma","year":"2017","journal-title":"Handb. Exp. Pharmacol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.ejps.2015.02.015","article-title":"Orodispersible drug formulations for children and elderly","volume":"75","author":"Slavkova","year":"2015","journal-title":"Eur. J. Pharm. Sci. official J. Eur. Fed. Pharm. Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: a revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"Bmj"},{"key":"B45","doi-asserted-by":"publisher","first-page":"20","DOI":"10.3969\/j.issn.1671-8194.2009.04.009","article-title":"A clinical conventionalled study of medilac-S and liuwei-anxiao capsuless in patients with functional constipation","volume":"7","author":"Tang","year":"2009","journal-title":"Guide China Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s41575-019-0222-y","article-title":"Management of functional constipation in children and adults","volume":"17","author":"Vriesman","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"48","DOI":"10.3969\/j.issn.1000-1174.2020.12.022","article-title":"Lactulose oral liquid combined with Bacillus subtilis bigeminy(live)in the treatment of infantile functional constipation: clinical study on 30 cases","volume":"40","author":"Wang","year":"2020","journal-title":"Chin. J. Coloproctology"},{"key":"B48","doi-asserted-by":"publisher","first-page":"208","DOI":"10.3969\/j.issn.1008-6455.2012.14.149","article-title":"Clinical observation of lactulose combined with microecological agents in the treatment of 120 cases of functional constipation","volume":"21","author":"Wu","year":"2012","journal-title":"Chin. J. Aesthetic Med."},{"key":"B49","doi-asserted-by":"publisher","first-page":"847","DOI":"10.7501\/j.issn.1674-6376.2016.05.030","article-title":"Long-term efficacy of medilac-vita combined with lactulose in treatment of functional constipation in children","volume":"39","author":"Wu","year":"","journal-title":"Drug Eval. Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"90","DOI":"10.3969\/j.issn.1008-7125.2016.02.006","article-title":"Therapeutic efficacy of lactulose combined with Bacillus subtilis and Enterococcus faecium preparation on chronic constipation","volume":"21","author":"Wu","year":"","journal-title":"Chin. J. Gastroenterology"},{"key":"B51","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1093\/postmj\/qgae112","article-title":"Chronic constipation and gut microbiota: current research insights and therapeutic implications","volume":"100","author":"Xu","year":"2024","journal-title":"Postgrad. Med. J."},{"key":"B52","first-page":"188","article-title":"A report of 40 cases of infantile constipation treated by live combined Bacillus subtilis and Enterococcus faecium granules with multivitamines","volume":"1","author":"Yang","year":"1999","journal-title":"Chin. J. Contemp. Pediatr."},{"key":"B53","doi-asserted-by":"publisher","first-page":"22","DOI":"10.3969\/j.issn.1674-0742.2008.36.015","article-title":"Clinical observation of live combined Bacillus subtilis and Enterococcus faecium granules in the treatment of functional constipation in infants","volume":"27","author":"Yi","year":"2008","journal-title":"China Foreign Med. Treat."},{"key":"B54","doi-asserted-by":"publisher","first-page":"52","DOI":"10.3969\/j.issn.1005-8257.2022.15.024","article-title":"Research of clinical effect by Medilac-vita in the treatment of pediatric constipation","volume":"29","author":"Zeng","year":"2022","journal-title":"Cap. Food Med."},{"key":"B55","doi-asserted-by":"publisher","first-page":"61","DOI":"10.3969\/j.issn.1671-945X.2016.07.041","article-title":"Efficacy of live combined bacillus subtilis and bacillus subtilis granules on the treatment of functional constipation in children","volume":"14","author":"Zhang","year":"2016","journal-title":"J. China Prescr. Drug"},{"key":"B56","doi-asserted-by":"publisher","first-page":"30","DOI":"10.3969\/j.issn.1006-5180.2019.02.018","article-title":"Effect of lactulose combined with live combined bacillus subtilis enteric-coated Capsuless on senile functional constipation","volume":"26","author":"Zhang","year":"2019","journal-title":"Chin. J. Rural Med. Pharm."},{"key":"B57","doi-asserted-by":"publisher","first-page":"111","DOI":"10.14164\/j.cnki.cn11-5581\/r.2017.10.052","article-title":"Research of clinical effect by Medilac-vita in the treatment of pediatric constipation","volume":"11","author":"Zhang","year":"2017","journal-title":"Chin. J. Mod. Drug Appl."},{"key":"B58","doi-asserted-by":"publisher","first-page":"2960","DOI":"10.1016\/j.clnu.2020.01.005","article-title":"Meta-analysis of randomized controlled trials of the effects of probiotics on functional constipation in adults","volume":"39","author":"Zhang","year":"2020","journal-title":"Clin. Nutr. Edinb. Scotl."},{"key":"B59","doi-asserted-by":"publisher","first-page":"97","DOI":"10.3969\/j.issn.1006-2440.2001.01.085","article-title":"Observation on the efficacy of live combined Bacillus subtilis and Enterococcus faecium granules in the treatment of infantile constipation","volume":"15","author":"Zhong","year":"2001","journal-title":"Med. J. Commun."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1688544\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T08:07:39Z","timestamp":1760515659000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1688544\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,15]]},"references-count":59,"alternative-id":["10.3389\/fphar.2025.1688544"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1688544","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,15]]},"article-number":"1688544"}}