Ultra-low-dose lactulose modulates the gut microbiota in healthy adults: A double-blind, randomized, placebo-controlled crossover trial | Functional Foods in Health and Disease - Online ISSN: 2160-3855; Print ISSN: 2378-7007 Skip to main content Skip to main navigation menu Skip to site footer Open Menu Functional Foods in Health and Disease - Online ISSN: 2160-3855; Print ISSN: 2378-7007 Home Food Science Publisher Functional Food Center Current Archives About About the Journal Aims and Scope Contact Editing Services Editorial Team Express Peer Review Graphical Abstract Journal Insights Privacy Statement Submissions Announcements Search Search Register Login Home / Archives / Vol. 15 No. 12 (2025): December 2025 / Research Articles Ultra-low-dose lactulose modulates the gut microbiota in healthy adults: A double-blind, randomized, placebo-controlled crossover trial Authors Ryo Sakiyama Seiya Miyashita Manabu Nakano Miyuki Tanaka DOI: https://doi.org/10.31989/ffhd.v15i12.1838 Abstract Background: Gut health, particularly the composition and function of the gut microbiota, is increasingly recognized as essential for overall well-being. Non-digestible oligosaccharides are established prebiotics that stimulate beneficial gut bacteria; however, excessive intake may cause gastrointestinal discomfort. This study aimed to determine the minimum effective dose of lactulose using 16S rRNA gene sequencing to support safe and sustainable dietary applications. Methods: In a double-blind, randomized, placebo-controlled crossover trial, 100 healthy Japanese adults received lactulose (500 mg/day) or placebo for 28 days, separated by a 14-day washout period. The relative abundance of Bifidobacterium was analyzed using a linear mixed model with centered log-ratio transformation. Results: As a result of the analyses conducted on the PPS (Per Protocol Set, n = 78) and FAS (Full Analysis Set, n = 99), lactulose intake significantly increased the relative abundance of Bifidobacterium. Overall alpha diversity remained unchanged, although participants with low baseline alpha diversity enterotypes showed a trend toward restoration of alpha diversity. No adverse events or gastrointestinal symptoms, such as bloating or diarrhea, were observed, confirming the safety of lactulose. Conclusions: These findings provide novel evidence that even minimal doses of lactulose can beneficially modulate the gut microbiota, notably by increasing the relative abundance of Bifidobacterium without inducing laxative effects. Ultra-low-dose lactulose may serve as a practical and safe functional food ingredient to support long-term gut health, and continued research on its incorporation into functional food matrices will be important. Trial registration: The study protocol was registered with UMIN-CTR (ID: UMIN000055862). Keywords: Lactulose; Prebiotics; Bifidobacterium; Improving gut microbiota, Gastrointestinal health Downloads [Abstract] [Full Article] [Supplementary Data] Published 2025-12-09 Issue Vol. 15 No. 12 (2025): December 2025 Section Research Articles License Copyright (c) 2025 Ryo Sakiyama, Seiya Miyashita, Manabu Nakano, Miyuki Tanaka This work is licensed under a Creative Commons Attribution 4.0 International License. Authors retain the copyright of their articles and grant the Functional Food Center (FFC) and its journals the right of first publication under the terms of the Creative Commons Attribution 4.0 International License. This license permits unrestricted use, distribution, and reproduction in any medium, including commercial use, provided the original author(s) and source are properly credited. Authors may post and share their published work freely, provided that the original publication in this journal is acknowledged. By submitting to this journal, authors confirm that their manuscripts are original, not under consideration elsewhere, and that they hold the necessary rights to grant this license. The Functional Food Center encourages open scientific exchange and allows derivative and extended works, provided attribution to the original publication is maintained. About the Journal      Editing Services      Graphical Abstract      Journal Insights        Submissions        Editorial Team       Privacy Statement        Contact        Current        Archives   Open Journal Systems Hosting and Support by: OpenJournalSystems.com