{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T18:35:57Z","timestamp":1792089357078,"version":"4.4.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T00:00:00Z","timestamp":1765238400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Kidney360"],"published-print":{"date-parts":[[2026,4]]},"abstract":"\n Key Points<\/jats:title>\n \n \n \n \n Lactulose, a synthetic disaccharide, promotes\n Akkermansia muciniphila<\/jats:italic>\n proliferation.\n <\/jats:p>\n <\/jats:list-item>\n \n \n The oral administration of both live and pasteurized forms of\n Akkermansia muciniphila<\/jats:italic>\n significantly improved renal function in CKD-induced mice.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Lactulose as a prebiotic therapeutic agent exerts the therapeutic effects on the gut-kidney axis\n via<\/jats:italic>\n enhancing\n Akkermansia muciniphila<\/jats:italic>\n production.\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n \n Recently, we reported that lactulose, a synthetic disaccharide used to treat chronic constipation, improved the gut-renal axis in mice with adenine-induced CKD. However, the underlying mechanism remains unclear.\n Akkermansia muciniphila<\/jats:italic>\n (AKK), a next-generation probiotic, mitigates multiorgan dysfunction, including kidney impairment, by modulating intestinal health. This study aimed to investigate whether lactulose induces AKK proliferation and contributes to its renoprotective effects.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n CKD was induced in 7-week-old male C57BL\/6N mice by administering 0.2% adenine for 4 weeks. After adenine discontinuation, the CKD mice received oral administration of lactulose (7.5% or 10%) or AKK (2\u00d710 CFU\/mouse) for 3 weeks. Intestinal permeability was assessed by measuring plasma levels of fluorescent probe for fluorescein isothiocyanate-dextran (4 kDa) and lipopolysaccharides. The composition of the gut microbiota was analyzed using 16S rRNA sequencing.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Lactulose administration significantly ameliorated renal impairment in CKD mice and improved intestinal barrier integrity by increasing intestinal mucosal thickness. In addition, lactulose modulated CKD-induced gut dysbiosis, thereby altering microbiota diversity and composition with a notable increase in AKK abundance. This was further supported by\n in vitro<\/jats:italic>\n findings that demonstrated a significant increase in AKK proliferation upon lactulose treatment. Similar to lactulose, oral administration of AKK (both live and pasteurized forms) for 3 weeks attenuated renal damage in CKD mice. Moreover, both forms of AKK significantly improved intestinal barrier function by enhancing mucosal integrity.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Our findings suggest that lactulose functions as an\n in vivo<\/jats:italic>\n AKK inducer, exerting renoprotective effects by improving intestinal barrier function in CKD. These results highlight the potential of lactulose as a prebiotic therapeutic agent for CKD management.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.34067\/kid.0000001040","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T17:00:44Z","timestamp":1765299644000},"page":"754-766","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":3,"title":["Lactulose, a Disaccharide Prebiotic, Improves the Gut-Kidney Axis via Enhancement of Akkermansia Muciniphila Production"],"prefix":"10.34067","volume":"7","author":[{"given":"Miyu","family":"Sueyoshi","sequence":"first","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan"},{"name":"Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5376-4109","authenticated-orcid":false,"given":"Moritaka","family":"Goto","sequence":"additional","affiliation":[{"name":"Pharmaceuticals Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Sato","sequence":"additional","affiliation":[{"name":"Kumamoto Industrial Research Institute, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8914-364X","authenticated-orcid":false,"given":"Mayu","family":"Oki","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4371-3698","authenticated-orcid":false,"given":"Ebenezer","family":"Ofori-Attah","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takehiro","family":"Nakano","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0794-9468","authenticated-orcid":false,"given":"Hitoshi","family":"Maeda","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan"},{"name":"Laboratory of Biopharmaceutics, Kyoto Pharmaceutical University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoko","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Akebono Clinic, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazutaka","family":"Matsushita","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Akebono Clinic, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7391-7966","authenticated-orcid":false,"given":"Hideaki","family":"Jinnouchi","sequence":"additional","affiliation":[{"name":"Diabetes Care Center, Jinnouchi Hospital, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Maruyama","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5166-7145","authenticated-orcid":false,"given":"Daisuke","family":"Kadowaki","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan"},{"name":"DDS Research Institute, Sojo University, Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2025,12,9]]},"reference":[{"issue":"6","key":"B1-20260430","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1111\/lam.13333","article-title":"Gut-organ axis: a microbial outreach and networking","volume":"72","author":"Ahlawat","year":"2021","journal-title":"Lett Appl Microbiol."},{"issue":"1","key":"B2-20260430","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/nyas.13033","article-title":"The human gut microbiome and its dysfunctions through the meta-omics prism","volume":"1372","author":"Mondot","year":"2016","journal-title":"Ann N Y Acad Sci."},{"issue":"1","key":"B3-20260430","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/jvim.14875","article-title":"The gastrointestinal microbiome: a review","volume":"32","author":"Barko","year":"2018","journal-title":"J Vet Intern Med."},{"issue":"5","key":"B4-20260430","doi-asserted-by":"crossref","first-page":"334","DOI":"10.3390\/toxins13050334","article-title":"An innovative synbiotic formulation decreases free serum indoxyl sulfate, small intestine permeability and ameliorates gastrointestinal symptoms in a randomized pilot trial in stage IIIb-IV CKD patients","volume":"13","author":"Cosola","year":"2021","journal-title":"Toxins."},{"issue":"3","key":"B5-20260430","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1159\/000071292","article-title":"Patients with chronic renal failure have abnormal small intestinal motility and a high prevalence of small intestinal bacterial overgrowth","volume":"67","author":"Strid","year":"2003","journal-title":"Digestion."},{"issue":"8","key":"B6-20260430","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1111\/j.1440-1797.2012.01647.x","article-title":"Gut bacterial translocation is associated with microinflammation in end\u2010stage renal disease patients","volume":"17","author":"Wang","year":"2012","journal-title":"Nephrology."},{"key":"B7-20260430","doi-asserted-by":"crossref","first-page":"837500","DOI":"10.3389\/fphar.2022.837500","article-title":"The intestinal microbiota and metabolites in the gut-kidney-heart axis of chronic kidney disease","volume":"13","author":"Huang","year":"2022","journal-title":"Front Pharmacol."},{"issue":"2","key":"B8-20260430","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41581-022-00655-z","article-title":"Molecular mechanisms of kidney crosstalk with distant organs","volume":"19","author":"Hasegawa","year":"2023","journal-title":"Nat Rev Nephrol."},{"issue":"6","key":"B9-20260430","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1016\/j.kint.2023.03.025","article-title":"Acute kidney injury and distant organ dysfunction-network system analysis","volume":"103","author":"Matsuura","year":"2023","journal-title":"Kidney Int."},{"issue":"2","key":"B10-20260430","doi-asserted-by":"crossref","first-page":"151409","DOI":"10.1016\/j.semnephrol.2023.151409","article-title":"Organ crosstalk contributes to muscle wasting in chronic kidney disease","volume":"43","author":"Wang","year":"2023","journal-title":"Semin Nephrol."},{"issue":"22","key":"B11-20260430","doi-asserted-by":"crossref","first-page":"6637","DOI":"10.3390\/jcm11226637","article-title":"Organ crosstalk in acute kidney injury: evidence and mechanisms","volume":"11","author":"Li","year":"2022","journal-title":"J Clin Med."},{"issue":"8","key":"B12-20260430","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1681\/ASN.2014060530","article-title":"Alteration of the intestinal environment by lubiprostone is associated with amelioration of adenine-induced CKD","volume":"26","author":"Mishima","year":"2015","journal-title":"J Am Soc Nephrol."},{"issue":"2","key":"B13-20260430","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1093\/ndt\/gfz126","article-title":"The guanylate cyclase C agonist linaclotide ameliorates the gut-cardio-renal axis in an adenine-induced mouse model of chronic kidney disease","volume":"35","author":"Nanto-Hara","year":"2020","journal-title":"Nephrol Dial Transplant."},{"issue":"1","key":"B14-20260430","doi-asserted-by":"crossref","first-page":"133","DOI":"10.2215\/CJN.04610510","article-title":"Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease","volume":"6","author":"McIntyre","year":"2011","journal-title":"Clin J Am Soc Nephrol."},{"issue":"5","key":"B15-20260430","doi-asserted-by":"crossref","first-page":"692","DOI":"10.2215\/CJN.12161018","article-title":"Blood microbiome profile in CKD: a Pilot Study","volume":"14","author":"Shah","year":"2019","journal-title":"Clin J Am Soc Nephrol."},{"issue":"7464","key":"B16-20260430","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/nature12506","article-title":"Richness of human gut microbiome correlates with metabolic markers","volume":"500","author":"Le Chatelier","year":"2013","journal-title":"Nature."},{"issue":"22","key":"B17-20260430","doi-asserted-by":"crossref","first-page":"9066","DOI":"10.1073\/pnas.1219451110","article-title":"Cross-talk between akkermansia muciniphila and intestinal epithelium controls diet-induced obesity","volume":"110","author":"Everard","year":"2013","journal-title":"Proc Natl Acad Sci."},{"issue":"1","key":"B18-20260430","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/nm.4236","article-title":"A purified membrane protein from akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice","volume":"23","author":"Plovier","year":"2017","journal-title":"Nat Med."},{"issue":"5","key":"B19-20260430","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1136\/gutjnl-2012-303839","article-title":"An increase in the akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice","volume":"63","author":"Shin","year":"2014","journal-title":"Gut."},{"issue":"10","key":"B20-20260430","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1101\/gr.194118.115","article-title":"Genetic and environmental control of host-gut microbiota interactions","volume":"25","author":"Org","year":"2015","journal-title":"Genome Res."},{"key":"B21-20260430","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.3389\/fmicb.2017.01765","article-title":"Next-generation beneficial microbes: the case of akkermansia muciniphila","volume":"8","author":"Cani","year":"2017","journal-title":"Front Microbiol."},{"issue":"7","key":"B22-20260430","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1038\/s41591-019-0495-2","article-title":"Supplementation with akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study","volume":"25","author":"Depommier","year":"2019","journal-title":"Nat Med."},{"key":"B23-20260430","doi-asserted-by":"crossref","first-page":"206","DOI":"10.3389\/fcimb.2019.00206","article-title":"Alterations to the gut microbiota and their correlation with inflammatory factors in chronic kidney disease","volume":"9","author":"Li","year":"2019","journal-title":"Front Cell Infect Microbiol."},{"key":"B24-20260430","doi-asserted-by":"crossref","first-page":"105891","DOI":"10.1016\/j.micpath.2022.105891","article-title":"Akkermansia muciniphila ameliorates chronic kidney disease interstitial fibrosis via the gut-renal axis","volume":"174","author":"Pei","year":"2023","journal-title":"Microb Pathog."},{"issue":"2","key":"B25-20260430","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1136\/gut.2010.227132","article-title":"Effect of laxatives and pharmacological therapies in chronic idiopathic constipation: systematic review and meta-analysis","volume":"60","author":"Ford","year":"2011","journal-title":"Gut."},{"issue":"7","key":"B26-20260430","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1007\/s10157-019-01727-4","article-title":"Effects of lactulose on renal function and gut microbiota in adenine-induced chronic kidney disease rats","volume":"23","author":"Sueyoshi","year":"2019","journal-title":"Clin Exp Nephrol."},{"issue":"18","key":"B27-20260430","doi-asserted-by":"crossref","first-page":"e01014-17","DOI":"10.1128\/AEM.01014-17","article-title":"Genome-scale model and omics analysis of metabolic capacities of akkermansia muciniphila reveal a preferential mucin-degrading lifestyle","volume":"83","author":"Ottman","year":"2017","journal-title":"Appl Environ Microbiol."},{"issue":"6","key":"B28-20260430","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1016\/j.kint.2017.04.032","article-title":"Impairment of the carnitine\/organic cation transporter 1-ergothioneine axis is mediated by intestinal transporter dysfunction in chronic kidney disease","volume":"92","author":"Shinozaki","year":"2017","journal-title":"Kidney Int."},{"issue":"4","key":"B29-20260430","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1681\/ASN.2016060656","article-title":"Constipation and incident CKD","volume":"28","author":"Sumida","year":"2017","journal-title":"J Am Soc Nephrol."},{"issue":"6","key":"B30-20260430","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1038\/ki.2012.440","article-title":"The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease","volume":"83","author":"Anders","year":"2013","journal-title":"Kidney Int."},{"issue":"1","key":"B31-20260430","doi-asserted-by":"crossref","first-page":"fnac103","DOI":"10.1093\/femsle\/fnac103","article-title":"Akkermansia muciniphila attenuates LPS-induced acute kidney injury by inhibiting TLR4\/NF-\u03baB pathway","volume":"369","author":"Shi","year":"2022","journal-title":"FEMS Microbiol Lett."},{"issue":"7770","key":"B32-20260430","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/s41586-019-1443-5","article-title":"Potential roles of gut microbiome and metabolites in modulating ALS in mice","volume":"572","author":"Blacher","year":"2019","journal-title":"Nature."},{"issue":"1","key":"B33-20260430","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s13073-016-0271-6","article-title":"Sub-clinical detection of gut microbial biomarkers of obesity and type 2 diabetes","volume":"8","author":"Yassour","year":"2016","journal-title":"Genome Med."},{"issue":"5","key":"B34-20260430","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1136\/gutjnl-2016-313432","article-title":"Recovery of ethanol-induced akkermansia muciniphila depletion ameliorates alcoholic liver disease","volume":"67","author":"Grander","year":"2018","journal-title":"Gut."},{"issue":"1","key":"B35-20260430","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1136\/gutjnl-2023-329996","article-title":"Novel tripeptide RKH derived from akkermansia muciniphila protects against lethal sepsis","volume":"73","author":"Xie","year":"2023","journal-title":"Gut."},{"issue":"5","key":"B36-20260430","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/s41564-021-00880-5","article-title":"Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice","volume":"6","author":"Yoon","year":"2021","journal-title":"Nat Microbiol."},{"issue":"2","key":"B37-20260430","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.eururo.2020.04.044","article-title":"Gut bacteria composition drives primary resistance to cancer immunotherapy in renal cell carcinoma patients","volume":"78","author":"Derosa","year":"2020","journal-title":"Eur Urol."},{"issue":"2","key":"B38-20260430","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1038\/s41591-021-01655-5","article-title":"Intestinal akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer","volume":"28","author":"Derosa","year":"2022","journal-title":"Nat Med."},{"key":"B39-20260430","doi-asserted-by":"crossref","first-page":"956203","DOI":"10.3389\/fendo.2022.956203","article-title":"The potential role of lactulose pharmacotherapy in the treatment and prevention of diabetes","volume":"13","author":"Chu","year":"2022","journal-title":"Front Endocrinol."},{"issue":"4","key":"B40-20260430","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1681\/ASN.2019080827","article-title":"Cellular and molecular mechanisms of kidney injury in 2,8-dihydroxyadenine nephropathy","volume":"31","author":"Klinkhammer","year":"2020","journal-title":"J Am Soc Nephrol."},{"issue":"3","key":"B41-20260430","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1007\/s13205-024-03959-y","article-title":"Adenine\u2019s impact on mice\u2019s gut and kidney varies with the dosage administered and relates to intestinal microorganisms and enzyme activities","volume":"14","author":"Zhou","year":"2024","journal-title":"3 Biotech."}],"container-title":["Kidney360"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.34067\/KID.0000001040","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T20:03:41Z","timestamp":1786478621000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.34067\/KID.0000001040"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,9]]},"references-count":41,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.34067\/kid.0000001040","relation":{},"ISSN":["2641-7650"],"issn-type":[{"value":"2641-7650","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,9]]},"assertion":[{"value":"2025-06-25","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-20","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}