{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:25:52Z","timestamp":1785803152358,"version":"3.56.0"},"reference-count":29,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T00:00:00Z","timestamp":1721088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Liraglutide, a glucagon-like peptide 1 analog used to treat type 2 diabetes and obesity, is a potential new treatment modality for bile acid (BA) diarrhea. Here, we show that administration of liraglutide significantly decreased total BAs, especially the primary BAs, including cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, and \u03b2-muricholic acid, in the liver and feces. In addition, liraglutide significantly decreased tryptophan metabolites, including L-tryptophan, serotonin, 5-hydroxy indole-3-acetic acid, L-kynurenine, and xanthurenic acid, in the colon, whereas it significantly increased indole-3-propionic acid. Moreover, the administration of liraglutide remarkably decreased the expression of apical sodium-dependent bile acid transporter, which mediates BA uptake across the apical brush border member in the ileum, ileal BA binding protein, and fibroblast growth factor 15 in association with decreased expression of the BA-activated nuclear receptor farnesoid X receptor and the heteromeric organic solute transporter Ost\u03b1\/\u03b2, which induces BA excretion, in the ileum. Liraglutide acutely decreased body weight and blood glucose levels in association with decreases in plasma insulin and serotonin levels in food-deprived mice. These findings suggest the potential of liraglutide as a novel inhibitor of primary BAs and serotonin in the colon.<\/jats:p>","DOI":"10.3390\/ijms25147784","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T16:35:58Z","timestamp":1721234158000},"page":"7784","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The GLP-1 Receptor Agonist Liraglutide Decreases Primary Bile Acids and Serotonin in the Colon Independently of Feeding in Mice"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6628-6246","authenticated-orcid":false,"given":"Katsunori","family":"Nonogaki","sequence":"first","affiliation":[{"name":"Division of Diabetes and Nutrition, RARiS, Tohoku University, 6-6-11 Aramakiaza-Aoba, Aoba-ku, Sendai 980-8579, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Kaji","sequence":"additional","affiliation":[{"name":"Division of Diabetes and Nutrition, RARiS, Tohoku University, 6-6-11 Aramakiaza-Aoba, Aoba-ku, Sendai 980-8579, Miyagi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/j.cmet.2013.04.008","article-title":"Pharmacology, physiology, and mechanisms of incretin hormone action","volume":"17","author":"Campbell","year":"2013","journal-title":"Cell Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101102","DOI":"10.1016\/j.molmet.2020.101102","article-title":"GLP-1 receptor agonists in the treatment of type 2 diabetes\u2014state-of-the-art","volume":"46","author":"Nauck","year":"2021","journal-title":"Mol. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Popoviciu, M.S., P\u0103duraru, L., Yahya, G., Metwally, K., and Cavalu, S. (2023). Emerging Role of GLP-1 Agonists in Obesity: A Comprehensive Review of Randomised Controlled Trials. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310449"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1016\/S2468-1253(22)00198-4","article-title":"Safety and efficacy of liraglutide versus colesevelam for the treatment of bile acid diarrhoea: A randomised, double-blind, active-comparator, non-inferiority clinical trial","volume":"7","author":"Forman","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Nonogaki, K. (2022). The Regulatory Role of the Central and Peripheral Serotonin Network on Feeding Signals in Metabolic Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031600"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Koopman, N., Katsavelis, D., Hove, A.S.T., Brul, S., Jonge, W.J., and Seppen, J. (2021). The Multifaceted Role of Serotonin in Intestinal Homeostasis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179487"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Chojnacki, J., Konrad, P., M\u0119drek-Socha, M., Kaczka, A., B\u0142o\u0144ska, A., Zajdel, R., Chojnacki, C., and Gasiorowska, A. (2024). The Variability of Tryptophan Metabolism in Patients with Mixed Type of Irritable Bowel Syndrome. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25052550"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2168101","DOI":"10.1080\/19490976.2023.2168101","article-title":"Gut microbiota alteration after cholecystectomy contributes to post-cholecystectomy diarrhea via bile acids stimulating colonic serotonin","volume":"15","author":"Xu","year":"2023","journal-title":"Gut Microbes"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"19802","DOI":"10.1073\/pnas.1909311116","article-title":"The gut microbiome regulates host glucose homeostasis via peripheral serotonin","volume":"116","author":"Martin","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.diabres.2016.08.009","article-title":"The acute anorexic effect of liraglutide, a GLP-1 receptor agonist, does not require functional leptin receptor, serotonin, and hypothalamic POMC and CART activities in mice","volume":"120","author":"Nonogaki","year":"2016","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6482958","DOI":"10.1155\/2018\/6482958","article-title":"Liraglutide, a GLP-1 Receptor Agonist, Which Decreases Hypothalamic 5-HT2A Receptor Expression, Reduces Appetite and Body Weight Independently of Serotonin Synthesis in Mice","volume":"2018","author":"Nonogaki","year":"2018","journal-title":"J. Diabetes Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/S2468-1253(22)00401-0","article-title":"Efficacy and safety of colesevelam for the treatment of bile acid diarrhoea: A double-blind, randomised, placebo-controlled, phase 4 clinical trial","volume":"8","author":"Borup","year":"2023","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"20436","DOI":"10.1038\/s41598-020-77374-7","article-title":"The pathophysiology of bile acid diarrhoea: Differences in the colonic microbiome, metabolome and bile acids","volume":"10","author":"Sagar","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.molmet.2018.03.004","article-title":"Enterochromaffin 5-HT cells\u2014A major target for GLP-1 and gut microbial metabolites","volume":"11","author":"Lund","year":"2018","journal-title":"Mol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3891","DOI":"10.1073\/pnas.0712328105","article-title":"The organic solute transporter alpha-beta, Ostalpha-Ostbeta, is essential for intestinal bile acid transport and homeostasis","volume":"105","author":"Rao","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lund\u00e5sen, T., Andersson, E.-M., Snaith, M., Lindmark, H., Lundberg, J., and \u00d6stlund-Lindqvist, A.-M. (2012). Inhibition of intestinal bile acid transporter Slc10a2 improves triglyceride metabolism and normalizes elevated plasma glucose levels in mice. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0037787"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/s41401-018-0195-3","article-title":"A novel ASBT inhibitor, IMB17-15, repressed nonalcoholic fatty liver disease development in high-fat diet-fed Syrian golden hamsters","volume":"40","author":"Ge","year":"2019","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"357ra122","DOI":"10.1126\/scitranslmed.aaf4823","article-title":"Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease in high-fat diet-fed mice","volume":"8","author":"Rao","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.jdiacomp.2017.01.011","article-title":"Bile acid sequestrants for glycemia control in patients with type 2 diabetes: A systematic review with meta-analysis of randomized controlled trials","volume":"31","author":"Hansen","year":"2017","journal-title":"J. Diabetes Complicat."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/s12072-022-10296-w","article-title":"Colesevelam ameliorates non-alcoholic steatohepatitis and obesity in mice","volume":"16","author":"Hartmann","year":"2022","journal-title":"Hepatol. Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1530\/EJE-12-0357","article-title":"Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21","volume":"167","author":"Iglesias","year":"2012","journal-title":"Eur. J. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/nm.3766","article-title":"Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis","volume":"21","author":"Crane","year":"2015","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3698","DOI":"10.1073\/pnas.0812874106","article-title":"Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites","volume":"106","author":"Wikoff","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zhang, B., Jiang, M., Zhao, J., Song, Y., Du, W., and Shi, J. (2022). The Mechanism Underlying the Influence of Indole-3-Propionic Acid: A Relevance to Metabolic Disorders. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.841703"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/s41387-018-0046-9","article-title":"Associations of serum indolepropionic acid, a gut microbiota metabolite, with type 2 diabetes and low-grade inflammation in high-risk individuals","volume":"8","author":"Tuomainen","year":"2018","journal-title":"Nutr. Diabetes"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"46337","DOI":"10.1038\/srep46337","article-title":"Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study","volume":"7","author":"Paananen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5985","DOI":"10.1111\/febs.16470","article-title":"Indolepropionic acid reduces obesity-induced metabolic dysfunction through colonic barrier restoration mediated via tuft cell-derived IL-25","volume":"289","author":"Chen","year":"2022","journal-title":"FEBS J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"15784","DOI":"10.1038\/s41598-020-72975-8","article-title":"Whey protein isolate inhibits hepatic FGF21 production, which precedes weight gain, hyperinsulinemia and hyperglycemia in mice fed a high-fat diet","volume":"10","author":"Nonogaki","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Nonogaki, K., and Kaji, T. (2023). Ingestion of whey protein and \u03b2-conglycinin exerts opposite effects on intestinal FGF15 and serotonin secretion in mice. Front. 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