Plumieride ameliorates type 2 diabetes and colitis by regulating intestinal functions.

ETHNOPHARMACOLOGICAL RELEVANCE: Plumeria rubra L. has been traditionally used to alleviate symptoms of intestinal disorders. Plumieride (PR), a major iridoid glycoside isolated from Plumeria rubra L., possesses a rare spirocyclic structure featuring a 5/5-spiro junction annulated to a six-membered ring. This unique structure sets it apart within the iridoid group and is linked to a variety of pharmacological activities. However, there is limited research on the mechanisms underlying PR's activity. AIM OF THE STUDY: Our work aims at elucidating PR's therapeutic effects and the mechanisms mediating its treatment of intestinal-related diseases, with particular emphasis on how its pharmacodynamic properties support its ethnopharmacological use. MATERIALS AND METHODS: PR was extracted from Plumeria rubra L., and the rest of the derivatives, including plumieride aglycone (PR-a), were modified based on PR. All of the compounds were characterized using nuclear magnetic resonance (NMR) spectroscopy. In vivo, the pharmacokinetic assessment was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). db/db diabetic mice were employed to assess PR's hypoglycemic effects, while mice exhibiting colitis resulting from dextran sulfate sodium (DSS) treatment were used to evaluate its anti-inflammatory properties. In vitro, the specific mechanisms of PR-a were investigated using intestinal L cells (STC-1) and bone marrow-derived macrophages (BMDMs), along with RT-qPCR and Western blot analysis. RESULTS: Pharmacokinetic analysis indicated that PR accumulated in the gut after oral administration, providing a material basis for its direct action on intestinal targets. PR treatment effectively alleviated hyperglycemia in db/db mice, partly through stimulating intestinal glucagon-like peptide-1 (GLP-1) secretion, and attenuated DSS-induced colitis by reducing intestinal oxidative stress and inflammatory signaling. PR-a, a metabolite of PR, was suggested to be the active form modulating the intestinal function through stimulating calcium signaling in intestinal endocrine cells and regulation of the nuclear factor erythroid 2-related factor 2 (NRF2) and NRF2-independent NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathways in macrophages. Additionally, 26 structurally diverse derivatives of PR were synthesized to explore structure-activity relationships, identify bioactive congeners, and optimize pharmacological potency. CONCLUSIONS: PR ameliorates type 2 diabetes (T2D) and colitis through gut-related mechanisms involving endocrine regulation, anti-oxidative effects, and anti-inflammatory actions. By mechanistically linking the gut accumulation of PR and the activity of its potential active in vivo metabolite PR-a to the traditional uses of Plumeria rubra, this study suggests PR and PR-a as promising candidates for treating intestinal function-related disorders pending further validation of their efficacy and safety, providing a theoretical basis for their structural modification, development, and application.