Lactiplantibacillus plantarum YZX21 Attenuates Type 2 Diabetes Mellitus by Modulating the Intestinal Microenvironment and Suppressing Gut Inflammation

Type 2 diabetes mellitus (T2DM) is associated with premature morbidity and disability worldwide. Although probiotic intake has been shown to enhance glycemic control, the underlying mechanisms remain incompletely defined. In this study, we employed a murine model of T2DM and integrated metabolomic, microbiomic, and molecular approaches to investigate the antidiabetic potential of Lactiplantibacillus plantarum YZX21 (L. plantarum YZX21). Our findings demonstrated that oral administration of L. plantarum YZX21 significantly decreased fasting blood glucose, insulin levels, and the HOMA-IR index. Histopathological examination revealed restoration of islet cell morphology accompanied by improved insulin secretion. ELISA and immunohistochemical analyses showed an increase in colonic glucagon-like peptide-1 (GLP-1) concentrations. Widely metabolomics using UPLC–MS/MS identified β-hydroxybutyric acid (BHB; also known as 3-hydroxybutyric acid) as inversely associated with diabetic and inflammatory indices but positively correlated with GLP-1 levels. In parallel, L. plantarum YZX21 altered intestinal microbial composition and metabolic function, notably reshaping relative dominant phyla (Bacteroidetes and Firmicutes) abundance and increasing Akkermansia muciniphila levels. Spearman correlation analyses revealed a strong link between Akkermansia abundance and BHB levels. Administration of exogenous BHB to diabetic C57BL/6 mice for 8 weeks improved glycemia, enhanced insulin sensitivity, and elevated intestinal GLP-1 concentrations. Mechanistically, BHB treatment modulated expression of GPR109a/NF-κB pathway, leading to the suppression of levels of IL-6, IL-1β, and TNF-α, thereby promoting GLP-1 secretion by alleviating intestinal injury. Collectively, these results indicate that L. plantarum YZX21 mitigates T2DM through its anti-inflammatory metabolite BHB, achieved via enrichment of Akkermansia and subsequent regulation of the GPR109a/NF-κB signaling axis. This work provides a theoretical foundation for using L. plantarum YZX21 as a probiotic intervention for T2DM.