Lacticaseibacillus paracasei Glu-07: A Promising Probiotic Candidate for the Management of Type 2 Diabetes Mellitus.

The global prevalence of type 2 diabetes mellitus (T2DM) is currently surging, posing significant health and socioeconomic burdens. Probiotics have emerged as promising interventions due to their safety and potential metabolic benefits. Gut microbiota plays a critical role in the pathophysiology of metabolic diseases in humans, offering valuable insights for therapeutic strategies such as probiotics. Here, aiming to identify novel probiotics from the human gut microbes to combat T2DM, a total of 203 human intestinal bacterial strains were screened in vitro to evaluate their enzymatic inhibition of α-glucosidase and α-amylase, in which Lacticaseibacillus paracasei Glu-07 (= QH-142 = CGMCC 23796) exhibited the highest inhibitory efficacy (81.05% and 72.56% for α-glucosidase and α-amylase, respectively). In HepG2 cells, L. paracasei Glu-07 elevated glucose uptake and consumption by 22.4% and 85.8%. Oral administration of strain Glu-07 in diabetic mice significantly improved hyperglycemia, hyperlipidemia, and restored the structure and composition of gut microbiota toward a healthier profile. Mechanistically, strain Glu-07 activated the AMPK-AKT1-GSK3β/FOXO1 signaling pathways by modulating the expression of key genes, enhanced glycolysis and fatty acid ꞵ-oxidation, and inhibited gluconeogenesis and lipogenesis. It also stimulated GLP-1 secretion, potentially via triggering the GPR41/43-GLP-1 axis, and increased the abundance of beneficial gut microbes, such as Akkermansia muciniphila (~ threefold). The dual regulations synergistically support strain Glu-07 as a promising probiotic candidate for T2DM management.