Supernatants from Water Extraction—Ethanol Precipitation of Fagopyrum tararicum Seeds Enhance T2DM Management in Mice by Regulating Intestinal Microbial Communities

Type 2 diabetes <i>mellitus</i> (T2DM) is an endocrine-metabolic disorder characterized by pancreatic islet dysfunction-induced hyperglycemia, which triggers hepatic injury, intestinal microbiota dysbiosis, and systemic complications. <i>Fagopyrum tararicum</i> seeds exhibit various biological activities, including antioxidant, hypolipidemic, and antihypertensive effects. However, there is limited research exploring how supernatants derived from the water extraction-ethanol precipitation of <i>Fagopyrum tararicum</i> seeds (SWEPFT) modulate the intestinal microbiota and their potential link to T2DM. This study evaluates SWEPFT's effects on hyperglycemia and intestinal microbiota in T2DM mice. After a 4-week therapeutic period, SWEPFT markedly ameliorated hyperglycemia, as evidenced by reduced body weight (BW), fasting blood glucose (FBG), and glycated serum protein (GSP) and improved insulin sensitivity/resistance indicators (HOMA-IS/IR) and β-cell function (HOMA-β). Furthermore, the levels of both <i>Akt1</i> and <i>Slc2a2</i> transcription displayed notable enhancement. SWEPFT-H (high-dose SWEPFT) exhibited superior effects to SWEPFT-L (low-dose SWEPFT) in improving BW, FBG, and HOMA-IS. Moreover, SWEPFT modulated the intestinal microbiota by decreasing the Firmicutes/Bacteroidetes ratio, augmenting the proportion of <i>Intestinimonas</i> and <i>Ruminiclostridium</i>, and increasing the short-chain fatty acid content. A correlation analysis identified <i>Candidatus_Arthromitus</i>, <i>Anaeroplasma</i>, <i>Candidatus_Stoquefichus</i>, and <i>Harryflintia</i> as potential T2DM biomarkers linked to glycemic regulation. These findings elucidate SWEPFT's critical role in microbiota modulation and hyperglycemia alleviation, providing a novel perspective for T2DM pathogenesis research and therapeutic development.