{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T03:49:26Z","timestamp":1785124166738,"version":"3.55.0"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T00:00:00Z","timestamp":1618444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>The novel Traditional Chinese Medicine Ramulus Mori (Sangzhi) alkaloid tablets (SZ-A) are approved by The China National Medical Products Administration for the treatment of type 2 diabetes mellitus (T2DM). However, the extensive pharmacological characteristics and the underlying mechanism are unknown. This study investigated the mechanisms by which SZ-A ameliorates glucose metabolism in KKAy mice, an animal model of T2DM. Diabetic KKAy mice were treated intragastrically with SZ-A once daily for 8 weeks, after which glucose levels, lipid metabolism, gut microbiome, systemic inflammatory factors, luminal concentrations of short-chain fatty acids (fecal samples), and ileal proteomic changes were evaluated. The ileum tissues were collected, and the effects of SZ-A on pathological inflammatory damage were evaluated by hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry. The mRNA and protein expression levels of various inflammatory markers, including monocyte chemoattractant protein-1 and phosphorylated nuclear factor kappa B p65, were detected in the ileum tissues. SZ-A improved glucose metabolism with enhanced insulin response and elevated glucagon-like peptide 1 (GLP-1) nearly 2.7-fold during the glucose tolerance test in diabetic KKAy mice. Gut microbiota analysis demonstrated that SZ-A administration elevated the abundance of <jats:italic>Bacteroidaceae<\/jats:italic> and <jats:italic>Verrucomicrobia<\/jats:italic>, reduced the levels of <jats:italic>Rikenellaceae<\/jats:italic> and <jats:italic>Desulfovibrionaceae;<\/jats:italic> and increased the concentrations of fecal acetic and propionic acids compared to the diabetic model group. Additionally, SZ-A markedly improved ileal inflammatory injury and pro-inflammatory macrophage infiltration and improved intestinal mucosal barrier function in diabetic KKAy mice. SZ-A also attenuated the levels of circulating endotoxin, pro-inflammatory cytokines, and chemokines in the mice sera. Collectively, SZ-A ameliorated the overall metabolic profile including glucose and lipid metabolism in KKAy mice, which may be associated with an improvement in GLP-1 and insulin secretion, at least in part by modulating the gut microbiome and relieving the degree of ileal and systemic inflammation.<\/jats:p>","DOI":"10.3389\/fphar.2021.642400","type":"journal-article","created":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T20:36:03Z","timestamp":1618518963000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":42,"title":["Ramulus Mori (Sangzhi) Alkaloids (SZ-A) Ameliorate Glucose Metabolism Accompanied by the Modulation of Gut Microbiota and Ileal Inflammatory Damage in Type 2 Diabetic KKAy Mice"],"prefix":"10.3389","volume":"12","author":[{"given":"Quan","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuainan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenming","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caina","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Huan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaxin","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefeng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuling","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhufang","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.cmet.2017.09.019","article-title":"Metformin alters upper small intestinal microbiota that impact a glucose-SGLT1-sensing glucoregulatory pathway","volume":"27","author":"Bauer","year":"2018","journal-title":"Cel Metab."},{"key":"B2","doi-asserted-by":"publisher","first-page":"411","DOI":"10.3920\/bm2020.0057","article-title":"Short chain fatty acids in human gut and metabolic health","volume":"11","author":"Blaak","year":"2020","journal-title":"Beneficial Micro."},{"key":"B3","doi-asserted-by":"publisher","first-page":"578943","DOI":"10.3389\/fphar.2020.578943","article-title":"Stachyose improves the effects of berberine on glucose metabolism by regulating intestinal microbiota and short-chain fatty acids in spontaneous type 2 diabetic KKAy mice","volume":"11","author":"Cao","year":"2020","journal-title":"Front. 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