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This study aimed to investigate whether baicalin, a microbiota\u2010modulating flavonoid derived from\n                    <jats:italic>Radix Scutellariae,<\/jats:italic>\n                    could restore metformin sensitivity and explored the underlying mechanisms. Fecal samples from metformin\u2010treated responders and non\u2010responders were collected and used to establish mouse models via fecal microbiota transplantation (FMT). The hypoglycemic efficacy of baicalin in combination with metformin was then evaluated. Serum levels of imidazole propionate (ImP) and the expression of downstream signaling proteins were assessed. Gut microbiota analysis identified ImP\u2010producing bacteria modulated by baicalin, which was further validated in\u00a0vitro. The roles of these bacteria and short\u2010chain fatty acids (SCFAs) in metformin responsiveness were also examined. In\u00a0vitro experiments were conducted to investigate the mechanism of SCFAs affect the production of ImP. Metformin responder and non\u2010responder mouse models were successfully established. Baicalin co\u2010administration significantly ameliorated insulin resistance in non\u2010responder mice, reduced serum ImP levels, suppressed p38\u03b3\/Akt\/AMPK (S485) signaling, and restored AMPK (T172) phosphorylation. Baicalin markedly suppressed key ImP\u2010producing bacteria\u2014\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Staphylococcus epidermidis<\/jats:italic>\n                    <\/jats:styled-content>\n                    and\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Streptococcus mutans<\/jats:italic>\n                    <\/jats:styled-content>\n                    . Notably, colonization with\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>S. epidermidis<\/jats:italic>\n                    <\/jats:styled-content>\n                    induced metformin non\u2010response in previously responsive mice. Furthermore, baicalin increased the abundance of SCFA\u2010producing bacteria and elevated colonic SCFAs levels. SCFAs reduced ImP production by inhibiting the growth of ImP\u2010producing bacteria, thereby enhancing metformin responsiveness. These findings indicate that baicalin restores metformin sensitivity by enriching SCFAs, suppressing ImP\u2010producing bacteria, and lowering serum ImP, thereby reinstating metformin's hypoglycemic action. This study supports the potential of baicalin as an adjunct therapy for overcoming metformin non\u2010response.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70186","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T02:30:36Z","timestamp":1768789836000},"page":"1060-1073","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Baicalin Restores the Hypoglycemic Effect of Metformin by Regulating the Microbial Imidazole Propionate and Short\u2010Chain Fatty Acids"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2723-888X","authenticated-orcid":false,"given":"Aiting","family":"Wang","sequence":"first","affiliation":[{"name":"Beijing Institute of Clinical Pharmacy, Beijing Friendship Hospital, Capital Medical University  Beijing 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