Houttuynia cordata Facilitates Metformin on Ameliorating Insulin Resistance Associated with Gut Microbiota Alteration in OLETF Rats

Abstract

Metformin and Houttuynia cordata are representative anti-diabetic therapeutics in western and oriental medicine, respectively. The current study examined the synergistic anti-diabetic effect of Houttuynia cordata extraction (HCE) and metformin combination in Otsuka Long–Evans Tokushima Fatty (OLETF) rats. Fecal microbiota were analyzed by denaturing gradient gel electrophoresis (DGGE) and real-time PCR. Combining HCE + metformin resulted in significantly ameliorated glucose tolerance (oral glucose tolerance test (OGTT))—the same as metformin alone. Particularly, results of the insulin tolerance test (ITT) showed that combining HCE + metformin dramatically improved insulin sensitivity as compared to metformin treatment alone. Both fecal and serum endotoxin, as well as cytokines (tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6)) were significantly ameliorated by HCE + metformin compared to metformin alone. Meanwhile, the activation of AMPK (adenosine monophosphate-activated protein kinase) by metformin was distinctly enhanced by HCE. Both of HCE and metformin evidently changed the gut microbiota composition, causing the alteration of bacterial metabolite, like short-chain fatty acids. H. cordata, together with metformin, exerts intensive sensibilization to insulin; the corresponding mechanisms are associated with alleviation of endotoxemia via regulation of gut microbiota, particularly Roseburia, Akkermansia, and Gram-negative bacterium.

Pharmaceutical Impact of Houttuynia Cordata and Metformin Combination on High-Fat-Diet-Induced Metabolic Disorders: Link to Intestinal Microbiota and Metabolic Endotoxemia

“…In the present study, treatment of HFD-fed animals with metformin and HCE in combination led to a greater improvement in OGTT parameters than higher doses of metformin or HCE alone, suggesting the synergistic beneficial impact of these two therapeutic agents on glucose tolerance as well as insulin sensitivity/resistance. Furthermore, in a previous study, using relevant in vitro and in vivo models, we showed that treatment with metformin + HCE was more beneficial than metformin alone in the improvement of glucose uptake, insulin secretion, glucose metabolism and insulin sensitivity ( 23 ).…”

“…After grinding, powder of Houttuynia cordata was extracted by 5 L ethanol recycling reflux for 4 h. The extract was then filtered and vacuum lyophilized at −70°C, which gave a 5.82% yield. The HCE contained 3.63% quercitrin, 0.45% quercetin and 0.99% of isoquercitrin ( 23 ). Metformin was purchased from Sigma-Aldrich (St. Louis, MO, USA).…”

“…The primer sequences targeting the 16S rRNA gene of the bacteria are listed in Table S2 . The standard conditions for the PCR amplification reactions were applied as previously described ( 23 ). The relative quantification of bacterial abundance is shown by 2 −Ct calculations (Ct, threshold cycle).…”

Sodium Houttuyfonate Alleviates Post-infarct Remodeling in Rats via AMP-Activated Protein Kinase Pathway

“…To elucidate the mechanism underlying SH treatment during post-infarct remodeling, the AMPK and NF-κB signal pathways were further investigated. It has been reported that AMPK was one of the downstream signal pathways of Cordata Houttuynia treatment under diseased situations ( Kang and Koppula, 2014b ; Wang J.H. et al, 2017 ).…”

“…Activation of AMPK has been confirmed exerting pleiotropic functions against inflammatory response and tissue fibrosis and owning beneficial properties in a series of diseases ( Peairs et al, 2009 ; Chiang et al, 2017 ; Kim et al, 2017 ). Intriguingly, recent studies have found activation of AMPK could be elicited or enhanced by H. cordata treatment in diseased situations ( Peairs et al, 2009 ; Xu et al, 2015 ; Wang J.H. et al, 2017 ).…”