The synchronized feature of <i>Saururus chinensis</i> and gut microbiota against T2DM, NAFLD, obesity and hypertension via integrated pharmacology

Type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), obesity (OB) and hypertension (HT) are categorized as metabolic disorders (MDs), which develop independently without distinct borders. Herein, we examined the gut microbiota (GM) and Saururus chinensis (SC) to confirm their therapeutic effects via integrated pharmacology. The overlapping targets from the four diseases were determined to be key protein coding genes. The protein–protein interaction (PPI) networks, and the SC, GM, signalling pathway, target and metabolite (SGSTM) networks were analysed via RPackage. Additionally, molecular docking tests (MDTs) and density functional theory (DFT) analysis were conducted to determine the affinity and stability of the conformer(s). TNF was the main target in the PPI analysis, and equol derived from Lactobacillus paracasei JS1 was the most effective agent for the formation of the TNF complex. The SC agonism (PPAR signalling pathway), and antagonism (neurotrophin signalling pathway) by SC were identified as agonistic bioactives (aromadendrane, stigmasta-5,22-dien-3-ol, 3,6,6-trimethyl-3,4,5,7,8,9-hexahydro-1H-2-benzoxepine, 4α-5α-epoxycholestane and kinic acid), and antagonistic bioactives (STK734327 and piclamilast), respectively, via MDT. Finally, STK734327-MAPK1 was the most favourable conformer according to DFT. Overall, the seven bioactives from SC and equol that can be produced by Lactobacillus paracasei JS1 can exert synergistic effects on these four diseases.2型糖尿病（T2DM）、非酒精性脂肪性肝病（NAFLD）、肥胖（OB）及高血压（HT）均归类为代谢紊乱性疾病（MDs），此类疾病独立发生且无明确发病边界。本研究采用整合药理学策略，探究肠道菌群（GM）与三白草（SC）的治疗效应。研究首先筛选得到四种疾病的重叠靶点，将其确定为关键蛋白编码基因；随后借助R软件包构建蛋白质相互作用（PPI）网络，并分析三白草-肠道菌群-信号通路-靶点-代谢物（SGSTM）调控网络。此外，通过分子对接实验（MDTs）与密度泛函理论（DFT）分析，测定复合物的结合亲和力与构象稳定性。PPI网络核心靶点为肿瘤坏死因子（TNF），副干酪乳杆菌JS1（Lactobacillus paracasei JS1）代谢生成的雌马酚是形成TNF复合物的最有效配体。经分子对接实验验证，三白草的活性成分中，香树烯、豆甾-5,22-二烯-3-醇、3,6,6-三甲基-3,4,5,7,8,9-六氢-1H-2-苯并氧杂卓、4α-5α-环氧胆甾烷与奎尼酸可作为激动剂调控过氧化物酶体增殖物激活受体（PPAR）信号通路；而STK734327与piclamilast则可作为拮抗剂靶向神经营养因子信号通路。最终密度泛函理论分析显示，STK734327-MAPK1为最稳定的优势构象。综上，三白草所含的7种活性成分，以及副干酪乳杆菌JS1可产生的雌马酚，能够对上述四种代谢疾病发挥协同治疗作用。