Gut microbiota-mediated C-sulfonate metabolism impairs the bioavailability and anti-cholestatic efficacy of andrographolide.

IF 12.2 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Gut Microbes Pub Date : 2024-09-12 DOI:10.1080/19490976.2024.2387402
Dafu Tang,Wanyu Hu,Bingxuan Fu,Xiaojie Zhao,Guoquan You,Cong Xie,Hong Yu Wang,Xueni Guo,Qianbing Zhang,Zhongqiu Liu,Ling Ye
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Abstract

Cholestatic liver injury results from the accumulation of toxic bile acids in the liver, presenting a therapeutic challenge with no effective treatment available to date. Andrographolide (AP) has exhibited potential as a treatment for cholestatic liver disease. However, its limited oral bioavailability poses a significant obstacle to harnessing its potent therapeutic properties and restricts its clinical utility. This limitation is potentially attributed to the involvement of gut microbiota in AP metabolism. In our study, employing pseudo-germ-free, germ-free and strain colonization animal models, along with 16S rRNA and shotgun metagenomic sequencing analysis, we elucidate the pivotal role played by gut microbiota in the C-sulfonate metabolism of AP, a process profoundly affecting its bioavailability and anti-cholestatic efficacy. Subsequent investigations pinpoint a specific enzyme, adenosine-5'-phosphosulfate (APS) reductase, predominantly produced by Desulfovibrio piger, which catalyzes the reduction of SO42- to HSO3-. HSO3- subsequently interacts with AP, targeting its C=C unsaturated double bond, resulting in the formation of the C-sulfonate metabolite, 14-deoxy-12(R)-sulfo andrographolide (APM). Inhibition of APS reductase leads to a notable enhancement in AP bioavailability and anti-cholestatic efficacy. Furthermore, employing RNA sequencing analysis and farnesoid X receptor (FXR) knockout mice, our findings suggest that AP may exert its anti-cholestatic effects by activating the FXR pathway to promote bile acid efflux. In summary, our study unveils the significant involvement of gut microbiota in the C-sulfonate metabolism of AP and highlights the potential benefits of inhibiting APS reductase to enhance its therapeutic effects. These discoveries provide valuable insights into enhancing the clinical applicability of AP as a promising treatment for cholestatic liver injury.
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肠道微生物群介导的C-磺酸盐代谢会损害穿心莲内酯的生物利用度和抗胆汁淤积功效。
胆汁淤积性肝脏损伤是有毒胆汁酸在肝脏中蓄积的结果,这给治疗带来了挑战,迄今为止尚无有效的治疗方法。穿心莲内酯(AP)具有治疗胆汁淤积性肝病的潜力。然而,其有限的口服生物利用度对利用其强大的治疗特性构成了重大障碍,并限制了其临床实用性。这一限制可能是由于肠道微生物群参与了 AP 的代谢。在我们的研究中,我们采用了假无胚胎、无菌和菌株定植动物模型,并结合 16S rRNA 和散弹枪元基因组测序分析,阐明了肠道微生物群在 AP 的 C-磺酸盐代谢过程中发挥的关键作用,这一过程对 AP 的生物利用率和抗胆汁淤积功效产生了深远影响。随后的研究确定了一种特殊的酶--5'-磷酸腺苷(APS)还原酶,它主要由皮格脱硫弧菌产生,能催化SO42-还原成HSO3-。HSO3- 随后与 AP 相互作用,以其 C=C 不饱和双键为目标,形成 C-磺酸盐代谢物 14-deoxy-12(R)-sulfo andrographolide (APM)。抑制 APS 还原酶可显著提高 AP 的生物利用率和抗胆汁淤积功效。此外,利用 RNA 测序分析和法尼类固醇 X 受体(FXR)基因敲除小鼠,我们的研究结果表明,AP 可能通过激活 FXR 途径来促进胆汁酸外流,从而发挥抗胆汁淤积作用。总之,我们的研究揭示了肠道微生物群在 AP 的丙磺酸盐代谢过程中的重要作用,并强调了抑制 APS 还原酶以增强其治疗效果的潜在益处。这些发现为提高 AP 的临床适用性提供了宝贵的见解,是治疗胆汁淤积性肝损伤的一种有前途的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Gut Microbes
Gut Microbes Medicine-Microbiology (medical)
CiteScore
18.20
自引率
3.30%
发文量
196
审稿时长
10 weeks
期刊介绍: The intestinal microbiota plays a crucial role in human physiology, influencing various aspects of health and disease such as nutrition, obesity, brain function, allergic responses, immunity, inflammatory bowel disease, irritable bowel syndrome, cancer development, cardiac disease, liver disease, and more. Gut Microbes serves as a platform for showcasing and discussing state-of-the-art research related to the microorganisms present in the intestine. The journal emphasizes mechanistic and cause-and-effect studies. Additionally, it has a counterpart, Gut Microbes Reports, which places a greater focus on emerging topics and comparative and incremental studies.
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