Impacts of gut microbiota on metabolism and efficacy of timosaponin A-III
10.16438/j.0513-4870.2024-0150
- VernacularTitle:肠道菌群对知母皂苷A-III的代谢及其药效的影响
- Author:
Wen-jin HUANG
;
Ling-yun PAN
;
Xin-xin GAO
;
Wei-ze ZHU
;
Hou-kai LI
- Publication Type:Research Article
- Keywords:
timosaponin A-III;
metabolic dysfunction-associated steatohepatitis;
gut microbiota;
rug metabolism;
italic>Akkermansia_muciniphila
- From:
Acta Pharmaceutica Sinica
2024;59(8):2372-2380
- CountryChina
- Language:Chinese
-
Abstract:
Intraperitoneal administration of timosaponin A-III (TA-III) has therapeutic effects on high-fat diet-induced metabolic dysfunction-associated steatotic liver disease (MASLD), but oral administration has no effect. This suggests that gut microbiota may affect the oral bioavailability of TA-III. Metabolic dysfunction-associated steatohepatitis (MASH) is an inflammatory subtype of MASLD. To investigate the therapeutic effect of different administration modes of TA-III on MASH and its relationship with gut microbiota metabolism. In this study, a MASH mouse model was induced by choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Comparing the therapeutic effect of intraperitoneal injection (10 mg·kg-1, ip) and intragastric administration (100 mg·kg-1, ig) of TA-III. The concentration of TA-III in serum of rats under the two administration modes was analyzed. On this basis, the metabolic effect of gut microbiota on TA-III in mice was verified by the experiment of metabolism of gut microbiota in vitro. The pharmacokinetic experiment of combined antibiotic intervention in mice further verified the metabolism of TA-III by gut microbiota in mice. Finally, the concentration of TA-III in serum of mice after the administration of TA-III by intragastric administration under different antibiotic intervention conditions was compared, and 16S rRNA sequencing analysis was combined to find the key bacteria that may participate in the metabolism of TA-III. The animal welfare and experimental procedures in this paper were in accordance with the provisions of the Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine. The ethics approval number is PZSHUTCM2307030004 and PZSHUTCM2310200003. The results showed that TA-III (10 mg·kg-1, ip) had definite therapeutic effect on MASH mice, but TA-III (100 mg·kg-1, ig) was ineffective. The analysis showed that the prototype concentration of TA-III in serum and liver of mice in TA-III (100 mg·kg-1, ig) was significantly lower than TA-III (10 mg·kg-1, ip), suggesting that the oral administration of TA-III may be metabolized by gut microbiota. The concentration of TA-III in serum of streptomycin (Str) treated mice was higher than normal mice. Combined with 16S rRNA gene sequencing analysis, it was found that the abundance of Akkermansia_muciniphila (A. muciniphila) was significantly reduced in the Str group. In vitro experiments showed that A. muciniphila could metabolize TA-III. In conclusion, gut microbiota is an important factor affecting the efficacy of TA-III administration through the gastrointestinal tract, in which A. muciniphila may play an important role.
