TY - JOUR
T1 - Gut microbiota-derived gamma-aminobutyric acid from metformin treatment reduces hepatic ischemia/reperfusion injury through inhibiting ferroptosis
AU - Wang, Fangyan
AU - Liu, Xiujie
AU - Huang, Furong
AU - Zhou, Yan
AU - Wang, Xinyu
AU - Song, Zhengyang
AU - Wang, Sisi
AU - Wang, Xiaoting
AU - Shi, Dibang
AU - Ruan, Gaoyi
AU - Ji, Xiawei
AU - Zhang, Eryao
AU - Tan, Zenglin
AU - Ye, Yuqing
AU - Wang, Chuang
AU - Zhu, Jesse
AU - Wang, Wantie
N1 - Publisher Copyright:
© Wang, Liu, Huang et al.
PY - 2024/3
Y1 - 2024/3
N2 - Hepatic ischemia/reperfusion injury (HIRI) is a common and inevitable factor leading to poor prognosis in various liver diseases, making the outcomes of current treatments in clinic unsatisfactory. Metformin has been demonstrated to be beneficial to alleviate HIRI in recent studies, however, the underpinning mechanism remains unclear. In this study, we found metformin mitigates HIRI-induced ferroptosis through reshaped gut microbiota in mice, which was confirmed by the results of fecal microbiota transplantation treatment but showed the elimination of the beneficial effects when gut bacteria were depleted using antibiotics. Detailedly, through 16S rRNA and metagenomic sequencing, we identified that the metformin-reshaped microbiota was characterized by the increase of gamma-aminobutyric acid (GABA) producing bacteria. This increase was further confirmed by the elevation of GABA synthesis key enzymes, glutamic acid decarboxylase and putrescine aminotransferase, in gut microbes of metformin-treated mice and healthy volunteers. Furthermore, the benefit of GABA against HIRI-induced ferroptosis was demonstrated in GABA-treated mice. Collectively, our data indicate that metformin can mitigate HIRI-induced ferroptosis by reshaped gut microbiota, with GABA identified as a key metabolite.
AB - Hepatic ischemia/reperfusion injury (HIRI) is a common and inevitable factor leading to poor prognosis in various liver diseases, making the outcomes of current treatments in clinic unsatisfactory. Metformin has been demonstrated to be beneficial to alleviate HIRI in recent studies, however, the underpinning mechanism remains unclear. In this study, we found metformin mitigates HIRI-induced ferroptosis through reshaped gut microbiota in mice, which was confirmed by the results of fecal microbiota transplantation treatment but showed the elimination of the beneficial effects when gut bacteria were depleted using antibiotics. Detailedly, through 16S rRNA and metagenomic sequencing, we identified that the metformin-reshaped microbiota was characterized by the increase of gamma-aminobutyric acid (GABA) producing bacteria. This increase was further confirmed by the elevation of GABA synthesis key enzymes, glutamic acid decarboxylase and putrescine aminotransferase, in gut microbes of metformin-treated mice and healthy volunteers. Furthermore, the benefit of GABA against HIRI-induced ferroptosis was demonstrated in GABA-treated mice. Collectively, our data indicate that metformin can mitigate HIRI-induced ferroptosis by reshaped gut microbiota, with GABA identified as a key metabolite.
UR - http://www.scopus.com/inward/record.url?scp=85187972297&partnerID=8YFLogxK
U2 - 10.7554/eLife.89045
DO - 10.7554/eLife.89045
M3 - Article
C2 - 38488837
AN - SCOPUS:85187972297
SN - 2050-084X
VL - 13
JO - eLife
JF - eLife
M1 - RP89045
ER -