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Parabacteroides goldsteinii and its metabolite 7-KLCA attenuate endometriosis via TGR5 to reprogram macrophages by
Yun Chen1,2, Yuqing Qiu1, Feifei Pan1,2
1Department of Gynecology and Obstetrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
Abstract:
Endometriosis (EMS) remains understudied in effective management strategies. The interplay between macrophage dysfunction and microbiota-derived immune signals emerges as a potential mechanism in EMS pathogenesis, suggesting its relevance for future therapeutic exploration. In this study, we established mouse models to demonstrate that gut microbiota modulated EMS development. Integrated microbial and metabolomic profiling identified Parabacteroides goldsteinii (Pg) as a promising probiotic candidate, whose downstream metabolite 7-ketolithocholic acid (7-KLCA) exhibiting therapeutic efficacy in ameliorating EMS phenotypes upon supplementation. Mechanistically, Pg reshapes its bile acid (BA) metabolism to elevate 7-KLCA. This bioactive metabolite acts via the receptor TGR5 to suppress PPARγ expression and activate GPR132, thereby enhancing efferocytosis and promoting M1 macrophage polarization. These findings uncover a gut-metabolite-immune regulatory axis through which Pg reprograms macrophage function to restrain EMS progression, offering a potential microbial perspective for this chronic condition.
Insights
A specific gut bacterium, Parabacteroides goldsteinii, and its metabolite 7-ketolithocholic acid show promise in treating endometriosis. This discovery highlights a gut-metabolite-immune axis for managing the chronic condition.
Area of Science:
- Microbiology
- Immunology
- Gastroenterology
Background:
- Endometriosis (EMS) lacks effective management strategies.
- Macrophage dysfunction and microbiota-derived immune signals are implicated in EMS pathogenesis.
- Exploring the gut microbiota's role in EMS offers therapeutic potential.
Purpose of the Study:
- To investigate the gut microbiota's influence on endometriosis development.
- To identify specific microbial species and metabolites with therapeutic potential for EMS.
- To elucidate the underlying mechanisms of microbial-mediated regulation of EMS.
Main Methods:
- Establishment of mouse models for endometriosis.
- Integrated microbial and metabolomic profiling of the gut microbiota.
- Supplementation with Parabacteroides goldsteinii and its metabolite 7-ketolithocholic acid.
- Analysis of macrophage polarization and efferocytosis.
Main Results:
- Gut microbiota composition significantly modulated EMS development in mouse models.
- Parabacteroides goldsteinii (Pg) was identified as a potential probiotic candidate.
- Supplementation with Pg-derived 7-ketolithocholic acid (7-KLCA) ameliorated EMS phenotypes.
- 7-KLCA acts via TGR5 and GPR132 to enhance efferocytosis and M1 macrophage polarization, suppressing PPARγ.
- Pg reprograms macrophage function through a gut-metabolite-immune axis.
Conclusions:
- Gut microbiota plays a crucial role in modulating endometriosis progression.
- Parabacteroides goldsteinii and its metabolite 7-KLCA represent a promising therapeutic strategy for EMS.
- The identified gut-metabolite-immune axis provides novel insights into EMS pathogenesis and treatment.
