Gut microbial bile acid metabolite skews macrophage polarization and contributes to high-fat diet-induced colonic inflammation

Gut Microbes

Chunyan Tian¹  Xiuyuan Zhang¹  Yuchen Liu¹  Chaozhi Jin¹  Yingwei Chen²  Congfeng Xu³  Xixi Du⁴  Zizhen Gong⁴  Lingyu Wang⁴  Wei Cai⁴  Fangxinxing Zhu⁴  Jin Wu⁴ 

[1] Beijing Proteome Research Center, National Center for Protein Sciences(Beijing), Beijing Institute of Lifeomics;Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University;Shanghai Jiao Tong University Affiliated Sixth People’s Hospital;Xinhua Hospital, School of Medicine, Shanghai Jiaotong University;

关键词: high fat diet;    microbiota;    colonic inflammaion;    bile acid;    macrophage polarization;    toll-like receptor;   

DOI  :  10.1080/19490976.2020.1819155

来源: DOAJ

【 摘 要 】

High-fat diet (HFD) leads to systemic low-grade inflammation, which has been involved in the pathogenesis of diverse metabolic and inflammatory diseases. Colon is thought to be the first organ suffering from inflammation under HFD conditions due to the pro-inflammatory macrophages infiltration, however, the mechanisms concerning the induction of pro-inflammatory phenotype of colonic macrophages remains unclear. In this study, we show that HFD increased the percentage of gram-positive bacteria, especially genus Clostridium, and resulted in the significant increment of fecal deoxycholic acid (DCA), a gut microbial metabolite produced by bacteria mainly restricted to genus Clostridium. Notably, reducing gram-positive bacteria with vancomycin diminished fecal DCA and profoundly alleviated pro-inflammatory macrophage infiltration in colon, whereas DCA-supplemented feedings to vancomycin-treated mice provoked obvious pro-inflammatory macrophage infiltration and colonic inflammation. Meanwhile, intra-peritoneal administration of DCA also elicited considerable recruitment of macrophages with pro-inflammatory phenotype. Mechanistically, DCA dose-dependently promoted M1 macrophage polarization and pro-inflammatory cytokines production at least partially through toll-like receptor 2 (TLR2) transactivated by M2 muscarinic acetylcholine receptor (M2-mAchR)/Src pathway. In addition, M2-mAchR mediated increase of TLR2 transcription was mainly achieved via targeting AP-1 transcription factor. Moreover, NF-κB/ERK/JNK signalings downstream of TLR2 are involved in the DCA-induced macrophage polarization. In conclusion, our findings revealed that high level DCA induced by HFD may serve as an initiator to activate macrophages and drive colonic inflammation, thus offer a mechanistic basis that modulation of gut microbiota or intervening specific bile acid receptor signaling could be potential therapeutic approaches for HFD-related inflammatory diseases.

【 授权许可】

Unknown