1. Academic Validation
  2. Gut microbial bile acid metabolite skews macrophage polarization and contributes to high-fat diet-induced colonic inflammation

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

  • Gut Microbes. 2020 Nov 9;12(1):1-20. doi: 10.1080/19490976.2020.1819155.
Lingyu Wang 1 2 3 Zizhen Gong 1 2 3 Xiuyuan Zhang 4 Fangxinxing Zhu 1 2 3 Yuchen Liu 4 Chaozhi Jin 4 Xixi Du 1 2 3 Congfeng Xu 5 6 Yingwei Chen 2 3 Wei Cai 1 2 3 Chunyan Tian 4 Jin Wu 1 2 3
Affiliations

Affiliations

  • 1 Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University , Shanghai, China.
  • 2 Department of Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University , Shanghai, China.
  • 3 Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition , Shanghai, China.
  • 4 State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences(Beijing), Beijing Institute of Lifeomics , Beijing, China.
  • 5 Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai, China.
  • 6 Department of Immunology, Shanghai Institute of Immunology, Shanghai Jiaotong University School of Medicine , Shanghai, China.
Abstract

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.

Keywords

High fat diet; bile acid; colonic inflammaion; macrophage polarization; microbiota; toll-like receptor.

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