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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Colitis / etiology*
  • Colitis / immunology
  • Colitis / microbiology
  • Colon / immunology
  • Colon / microbiology
  • Cytokines / metabolism
  • Deoxycholic Acid / analysis
  • Deoxycholic Acid / metabolism*
  • Deoxycholic Acid / pharmacology
  • Diet, High-Fat*
  • Feces / chemistry
  • Gastrointestinal Microbiome* / drug effects
  • Gastrointestinal Microbiome* / physiology
  • Gram-Positive Bacteria / growth & development*
  • Gram-Positive Bacteria / metabolism*
  • MAP Kinase Signaling System
  • Macrophage Activation
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Phosphorylation
  • Receptor, Muscarinic M2 / metabolism
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism
  • Tyrosine / metabolism
  • Vancomycin / pharmacology

Substances

  • Anti-Bacterial Agents
  • Cytokines
  • NF-kappa B
  • Receptor, Muscarinic M2
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • Deoxycholic Acid
  • Tyrosine
  • Vancomycin

Grants and funding

This work was supported by grants from Natural Science Foundation of Shanghai [20ZR1446200]; Research Foundation of Shanghai Health and Family Planning Commission [201940219]; Xinhua Hospital [18YJ02]; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition [17DZ2272000] and Foundation of Shanghai Municipal Health Commission [Key weak discipline construction project 2019ZB0101].