Farnesoid X receptor mediates macrophage-intrinsic responses to suppress colitis-induced colon cancer progression
Xingchen Dong, Ming Qi, Chunmiao Cai, Yu Zhu, Yuwenbin Li, Sally Coulter, Fei Sun, Christopher Liddle, Nataliya V. Uboha, Richard Halberg, Wei Xu, Paul Marker, Ting Fu
Xingchen Dong, Ming Qi, Chunmiao Cai, Yu Zhu, Yuwenbin Li, Sally Coulter, Fei Sun, Christopher Liddle, Nataliya V. Uboha, Richard Halberg, Wei Xu, Paul Marker, Ting Fu
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Research Article Endocrinology Gastroenterology

Farnesoid X receptor mediates macrophage-intrinsic responses to suppress colitis-induced colon cancer progression

Abstract

Bile acids (BAs) affect the intestinal environment by ensuring barrier integrity, maintaining microbiota balance, regulating epithelium turnover, and modulating the immune system. As a master regulator of BA homeostasis, farnesoid X receptor (FXR) is severely compromised in patients with inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). At the front line, gut macrophages react to the microbiota and metabolites that breach the epithelium. We aim to study the role of the BA/FXR axis in macrophages. This study demonstrates that inflammation-induced epithelial abnormalities compromised FXR signaling and altered BAs’ profile in a mouse CAC model. Further, gut macrophage–intrinsic FXR sensed aberrant BAs, leading to pro-inflammatory cytokines’ secretion, which promoted intestinal stem cell proliferation. Mechanistically, activation of FXR ameliorated intestinal inflammation and inhibited colitis-associated tumor growth, by regulating gut macrophages’ recruitment, polarization, and crosstalk with Th17 cells. However, deletion of FXR in bone marrow or gut macrophages escalated the intestinal inflammation. In summary, our study reveals a distinctive regulatory role of FXR in gut macrophages, suggesting its potential as a therapeutic target for addressing IBD and CAC.

Authors

Xingchen Dong, Ming Qi, Chunmiao Cai, Yu Zhu, Yuwenbin Li, Sally Coulter, Fei Sun, Christopher Liddle, Nataliya V. Uboha, Richard Halberg, Wei Xu, Paul Marker, Ting Fu

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Figure 4

FXR modulates macrophages’ response to inflammatory insult.

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FXR modulates macrophages’ response to inflammatory insult. (A) Relative...
(A) Relative expression (FPKM values) of presented genes based on RNA-Seq data of normal and inflamed colorectal tissue samples from combined IBD (TaMMA) cohorts. Box plots show the interquartile range (box), median (line), and minimum and maximum (whiskers). (B) The scheme of FexD early intervention in WT mice under chronic DSS (CDSS) regimen or distilled water (dH2O) as control. After first week of CDSS administration, mice were treated with FexD (50 mg/kg BW/d orally) for 4–5 weeks, with corn oil as vehicle control. (C) Expression of FXR target genes in the small intestine, measured by qRT-PCR. (D–F) Expression of pro-inflammatory cytokines (D), M1-like macrophage cell marker genes (E), and M2-like macrophages marker genes (F) measured by qRT-PCR in small intestinal lamina propria cells from above treatment groups. (G and H) Representative flow cytometry analyses of the percentages of macrophages and monocytes and IL23+ and TNF-α+ macrophages (G) from small intestinal lamina propria cells. Data quantifications presented (H). n = 3–4/group. Experiments were independently replicated 3 times, and representative data are shown as the mean ± SEM. Wilcoxon test and 1-way ANOVA test followed by Tukey’s multiple comparisons are used; *CDSS versus dH2O, #FexD versus CDSS; *, #P < 0.05; **, ##P < 0.01; ***, ###P < 0.005.