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Review
. 2020 May;295(1):220-239.
doi: 10.1111/imr.12856.

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti-tumor immunity

Laura M Sipe  1 , Mehdi Chaib  2 , Ajeeth K Pingili  1 , Joseph F Pierre  3 , Liza Makowski  1   2   4
Affiliations
Review

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti-tumor immunity

Laura M Sipe et al. Immunol Rev. 2020 May.

Abstract

Bile acids (BAs) are known facilitators of nutrient absorption but recent paradigm shifts now recognize BAs as signaling molecules regulating both innate and adaptive immunity. Bile acids are synthesized from cholesterol in the liver with subsequent microbial modification and fermentation adding complexity to pool composition. Bile acids act on several receptors such as Farnesoid X Receptor and the G protein-coupled BA receptor 1 (TGR5). Interestingly, BA receptors (BARs) are expressed on immune cells and activation either by BAs or BAR agonists modulates innate and adaptive immune cell populations skewing their polarization toward a more tolerogenic anti-inflammatory phenotype. Intriguingly, recent evidence also suggests that BAs promote anti-tumor immune response through activation and recruitment of tumoricidal immune cells such as natural killer T cells. These exciting findings have redefined BA signaling in health and disease wherein they may suppress inflammation on the one hand, yet promote anti-tumor immunity on the other hand. In this review, we provide our readers with the most recent understanding of the interaction of BAs with the host microbiome, their effect on innate and adaptive immunity in health and disease with a special focus on obesity, bariatric surgery-induced weight loss, and immune checkpoint blockade in cancer.

Keywords: bariatric surgery; immunometabolism; microbiome; mitochondria; obesity; tumor microenvironment.

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Conflict of interest statement

CONFLICT OF INTEREST

No authors have conflict.

Figures

FIGURE 1
FIGURE 1
The gut microbiome, enterohepatic circulation, and obesity. The liver generates primary bile acids (BAs), usually conjugated with taurine and glycine, in part to aid with lipid and nutrient absorption immediately following meals. Within the gut, the microbiota deconjugate and ferment BAs into secondary BAs that are subsequently reabsorbed and may be further modified by the liver, a cycle known as “enterohepatic circulation.” This iterative process leads to diverse composition in the BA pools within the gut lumen, in circulation, and within various tissues. In addition to nutrient absorption, BAs serve as potent hormone-like signaling molecules through numerous receptors that confer a variety of metabolic and immunological effects throughout the body. Obesity disturbs this process, leading to blunted postprandial BA release, increased levels of the 12 alpha-hydroxylated BA forms, decreased intestinal microbiome diversity, and changes in taxonomic composition. Obesity is associated with a loss of the mucosal colonizing microbe, Akkermansia muciniphila, which has been shown to confer beneficial metabolic and immunotherapeutic anti-tumor benefits when administered to mouse and man
FIGURE 2
FIGURE 2
Bile acids or small molecule effects of bile acid receptors (BARs) Farnesoid X Receptor (FXR) and G Protein-coupled bile acid receptor (TGR5) agonism on immune cell populations. BAR agonism impairs pro-inflammatory functions of immune cells by downregulating tumor necrosis factor alpha (TNFα) and interleukin 12 (IL-12) on dendritic cells (DCs) and monocytes. BAR agonism also impairs M1-like pro-inflammatory polarization of macrophages (Mϕ) by downregulating TNFα, IL-6, and interferon gamma (IFNγ). Additionally, BAR agonism decreases the abundance of B cells and CD4 T cells, downregulates protein death receptor 1 (PD-1) and its ligand PD-L1 on CD4 T cells and impairs Th1 and Th17 polarization. On the other hand, BAR agonism favors anti-inflammatory cells such as myeloid-derived suppressor cells (MDSC) via upregulation of the calcium-binding protein S100A8, T regulatory cells (Treg), and immunoregulatory M2-like polarization of macrophages via upregulation of IL-10. BAR agonism also induces the expansion of CD8 T cells and their upregulation of PD-1; however, BA-induced expansion of CD8 T cells remains unknown. Finally, primary BAs induce liver sinusoidal endothelial cells (LSEC) to release the chemokine CXCL16 which will attract Natural Killer T cells (NKT) into the tumor site and inhibit cancer growth
FIGURE 3
FIGURE 3
Correlation of GPBAR1 (TGR5) expression with immune cell infiltration levels in breast cancer and skin cutaneous melanoma. Breast cancer is depicted in top graphs and skin cutaneous melanoma in bottom graphs. A, GPBAR1 expression has significant positive correlations with infiltrating levels of CD8+ T cells and dendritic cells determined by using TIMER database. B, High expression of GPBAR1 has a significant favorable overall survival when correlated with high infiltration of CD8+ T cells and dendritic cells as compared to low expression of GPBAR1 in both breast cancer and skin cutaneous melanoma (TIMER database). Cumulative survival is shown for 80 mo
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