Once known exclusively for their role in nutrients absorption, bile acids have emerged as signaling molecules, generated from cholesterol breakdown, acting on several immune cells by activating a variety of receptors including the G protein-coupled bile acid receptor 1 (GPABR1 or TGR5), the Farnesoid-X-receptor (FXR) and, as recently discovered, the retinoid-related orphan receptors (ROR)γt. GPBAR1, FXR, and RORγt are highly expressed in cells of the innate and adaptive immune system (i.e., dendritic cells (DCs), macrophages, innate lymphoid 3 cells (ILC3s), and T helper 17 (Th17) lymphocytes) and plays an important role in regulating intestinal and liver immunity, highlighting a role for various bile acid species in regulating immune responses to intestinal microbial antigens. While primary bile acids are generated from the cholesterol breakdown secondary bile acids, the GPBAR1 ligands, and oxo-bile acids derivatives, the RORγt ligands, are generated by the intestinal microbiota, highlighting the potential of these bile acids in mediating the chemical communication between the intestinal microbiota and the host. Changes in intestinal microbiota, dysbiosis, alter the composition of the bile acid pool, promoting the activation of the immune system and development of chronic inflammation. In this review, we focus on the molecular mechanisms by which an altered bile acid signaling promotes intestinal inflammation.

A growing body of evidence suggests that probiotic functionality is not accurately predicted by their taxonomy. Here, we have set up a study to investigate the effectiveness of two probiotic formulations containing a blend of seven bacterial species in modulating intestinal inflammation in two rodent models of colitis, induced by treating mice with 2,4,6-Trinitrobenzenesulfonic acid (TNBS) or dextran sodium sulfate (DSS). Despite the taxonomy of the bacterial species in the two probiotic formulations being similar, only one preparation (Blend 2-Vivomixx) effectively attenuated the development of colitis in both models. In the TNBS model of colitis, Blend 2 reduced the expression of pro-inflammatory genes while increasing the production of anti-inflammatory cytokines, promoting the expansion M2 macrophages and the formation of IL-10-producing Treg cells in the colon’s lamina propria. In the DSS model of colitis, disease attenuation and Treg formation was observed only in mice administered with Blend 2, and this effect was associated with intestinal microbiota remodeling and increased formation of lactate, butyrate, and propionate. None of these effects were observed in mice administered with Blend 1 (VSL#3). In summary, we have shown that two probiotic mixtures obtained by combining taxonomically similar species produced with different manufacturing methods exert divergent effects in mouse models of colitis.

Non-alcoholic steatohepatitis (NASH) is a progressive, chronic, liver disease whose prevalence is growing worldwide. Despite several agents being under development for treating NASH, there are no drugs currently approved. The Farnesoid-x-receptor (FXR) and the G-protein coupled bile acid receptor 1 (GPBAR1), two bile acid activated receptors, have been investigated for their potential in treating NASH. Here we report that BAR502, a steroidal dual ligand for FXR/GPBAR1, attenuates development of clinical and liver histopathology features of NASH in mice fed a high fat diet (HFD) and fructose (F). By RNAseq analysis of liver transcriptome we found that BAR502 restores FXR signaling in the liver of mice feed HFD–F, and negatively regulates a cluster of genes including Srebf1 (Srepb1c) and its target genes—fatty acid synthase (Fasn) and Cell death-inducing DFF45-like effector (CIDE) genes, Cidea and Cidec—involved in lipid droplets formation and triglycerides storage in hepatocytes. Additionally, BAR502 increased the intestinal expression of Fgf15 and Glp1 and energy expenditure by white adipose tissues. Finally, exposure to BAR502 reshaped the intestinal microbiota by increasing the amount of Bacteroidaceae. In conclusion, we have shown that dual FXR/GPBAR1 agonism might have utility in treatment of NASH.

Pelargonidins are anthocyanidins thought to be beneficial for the human health, although controversies exist over the doses needed and the unclear mechanism of action, along with poor systemic bioavailability. One putative target of pelargonidins is the aryl hydrocarbon receptor (AhR). A synthetic pelargonidin (Mt-P) was synthesized by the methylation of the pelargonidin (the natural compound indicated as P). Mt-P transactivated the AhR with an EC₅₀ of 1.97 µM and was ~2-fold more potent than the natural compound. In vitro Mt-P attenuated pro-inflammatory activities of Raw264.7 macrophage cells in an AhR-dependent manner. In vivo, administration of the Mt-P in Balb/c mice resulted in a dose-dependent attenuation of signs and symptoms of colitis induced by TNBS. A dose of 5 mg/kg Mt-P, but not the natural compound P, reversed intestinal inflammation and increased expression of Tnf-α, Ifn-ƴ, and Il-6, while promoted the expansion of regulatory T cells and M2 macrophages. In C57BL/6J mice fed a high fat diet (HFD), Mt-P attenuated body weight gain, intestinal and liver inflammation, and ameliorated insulin sensitivity, while worsened liver steatosis by up-regulating the liver expression of Cd36 and Apo100b. These effects were abrogated by AhR gene ablation. Mt-P is a synthetic pelargonidin endowed with robust AhR agonist activity that exerts beneficial effects in murine models of inflammation and metabolic dysfunction.

The current definition of a postbiotic is a “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”. Postbiotics can be mainly classified as metabolites, derived from intestinal bacterial fermentation, or structural components, as intrinsic constituents of the microbial cell. Secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) are bacterial metabolites generated by the enzymatic modifications of primary bile acids by microbial enzymes. Secondary bile acids function as receptor ligands modulating the activity of a family of bile-acid-regulated receptors (BARRs), including GPBAR1, Vitamin D (VDR) receptor and RORγT expressed by various cell types within the entire human body. Secondary bile acids integrate the definition of postbiotics, exerting potential beneficial effects on human health given their ability to regulate multiple biological processes such as glucose metabolism, energy expenditure and inflammation/immunity. Although there is evidence that bile acids might be harmful to the intestine, most of this evidence does not account for intestinal dysbiosis. This review examines this novel conceptual framework of secondary bile acids as postbiotics and how these mediators participate in maintaining host health.

Background & Aims: ACE2, a carboxypeptidase that generates Ang-(1-7) from Ang II, is highly expressed in the lung, small intestine and colon. GPBAR1, is a G protein bile acid receptor that promotes the release of the insulinotropic factor glucagon-like peptide (GLP)-1 and attenuates intestinal inflammation. Methods: We investigated the expression of ACE2, GLP-1 and GPBAR1 in two cohorts of Crohn’s disease (CD) patients and three mouse models of colitis and Gpbar1^−/− mice. Activation of GPBAR1 in these models and in vitro was achieved by BAR501, a selective GPBAR1 agonist. Results: In IBD patients, ACE2 mRNA expression was regulated in a site-specific manner in response to inflammation. While expression of ileal ACE2 mRNA was reduced, the colon expression was induced. Colon expression of ACE2 mRNA in IBD correlated with expression of TNF-α and GPBAR1. A positive correlation occurred between GCG and GPBAR1 in human samples and animal models of colitis. In these models, ACE2 mRNA expression was further upregulated by GPABR1 agonism and reversed by exendin-3, a GLP-1 receptor antagonist. In in vitro studies, liraglutide, a GLP-1 analogue, increased the expression of ACE2 in colon epithelial cells/macrophages co-cultures. Conclusions: ACE2 mRNA expression in the colon of IBD patients and rodent models of colitis is regulated in a TNF-α- and GLP-1-dependent manner. We have identified a GPBAR1/GLP-1 mechanism as a positive modulator of ACE2.