Anti-infective bile acids bind and inactivate a Salmonella virulence regulator. Nature chemical biology Bile acids are prominent host and microbiota metabolites that modulate host immunity and microbial pathogenesis. However, the mechanisms by which bile acids suppress microbial virulence are not clear. To identify the direct protein targets of bile acids in bacterial pathogens, we performed activity-guided chemical proteomic studies. In Salmonella enterica serovar Typhimurium, chenodeoxycholic acid (CDCA) most effectively inhibited the expression of virulence genes and invasion of epithelial cells and interacted with many proteins. Notably, we discovered that CDCA can directly bind and inhibit the function of HilD, an important transcriptional regulator of S. Typhimurium virulence and pathogenesis. Our characterization of bile acid-resistant HilD mutants in vitro and in S. Typhimurium infection models suggests that HilD is one of the key protein targets of anti-infective bile acids. This study highlights the utility of chemical proteomics to identify the direct protein targets of microbiota metabolites for mechanistic studies in bacterial pathogens. 10.1038/s41589-022-01122-3

Bile Acid-Microbiome Interaction Promotes Gastric Carcinogenesis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Bile reflux gastritis (BRG) is associated with the development of gastric cancer (GC), but the specific mechanism remains elusive. Here, a comprehensive study is conducted to explore the roles of refluxed bile acids (BAs) and microbiome in gastric carcinogenesis. The results show that conjugated BAs, interleukin 6 (IL-6), lipopolysaccharide (LPS), and the relative abundance of LPS-producing bacteria are increased significantly in the gastric juice of both BRG and GC patients. A secondary BA, taurodeoxycholic acid (TDCA), is significantly and positively correlated with the LPS-producing bacteria in the gastric juice of these patients. TDCA promotes the proliferation of normal gastric epithelial cells (GES-1) through activation of the IL-6/JAK1/STAT3 pathway. These results are further verified in two mouse models, one by gavage of TDCA, LPS, and LPS-producing bacteria (Prevotella melaninogenica), respectively, and the other by bile reflux (BR) surgery, mimicking clinical bile refluxing. Moreover, the bile reflux induced gastric precancerous lesions observed in the post BR surgery mice can be prevented by treatment with cryptotanshinone, a plant-derived STAT3 inhibitor. These results reveal an important underlying mechanism by which bile reflux promotes gastric carcinogenesis and provide an alternative strategy for the prevention of GC associated with BRG. 10.1002/advs.202200263

Ursodeoxycholic acid reduces antitumor immunosuppression by inducing CHIP-mediated TGF-β degradation. Nature communications TGF-β is essential for inducing systemic tumor immunosuppression; thus, blocking TGF-β can greatly enhance antitumor immunity. However, there are still no effective TGF-β inhibitors in clinical use. Here, we show that the clinically approved compound ursodeoxycholic acid (UDCA), by degrading TGF-β, enhances antitumor immunity through restraining Treg cell differentiation and activation in tumor-bearing mice. Furthermore, UDCA synergizes with anti-PD-1 to enhance antitumor immunity and tumor-specific immune memory in tumor-bearing mice. UDCA phosphorylates TGF-β at T282 site via TGR5-cAMP-PKA axis, causing increased binding of TGF-β to carboxyl terminus of Hsc70-interacting protein (CHIP). Then, CHIP ubiquitinates TGF-β at the K315 site, initiating p62-dependent autophagic sorting and subsequent degradation of TGF-β. Notably, results of retrospective analysis shows that combination therapy with anti-PD-1 or anti-PD-L1 and UDCA has better efficacy in tumor patients than anti-PD-1 or anti-PD-L1 alone. Thus, our results show a mechanism for TGF-β regulation and implicate UDCA as a potential TGF-β inhibitor to enhance antitumor immunity. 10.1038/s41467-022-31141-6

Bile acids and colon cancer: Solving the puzzle with nuclear receptors. Degirolamo Chiara,Modica Salvatore,Palasciano Giuseppe,Moschetta Antonio Trends in molecular medicine Colorectal cancer is the third most common malignancy worldwide and is often linked to obesity, a sedentary lifestyle, carbohydrate- and fat-rich diets and elevated fecal excretion of secondary bile acids. Accumulation of toxic bile acids triggers oxidative damage, mitochondrial dysfunction and tumor progression. Nuclear receptors are transcription factors crucially involved in the regulation of bile acid metabolism and detoxification, and their activation may confer protection from bile acid tumor-promoting activity. In this review, we explore the tangled relationships among bile acids, nuclear receptors and the intestinal epithelium, with particular emphasis on the role of the farnesoid X receptor in colorectal cancer prevention and on novel nuclear receptor-based approaches to expand the portfolio of chemotherapeutic agents. 10.1016/j.molmed.2011.05.010

Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nature reviews. Gastroenterology & hepatology Emerging evidence points to a strong association between the gut microbiota and the risk, development and progression of gastrointestinal cancers such as colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Bile acids, produced in the liver, are metabolized by enzymes derived from intestinal bacteria and are critically important for maintaining a healthy gut microbiota, balanced lipid and carbohydrate metabolism, insulin sensitivity and innate immunity. Given the complexity of bile acid signalling and the direct biochemical interactions between the gut microbiota and the host, a systems biology perspective is required to understand the liver-bile acid-microbiota axis and its role in gastrointestinal carcinogenesis to reverse the microbiota-mediated alterations in bile acid metabolism that occur in disease states. An examination of recent research progress in this area is urgently needed. In this Review, we discuss the mechanistic links between bile acids and gastrointestinal carcinogenesis in CRC and HCC, which involve two major bile acid-sensing receptors, farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5). We also highlight the strategies and cutting-edge technologies to target gut-microbiota-dependent alterations in bile acid metabolism in the context of cancer therapy. 10.1038/nrgastro.2017.119