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Physiology-forward identification of bile acid-sensitive vomeronasal receptors.

ABSTRACT: The mouse accessory olfactory system (AOS) supports social and reproductive behavior through the sensation of environmental chemosignals. A growing number of excreted steroids have been shown to be potent AOS cues, including bile acids (BAs) found in feces. As is still the case with most AOS ligands, the specific receptors used by vomeronasal sensory neurons (VSNs) to detect BAs remain unknown. To identify VSN BA receptors, we first performed a deep analysis of VSN BA tuning using volumetric GCaMP6f/s Ca²⁺ imaging. These experiments revealed multiple populations of BA-receptive VSNs with submicromolar sensitivities. We then developed a new physiology-forward approach for identifying AOS ligand-receptor interactions, which we call Fluorescence Live Imaging for Cell Capture and RNA sequencing, or FLICCR-seq. FLICCR-seq analysis revealed five specific V1R family receptors enriched in BA-sensitive VSNs. These studies introduce a powerful new approach for ligand-receptor matching and reveal biological mechanisms underlying mammalian BA chemosensation.

SUBMITTER: Wong WM

PROVIDER: S-EPMC7259934 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Physiology-forward identification of bile acid-sensitive vomeronasal receptors.

Wong Wen Mai WM Cao Jie J Zhang Xingjian X Doyle Wayne I WI Mercado Luis L LL Gautron Laurent L Meeks Julian P JP

Science advances 20200529 22

The mouse accessory olfactory system (AOS) supports social and reproductive behavior through the sensation of environmental chemosignals. A growing number of excreted steroids have been shown to be potent AOS cues, including bile acids (BAs) found in feces. As is still the case with most AOS ligands, the specific receptors used by vomeronasal sensory neurons (VSNs) to detect BAs remain unknown. To identify VSN BA receptors, we first performed a deep analysis of VSN BA tuning using volumetric GCa ...[more]

PMID: 32523992

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Project description:Pathogen infections remain a significant public health problem worldwide. Accumulating evidence regarding the crosstalk between bile acid (BA) metabolism and immune response reveals that BA metabolism regulates host immunity and microbial pathogenesis, making it an attractive target for disease prevention and infection control. However, the effect of infection on circulating BA profiles, the biosynthesis-related enzymes, and their receptors remains to be depicted. Here, we investigated the effect of viral (vesicular stomatitis virus, VSV) and bacterial (lipopolysaccharide, LPS) infections on BA metabolism and signaling. Infection models were successfully established by intraperitoneally injecting VSV and LPS, respectively. VSV and LPS injection significantly changed the circulating BA profiles, with highly increased levels of taurine-conjugated BAs and significant decreases in unconjugated BAs. Consistent with the decreased levels of circulating cholic acid (CA) and chenodeoxycholic acid (CDCA), the expression of BA biosynthesis-related rate-limiting enzymes (Cyp7a1, Cyp27a1, Cyp8b1, and Hsd3b7) were significantly reduced. Furthermore, hepatic and pulmonary BA receptors (BARs) expression varied in different infection models. LPS treatment had an extensive impact on tested hepatic and pulmonary BARs, resulting in the upregulation of TGR5, S1PR2, and VDR, while VSV infection only promoted VDR expression. Our study provides insights into the involvement of BA metabolism in the pathophysiology of infection, which may provide potential clues for targeting BA metabolism and BAR signaling to boost innate immunity and control infection.ImportanceThis study focuses on the crosstalk between bile acid (BA) metabolism and immune response in VSV infection and LPS treatment models and depicts the effect of infection on circulating BA profiles, the biosynthesis-related enzymes, and their receptors. These findings provide insights into the effect of infection on BA metabolism and signaling, adding a more comprehensive understanding to the relationship between infection, BA metabolism and immune responses.

Project description:Drug-induced liver injury (DILI) is a matter of concern in the course of drug development and patient safety, often leading to discontinuation of drug-development programs or early withdrawal of drugs from market. Hepatocellular toxicity or impairment of bile acid (BA) metabolism, known as cholestasis, are the two clinical forms of DILI. Whole-body physiology-based modelling allows a mechanistic investigation of the physiological processes leading to cholestasis in man. Objectives of the present study were: (1) the development of a physiology-based model of the human BA metabolism, (2) population-based model validation and characterisation, and (3) the prediction and quantification of altered BA levels in special genotype subgroups and after drug administration. The developed physiology-based bile acid (PBBA) model describes the systemic BA circulation in humans and includes mechanistically relevant active and passive processes such as the hepatic synthesis, gallbladder emptying, transition through the gastrointestinal tract, reabsorption into the liver, distribution within the whole body, and excretion via urine and faeces. The kinetics of active processes were determined for the exemplary BA glycochenodeoxycholic acid (GCDCA) based on blood plasma concentration-time profiles. The robustness of our PBBA model was verified with population simulations of healthy individuals. In addition to plasma levels, the possibility to estimate BA concentrations in relevant tissues like the intracellular space of the liver enhance the mechanistic understanding of cholestasis. We analysed BA levels in various tissues of Benign Recurrent Intrahepatic Cholestasis type 2 (BRIC2) patients and our simulations suggest a higher susceptibility of BRIC2 patients toward cholestatic DILI due to BA accumulation in the liver. The effect of drugs on systemic BA levels were simulated for cyclosporine A (CsA). Our results confirmed the higher risk of DILI after CsA administration in healthy and BRIC2 patients. The presented PBBA model enhances our mechanistic understanding underlying cholestasis and drug-induced alterations of BA levels in blood and organs. The developed PBBA model might be applied in the future to anticipate potential risk of cholestasis in patients.

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Physiology-forward identification of bile acid-sensitive vomeronasal receptors.

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Physiology-forward identification of bile acid-sensitive vomeronasal receptors.

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