We demonstrated for the first time that butyrate represses IDO-1 expression by two distinct mechanisms.
This butyrate-driven effect was independent of the G-protein coupled receptors GPR41, GPR43, and GPR109a and of the transcription factors SP1, AP1, and PPARγ for which binding sites were reported in the IDO-1 promoter. Therefore, we investigated the impact of individual cultivable commensal bacteria on IDO-1 transcriptional expression and found that the short chain fatty acid (SCFA) butyrate was the main metabolite controlling IDO-1 expression in human primary IECs and IEC cell-lines. IDO-1 expression is dependent on the microbiota and despites its central role, how the commensal bacteria impacts its expression is still unclear. Amongst the numerous effector molecules modulating the immune responses produced by IECs, indoleamine 2,3-dioxygenase-1 (IDO-1) is essential for gut homeostasis. The intestinal epithelial cells (IECs) take a central part in the host-microbiota dialogue by inducing the first microbial-derived immune signals. A wide variety of metabolites produced by commensal bacteria are influencing host health but the characterization of the multiple molecular mechanisms involved in host-microbiota interactions is still only partially unraveled. Such signaling systems have been therapeutically targeted for the treatment of pain, inflammation, depression, obesity, and diabetes.Ĭommensal bacteria are crucial for the development and maintenance of a healthy immune system therefore contributing to the global well-being of their host. (E) Endogenous long-chain N-acyl-amides that are structurally related to commendamide are reported to function as agonists for numerous receptors, including many GPCRs. (D) Purified commendamide activates the HEK293:NFκB GFP reporter assay. (C) The structures for three minor clonespecific metabolites related to commendamide (compounds 2-4) were also determined using NMR and MS data. coli transformed with Cbeg12-1, are shown. (B) Key NMR correlations used to define the structure of commendamide (1), the major clone-specific peak found in cultures of E. coli transformed with an empty pJWC1 cosmid vector (i), cosmid Cbeg12-1 (ii), cosmid Cbeg12-2 (iii), cosmid Cbeg12-3 (iv), cosmid Cbeg12-1 with a transposon insertion in the Cbeg12-1 gene (v), Cbeg12-1 subcloned into pJWC1 (vi), and synthetic commendamide (vii). (A) Electrospray ionization (ESI)-mass spectroscopy (MS) traces of culture broth extracts from E. This study shows the utility of functional metagenomic for identifying potential mechanisms used by commensal bacteria for host interaction and outlines a functional metagenomics-based pipeline for the systematic identification of diverse commensal bacteria effectors that impact host cellular functions.Ĭharacterization of commendamide. G2A/GPR132 has been implicated in disease models of autoimmunity and atherosclerosis. Commendamide resembles long chain N-acyl amides that function as mammalian signaling molecules through activation of GPCRs, which lead us to the observation that commendamide activates theGPCR G2A/GPR132. This metabolite was also found in culture broth from the commensal bacterium Bacteroides vulgatus, which harbors a gene highly similar to Cbeg12. Detailed analysis of one effector gene family (Cbeg12) recovered from all three patient libraries found that it encodes for the production of N-acyl-3-hydroxypalmitoyl-glycine (commendamide). With diverse catabolic, anabolic and ligand binding functions which most frequently interact with either glycans or lipids. Identification of 26 unique commensal bacteria effector genes (Cbegs) that are predicted to encode proteins Known to play a central role in mediating responses to environmental stimuli. Here we examine 3,000-megabases of metagenomic DNA cloned from three phenotypically distinct patients for effectors that activate NF-κB, a transcription factor Functional metagenomics provides a systematic means of surveying commensal bacterial DNA for genes that encode effector functions.
The trillions of bacteria that make up the human microbiome are believed to encode functions that are important to human health however, little is known about the specific effectors that commensal bacteria use to interact with the human host.
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