Gut metabolites: make orphans adopted

Precision Clinical Medicine, 2(2), 2019, 87–89 doi: 10.1093/pcmedi/pbz012 Advance Access Publication Date: 24 June 2019 Comments COMMENTS Weiqiao Zhang1 and Shu Zhu1,2,* 1 Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, University of Science and Technology of China, Hefei 230027, China, and 2School of Data Science, University of Science and Technology of China, Hefei 230026, China *Correspondence: Shu Zhu, Editor’s note A commentary on “A forward chemical genetic screen reveals gut microbiota metabolites that modulate host physiology”. G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and contain seventransmembrane helices. GPCRs are versatile membrane receptors and regulate diverse intracellular signaling pathway in response to many extracellular stimuli. Upon activation by ligands, GPCRs couple to intracellular effectors, including G proteins and arrestins,1 which in turn mediate diverse downstream signaling pathways that shape a broad range of physiological functions. Many well-characterized GPCR ligands/agonists, including light, odors, hormones, neurotransmitters and intestinal metabolites, exert different physiological functions in different cell types and tissues. Hence GPCRs represent readily druggable targets of more than one-third of currently prescribed medications.2 There are approximately 350 nonolfactory GPCRs, comparable to the number of olfactory GPCRs, but at least one-third of nonolfactory GPCRs are orphan receptors with unknown endogenous or inherent ligands.3 Thus ‘deorphanization’ of orphan GPCRs is a major challenge of this field. The screening of ligands for orphan or unannotated GPCRs is difficult because of the inherent diversity of signal-transducing cascades. To date, functional assays of GPCR activity typically depend on heterotrimeric G protein-coupling,4 whereas studies indicate that certain GPCRs mediate signal transduction independent of canonical G protein coupling,5 suggesting this approach is not suitable for GPCRome-wide screening. However, since nearly all characterized GPCRs recruit β-arrestin,6,7 the measurement of G protein-independent β-arrestin recruitment provides an alternative assay platform. Many GPCR-β-arrestin interaction-based approaches have been documented, including high-content screening (HCS), bioluminescence resonance energy transfer (BRET), enzyme complementation, and transcriptional activation following arrestin translocation (Tango),8–11 but none of these approaches are routinely performed in a genome-wide, parallel manner. The Tango assays have many advantages, including G protein independence, high signal to background ratio, and stable amplification of relatively small inputs into large output signals.11 Based on the Tango assay, Kroeze et al. developed a method called PRESTO-Tango (parallel receptorome expression and screening via transcriptional output, with transcriptional activation following arrestin translocation), which facilitates rapid, efficacious, parallel, and simultaneous screening of bioactive Received: 4 June 2019; Accepted: 17 June 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of West China School of Medicine & West China Hospital of Sichuan University. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact 87 Gut metabolites: make orphans adopted 88 | Weiqiao Zhang and Shu Zhu which regulate diverse core physiological process.20 Among these bacterial isolates, all eight Morganella morganii strains activated both DRDs and HRHs, and two Lactobacillus reuteri strains activated HRHs. Furthermore, Chen et al. found that M. morganii produced trace amounts of dopamine and undetectable tyramine, but significant quantities of phenethylamine (PEA), a chemical with mood enhancing properties that can readily cross the blood-brain barrier. Mechanistically, L-Phe, L-DOPA and L-Tyr are the natural precursors for PEA, dopamine and tyramine production, respectively, all catalyzed by the human enzyme aromatic L-amino acid decarboxylase. However, M. morganii selectively converted L-Phe to PEA, but not L-DOPA to dopamine or L-Tyr to tyramine. Notably, by using the cAMP response element-secreted human placental alkaline phosphatase (CRE-SEAP) assay, they found that PEA is a full agonist for DRD2-4, but may be a biased agonist for DRD1 and DRD5 that activates G protein-dependent signaling but not β-arrestin recruitment. Chen et al. also found another bacteria strain, assigned to the species B. theta (B. theta C34), that produced the essential amio acid L-Phe, which acts as an agonist for GPR56/AGRG1. Interestingly, B. theta C34-produced L-Phe could be efficiently converted to PEA by M. morganii C135 in vitro and in vivo, and thus the metabolic exchange between the two bacterial species contributes to the production of a bioactive trace amine that can affect systemic host physiology. Consistent with previous reports, Chen et al. found that M. morganii secreted significant amounts of histamine, and that two L. reuteri strains and two Enterobacteriaceae strains also secreted histamine. Supplementation of L-His in the culture medium enhanced the production of histamine by these strains. They further found that in vivo, germ-free mice colonized with either M. morganii or L. reuteri, exhibited high levels of gut histamine production. M. morganii primarily colonized the cecum and colon, and caused increased colon motility, which is a well-known physiological function mediated by histamine. In contrast to histamine, the level of PEA accumulation was low in the gut upon M. morganii colonization. However, host monoamine oxidase (MAO) enzymes are known to degrade PEA and other biogenic amines in the gut and elsewhere in the body, which may restrict their accumulation both locally and systemically. Indeed, treatment of mice monocolonized with M. morganii with an antidepression MAO inhibitor resulted in ‘phenethylamine poisoning’. These results suggest that gut bacteriaderived metabolites exert potent physiological effects in vivo and demonstrate how gut bacteria can impact responses to medical drugs. Altogether, Chen et al. used host GPCR activation as a lens to parse bioactive metabolites produced by intestinal microbes. They revealed a diet-microbe-host axis where microbiota-derived histamine regulates gut motility, and a tripartite microbe-microbe-host relationship that compounds across the entire conventional human GPCRome.12 By using this unique platform, Kroeze et al. validated more than 120 nonorphan human GPCR targets. Furthermore, by screening approved drugs (NIH Clini (...truncated)