Gut-inhabiting Clostridia build human GPCR ligands by conjugating neurotransmitters with diet- and human-derived fatty acids

Chang, Frank; Siuti, Piro; Laurent, Stéphane; Williams, Thomas L.; Glassey, Emerson; Sailer, Andreas W.; Gordon, D. Benjamin; Hemmerle, Horst; Voigt, Christopher A.

doi:10.1038/s41564-021-00887-y

Cited by 42 publications

(37 citation statements)

References 107 publications

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“…It is also possible that M. tuberculosis produces itself antagonists against GPR183, as has been demonstrated for other bacteria. Eubacterium rectale , for instance, produces lauroyl tryptamine, which is able to bind to and antagonize GPR183 against its endogenous agonist 7α,25-OHC at a 0.98 μM half-maximal inhibitory concentration [ 64 ]. Whether M. tuberculosis is able to produce antagonists for GPR183 or other oxysterol receptors remains to be elucidated.…”

Section: Oxysterols In Bacterial Infectionsmentioning

confidence: 99%

Oxysterols in the Immune Response to Bacterial and Viral Infections

Foo

Bartlett

Ronacher

2022

Cells

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Oxidized cholesterols, the so-called oxysterols, are widely known to regulate cholesterol homeostasis. However, more recently oxysterols have emerged as important lipid mediators in the response to both bacterial and viral infections. This review summarizes our current knowledge of selected oxysterols and their receptors in the control of intracellular bacterial growth as well as viral entry into the host cell and viral replication. Lastly, we briefly discuss the potential of oxysterols and their receptors as drug targets for infectious and inflammatory diseases.

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Section: Oxysterols In Bacterial Infectionsmentioning

confidence: 99%

Oxysterols in the Immune Response to Bacterial and Viral Infections

Foo

Bartlett

Ronacher

2022

Cells

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“…Numerous studies have revealed that diet plays an important role in mediating the composition and metabolic function of gut microbiota ( Sonnenburg and Bäckhed, 2016 ). Consumption of dietary fiber interacts directly with gut microbes and leads to the production of key metabolites such as short-chain fatty acids (SCFAs), thus impacting gut microbial ecology, host physiology, and health ( Makki et al, 2018 ; Chang et al, 2021 ). An industrialized diet consisting of highly refined foods and low in dietary fiber usually induces the dysfunctional intestinal barrier and chronic diseases ( Martínez et al, 2015 ; Yeagle, 2015 ; García-Montero et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Effect of Fiber and Fecal Microbiota Transplantation Donor on Recipient Mice Gut Microbiota

et al. 2021

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Both fecal microbiota transplantation (FMT) and dietary fiber intervention were verified as effective ways to manipulate the gut microbiota, whereas little is known about the influence of the combined methods on gut microbiota. Here, we constructed “non-industrialized” and “industrialized” gut microbiota models to investigate the donor effect of FMT and diet effect in shaping the gut microbiota. Mice were transplanted fecal microbiota from domestic pig and received a diet with low-fiber (D) or high-fiber (DF), whereas the other two groups were transplanted fecal microbiota from wild pig and then received a diet with low-fiber (W) or high-fiber (WF), respectively. Gut microbiota of WF mice showed a lower Shannon and Simpson index (P < 0.05), whereas gut microbiota of W mice showed no significant difference than that of D and DF mice. Random forest models revealed the major differential bacteria genera between four groups, including Anaeroplasma or unclassified_o_Desulfovibrionales, which were influenced by FMT or diet intervention, respectively. Besides, we found a lower out-of-bag rate in the random forest model constructed for dietary fiber (0.086) than that for FMT (0.114). Linear discriminant analysis effective size demonstrated that FMT combined with dietary fiber altered specific gut microbiota, including Alistipes, Clostridium XIVa, Clostridium XI, and Akkermansia, in D, DF, W, and WF mice, respectively. Our results revealed that FMT from different donors coupled with dietary fiber intervention could lead to different patterns of gut microbiota composition, and dietary fiber might play a more critical role in shaping gut microbiota than FMT donor. Strategies based on dietary fiber can influence the effectiveness of FMT in the recipient.

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“…Of note, our proteomic studies of IAA-interacting proteins also identified additional candidate GPCRs (GPR107 and GPR108) that have no reported small molecule ligands and numerous other proteins, which may reveal additional mechanisms of action for IAA. Chemoproteomics therefore provides a complementary approach to targeted screening of individual microbiota species 19,57,58 or biosynthetic gene clusters 19,57,58 for novel GPCR ligands.…”

Section: Discussionmentioning

confidence: 99%

Chemoproteomics of microbiota metabolites reveals small-molecule agonists for orphan receptor GPRC5A

Zhao

Stein

Chen

et al. 2021

Preprint

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The microbiota generates diverse metabolites that can engage multiple pathways to modulate host physiology and disease, but their protein targets and mechanism(s) of action have not been fully elucidated. To address this challenge, we focused on indole-3-acetic acid (IAA), a prominent microbiota metabolite, and developed IAA-based chemical reporters for proteomic studies. We discovered that IAA interacts with many proteins in host cells, including small-molecule transporters, receptors and metabolic enzymes. Notably, our functional studies revealed that IAA binds to orphan G protein-coupled receptors such as GPRC5A, but only aromatic monoamines were capable of inducing GPRC5A signaling. Functional profiling of microbiota uncovered specific bacterial species and enzymes that generate GPRC5A agonists. Finally, biochemical characterization of GPRC5A activation identified more potent synthetic agonists as well as key amino acid residues involved in ligand binding. These studies highlight the utility of chemoproteomics to dissect protein targets and mechanisms of action for microbiota metabolites.

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Gut-inhabiting Clostridia build human GPCR ligands by conjugating neurotransmitters with diet- and human-derived fatty acids

Cited by 42 publications

References 107 publications

Oxysterols in the Immune Response to Bacterial and Viral Infections

Oxysterols in the Immune Response to Bacterial and Viral Infections

Effect of Fiber and Fecal Microbiota Transplantation Donor on Recipient Mice Gut Microbiota

Chemoproteomics of microbiota metabolites reveals small-molecule agonists for orphan receptor GPRC5A

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