Abstract
Phloroglucinol is a key byproduct of gut microbial metabolism that has been widely used as a treatment for irritable bowel syndrome. Here, we demonstrate that phloroglucinol tempers macrophage responses to pro-inflammatory pathogens and stimuli. In vivo, phloroglucinol administration decreases gut and extraintestinal inflammation in murine models of inflammatory bowel disease and systemic infection. The metabolite induces modest modifications in the microbiota. However, the presence of an active microbiota is required to preserve its anti-inflammatory activity. Remarkably, the protective effect of phloroglucinol lasts partially at least 6 months. Single-cell transcriptomic analysis of bone marrow progenitors demonstrates the capacity of the metabolite to induce long-lasting innate immune training in hematopoietic lineages, at least partially through the participation of the receptor and transcription factor, aryl hydrocarbon receptor (AhR). Phloroglucinol induces alterations in metabolic and epigenetic pathways that are most prevalent in upstream progenitors as hallmarks of central trained immunity. These data identify phloroglucinol as a dietary-derived compound capable of inducing central trained immunity and modulating the response of the host to inflammatory insults.
Keywords:
Microbiota byproducts; central trained immunity; inflammation; phenolic derivatives.
MeSH terms
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Animals
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Anti-Inflammatory Agents / pharmacology
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Disease Models, Animal
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Gastrointestinal Microbiome* / drug effects
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Immunity, Innate / drug effects
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Inflammation* / metabolism
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Inflammation* / prevention & control
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Inflammatory Bowel Diseases / drug therapy
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Inflammatory Bowel Diseases / immunology
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Inflammatory Bowel Diseases / metabolism
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Inflammatory Bowel Diseases / microbiology
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL*
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Phloroglucinol* / metabolism
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Phloroglucinol* / pharmacology
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Receptors, Aryl Hydrocarbon* / metabolism
Substances
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Phloroglucinol
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Receptors, Aryl Hydrocarbon
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Anti-Inflammatory Agents
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Ahr protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
Grants and funding
This work was supported by MCIN/AEI/10.13039/501100011033 (PID2021-124328OB-100 to JA, AGL2017-86757-R and RYC-2013-13666 to LA, SAF2015-73549-JIN to HR, PID2020-117911RB-100 to AFT). MGA is funded by the Deutsche Forschungsgemeinschaft (DFG, German research Foundation) – SFB 1583/1 [Project number: 492620490] and SPP 2330 [Project number: 465341196]. Supported in part by Fundación Jesús de Gangoiti and by fellowships from Getteccu (Geteccu-MSD to HR and LA, and Geteccu-FreseniusKabi to JA). CIC bioGUNE is the recipient of a Severo Ochoa Centro de Excelencia award [CEX2021-001136-S].JC was partly supported by a FEMS Research and Training Grant [1816] and an EMBO Scientific Exchange Grant [9792]. APa and IS were supported by a predoctoral fellowship from the Basque Government. APe was supported by a postdoctoral fellowship from the Basque Government. DB [BES-2016-078437], SAA [PRE-2019-091720], APl [PRE2018-085772] and ESF [PRE2022-104669] were recipients of MCIU FPI fellowships from MCIN/AEI/10.13039/501100011033. APC was a recipient of a fellowship from the University of the Basque Country. NG held a predoctoral grant from the Scientific Foundation of the Spanish Association Against Cancer in Biscay [PRDVZ222452GUTI]. We thank the Basque Department of Industry, Tourism and Trade (Etortek and Elkartek programs) and the Innovation Technology Department of the Bizkaia Province. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement Nº 860325 to STP and JA.