The microbiota metabolite, phloroglucinol, confers long-term protection against inflammation.

 The joint work of up to 14 research groups, including the Institute of Physical Chemistry Blas Cabrera, has provided clues about the anti-inflammatory effect of phloroglucinol. Phloroglucinol is a key byproduct of gut microbial metabolism that has been widely used as a treatment for irritable bowel syndrome. Her, 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 antiinflammatory activity. Remarkably, the protective effect of phloroglucinol lasts partially at least 6 months. Single-cell transcriptomic analysis of bone marrow progenitors demosntrates the capacity of the matobolite to induce long-lasting innate inmune 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. Gut Microbes: https://doi.org/10.1080/19490976.2024.2438829