Microbiota-derived metabolite promotes HDAC3 activity in the gut

Abstract

The coevolution of mammalian hosts and their beneficial commensal microbes has led to development of a symbiotic host-microbiota relationship 1 . Epigenetic machinery permits mammalian cells to integrate environmental signals 2 , however, how these pathways are finely tuned by diverse cues from commensal bacteria is not well understood. Here, we reveal a highly selective pathway through which microbiota-derived inositol phosphate regulates histone deacetylase 3 (HDAC3) activity in the intestine. Despite abundant HDAC inhibitors in the intestine such as butyrate, we unexpectedly found that HDAC3 activity was sharply increased in intestinal epithelial cells (IECs) of microbiota-replete mice compared to germ-free mice. This discordance was reconciled by finding that commensal bacteria, including E. coli , stimulated HDAC activity through metabolism of phytate and inositol trisphosphate production. Intestinal exposure to inositol trisphosphate and phytate ingestion both promoted recovery following intestinal damage. Remarkably, inositol trisphosphate also induced growth of patient-derived intestinal organoids, stimulated HDAC3-dependent proliferation, and countered butyrate inhibition of colonic growth. Collectively, these data reveal inositol trisphosphate as a microbiota-derived metabolite that activates a mammalian histone deacetylase to promote epithelial repair. Thus, HDAC3 represents a converging epigenetic sensor of distinct metabolites that calibrates host responses to diverse microbial signals.

Nutritional Therapy Strategies in Pediatric Crohn’s Disease

“…As EEN is typically very low in fiber, EEN has been shown to reduce fecal levels of SCFAs such as butyrate [ 114 ]. Butyrate regulates the expression of epigenetic enzymes, notably, histone deacetylases (HDACs) that have a role in controlling the immune response and gut activity [ 115 , 116 ].…”

Commensal bacterial-derived retinoic acid primes host defense to intestinal infection

“…In addition to canonical microbial sensing pathways, epigenetic mechanisms enable environmental signals to instruct cellular responses and represent another interface by which microbiota can impact mammalian cells (Amatullah and Jeffrey, 2020;Woo and Alenghat, 2017). Consistent with this, epigenetic-modifying enzymes in IECs integrate microbiota-derived signals to regulate intestinal homeostasis and immunity (Ansari et al, 2020;Navabi et al, 2017;Takahashi et al, 2009;Wu et al, 2020). Epigenetic-modifying enzymes mediate covalent chromatin modifications that alter DNA accessibility and gene expression.…”

Microbiota-mediated phytate metabolism activates HDAC3 to contribute intestinal homeostasis

“…In a recent study in Nature, Wu et al discovered a fundamental host-microbe interaction that is crucially involved in responding to dietary change thereby maintaining healthy intestinal dynamics. 1 They demonstrated that HDAC3 activity can be promoted by microbiota-mediated phytate metabolism to contribute intestinal homeostasis and repair.…”

“…In a recent study of Wu et al, they identified a novel microbiota-mediated metabolic pathway that could activate HDAC to contribute intestinal homeostasis. 1 Butyrate is well-documented for suppressing HDAC activation. 4 Indeed, colonising germ-free (GF) mice with butyrate-producing bacteria (Faecalibacterium prausnitzii) largely inhibited HDAC enzymatic activity in IECs.…”

“…1 Gut microbes metabolise dietary fibres to produce butyrate, which is known for suppressing the activity of an epigenetic regulator HDAC3. By contrast, metabolising dietary phytate (enriched in nuts and beans) with aid of microbes-secreted phytase can produce IP3, which can induce HDAC3 activation as newly discovered by Wu et al 1 HDAC3 promotes the removal of the acetyl group (abbreviated as Ac) from the histone tail of chromatin. While HDAC3 activation can contribute intestinal homeostasis and repair.…”