Stable Isotope Tracing In Vivo Reveals A Metabolic Bridge Linking The Microbiota To Host Histone Acetylation

Abstract

The gut microbiota influences host epigenetics by fermenting dietary fiber into butyrate. Although butyrate could promote histone acetylation by inhibiting histone deacetylases, it may also undergo oxidation to acetyl-CoA, a necessary cofactor for histone acetyltransferases. Here, we find that epithelial cells from germ-free mice harbor a loss of histone H4 acetylation across the genome except at promoter regions. Using stable isotope tracing in vivo with 13C-labeled fiber, we demonstrate that the microbiota supplies carbon for histone acetylation. Subsequent metabolomic profiling revealed hundreds of labeled molecules and supported a microbial contribution to host fatty acid metabolism, which declined in response to colitis and correlated with reduced expression of genes involved in fatty acid oxidation. These results illuminate the flow of carbon from the diet to the host via the microbiota, disruptions to which may affect energy homeostasis in the distal gut and contribute to the development of colitis.

Microbiome mediation of animal life histories via metabolites and insulin‐like signalling

“…For example, recent studies using isotopically labelled food, and targeted metabolites through prebiotics, have identified in vivo the metabolically active bacteria responsible for specific metabolites (i.e. stable isotope probing) and enabled quantification of use by hosts (Frost et al ., 2014; Oberbach et al ., 2017; Berry & Loy, 2018; Hatzenpichler et al ., 2020; Lund et al ., 2021). Future research incorporating ‐omics with metabolite probes within a systems biology framework, including machine learning approaches, holds great promise to reveal novel and critical insight into the precise mechanistic pathways that determine microbiome–host dynamics (Rosato et al ., 2018; Qian & Ho, 2020; Leggieri et al ., 2021).…”

Gut bacterial nutrient preferences quantified in vivo

“…The availability of dietary nutrients to gut microbiota depends on the extent of host absorption: nutrients that are absorbed in the small intestine, like starch, are not available to the colonic microbiome. In contrast, nutrients that are poorly digested in the upper gastrointestinal tract, like fiber, can be key microbiome feedstocks (Lund et al, 2021;Wong and Jenkins, 2007).…”

Microbiota-dependent histone butyrylation in the mammalian intestine

“…Many studies have investigated how SCFAs bind to receptors, feed into energy pathways, and can act as inhibitors of histone deacetylase (HDAC) enzymes (den Besten et al, 2013; Brown et al, 2003; Donohoe, Collins, et al, 2012; Fleming et al, 1991; Poul et al, 2003; Roediger, 1982; Vidali et al, 1978). In addition, acetylation can be traced from bacterial fermentation of fiber to be deposited onto histones as PTMs (Lund et al, 2021). Alterations in the commensal microbiota or SCFA levels have also been demonstrated to regulate select histone acetylation and methylation PTMs, as well as crotonylation (Fellows et al, 2018; Krautkramer et al, 2016).…”