Metabolic, Epigenetic, and Transgenerational Effects of Gut Bacterial Choline Consumption

Abstract

SUMMARY Choline is an essential nutrient and methyl donor required for epigenetic regulation. Here, we assessed the impact of gut microbial choline metabolism on bacterial fitness and host biology by engineering a microbial community that lacks a single choline-utilizing enzyme. Our results indicate that choline-utilizing bacteria compete with the host for this nutrient, significantly impacting plasma and hepatic levels of methyl-donor metabolites and recapitulating biochemical signatures of choline deficiency. Mice harboring high levels of choline-consuming bacteria showed increased susceptibility to metabolic disease in the context of a high-fat diet. Furthermore, bacterially-induced reduction of methyl-donor availability influenced global DNA methylation patterns in both adult mice and their offspring and engendered behavioral alterations. Our results reveal an underappreciated effect of bacterial choline metabolism on host metabolism, epigenetics, and behavior. This work suggests that interpersonal differences in microbial metabolism should be considered when determining optimal nutrient intake requirements.

Innate immune signaling inDrosophilashifts anabolic lipid metabolism from triglyceride storage to phospholipid synthesis in an ER stress-dependent manner

“…An increase in host PE and PC synthesis would lead to increased consumption of ethanolamine and choline. These molecules can be used as carbon and nitrogen sources for bacteria (Garsin, 2010;Romano et al, 2017), therefore increased host Kennedy pathway activity may lead to reduced growth for some species of bacteria. On the other hand, it is critical to tightly regulate ER function during infection because unrestrained Ire1 activity and Xbp1 splicing in sigma-1 receptor knockout mice leads to elevated proinflammatory cytokine production and increased rates of sepsis in response to LPS treatment (Rosen et al, 2019).…”

The impact of cellular metabolism on chromatin dynamics and epigenetics

“…For example, individuals exposed to famine during the Dutch Hunger Winter displayed altered DNA methylation patterns for over six decades 48 . Moreover, factors such as diet 49–52 , microbiome 53 , temperature 54 , malnutrition 55 , chemical exposure 56 and many others are able to induce heritable alterations in nucleic acid or histone methylation profiles that can be stably transmitted through more than 10 generations 54 . How epigenomic states are stably inherited is unknown, but perturbations to chromatin-modifying enzymes in the germline in controlled laboratory settings have yielded comparable heritable effects to what is observed in settings of human exposure 57 .…”

Meta‐Omics‐ and Metabolic Modeling‐Assisted Deciphering of Human Microbiota Metabolism

“…BLAST searches revealed that the PLD‐encoding genes within the cut gene cluster in the PC‐utilizing strains have a 40–63% identity with the PLD gene in Streptomyces sp. strain PMF, subsequently confirmed by activity tests in a PC‐utilizing strain E. coli MS 200‐1 and its pld ‐deletion mutant . Specifically, E. coli MS 200‐1 was able to convert PC into choline and then into TMA, and the mutant strain lacked such activity, which was restored when pld was reintroduced.…”

“…Building on this link, they screened the homologs of ethanolamine‐utilizing enzymes in the genomes of bacteria known to metabolize choline. This resulted in the discovery of the choline utilization (cut) gene cluster encoding choline TMA‐lyase (CutC), a glycyl radical enzyme (GRE) responsible for the conversion of choline into TMA …”