Histone acylations as a mechanism for regulation of intestinal epithelial cells.

Histone post-translational modifications are reversible epigenetic mechanisms that regulate chromatin structure and gene transcription. In recent years, in addition to the well-characterized histone acetylation, new acylations such as propionylation, crotonylation, butyrylation and beta-hydroxybutyrylation have been described and explored in different cell types at contexts of health and disease. Understanding how histone acylations contribute to gene expression regulation is especially important in intestinal epithelial cells (IECs) because they receive many different signals from other cells and the external environment and must adapt to maintain essential functions such as nutrient and water absorption, maintenance of tolerance and protection against pathogens. In this review, we describe how cells regulate these modifications, how they are recognized by other proteins and impact gene expression. We summarize recent studies that explored the role of these distinct epigenetic marks in the regulation of IECs and discuss their biological importance for the intestinal epithelium's adaptations to changes in metabolism and to respond to environmental signals provided, for example, by the diet, components of the intestinal microbiota and pathogens. Finally, we discuss how the histone acylations are affected by inflammatory signals and how this knowledge may provide new targets for treatment of pathologies such as the inflammatory bowel diseases.

Inulin diet uncovers complex diet-microbiota-immune cell interactions remodeling the gut epithelium.

BACKGROUND: The continuous proliferation of intestinal stem cells followed by their tightly regulated differentiation to epithelial cells is essential for the maintenance of the gut epithelial barrier and its functions. How these processes are tuned by diet and gut microbiome is an important, but poorly understood question. Dietary soluble fibers, such as inulin, are known for their ability to impact the gut bacterial community and gut epithelium, and their consumption has been usually associated with health improvement in mice and humans. In this study, we tested the hypothesis that inulin consumption modifies the composition of colonic bacteria and this impacts intestinal stem cells functions, thus affecting the epithelial structure. METHODS: Mice were fed with a diet containing 5% of the insoluble fiber cellulose or the same diet enriched with an additional 10% of inulin. Using a combination of histochemistry, host cell transcriptomics, 16S microbiome analysis, germ-free, gnotobiotic, and genetically modified mouse models, we analyzed the impact of inulin intake on the colonic epithelium, intestinal bacteria, and the local immune compartment. RESULTS: We show that the consumption of inulin diet alters the colon epithelium by increasing the proliferation of intestinal stem cells, leading to deeper crypts and longer colons. This effect was dependent on the inulin-altered gut microbiota, as no modulations were observed in animals deprived of microbiota, nor in mice fed cellulose-enriched diets. We also describe the pivotal role of γδ T lymphocytes and IL-22 in this microenvironment, as the inulin diet failed to induce epithelium remodeling in mice lacking this T cell population or cytokine, highlighting their importance in the diet-microbiota-epithelium-immune system crosstalk. CONCLUSION: This study indicates that the intake of inulin affects the activity of intestinal stem cells and drives a homeostatic remodeling of the colon epithelium, an effect that requires the gut microbiota, γδ T cells, and the presence of IL-22. Our study indicates complex cross kingdom and cross cell type interactions involved in the adaptation of the colon epithelium to the luminal environment in steady state. Video Abstract.

STING is an intrinsic checkpoint inhibitor that restrains the TH17 cell pathogenic program.

External and intrinsic factors regulate the transcriptional profile of T helper 17 (TH17) cells, thereby affecting their pathogenic potential and revealing their context-dependent plasticity. The stimulator of interferon genes (STING), a component of the intracellular DNA-sensing pathway, triggers immune responses but remains largely unexplored in T cells. Here, we describe an intrinsic role of STING in limiting the TH17 cell pathogenic program. We demonstrate that non-pathogenic TH17 cells express higher levels of STING than those activated under pathogenic conditions. Activation of STING induces interleukin-10 (IL-10) production in TH17 cells, decreasing IL-17A and IL-23R expression in a type I interferon (IFN)-independent manner. Mechanistically, STING-induced IL-10 production partially requires aryl hydrocarbon receptor (AhR) signaling, while the decrease of IL-17A expression occurs due to a reduction of Rorγt transcriptional activity. Our findings reveal a regulatory function of STING in the TH17 cell activation program, proposing it as a valuable target to limit TH17-cell-mediated inflammation.

Enoxacin induces oxidative metabolism and mitigates obesity by regulating adipose tissue miRNA expression.

MicroRNAs (miRNAs) have been implicated in oxidative metabolism and brown/beige adipocyte identity. Here, we tested whether widespread changes in miRNA expression promoted by treatment with the small-molecule enoxacin cause browning and prevent obesity. Enoxacin mitigated diet-induced obesity in mice, and this was associated with increased energy expenditure. Consistently, subcutaneous white and brown adipose tissues and skeletal muscle of enoxacin-treated mice had higher levels of markers associated with thermogenesis and oxidative metabolism. These effects were cell autonomous since they were recapitulated in vitro in murine and human cell models. In preadipocytes, enoxacin led to a reduction of miR-34a-5p expression and up-regulation of its target genes (e.g., Fgfr1, Klb, and Sirt1), thus increasing FGF21 signaling and promoting beige adipogenesis. Our data demonstrate that enoxacin counteracts obesity by promoting thermogenic signaling and inducing oxidative metabolism in adipose tissue and skeletal muscle in a mechanism that involves, at least in part, miRNA-mediated regulation.

Effect of Short Chain Fatty Acids on Age-Related Disorders.

Recent studies have indicated a prominent role of intestinal microbiota in regulation of several physiological aspects of the host including development and activation of the immune system and control of metabolism. In this review, we focused our discussion on bacterial metabolites produced from dietary fiber fermentation called short-chain fatty acids, which act as a link between the microbiota and host cells. Specifically, we described how modifications in their intestinal levels are associated with development of age-related pathologies including metabolic diseases and type 2 diabetes, hypertension, cardiovascular and neurodegenerative diseases. We also highlight their impact on the development of cancer.