Butyrate Shapes Immune Cell Fate and Function in Allergic Asthma

Abstract

The microbiome plays a fundamental role in how the immune system develops and how inflammatory responses are shaped and regulated. The "gut-lung axis" is a relatively new term that highlights a crucial biological crosstalk between the intestinal microbiome and lung. A growing body of literature suggests that dysbiosis, perturbation of the gut microbiome, is a driving force behind the development, and severity of allergic asthma. Animal models have given researchers new insights into how gut microbe-derived components and metabolites, such as short-chain fatty acids (SCFAs), influence the development of asthma. While the full understanding of how SCFAs influence allergic airway disease remains obscure, a recurring theme of epigenetic regulation of gene expression in several immune cell compartments is emerging. This review will address our current understanding of how SCFAs, and specifically butyrate, orchestrates cell behavior, and epigenetic changes and will provide a detailed overview of the effects of these modifications on immune cells in the context of allergic airway disease.

Keywords: HDAC inhibitor (histone deacetylase inhibitor); SCFA (short chain fatty acids); allergic asthma; butyrate; cell fate and differentiation; epigenetics; inflammation; microbiome.

Figure 1

Concentration of butyrate in portal vein and peripheral circulation in humans. The reported concentration of butyrate in plasma sampled from the portal vein plasma (solid squares) or peripheral circulation (solid circles). Values from original references were plotted and are displayed as means ± SEM as reported in original articles.

Figure 2

Butyrate production in the intestinal lumen, absorption in the gut, and peripheral distribution. (A) Butyrate is produced from the fermentation of dietary fiber by commensal bacteria (mainly Firmicutes phylum) in the gut lumen. Butyrate can stimulate butyrate-sensitive G protein coupled receptors (GPCRs) expressed on luminal epithelia. However, most of the butyrate is efficiently absorbed by colonocytes through H⁺- or Na⁺-coupled monocarboxylate transporters (MCT1 and SMCT1, respectively) expressed on the apical surface of intestinal epithelia. Most of the butyrate is consumed by colonocytes for energy. The remainder is passed through the basolateral membrane into the liver portal system via monocarboxylate transports (MCT3-5). Butyrate then transits to the liver and is absorbed by hepatocytes. Any remaining butyrate not used as an energy source by hepatocytes is then distributed through the circulation to peripheral tissues. The effects of butyrate on immune cells, and most other cell types are mediated through direct activation of surface GPCRs or, following influx into the cell by activation of peroxisome proliferator-activated receptor gamma (PPARγ) or inhibition of butyrate-sensitive histone deacetylase (HDAC) isoforms. (B) Most of the reported effects of butyrate on immune cells discussed in the review are dependent on HDAC inhibitory activity of butyrate. Side chain lysine in histone complexes (nucleosomes) in condensed, closed, chromatin are acetylated by histone acetyltransferases (HATs) to provide access for transcription machinery. HDACs remove acetyl groups from histone lysines to promote chromatin condensation and, in general, attenuate gene transcription at targeted loci. Butyrate is the most potent “endogenous” HDAC inhibitor (HDACi) and thereby promotes open chromatin and encourages active transcription. The shown concentrations are those reported for butyrate in the indicated compartments in humans. Created with https://biorender.com/.

Figure 3

Widespread effects of butyrate on immune cells in allergic asthma. Allergic asthma is a complex inflammatory disease with several immune cells involved in the pathogenesis. Exposure to an allergen induces eosinophilia, airway hyperreactivity, and goblet cell hyperplasia. These effects are collectively driven by dendritic cells (DCs), Th2 cells, Th9 cells, ILC2s, B cells, mast cells, and eosinophils. Butyrate ameliorates allergic asthma by modulating various steps in pathways of different immune cell compartments. Butyrate suppresses both DC activation and migration to local lymph nodes where activated DCs function to stimulate immature/naive CD4+ T cells to polarize to the Th2 lineage. In the B cell compartment, butyrate suppresses both B cell isotype class switching and plasma cell differentiation leading to decreased levels of circulating IgE. Subsequent binding of allergens and cross-linking of surface bound IgE to Fc receptors expressed on mast cells induces degranulation; however, butyrate inhibits IgE-mediated mast cell degranulation. In the Th9 cell lineage, butyrate functions to divert the fate of naïve CD4+ T cells from Th9 to FoxP3+ regulatory-T cells (T regs) effectively promoting a regulatory phenotype. In ILC2s, butyrate suppresses the secretion of IL-5 and IL-13 cytokines that have downstream effects on eosinophils. Butyrate inhibits both the adhesion of eosinophils to the blood vessel endothelium, chemotaxis in response to CCL24, and directly promotes eosinophil apoptosis. Created with https://biorender.com/.

Figure 4

Cellular and molecular mechanisms of butyrate on immune cells in allergic asthma. Created with https://biorender.com/.