Gut microbes from the phylogenetically diverse genus Eubacterium and their various contributions to gut health

Abstract

Over the last two decades our understanding of the gut microbiota and its contribution to health and disease has been transformed. Among a new 'generation' of potentially beneficial microbes to have been recognized are members of the genus Eubacterium, who form a part of the core human gut microbiome. The genus consists of phylogenetically, and quite frequently phenotypically, diverse species, making Eubacterium a taxonomically unique and challenging genus. Several members of the genus produce butyrate, which plays a critical role in energy homeostasis, colonic motility, immunomodulation and suppression of inflammation in the gut. Eubacterium spp. also carry out bile acid and cholesterol transformations in the gut, thereby contributing to their homeostasis. Gut dysbiosis and a consequently modified representation of Eubacterium spp. in the gut, have been linked with various human disease states. This review provides an overview of Eubacterium species from a phylogenetic perspective, describes how they alter with diet and age and summarizes its association with the human gut and various health conditions.

Keywords: Eubacterium; Eubacterium hallii; Eubacterium rectale; bile acids; butyrate; cholesterol; gut microbiota; irritable bowel syndrome; phylogeny; short-chain fatty acids.

Figure 1.

Phylogenetic relationship of Eubacterium spp. Complete genomes for Eubacterium species (current and recently reassigned) were obtained from NCBI along with other closely related gut microbes. 16 ribosomal marker proteins (including rpL14, rpL15, rpL16, rpL18, rpL22, rpL24, rpL2, rpL3, rpL4, rpL5, rpL6, rpS10, rpS17, rpS19, rpS3 and rpS8) were extracted from each genome, aligned with MAFFT v7.271 and concatenated to create a RP16 protein alignment. Phylogenetic reconstruction using maximum likelihood was carried out in IQ-TREE with the following settings: -mset WAG,LG,JTT,Dayhoff -mrate E,I,G,I + G -mfreq FU -wbtl. Only genomes with at least 4 ribosomal marker proteins were included in the tree. The resulting tree was visualized using iTOL. Possible misclassifications are denoted by filled, inverted triangles in the phylogram. Tree nodes are depicted by filled circles.

Figure 2.

Modulation of various processes through short-chain fatty acids (SCFAs) produced by Eubacterium spp. Upon reaching the gut, carbohydrates resistant to digestion (commonly derived from dietary fibers) are degraded by gut microbiota to produce monosaccharides. These monosaccharides can be utilized by certain bacteria, including Eubacterium spp., in the gut to produce SCFAs such as butyrate, propionate, and acetate. SCFAs interact with G-protein-coupled receptors such as GPR43, GPR41, and GPR109a to modulate inflammation, intestinal barrier integrity, glycemic response, energy homeostasis and other host responses. Inflammation is suppressed by SCFAs primarily through inhibition of the NF-κB pathway and/or histone deacetylase function (HDACi) to downregulate pro-inflammatory cytokines such as TNFα, IL-6, IL-12, IFNγ and upregulate anti-inflammatory cytokines such as IL-10, TGF-β in a variety of cells including immune cells such as macrophages in lamina propria. IL-18 expression upregulated by GPR109a contributes to the enhancement of intestinal barrier integrity. SCFAs can also be taken up by enterocytes through the monocarboxylate transporter (MCT) and along with peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) variably stimulates the liver, muscles, pancreas and adipose tissues to influence glycemic response, lipolysis, fatty acid oxidation and gluconeogenesis.

Figure 3.

Cholesterol metabolism by Eubacterium coprostanoligenes in the gut. Cholesterol can reach the gut from two sources: endogenous (synthesized in the liver) or exogenous (in the form of dietary uptake). Cholesterol can be reabsorbed from the gut. The cholesterol that is not reabsorbed can be metabolized by Eubacterium coprostanoligenes to coprostanol both directly and indirectly through the intermediate, coprostanone. It can also reduce cholesterol to coprostanol upon epimerization to allocholesterol through a pathway that remains poorly studied. Unlike cholesterol, coprostanol is taken up poorly in the intestine and most of it is excreted in feces, thereby providing a route for cholesterol removal from the gut and systemic circulation.

Figure 4.

Bile acid (BA) modification by Eubacterium spp. and enterohepatic circulation. BAs are produced from cholesterol in the liver and are continually released into the bile canaliculi via the bile salt export pump (BSEP). The bile canaliculi drain into the gallbladder where BAs are temporarily stored and undergo postprandial release into the gut. Before release into the bile canaliculi, cholic acid (CA) and chenodeoxycholic acid (CDCA), the primary BAs produced in liver hepatocytes, can be conjugated to taurine/glycine moieties to form conjugated BAs (T/G-CA, T/G-CDCA). In the gut, primary BAs can be metabolized by gut bacteria including Eubacterium spp. into diverse secondary forms. BAs can undergo deconjugation to form deconjugated primary BAs and/or hydroxylation reactions to produce secondary BAs such as deoxycholic acid (DCA) and lithocholic acid (LCA). 95% of BAs are reabsorbed in the gut and recycled back to the liver through the portal vein, with conjugated BAs exhibiting highest rates of reabsorption. This circular movement of BAs from liver hepatocytes to the gut and back to the liver is known as the enterohepatic circulation.

Figure 5.

Bile acid (BA) induced signaling pathways influence BA homeostasis and inflammation. BAs in the gut are taken up by enterocytes via the apical sodium-bile acid transporter (ASBT) and bind to the farnesoid X receptor (FXR) which in turn upregulates the expression of the fibroblast growth factor 19 (FGF19). FGF19 can then bind to FGF receptor 4 in hepatocytes to downregulate BA synthesis in liver through the JNK/ERK pathway. Additionally, BAs transported through the portal vein can inhibit BA synthesis in hepatocytes in a FXR-mediated manner by entry through the organic anion transporting polypeptide 1 (OATP1) or sodium-taurocholate cotransporting polypeptide (NTCP) and upregulating the BA synthesis inhibiting transcription factor small heterodimer protein (SHP). FXR can also influence BA homeostasis through the peroxisome proliferator-activated receptor alpha (PPARα). LCA and DCA produced by Eubacterium spp. are high-affinity ligands for TGR5, which upon binding of said BAs can modulate glycemic response, immune response, BA homeostasis and BA detoxification in various tissues.