Role of polyamines in intestinal mucosal barrier function

Abstract

The intestinal epithelium is a rapidly self-renewing tissue; the rapid turnover prevents the invasion of pathogens and harmful components from the intestinal lumen, preventing inflammation and infectious diseases. Intestinal epithelial barrier function depends on the epithelial cell proliferation and junctions, as well as the state of the immune system in the lamina propria. Polyamines, particularly putrescine, spermidine, and spermine, are essential for many cell functions and play a crucial role in mammalian cellular homeostasis, such as that of cell growth, proliferation, differentiation, and maintenance, through multiple biological processes, including translation, transcription, and autophagy. Although the vital role of polyamines in normal intestinal epithelial cell growth and barrier function has been known since the 1980s, recent studies have provided new insights into this topic at the molecular level, such as eukaryotic initiation factor-5A hypusination and autophagy, with rapid advances in polyamine biology in normal cells using biological technologies. This review summarizes recent advances in our understanding of the role of polyamines in regulating normal, non-cancerous, intestinal epithelial barrier function, with a particular focus on intestinal epithelial renewal, cell junctions, and immune cell differentiation in the lamina propria.

Keywords: Cell proliferation; Inflammation; Intestinal microbiome; Intestinal mucosal barrier; Polyamines.

Fig. 1

Polyamine biosynthesis and EIF5A hypusination pathway in mammals. a Polyamine biosynthesis pathway. Enzymes and proteins are denoted by squares, and those related to synthesis and degradation/inhibition are shown by white text in black boxes and red text in white boxes, respectively. Sadenosylmethionine decarboxylase (SAMDC) and ornithine decarboxylase (ODC) are rate-limiting enzymes involved in polyamine synthesis. SAMDC decarboxylates S-adenosylmethionine to decarboxylated S-adenosylmethionine (dcSAM), such that dcSAM can provide aminopropyl groups to putrescine to produce spermidine using spermidine synthase (SPDS) and is added to spermidine to generate spermine by spermine synthase (SPMS). Spermine can be directly recycled into spermidine by spermine oxidase (SMOX). Spermine and spermidine can be recycled to spermidine and putrescine, respectively, by spermidine/spermine-N1-acetyltransferase (SSAT), followed by oxidation by polyamine oxidase (PAO) through N-acetylspermine and N-acetylspermidine, respectively. Antizymes (AZ) function as ODC inhibitors under the negative feedback regulation of polyamines. AZ is regulated by AZ inhibitors (AZI). DFMO (Difluoromethylornithine) is an irreversible suicide inhibitor of the ODC. MTA: methylthioadenosine. b The mammalian EIF5A hypusination pathway. Hypusine modification of the lysine residue of EIF5A occurs by adding spermidine via two enzymatic reactions. First, deoxyhypusine synthase (DHPS) transfers the aminobutyl group of spermidine to the amino group of lysine, generating an intermediate substrate. Second, deoxyhypusine hydroxylase (DOHH) adds a hydroxyl group and forms the hypusine residue of EIF5A. EIF5A is active in this hypusination form. GC7 (N1-guanyl-1,7diaminoheptane) is a potent inhibitor of DHPS. Enzymes are denoted by squares

Fig. 2

Polyamines and cell junctions in the intestinal epithelium. Decreased polyamine levels disrupt the intestinal barrier by reducing the proteins that comprise the tight junctions and adherens junctions of the intestine. Subsequently, it increases permeability, allowing molecular components derived from diet and intestinal bacteria to invade the host body

Fig. 3

The role of polyamines in polarization and function of macrophage. The expression of alternatively activated macrophage (AAM) genes, including ARG1, is dependent on polyamines, and stimulation with IL-4, which induces differentiation into M2 macrophages, enhances polyamine synthesis. In contrast, M1 macrophages are activated by Th1 responses and are characterized by high levels of proinflammatory cytokines and nitric oxide (NO) production. A part of arginine is consumed for the production of NO in M1 microphages. The polarization of M1/M2 macrophages involves the metabolic reprogramming of mitochondria. Hyp-EIF5A regulates the expression of oxidative phosphorylation-related mitochondrial proteins and induces M2 activation. Exogenouspolyamines are taken up and drive the M2 phenotype. Conversely, the absence of ODC by genetic deletion or inhibition of ODC by chemicals reduces polyamines and enhances the M1 phenotype. Open arrows represent metabolic pathways, red and purple arrows represent gene expression, and black arrows and T bars represent activated and inhibitory interactions, respectively

Fig. 4

Hybrid putrescine biosynthesis system in the intestinal microbiome. A mechanistic model of a pathway for putrescine production from arginine through agmatine involving the collaboration of three different bacterial species. (1) This pathway is triggered by environmental acidification due to acetate and lactate roduced by acid-producing bacteria, represented by B. animalis subsp. lactis (strain LKM512). (2) In the second step, the acid-tolerance system of Escherichia coli [Arg-dependent acid resistance system consisting of arginine decarboxylase (AdiA) and an arginine-agmatine antiporter (AdiC)] is activated by acidic stress. Arg is taken up from the environment into E. coli cells by AdiC and converted to agmatine (Agm) by AdiA. The generated Agm is then exported from the E. coli cells to the environment via AdiC. (3) In the third step, the ATP synthesis system of Enterococcus faecalis consisting of agmatine deiminase (AguA), putrescine carbamoyltransferase (AguB), and agmatine-putrescine antiporter (AguD) is activated. En. faecalis takes up the Agm derived from E. coli using AguD. Agm is then converted to PUT by the sequential actions of AguA and AguB in the process of ATP production. (4) In the final step, the generated PUT is exported from E. faecalis cells via AguD as a byproduct of the collaboration between these different bacterial species

Fig. 5

Overview of polyamine sources in the intestinal lumen and effects of polyamines on intestinal barrier function. Bacterial polyamines, i.e., PUT and SPD, are the primary source of polyamines in the lower intestinal tract because almost all dietary polyamines are absorbed in the small intestine. Bacterial PUT, the most abundant in the human intestinal lumen, is produced by intestinal microbial metabolism systems, such as the hybrid biosynthetic system of multiple bacteria (Figure 4). Absorbed PUT is converted to SPD, which is involved in many biological processes, including EIF5a hypusination, autophagy, and mitochondrial fatty acid oxidation, in intestinal epithelial cells. In the intestinal lamina propria, polyamines contribute to healthy intestinal barrier function, mainly playing roles in intestinal epithelial renewal promoted by AJs and TJs (Figure 2) and in the reduction of inflammation induced by the regulation of macrophage differentiation (Figure 3)