Succinate metabolism and its regulation of host-microbe interactions

Abstract

Succinate is a circulating metabolite, and the relationship between abnormal changes in the physiological concentration of succinate and inflammatory diseases caused by the overreaction of certain immune cells has become a research focus. Recent investigations have shown that succinate produced by the gut microbiota has the potential to regulate host homeostasis and treat diseases such as inflammation. Gut microbes are important for maintaining intestinal homeostasis. Microbial metabolites serve as nutrients in energy metabolism, and act as signal molecules that stimulate host cell and organ function and affect the structural balance between symbiotic gut microorganisms. This review focuses on succinate as a metabolite of both host cells and gut microbes and its involvement in regulating the gut - immune tissue axis by activating intestinal mucosal cells, including macrophages, dendritic cells, and intestinal epithelial cells. We also examined its role as the mediator of microbiota - host crosstalk and its potential function in regulating intestinal microbiota homeostasis. This review explores feasible ways to moderate succinate levels and provides new insights into succinate as a potential target for microbial therapeutics for humans.

Keywords: Succinate; gut microbiota; gut–immune tissue axis; immune cells; inflammation.

Figure 1.

Synthesis and degradation of succinate by host and gut microbiota. (1) the left part shows the synthesis and degradation of gut microbiota-produced succinate. During this process, the gut microbiota metabolizes dietary fiber into succinate. As presented in the green part, succinate is the intermediate product of gut microbiota-produced SCFAs. The black line represents the biosynthetic pathway of succinate in the gut microbiota. The blue line represents the pathway through which succinate is metabolized to butyrate. The yellow line represents the degradation pathway of succinate to propionate. The red line represents the conversion relationship between succinate and acetate. (2) the right part shows the synthesis and degradation of host-produced succinate. Within a series of biochemical steps, carbohydrates, lipids, and proteins ultimately participate in the mitochondrial TCA cycle to generate energy. Succinate is generated during this process.

Figure 2.

The interaction between succinate and gut microbiota. (A) in the healthy state, the number of succinate-producing bacteria and succinate-consuming bacteria related to succinate levels is in a dynamic equilibrium. (B) Dietary succinate can tip the balance and increase the number of bacteria that utilize succinate. (C) Dietary intervention with high protein, fat and fiber can increase the number of succinate-producing bacteria, and it is often accompanied by an increase in the number of succinate-producing bacteria under the pathological state of the host.

Figure 3.

Succinate regulates the function of mucosal immune cells in the intestine. Succinate affects the functions of intestinal macrophages, tuft cells, and dendritic cells (DCs): (1) the left section shows that succinate regulates the function of both M1 and M2 macrophages. Specifically, increased concentrations of succinate in M1 macrophages promote HIF-1α production. This further promotes macrophage release IL-1β, a proinflammatory cytokine, thus triggering the inflammatory response. Succinate produced by M1 macrophages can also bind to SUCNR1 on neighboring M1 macrophages to regulate the same inflammatory response. The inflammatory response of macrophages can attack Salmonella Typhimurium, but Salmonella Typhimurium can also utilize succinate secreted by macrophages. In addition, succinate has the potential ability to promote M2 macrophage polarization. By binding to SUCNR1 expressed in BMDMs, succinate can induce IL-4, which promotes M2 phenotype differentiation. Succinate also stimulates M2 phenotype polarization via SUCNR1-activated G_q signaling in M2 macrophages. (2) the middle section shows that gut microbiota-produced succinate can cross IECs via the SLC13A family expressed on epithelial cells into the lamina propria and can be metabolized into glucose in IECs. Furthermore, Tritrichomonas-generated succinate binds to SUCNR1 on tuft cells and stimulates them to release IL-25, which acts on ILC2s to promote the secretion of IL-13. IL-13 directly enhances type 2 immunity, acts on DCs and promotes their migration into the mesenteric lymph nodes. This induces the polarization of CD4+ T cells into Th2 cells, thereby indirectly enhancing type 2 immunity. In addition, IL-13 promotes tuft cell proliferation and activates goblet cell transformation to increase the amount of mucin, thus enhancing mucosal immunity. (3) the right section shows that succinate regulates the antigen presentation and inflammatory function of DCs. Specifically, succinate acts on iModcs expressing relatively high levels of SUCNR1 and can promote the maturation of iModcs and the migration of mature DCs into the lymph nodes. Exogenous succinate can also enhance antigen presentation by DCs. Moreover, succinate generated by mature DCs has the same function as exogenous succinate in promoting the release of IL-1β from macrophages. Furthermore, succinate influences T-cell function. In the inflammatory microenvironment, SDHA or SDHB deficiency causes increases in succinate level and changes in T-cell metabolism, thus promoting the inflammatory response. In the tumor microenvironment, succinate inhibits CD4+ T cells from secreting antitumor cytokines but enhances the cytotoxicity of CD8+ T cells.

Figure 4.

Possible ways to reduce abnormally elevated succinate concentrations. (1) the left section “Blockage of succinate production” shows that methods to block the succinate production pathway in mitochondria include inhibiting SDH activity by promoting itaconate production and inhibiting OGDH activity by using succinyl phosphonate, thereby reducing the production of succinate in the TCA pathway. In addition, blocking the transmembrane transport of succinate can also reduce the level of circulating succinate; that is, increasing SLC26A6 activity to inhibit SLC13A2 or decreasing MCT1 activity may reduce the MCT1-dependent succinate level. Most of the function of succinate is dependent on its binding to SUCNR1 in cells. SUCNR1 antagonist 4c and SUCNR1 antagonist 7a are expected to reduce the negative effects of excessive succinate accumulation by inhibiting SUCNR1 activity. Transplantation of SUCNR1-expressing stem cells can absorb excess succinate. (2) the middle section “Intake dietary fibers” shows that dietary fiber promotes the colonization of succinate-consuming bacteria, which helps to absorb excessive succinate. Some succinate-consuming bacteria can activate T cells, ILC2s and other immune cells to exert immune functions and even promote the proliferation of beneficial succinate-consuming bacteria. Beneficial succinate-consuming bacteria can compete with Clostridioides difficile, harmful bacteria that also utilize succinate, and resist their colonization. (3) the right section “Stimulating beige adipose tissue” shows that interaction between tissues is a possible way to reduce the succinate concentration. Beige adipose tissue can absorb succinate in response to cold stimulation, which affects the internal environment of the liver tissue, thereby reducing excessive levels of succinate in the liver. The close connection of the gut–tissue axis suggests that succinate in the intestinal environment can be affected by regulating succinate levels in the internal environment of other tissues.