Metabolites produced by gut microbes exacerbate colon inflammation, a study has found.
Professor Jaehee Cheon, Department of Gastroenterology, Severance Hospitalpicture) The research team, together with Professor Ohana’s research team at Ben Gurion University in Israel, announced on the 17th that succinic acid, a metabolite produced in intestinal microbes, causes colon inflammation. This research was introduced in the latest issue of Cell Reports (IF: 9.423), an online sister journal of the world-renowned scientific journal Cell and an international journal in life sciences.
Inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis are chronic rare and incurable diseases that cause inflammation or ulceration in the intestine. The incidence is increasing in Korea due to irregular and westernized eating habits. According to the Health Insurance Review and Assessment Service, the number of patients with ulcerative colitis and Crohn’s disease doubled in 2020 compared to 2010. In particular, the incidence of children is increasing, and it is fatal because it causes problems such as malnutrition, growth disorders, and delayed puberty in children. Currently, there is no clear treatment, so the goal of treatment is to relieve symptoms by administering anti-inflammatory drugs and immunomodulators.
Although the cause of inflammatory bowel disease is still unclear, it is known that an imbalance in the intestinal flora exacerbates inflammatory bowel disease. Abnormal excess of metabolites due to imbalance of intestinal flora causes pathological abnormalities such as inflammatory reactions. In particular, succinic acid has been pointed out as a cause of chronic inflammation by activating macrophages that promote the inflammatory response, but the exact induced process has not been identified.
Prof. Cheonhee’s research team discovered for the first time the process by which succinic acid activates macrophages and the activation of macrophages causes colon inflammation.
First, by culturing macrophages in various environments, the state of macrophages that absorb a lot of succinic acid and the inflammatory process of succinic acid were studied. When macrophages were treated with succinic acid, the macrophages differentiated into macrophages that induce inflammatory action. When macrophages were treated with lipopolysaccharide and interferon-gamma, which cause inflammation, the absorption of succinic acid was faster. Conversely, succinic acid absorption was slow when treated with interleukin-4 and interleukin-13, which control the immune system.
When macrophages and succinic acid were co-cultured in one medium, the absorption of succinic acid was faster. Macrophages incubated with succinic acid had 2.5 times more succinic acid content than cells without succinic acid in 16 hours. When the absorption of succinic acid decreased, they differentiated into macrophages with reduced inflammatory response.
The uptake of succinic acid into macrophages was affected by sodium ions (Na+). Macrophages cultured in a solution without Na+ had 30% less succinic acid uptake than cells cultured in a solution with Na+. It was revealed that Na+-dependent SLC13 is responsible for succinic acid transport in the high succinic acid uptake from Na+. Among the factors belonging to SLC13, the SLC13A3 transporter and the succinic acid receptor were responsible for transporting succinic acid to macrophages, whereas the SLC26A6 transporter reduced succinic acid uptake.
The team monitored intestinal cell lines to understand how the intestine absorbs succinic acid. Like macrophages, in the intestinal epithelium, the presence or absence of Na+ had a significant effect on the uptake of succinic acid, and SLC13A3 and others performed the same transport role.
 |
↑The pathway of succinic acid into cells and the process of exacerbating colonic inflammation
Next, we compared the feces and serum of inflammatory bowel disease patients with normal people to investigate whether succinic acid actually induces inflammation in the colon. In the feces and serum of the patient, the concentration of succinic acid was about 4 times higher than that of the normal person, and the protein expression of the SLC26A6 transporter was decreased, so that the succinic acid could not be controlled and inflammation was occurring.
Gene sequencing was performed using fecal and intestinal mucosa samples to determine whether intestinal microbes produced succinic acid in feces. Through sequencing, the state of the intestinal microflora can be confirmed. As a result of the analysis, it was confirmed that the microbial imbalance and the increase of microorganisms that produce succinic acid and the decrease of microorganisms that reduce succinic acid in the large intestine of patients with inflammatory bowel disease and inflamed animals were respectively confirmed.
The research team suggested that succinic acid, which is increased in inflammatory bowel disease, causes chronic inflammation by exacerbating inflammation, and that factors that regulate succinic acid, such as the SLC26A6 transporter, may be a good target for treating inflammation.
Professor Jaehee Cheon said, “This study will not only elucidate the disease mechanism in inflammatory bowel disease for which the pathophysiology and treatment have not been clearly identified, but will also be of great help in the development of therapeutic agents.” Reporter Kang Kyung-nam
