Role of Serotonin in MODS: Deficiency of Serotonin Protects Against Zymosan-Induced Multiple Organ Failure in Mice: Reply.

Abstract

Reply: With interest, we read the letter to the editor in response to our publication, “Role of Serotonin in MODS: Deficiency of Serotonin Protects Against Zymosan-Induced Multiple Organ Failure in Mice” (1). We would like to compliment the authors for carefully reading our article and providing insights about the role of serotonin in the multiple organ dysfunction syndrome (MODS). Multiple organ dysfunction syndrome is characterized by progressive inflammatory response leading to deterioration of several organ functions, starting mostly with lung failure and followed by failure of the liver, gut, and kidneys (2). In their letter, Panteli et al. cite some studies and reviews proposing that the conclusion of “increased 5-HT inhibits infections” needs to be made carefully. Serotonin, also known as 5-hydroxytryptamine (5-HT), is a best known neurotransmitter that modulates neural signaling in a wide range of neuropsychological activities in the past. About 95% of serotonin in the body is located in the gastrointestinal tract; the remaining (5%) is found in brain (3). Although most of serotonin locates in the periphery, only a few researches pay attention to its peripheral role. Recently, scientists found that serotonin played an important role in the peripheral immune system and inflammatory process. The peripheral serotonin can promote the inflammation by facilitating inflammatory cell recruitment and cytokines production (4,5). Based on our own results, the conclusion of serotonin aggravating MODS has the theoretical and experimental evidence. Metronidazole is a nitroimidazole antimicrobial and antiparasitic medication, which is commonly used for the treatment of infections caused by susceptible organisms, particularly anaerobic bacteria and protozoa. Although Karamanakos et al. (6) found that metronidazole could produce a tremendous increase in the levels of brain 5-HT in Wistar rats, possibly through inhibition of monoamine oxidase A, the literature demonstrating a proinflammatory effect of serotonin in mice was undoubtedly overwhelming. First, according to the previous studies, metronidazole promotes increased 5-HT in the brain, but the effect of metronidazole on the peripheral serotonin was not detected. Meanwhile, even though metronidazole may increase the peripheral 5-HT by inhibiting monoamine oxidase A, metronidazole may have multiple mechanisms that could neutralize the “serotonergic” effect to suppress inflammation. Second, although metronidazole is widely used in the treatment of infections, it is always used as the combined application, and the detailed mechanism is not illuminated. Third, based on our own data, which are not published yet, we find that deficiency of serotonin not only protects against MODS, but can also decrease the damage of cecal ligation and puncture–induced sepsis in mice. Therefore, the conclusion of “increased 5-HT inhibits infections” cannot be made from the clues of “metronidazole promotes increased 5-HT” and “metronidazole inhibits infections,” which is concluded based on the clinical facts and experimental studies. In the following research, two basic experiments need to be launched, one is to detect the effect of metronidazole on the peripheral serotonin and another is to study the role of metronidazole on MODS in the animal models. Meanwhile, as Panteli indicated, we should notice the possible adverse effect of metronidazole when used in the infectious patients. In conclusion, while metronidazole might promote the production of serotonin and inhibit infections, depending on the clinical facts and experimental test of specific site, the result of our work, together with our unpublished studies, supports the notion that serotonin promotes inflammation.