Sarah Cooke ’20 and Alania Lurie ’21
Each year in the United States, there are 200,000 cases of Irritable Bowel Syndrome. It’s estimated that 10-15 percent of the adult population suffers from IBS symptoms, making nearly 35 million people subject to abdominal pain with no apparent cause. The origins of IBS are still unknown, and research has yet to determine why and how a particular person may develop this syndrome. If you are not already familiar with Irritable Bowel Syndrome, it is a gastrointestinal disease commonly associated with chronic symptoms such as abdominal pain, constipation, diarrhea, and bloating. Flare-ups of IBS can have disastrous consequences for those affected, such as having to miss work, school, or other important responsibilities because of the pain. In addition, those with IBS usually have to restrict their diet and daily routine, because stress, alcohol, caffeine, and even some leafy vegetables can aggravate an already fickle condition. Since so many people suffer from this illness, and the symptoms can impede daily functioning, it is imperative that research examines the origins of this disease, along with new and improved therapies to help those affected.
In the media, serotonin is often introduced as a brain chemical that is important in depression and anxiety disorders. However, serotonin also has a diverse set of functions within the digestive system, where it can induce gut movement, allow for the release of digestive fluids, and is involved in sensation. Serotonin levels in the gut are important, and need to be controlled, so that the digestive system can accurately respond to the food that you eat. High levels of serotonin in the gut have been associated with IBS, which led researchers to study how the body removes serotonin from the digestive system. A protein known as SERT (a serotonin transport) is responsible for absorbing serotonin and removing it from the digestive system, so that it does not continuously activate digestive processes. Otherwise, your belly would always be rumbling! This caused researchers to wonder if there was a problem in regulating SERT, and they searched to determine what was responsible for controlling the amount of protein present. To fully understand their findings, we will quickly go over how proteins are made in our cells.
The genes in DNA are your body’s instruction manual for how to make the proteins you need in order to survive. The first step in making a protein is known as transcription, where a copy of your already existing DNA is made. This copy is called messenger RNA, and it is used to deliver information to other parts of the cell. In some cases, the messenger RNA copy never reaches the place that it is supposed to, which means that the protein it contains instructions for is never made. This is not always a mistake though, it is simply a different method your body uses to control its protein levels. One way the body accomplishes this is through something called microRNA. MicroRNA attaches to certain messenger RNAs, which blocks that messenger RNA from being used as instructions to make the protein. It is very important for a certain microRNA to stick only to certain messenger RNA, like a puzzle piece that only has one match. Otherwise, different proteins that the body needs more of may not be made, and proteins the body needs less of will stick around. Right now, the microRNAs that keep SERT from being made are under research, as they may be the key to finding better ways to treat people with IBS.
Hou et al (2018) used rats to figure out which microRNAs the body uses to reduce SERT protein levels2. To try to give rats IBS-like symptoms, they put the rats through a stressful experience, which caused them to have stomach pain similar to those with the disorder. Then they looked at many different types of microRNA, in both the rats with the IBS-like symptoms and without, to see if there was a difference in how much of each type of microRNA was available. The researchers found that one microRNA, known as microRNA-200a, was less common in the rats with IBS-like symptoms. The next step was to see if this microRNA matched with the messenger RNA that had the instructions to make SERT. If it did match, it meant that it would be able to affect SERT levels. As it turns out, they did find that microRNA-200a can fit with the messenger RNA responsible for SERT. Additionally, when there was a higher than normal amount of microRNA-200a in a rat, there was less of the SERT protein. While they did not see the microRNA-200a bind to the SERT messenger RNA in live rats, their study gave enough evidence to believe that this really happens.
Other researchers found additional microRNAs that affect the amount of SERT protein produced. However, instead of using rats, Liao, Xiu-Jun, et al. (2016) used human patients with IBS-D, or diarrhea predominant IBS3. They found that microRNA-24 was much higher in the patients who suffered from IBS than those who had normal digestion. Similar to the study before, these researchers found that the higher the quantity of microRNA they were looking at, the lower the amount of SERT present. To make sure that microRNA-24 was actually the reason why SERT levels decreased, they gave mice a chemical that kept microRNA-24 from attaching to SERT messenger RNA. This allowed the amount of SERT in the gut to increase, implying that too much microRNA-24 may be one of the reasons behind diarrhea predominant IBS. This means that reducing microRNA-24 in IBS patients may be another possible treatment method.
There is a lot of information that ties microRNA levels and the diagnosis of IBS together, so Zhu, He, et al (2019) wanted to further examine how the amount of microRNA related to stomach pain experienced with IBS5. They used mice as a way to model IBS; to do this, they first showed that the IBS-like mice were more sensitive to pain inside of the gut, which mimics what humans with the disease experience. In this set of IBS-like mice, there was a higher level of microRNA-29a than what was seen in normal mice, and they found that reducing the quantity of microRNA-29a also reduced intestinal pain. Unlike the previous studies, the microRNA-29a affected the amount of a serotonin receptor in the gut, as opposed to the amount of SERT. However, this still helps to show that serotonin has a great deal of impact on IBS, and the symptoms that patients with it experience.
Understanding the role that microRNAs play in intestinal health is important for developing treatments, since many intestinal disorders do not have treatments that focus on the cause of the disease. Instead, the individual symptoms a patient has are treated with medications and other remedies, as opposed to dealing with the disease itself. This can be very challenging for those who are affected by IBS, because the symptoms can have a significant impact on day-to-day functioning with seemingly no end in sight. Due to this hopelessness, IBS is associated with higher levels of depression, anxiety, and other mood disorders. The brain and the gut are closely linked, and oftentimes problems in our gut lead to problems in our heads. Extreme stomach pain and intestinal damage are the most prominent symptoms of IBS, and research needs to be done to solve the difficult puzzle of where it all comes from.
Zhou, Qiqi, and Verne (2011) debate the possibilities of eventually using microRNA based techniques as treatments for IBS and other intestinal disorders6. There are several reasons that the authors believe microRNA therapies are the future of treating intestinal diseases. Mainly, it is because it has been shown that microRNA levels are different in the intestinal tissues of those with IBS compared to those with normal digestion. The logical step from there is fixing the microRNA levels, which would hopefully treat or get rid of IBS symptoms. There are barriers to using microRNA techniques, however, like how to put enough microRNA into a living person to have any effect. Overall, the research looking at irritable bowel syndrome has flaws, but there is hope for the future. Every study that is done leads researchers closer to finding a potential cure for this disease that affects millions of people.
- Collins, Francis. “MicroRNA Research Takes Aim at Cholesterol.” NIH Director’s Blog, 26 Nov. 2013, directorsblog.nih.gov/2013/11/26/microrna-research-takes-aim-at-cholesterol/.
- Hou, Qiuke, et al. “MicroRNA-200a Targets Cannabinoid Receptor 1 and Serotonin Transporter to Increase Visceral Hyperalgesia in Diarrhea-Predominant Irritable Bowel Syndrome Rats.” Journal of Neurogastroenterology and Motility, vol. 24, no. 4, 2018, pp. 656–668., doi:10.5056/jnm18037.
- Liao, Xiu-Jun, et al. “MicroRNA-24 Inhibits Serotonin Reuptake Transporter Expression and Aggravates Irritable Bowel Syndrome.” Biochemical and Biophysical Research Communications, vol. 469, no. 2, 8 Jan. 2016, pp. 288–293., doi:10.1016/j.bbrc.2015.11.102.
- Camilleri, Michael. “Peripheral Mechanisms in Irritable Bowel Syndrome.” The New England Journal of Medicine, vol. 367, no. 17, 2012, pp. 1626-1635. ProQuest, https://proxy.lib.umich.edu/login?url=https://search-proquest-com.proxy.lib.umich.edu/docview/1115278974?accountid=14667, doi:http://dx.doi.org.proxy.lib.umich.edu/10.1056/NEJMra1207068.
- Zhu, He, et al. “MiRNA-29a Modulates Visceral Hyperalgesia in Irritable Bowel Syndrome by Targeting HTR7.” Biochemical and Biophysical Research Communications, vol. 511, no. 3, 23 Feb. 2019, pp. 671–678., doi:10.1016/j.bbrc.2019.02.126.
- Zhou, Qiqi, and G Nicholas Verne. “MiRNA-Based Therapies for the Irritable Bowel Syndrome.” Expert Opinion on Biological Therapy, vol. 11, no. 8, 2011, pp. 991–995., doi:10.1517/14712598.2011.577060.
- Jin, Duo-Chen, et al. “Regulation of the Serotonin Transporter in the Pathogenesis of Irritable Bowel Syndrome.” World Journal of Gastroenterology, vol. 22, no. 36, 15 June 2016, p. 8137., doi:10.3748/wjg.v22.i36.8137.