Ulcerative Colitis

Fecal transplantation in ulcerative colitis 

Colitis Ulcerosa is a chronic inflammation of the bowels that can cause great discomfort for the patient. The patient may suffer from diarrhea, abdominal pain and a bloody stool. Since the incidence is increasing over the last few years, it has become a more serious problem. The incidence is now 7-12 new cases per 100.000 inhabitants per year. The disease is diagnosed between the age of 15 and 30. Ulcerative colitis is more common in men than in women. The exact reason why it is more common in men is unknown, there are theories that smoking or stopping with smoking could influence the disease.

Current medications for ulcerative colitis
There wouldn't be a need for an alternative approach of treating ulcerative colitis if the current medication would leave the patients symptom-free. But that isn't the case. Many patients that are currently treated with the standard medicines still suffer from many problems as the ones mentioned before. It also is difficult to find the right medication for each patient, since every patient reacts differently to their medication. It can take years before the right medication in the right amount is found and until that time the patients are limited in what they can do.

When a patient is diagnosed with UC, the first medication that is prescribed is mesalazine, a local anti-inflammatory drug that acts on the intestinal wall. This is mainly used in mild to moderate UC. When this doesn't work, the medication is changed to corticosteroids, to reduce inflammation. After this, the physician will switch to cyclosporine, which is a polypeptide that works immunosuppressive. As a last resort, the physician can decide, in consultation with the patient, to remove the part of the intestine that is affected. This is only done when the medication isn't effective enough to relieve the patients (partly) from their symptoms and it is affecting the quality of life. Since the current medication isn't good enough to treat all patients, it is important to seek for a new cure.

Manipulation the microbiome
Over the last couple years, more and more studies have been done to observe the influence of the microbiome. It became clear how influential the microbiome was and how it can differ between different ethnicities, age groups, etc. Since the influence of the microbiome on our health became more and more apparent, the need to manipulate the microbiome grew stronger. And after studies were published about the treatment of Clostridium difficile with a fecal microbiota transplantation (FMT), researchers wanted to find out if the same could be done to treat inflammatory bowel diseases (IBD), such as Colitis Ulcerosa (UC). Researchers had already conducted several studies to observe the microbiome of patients with ulcerative colitis and they discovered a relation between the illness and the microbiome [4,5]

To study the correlation between FMT and the course of the inflammatory bowel disease ulcerative colitis, researchers have conducted a couple of randomized controlled trials. The first one was in 2015 and the last in 2017. 3 of the studies will be discussed.

The studies
The study in 2015 was the first randomized controlled trial that was conducted. Before this, there were some case reports, but there was no robust evidence. In this trial, 65 patients were enrolled and divided between two arms: a placebo arm and a fecal microbiota transplantation arm. The patients received either 50 ml of FMT of 50 ml of water as a retention anema every week for 6 weeks. At week 7 the clinician performed a colonoscopy and the patients had to fill in a questionnaire to assess the state of the disease. The outcome of this study was that of the patients who received FMT, significantly more were in remission compared to those who received placebo (24% vs 5%) Another interesting outcome was that there was one donor that induced remission in more patients than the other donors (39% vs 10%), suggesting statistical evidence for donor dependence. What was also noticed, is that people who were diagnosed recently (within one year) had a higher chance of remission (75% compared to 18% in those who had the disease for longer) [1]

In the second study, performed in 2017, the aim was to study the safety and efficacy of using multiple donors per patient and there was a more intensive approach: patients had to self-administer an enema 5 times per week for 8 weeks. At the beginning of the study and at the end, they performed a colonoscopy to look for signs of active inflammation in the bowel. Stool samples were collected twice during the study. The goal of the study was to have patients steroid free at the end of week 8, to induce a steroid-free remission. At the end of the study, 44% of the FMT group was in clinical remission (compared to 20% of the placebo group). Endoscopic response was much lower in both groups, 12% in the FMT arm compared to 8% in the placebo arm. The researchers also looked at the microbiome of both groups. The diversity of the microbiome was higher in the FMT arm than in the placebo group. The diversity of the placebo group didn't change, whereas the diversity of the FMT group started to resemble the diversity of the microbiome of the donors. [2]

In the last study, performed in the Netherlands, the main design of the study was similar to the ones before. The big difference was, however, that instead of a placebo control, they performed an autologous fecal microbiota transplantation. This means that the patient in the control group will not receive a placebo like in the other studies, but his own fecal microbiota. The outcome of this study was that 30% of the patients in the FMT group from healthy donors was in remission and 20% of the patients that received their own stool. Unlike the other studies, there was no significant difference between the groups, but this could also have been caused by the study population (total of 48 patients). The other big difference was that the control group received their own microbiota and it was suggested that this could also have influenced the result. [3]

Conclusion
Fecal microbiota transplantations can be effective in patients with active ulcerative colitis. The first two studies showed a significant difference between the intervention and the control group. The last study did not show that significant difference, but this was a smaller study and the autologous fecal microbiota transplantation could also have had a positive effect on the colitis. It is not yet very clear what the long term effects are of the FMT, the longest trial lasted 12 weeks, so more research has to be conducted to determine the effects in the long term. But so far fecal microbiota transplantation looks promising in inducing remission in ulcerative colitis.

                                                                                                                               Written by Inge van Eijsden
                                                                                                                                           Posted on 12 oct 2018

[1] Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial. Moayyedi, Paul et al.Gastroenterology , Volume 149 , Issue 1 , 102 - 109.e6

[2] Findings From a Randomized Controlled Trial of Fecal Transplantation for Patients With Ulcerative Colitis. Rossen, Noortje G. et al. Gastroenterology , Volume 149 , Issue 1 , 110 - 118.e4

[3] Reinshagen M, Stallmach A: Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Zeitschrift fur Gastroenterologie, vol. 55, no. 8, 2017, pp. 779-780,

[4] Kostic AD, Xavier RJ, Gevers D. The Microbiome in Inflammatory Bowel Diseases: Current Status and the Future Ahead. Gastroenterology. 2014;146(6):1489-1499. doi:10.1053/j.gastro.2014.02.009.

[5] Kostic AD, Xavier RJ, Gevers D. The Microbiome in Inflammatory Bowel Diseases: Current Status and the Future Ahead. Gastroenterology. 2014;146(6):1489-1499. doi:10.1053/j.gastro.2014.02.009.