The Long-term Effects of Faecal Microbiota Transplantation for Gastrointestinal Symptoms and General Health in Patients With Recurrent Clostridium Difficile Infection

J. Jalanka; A. Hillamaa; R. Satokari; E. Mattila; V.-J. Anttila; P. Arkkila

Disclosures

Aliment Pharmacol Ther. 2018;47(3):371-379. 

In This Article

Discussion

We present here the first controlled long-term follow-up study of FMT treated patients compared with antibiotic therapy, focusing on the safety aspects of these treatments. The long-term safety of FMT has been under a lot of discussion, and several studies have pointed out the need for longer follow-up times where adverse effects are actively sought.[17,25,31] Especially the development of extra-intestinal conditions, such as autoimmune diseases or weight gain, has been an issue of concern. Our study confirms that FMT is an effective and safe treatment for recurrent C. difficile infection also in long term. FMT did not affect the patients weight or increase the risk of severe diseases such as cancer, autoimmune diseases or allergies compared to patients treated only with antibiotics. Furthermore, our results suggest that FMT has some favourable effects for the GI symptoms compared to the antibiotic treatment and also the clearance of GI symptoms after the infection was faster in patients receiving FMT. Although, this treatment suffers from prejudice against faeces and the need of endoscopy, which both could decrease the patient's adherence to the treatment. We found that the majority of patients both in the antibiotic and FMT groups would prefer FMT treatment over the antibiotics for recurrent C. difficile infection.

The recently published European consensus conference indicates the history of chronic, systemic autoimmune disorders with GI involvement and the history of, or high risk for, GI cancer or polyposis as some of the key issues in selecting potential donors.[7] We have selected our donors in accordance with this recommendation. None of our patients developed cancer during the follow-up period and autoimmune disease appeared in only few new patients equally in both groups. Unbalanced gut microbial population, so called dysbiosis, may also increase the risk for allergies[31] and antibiotic treatment taken by all study participants would result into considerable changes to their intestinal microbial composition. The incidence of allergies before or after the treatment between the groups were not different, although twice as many patients in the antibiotic group developed new allergies during the follow-up period compared to those receiving the FMT. The limitation of this study is that the study population could have been even lager and the follow-up period longer to better highlight differences in, eg, cancer or neurological disease development. Although FMT is a curative therapy for recurrent C. difficile infection and seems to be a very safe treatment, we stand for the implementation of national registry data collections to further investigate the long-term health implications. Taken together, during the long-term follow-up there was no difference in the incidence of any severe diseases between the FMT or antibiotic treated patients.

Higher prevalence of functional gastrointestinal disorders in patients with C. difficile infection has been shown,[32] however how these numbers are related to the treatment avenue has not been addressed in detail. In this study, we showed that patients in the FMT group recorded that their bowel function had become significantly better and more regular after the treatment compared to those who received the traditional antimicrobial therapy. In addition, they also reported less symptoms of functional gastrointestinal disorders than the AB group patients. Previously it has been shown that a quarter of C. difficile infection patients without prior irritable bowel syndrome (IBS) diagnosis develop post-infectious IBS (PI-IBS) during 6 months after clearing the infection.[29] Faecal microbiota diversity has been found to be reduced in PI-IBS, which has been shown to inversely correlate with lamina propria lymphocytes, immunological markers and psychological scores suggesting a possible link between dysbiosis, inflammation and stress in PI-IBS.[33,34] The reason for this has been hypothesised and some risk factors for PI-IBS in patients with C. difficile infection have been found including anxiety and age under 60 years.[29,35] Interestingly, in this cohort one-third of the FMT treated patients showed improved mental status. Thereby, the risk of newly developed mental problems after FMT seems low with carefully selected and screened donors. There is some evidence that gut microbiota can influence cognition and behaviour, and that modifications of the microbiota can induce depressive-like behaviours. Vice versa, changes in behaviour can also alter gut microbiota composition.[36]

The use of broad-spectrum antibiotics, particularly macrolides or tetracyclines, has been speculated to be associated with IBS development in this patient group, linking the C. difficile infection treatment and symptom development.[37] Aroniadis and colleagues recently showed in a small study that abdominal symptoms such as pain and tenderness improved after FMT.[20] Our study, evaluating more thoroughly the different GI symptoms showed that patients receiving FMT had significantly less symptoms of functional GI-disorders when compared to the patients treated with antibiotics. This all suggests that restoration of the microbiota ecosystem could be more beneficial to the host than antibiotic treatment alone.

A recent study showed that patients with C. difficile infection have higher prevalence of upper intestinal tract symptoms than controls.[32] Interestingly, we found a significant difference in the recorded functional dyspepsia-like symptoms including pain in the upper GI-tract and feeling of fullness between the FMT treated and antibiotic treated subjects. The number of C. difficile infection patients without GI symptoms was more frequent after FMT than after receiving only antibiotics, which along with significantly better bowel function, might be one reason for the higher mental well-being in FMT patients compared to the AB-group. These findings suggest that the re-establishment of the patient's intestinal microbiota as opposed to decreasing of the microbial diversity may play a protective role in the development of upper GI symptoms in patients with C. difficile infection after treatment.

The intestinal microbiota of patients with C. difficile infection has been shown to be greatly impoverished due to both the condition and the antimicrobial treatments attempted for treatment.[2,28] We recently showed that the intestinal microbiota composition of a C. difficile infection patient could be relatively permanently altered with FMT to resemble that of their own donor, and that this shift in the microbial composition lasted throughout the 1-year follow-up period.[28] Building on these findings, the results of this retrospective trial suggest that the FMT treatment is not only safe for the patient, but also more beneficial to the patient as compared to AB treatment. This success could lie in the re-establishment of the microbial ecosystem to resemble that of a healthy gut rather than only successfully removing the pathogen. Therefore, on the bases of the presented results as well as the past literature the current recommendation to use FMT therapy only after three recurrences of C. difficile infection, could be revised. The safety of the FMT, both short- and long term as well as reduced GI symptoms in the FMT group suggest that FMT treatment could be considered earlier as a treatment option.

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