The potential of fecal microbiota transplantation in systemic sclerosis

KEYWORDS:

• Systemic sclerosis
• auto-immune disease
• gastrointestinal involvement
• fecal microbiota transplantation
• microbiome
• treatment
• regulatory affairs

Systemic sclerosis (SSc) is an orphan multi-organ disorder hallmarked by thickened skin (scleroderma), interstitial lung disease, pulmonary hypertension and major gastro-intestinal tract (GIT) involvement [1,2]. SSc has a high disease burden and reduced life expectancy, mainly explained by poor responses to all therapies; with the conceptually important exception of autologous hematopoietic stem cell transplantation, shown to reduce mortality, but limited by narrow indication, side effects, and cost [3,4]. Mechanistic insights on SSc are rudimentary, but converge on a model where modest immune-related genetic risk factors and unknown environmental risk factors act together to shape complex phenotypes with variable extent and timing of immune-mediated inflammations, organ fibrosis and end organ arterial obliteration [5,6].

Key observations indicate that there is an abnormal gut microbiome signature in SSc across time, ethnicity and geography [7–9]. This signature appears to be associated with GIT symptoms; such as dysphagia, intermittent and progressive diarrhea and/or anal incontinence, arguing for a primary association in SSc between gut microbiome and GIT involvement [7,9]. Whether the abnormal gut microbiota signature observed in the patients is an effect of the disease, or vice versa is not clear. However, given the existence of major, unknown environmental factors in the disease, it is tempting to speculate that specific gut microbiota components could represent the environmental triggers and drivers of immune-related pathologies in SSc; implying that targeted microbiota interventions could have effects beyond the level of the GIT [10,11].

At the clinical level, the observed associations between GIT symptoms and gut microbiota provide a rationale for interventions targeting gut bacteria as a mean to alleviate GIT symptoms in SSc [7]. Notably, this is not a completely new treatment strategy in SSc. Small intestine bacterial overgrowth (SIBO) is relatively common in SSc and several studies have shown improvement of GIT symptoms in SSc patients after treatment with antibiotics, supporting the notion of gut microbiota-mediated effects on disease-related GIT symptoms in SSc.

Fecal microbiota transplantation (FMT) is currently the favored therapeutic intervention strategy for targeting gut bacteria in humans. In the modern era, FMT has proven very successful in patients with Clostridium difficile enteritis, and has also shown promise in complex inflammatory GIT disorders, such as the inflammatory bowel diseases (IBD) [12,13]. FMT appears to have a good safety profile, partly explaining why this intervention is highly popular as a novel therapeutic option for diseases in which current treatment regimens are not satisfactory, as described in a very recent Editorial in this journal [13].

Based on the hypothesis that gut microbiota drives GIT symptoms in SSc, we recently conducted a placebo-controlled pilot study on FMT in SSc. For this study, we wanted to be able to track the effects of the active intervention across the patient group. Hence, rather than performing a regular FMT with random donor feces, we applied a standardized FMT design where all patients received intestinal infusions with the same set of fecal bacteria [14]. In more detail, we performed the FMT with a commercially available, patented bacterial culture which is derived from one single healthy donor, and given the brand name ACHIM (anaerobic cultivated human intestinal microbiota). All the included patients had limited cutaneous SSc and 90% had anti-centromere antibodies, were female with clinical apparent GI symptoms, mean age of 62 years and mean time from diagnosis of 12 yrs. The pilot study is not yet published, but preliminary results indicate effects on lower GIT symptoms (predominant on bloating and diarrhea) in patients receiving ACHIM, while no effects were seen in the placebo group [14]. Moreover, we found that the intestinal infusions of ACHIM by gastroduodenoscopy, induced changes in the patients’ fecal microbiota composition. Importantly, although the side effects of FMT by ACHIM were mild and transient, there were two severe adverse events in the study, both related to gastroduodenoscopy procedures. Randomized placebo-controlled double-blind clinical trials with a sufficient number of patients are the gold standard to evaluate new treatment options in general, and are also a necessity to further assess these safety issues and to determine clinical effects of FMT in SSc patients. Nevertheless, from the pilot study, it appears that FMT by ACHIM has potential for GIT symptom reduction in SSc. However, there are many issues to address before FMT is ready for implementation in SSc, and most other diseases. One main issue is the characteristics of the FMT used. On 13 June 2019, the New York Times reported that the Food and Drug Administration (FDA) had concerns regarding the safety of FMT after two immune-compromised patients contracted drug-resistant infections due to donor feces containing drug-resistant E. coli, very recently published in the New England journal of medicine [15]. The patients received transplants from the same donor, and one of the patients died. It should however be emphasized that many stool banks screen carefully for potential diseases but effects of co-transferring viruses and other microbes are difficult to identify and have not been extensively studied [16]. Other existing data support the safety of FMT even in immunocompromised hosts; this is an important issue especially in patients with rheumatic diseases including SSc. As mentioned above, we used ACHIM in the pilot FMT trial including SSc patients, which has been re-cultivated regularly since 1995 and consequently is free of all human genes, viruses, and all new antibiotic resistance genes. Another general issue is about regulation and classification of FMT [16]. The FDA has modified its position on regulating FMT several times and other specific country agencies including the Norwegian Medicines Agency have not yet decided whether to classify fresh frozen feces and fecal cultures as drugs. This is not only an important issue for clinical use of FMT but also for planning and conducting clinical trials.

When discussing the future of FMT in SSc there are a lot of other important and specific issues that need to be addressed. In some SSc cases, we observed that the beneficial effects on lower GIT symptoms by FMT were reduced after some weeks and it seems that repeated FMT is necessary to maintain the beneficial effects but both the dosage and the right intervals need to be assessed and may even differ between patients [14]. In our trial, FMT was given as infusion by gastroduodenoscopy, which is also in other diseases, together with colonoscopy the typical mode of FMT intervention. This was in SSc not only associated with safety issues but will also limit the number of patients being able to be treated with FMT due to sedation, post-interventional observation and hospitalization in the future. If repeated FMT over several years is necessary, encapsulated fecal microbiota mixtures given on an oral basis might be a better solution [17].

In conclusion, although there are clearly several obstacles that need to be overcome and many important issues that need to be investigated before implementing FMT as a standard treatment for GIT disease in SSc we are very confident that FMT will be a treatment option in SSc patients with GIT disease in the future. The next years will be exciting and we are looking forward to see results of RCTs in the future.

Declaration of interest

AM Hoffmann-Vold has received research funding and/or consulting fees or other remuneration from Boehringer Ingelheim, Actelion, Roche, and GlaxoSmithKline. H Fretheim and H Dirdriksen have received consulting fees or other remuneration from Actelion and GlaxoSmithKline. Ø Molberg does not have any. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

AM Hoffmann-Vold has funding from South-Eastern Norway Regional Health Authority. H Fretheim has funding from The Norwegian Women’s Public Health Association.