Introduction

We previously demonstrated that fecal microbiota transplantation (FMT) following bowel cleaning with amoxicillin, fosfomycin, and metronidazole (AFM therapy) improved short-term efficacy and recovery of the Bacteroidetes composition, which is associated with ulcerative colitis (UC) severity in patients [1]. Besides, the proportion of certain Bacteroidetes species is decreased in UC and is associated with the efficacy of FMT combined with AFM (A-FMT) [2]. We speculate that Bacteroidetes species may be an important breakthrough driving the progress of UC treatment.

Aims & Methods

We have carried out in vitro and in vivo study on whether Bacteroidetes species are the key species for UC treatment by reverse-translational approach. We focused on cases of UC that had a significant response to FMT, then isolated Bacteroidetes species from effective donor stools. The immune function of Bacteroidetes was then evaluated by in vitroand in vivo studies.

Results

Twenty-four Bacteroidetes species were isolated and identified. From in vitro IL-10 induction assays, we found 4 Bacteroidetes species that showed remarkable IL-10 induction activity. The full genome sequences of the isolated strains differed in some structures from those in conventional databases. We found that stronger IL-10 inducing activity was observed when accidentally mixed Veillonella.sp (VE) was stimulated together with acquired Bacteroidetes spp. In the transplantation of isolated Alistipes putredinis (AP), including VE, into a gnotobiotic mice model of enteritis induced by 2.5% DSS and 1% Oxazolone, which has been verified to have strong IL-10 inducing activity, can significantly improve the symptoms of colitis and suppress body weight loss compared to vehicle (p = 0.01).

Conclusion

As a representative of Bacteroidetes species, AP has been confirmed to exhibit anti-inflammatory characteristics in in vivoand in vitro studies, and other Bacteroidetes species have yet to be further explored. And although our evaluation methods and conditional settings also need to be further improved. But the A-FMT-based reverse-translational approach of promising bacterial species has proven to be a breakthrough for microbiome drug development.

References

1. Ishikawa, D., et al., Changes in Intestinal Microbiota Following Combination Therapy with Fecal Microbial Transplantation and Antibiotics for Ulcerative Colitis. Inflamm Bowel Dis, 2017. 23(1): 116-125.
2. Nomura, K., et al., Bacteroidetes Species Are Correlated with Disease Activity in Ulcerative Colitis. J Clin Med, 2021. 10(8): 1749.

Disclosure

Kyowa Kirin Co., Ltd., Kyowa Hakko Bio Co., Ltd., Kirin Holdings Co., Ltd., and Metagen Therapeutics Co., Ltd.

Introduction

Recently, the dysbiosis of intestinal microbiota has been identified as a cause of ulcerative colitis (UC). We have reported that controlling the intestinal microbiota influences the efficacy of antibiotic-fecal microbiota transplantation (A-FMT) for UC. Hydrogen (H₂) has a cytoprotective function by removing active oxygen from cells, and it was reported that H₂ water maintained the balance of the intestinal microbiota and suppressed the progression in UC model mice.

Aims & Methods

In this study, we investigated changes in the intestinal microbiota, therapeutic effects, and safety of H₂ gas inhalation in UC patients.
We included active UC patients who participated in the clinical study "A randomized, double-blind, parallel-group study of hydrogen gas inhalation for ulcerative colitis" (UMIN000042017) between October 2020 and August 2021. Eligible participants are at least 20 years old and have been diagnosed with active UC {Lichtiger’s Clinical Activity Index (CAI) of 3 to 10 and Mayo endoscopic subscores (MES) ≥ of 1}. 10 participants with UC were registered and were assigned to either the H₂ inhalation group or the air inhalation group. The H₂-producing machine (Jobs-α) was developed to generate 5-6% H₂ gas in 4 L/min mixed air by electrolysis. The placebo air machine was also developed and uses an air pump to generate 4 L/min of air. All participants will inhale the gas 4 hours every day for 8 weeks, and they are checked the inhalation time of the machine.
Patients are assessed the changes in the partial Mayo Score and CAI scores from baseline to the 8th weeks while checking for adverse events, and defined "remission" when their Mayo score improved to less than 2 points at 8 weeks after inhalation. The intestinal microbiota was analyzed by 16S rRNA sequencing of stool samples before and after inhalation.

Results

10 patients (4 males and 6 females, age 38.1±8.9 years, disease duration 9.4±9.6 years, Mayo score 4.8±1.4, MES 1.2±0.4) participated in the study, and the total inhalation time was 225.6±100.0 hours. In the H₂ group, the Mayo score decreased from 4.6±1.4 to 3.0±1.3, and the remission induction rate was 3 out of 5 patients. In the placebo group, the Mayo score decreased from 5.0±1.4 to 3.8±1.5 (p = 0.59), and the remission induction rate was 1 out of 5 cases (p = 0.24). There were no adverse events due to inhalation. Analysis of the intestinal microbiota showed that the Chao1 index, a measure of alpha diversity and species richness, tended to be more diverse after H₂ inhalation (p = 0.12). Principal coordinate analysis was performed to compare differences in bacterial composition between H₂ group and placebo group. β-diversity tended to differ after inhalation from before in the H₂ group (ANOSIM, p = 0.35). The proportion of intestinal microbiota was compared between before and after H₂ inhalation. In the placebo group, the change of intestinal microbiota was not observed, wearers, in the H₂ group, Gordonibacter increased (p = 0.07), Clostridium ramosum (p = 0.07) and Schalia odontolytica (p = 0.09) decreased, and Gordonibacter pamelaeae (p = 0.07) increased, resulting in improvement the diversity of intestinal microbiota.

Conclusion

There are some limitations the small number of cases and a single-center clinical trial. H₂ inhalation increase the diversity of the intestinal microbiota and may have a possibility to lead to a therapeutic option of UC.

Introduction

The effectiveness of fecal microbiota transplantation (FMT) in Ulcerative colitis (UC) remains unclear, with significant differences in protocols and procedures among clinical trials (1).

Aims & Methods

This study aimed to investigate the feasibility and effectiveness of a FMT protocol with close infusions in patients with active UC, also exploring the microbial modulation underlying its therapeutic efficacy.

In this prospective cohort study, subjects with mild-to-moderately active UC received three consecutive fecal infusions by colonoscopy, at baseline, T1 (2 weeks) and T2 (6 weeks) respectively. Faeces were collected by the donor on the day of the infusion and processed within 6 hours. A control population with the same baseline features undergoing Infliximab treatment was enrolled. Primary outcomes were the number of adverse events and the compliance rate. Secondary outcomes were: clinical remission; clinical response; endoscopic remission; microbial differences.

Results

Nineteen patients with mild-to-moderately active UC were enrolled.
During the protocol, 2 patients dropped out because of disease worsening and 1 patients dropped out because of hospitalization due to nephrolithiasis.
Clinical response was obtained in 6 of 16 patients at week-2 (PP=37%; ITT=31%), in 8 of 16 at week-6 (PP=50%; ITT=42%), and in 9 at week-12 (PP=56%; ITT=47%). Clinical response was maintained in 8 patients at week 24 (PP=50%; ITT=42%). Clinical remission was achieved in 4 subjects at week-2, in 5 at week-6 (PP=31%; ITT=26%), and in 5 at week-12 (PP=31%; ITT=26%). Endoscopic remission at week 12 was reached in 6 patients (PP=37%; ITT=31%). In the control population, 13 of 19 patients achieved clinical response at week 6 and 10 of 19 patients maintained clinical response after 6 months.
During the time course, the microbiota richness was higher in responders compared with the non-responders. Peptostreptococcus, Lactobacillus and Veillonella were higher in non-responders while Parabacteroides, Bacteroides, Faecalibacterium and Akkermansia were higher in responders in all time points.

Conclusion

Serial FMT infusions appear to be feasible, safe, and able to provide a considerable clinical and microbial response in UC patients. In particular, the comparison with patients under biologic therapy suggests a potential role in maintaining clinical response or enhancing maintenance. Gut microbiota profiling highlighted the role of specific intestinal bacteria in predicting both negative and positive response to FMT.

References

1. Tan XY, Xie YJ, Liu XL, Li XY, Jia B. A Systematic Review and Meta-Analysis of Randomized Controlled Trials of Fecal Microbiota Transplantation for the Treatment of Inflammatory Bowel Disease. Evid Based Complement Alternat Med. 2022;2022:8266793. Published 2022 Jun 26. doi:10.1155/2022/8266793

Introduction

Refractory ulcerative proctitis (UP) represents a clinical conundrum, often necessitating systemic therapy for localised disease. Faecal microbiota transplant (FMT) has proven efficacy for remission induction ulcerative colitis, yet has not been evaluated in UP.

Aims & Methods

Aims: To undertake a prospective open-label study examining the safety and efficacy of Faecal Microbiota Transplant (FMT) enema therapy for management of resistant ulcerative proctitis (UP).
Methods: Patients with mild-moderately active UP (total Mayo score 3-10 with endoscopic Mayo subscore ≥ 1) resistant to 5-Aminosalicylates (5-ASA) were prospectively enrolled. After an initial conditioning phase of vancomycin therapy and dietary education, participants received six anaerobically prepared single donor FMT retention enemas over an eight-week period. The primary end point was clinical and endoscopic remission (total Mayo score ≤2) at 8 weeks. Secondary endpoints included safety, histological remission and patient reported outcomes (Inflammatory Bowel Disease Questionnaire). Disease activity assessments including clinical, endoscopic, histological and quality of life measures were performed at week 0 and week 8 to assess response to FMT therapy. Systematic adverse event reporting was completed at each study visit.

Results

Among 30 participants enrolled (mean age 41 years, 17 (57%) women) , 26 completed the study protocol. Clinical and endoscopic remission was achieved in 10 patients (33.3%).
Serious adverse events necessitating study withdrawal occurred in 3 enrolled patients due to flare of UP (n=2) and Clostridioides difficile (C. difficile) colitis (n=1).

Conclusion

FMT enema therapy was well tolerated and demonstrated efficacy in inducing clinical and endoscopic remission in resistant UK. The role of antibiotic preconditioning of recipients and choice of antibiotic therapy remains unclear. Further controlled studies in this area are warranted.

References

Disclosure

SSR does not have any conflicts of interest to declare. This project did not receive any financial support from any organisation or institution. FMT enemas were supplied in kind by BiomeBank. CKR has received research funding from AstraZeneca, Merck Sharp & Dohme, Eli Lilly and Company, Novartis, and Sanofi and has participated in advisory boards for Allergan (now AbbVie). SPC has received advisory, speaking fees, or research support from Ferring, Shire, Microbiotica and Janssen. RVB has received grant/research support/speaker fees (all paid to employer for research support): AbbVie, Ferring, Janssen, Shire, Takeda, Emerge Health. SPC and RVB are shareholders in BiomeBank.