Fecal Microbiota Transplantation for Ulcerative Colitis: The Optimum Timing and Gut Microbiota as Predictors for Long-Term Clinical Outcomes

Abstract

Introduction: The previous researches aimed to evaluate the efficacy and safety of fecal microbiota transplantation (FMT) for ulcerative colitis (UC) in a short-term observation. The present study aimed to explore the optimum timing of FMT for maintaining the long-term clinical benefits and to target the gut microbiota that may help to predict the long-term success or failure of FMT in UC.

Methods: Two hundred two patients with UC were recruited from November 2012 to September 2018. The primary endpoint of this study was the maintaining time of the first and second courses of FMT. Relapse was defined as partial Mayo score ≥2 after achieving clinical remission and an increase of partial Mayo score ≥1 after achieving clinical response. The stool samples were analyzed by 16S rRNA gene sequencing.

Results: The median maintaining time of the efficacy was 120 days (IQR, 45-180) and 182.5 days (IQR, 105-311.25) from the first course and second course of FMT, respectively. No FMT-related serious adverse events were observed. The differences of the relative abundance in Eggerthella, Lactobacillus, and Ruminococcus between pre-FMT and 5 days post-FMT were remarkably correlated with the long-term clinical remission (P < 0.05).

Discussion: This study demonstrated that patients with UC should undergo the second course of FMT within 4 months after the first course of FMT for maintaining the long-term clinical benefits. The short-term alterations of microbiota after FMT may be conducive to predicting the long-term efficacy of FMT in UC (see Visual Abstract, Supplementary Digital Content, http://links.lww.com/CTG/A363).

Trial registration: ClinicalTrials.gov NCT01790061.

Figure 1.

Flowchart of the study. FMT, fecal microbiota transplantation; UC, ulcerative colitis.

Figure 2.

Maintaining time of the efficacy from FMT. (a) The maintaining time of the first course of FMT in 122 patients with UC. Compared with the maintaining time of the NCT group (n = 99), the CT group (n = 23) achieved longer maintaining time significantly (P < 0.001). The median maintaining time of the first course of FMT in the nonconsolidation group was 120 days (IQR, 45–180). (b) The maintaining time of the second course of FMT in 24 patients with UC. The median maintaining time of the second course of FMT was 182.5 days (IQR, 105–311.25). Kaplan–Meier survival curves were used to describe the time for relapse. P value less than 0.05 was considered statistically significant. CT, consolidation treatment; FMT, fecal microbiota transplantation; NCT, nonconsolidation treatment.

Figure 3.

The partial Mayo scores at various visits. (a) The partial Mayo scores of 99 patients before and after the first course of FMT. (b) The partial Mayo scores of 24 patients before and after the second course of FMT. More than 2 groups were analyzed by the ANOVA test. P value less than 0.05 was considered statistically significant. Significance levels: *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. ANOVA, analysis of variance; FMT, fecal microbiota transplantation.

Figure 4.

The diversity of microbiota in donors and patients with UC before and after FMT. (a and b) Alpha diversity was calculated by Shannon evenness and Chao 1 index. The donors' and post-FMT patients' samples were compared with pre-FMT patients' samples. (c and d) Beta diversity was calculated by MDS and CAP coordinates. Each dot stands for 1 sample. P value less than 0.05 was considered statistically significant. Significance levels: *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. The number of samples: donors (n = 19), patients with UC pre-FMT (n = 22), patients with UC post-FMT (n = 20). CAP, canonical analysis of principal; FMT, fecal microbiota transplantation; MDS, multidimensional scaling; UC, ulcerative colitis.

Figure 5.

Nineteen significant differential genera between patients with UC and donors. Differences were analyzed by the Kruskal-Wallis test. P value less than 0.05 was considered statistically significant. Significance levels: *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. (a) Pre-FMT vs donor, (b) Post-FMT vs donor, and (c) Pre-FMT vs post-FMT. The number of samples: donors (n = 19), patients with UC pre-FMT (n = 22), patients with UC post-FMT (n = 20). FMT, fecal microbiota transplantation; UC, ulcerative colitis.

Figure 6.

Microbiota related to the long-term efficacy of FMT in patients with UC. (a) The partial Mayo score of the 22 patients at various visits (pre-FMT, 1 week post-FMT and 1 month post-FMT). The 7 patients (boxed) achieved clinical remission and maintaining time was at least 4 months. (b and c) Beta diversity was calculated by MDS and CAP coordinates in the remission (R) and nonremission (NR) groups. Each dot stands for 1 sample. (d–f) The relative abundance differences of genera Eggerthella (r = 0.542, P = 0.014), Lactobacillus (r = 0.471, P = 0.036), and Ruminococcus (r = 0.523, P = 0.018) between pre-FMT and 5 days post-FMT were positively correlated to the long-term efficacy (4 months after FMT) significantly. P value less than 0.05 was considered statistically significant. The number of samples: Rdonor (n = 7), NRdonor (n = 12), Rpre (n = 7), NRpre (n = 15), Rpost (n = 5), and NRpost (n = 15). CAP, canonical analysis of principal; FMT, fecal microbiota transplantation; NRpre, genera in the nonremission group before FMT; NRpost, genera in the nonremission group after FMT; Rdonor, genera in the remission group of donor; Rpre, relative abundance of genera in the remission group before FMT; Rpost, genera in the remission group after FMT; MDS, multidimensional scaling; NRdonor, genera in the nonremission group of donor; UC, ulcerative colitis.

Figure 7.

Comparisons of the 19 genera relative abundance between UC patients with sustained remission and nonremission from FMT. NRpre, genera in the nonremission group before FMT; NRpost, genera in the nonremission group after FMT; Rpost, genera in the remission group after FMT; Rpre, relative abundance of genera in the remission group before FMT. P value less than 0.05 was considered statistically significant. Significance levels: *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. The number of samples: donor (n = 19), Rpre (n = 7), NRpre (n = 15), Rpost (n = 5), and NRpost (n = 15).