Fecal microbiota transplantation for refractory immune-checkpoint-inhibitor colitis.
Authors: Elkrief Arielle , Nicholas Waters , Smith Natalie , Dai Angel , Slingerland John B , Aleynick Nathaniel , Lumish Melissa Amy , Giardina Paul , Chaft Jamie E. , Chapman Paul B. , Eng Juliana , Motzer Robert J. , Mendelsohn Robin B , Van Den Brink Marcel R. M. , Shia Jinru , DeWolf Susan , Hellmann Matthew David , Peled Jonathan U. , Faleck David M. 
Published: June 2023

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Background: Immune-related colitis (irColitis) is associated with significant morbidity and mortality among patients treated with immune checkpoint inhibition (ICI). The gut microbiota has been implicated in the pathophysiology of irColitis. We hypothesized that abnormal fecal microbiome features would be present at the time of irColitis onset, and that restoring the microbiome to a healthy state would mitigate disease severity. Methods: We present fecal microbiota profiles from N = 18 patients with irColitis and describe our clinical experience of N = 5 patients treated with healthy donor fecal microbial transplantation (FMT). Recipients of ICI between May 2019 and June 2021 at Memorial Sloan Kettering Cancer Center whose stool samples were investigated for diarrhea were included in our dataset (N = 100). N = 18 patients with a diagnosis of irColitis were identified. Patients that had other causes of diarrhea were classified as part of the “no-colitis” comparator group (N = 32). All patients with infectious causes of diarrhea ( C. difficile, other GI pathogen) were excluded from the analysis. Stool samples were profiled by whole metagenomic shotgun sequencing. FMT products from individual healthy donors were procured from the OpenBiome fecal bank and delivered via colonoscopy. Results: There was no difference in alpha diversity between the irColitis and no-colitis groups. Patients in the irColitis group had significantly higher relative abundance of Proteobacteria at the time of symptom onset compared to the no-colitis group (p = 0.04). Escherichia spp. and Klebsiella spp. were associated with irColitis, also described in multivariate analyses. Five patients with irColitis refractory to steroids and biologics received healthy-donor FMT, with initial clinical improvement in irColitis symptoms observed in four of five (80%) patients. Two out of five subsequently exhibited recurrence of irColitis symptoms following a course of antibiotics for pneumonia and urinary tract infection, respectively. Both received a second “salvage” FMT that was, again, followed by clinical improvement of irColitis. In these two cases, fecal profiles demonstrated dysbiotic shifts in the gut microbiome post-antibiotics characterized by Proteobacteria expansion, which was salvaged post salvage FMT, mirroring clinical resolution of irColitis symptoms. Conclusions: We observed that Proteobacteria expansion is characteristic of irColitis at time of symptom onset. FMT was followed by clinical improvements in several cases of refractory irColitis. Strategies to restore or prevent microbiome injury—with a particular focus on salvage FMT after antibiotic injury—in the context of immunotherapy toxicities could be further explored in prospective clinical trials.