Treating Steroid Refractory Intestinal Acute Graft-vs.-Host Disease With Fecal Microbiota Transplantation: A Pilot Study

Xiaofei Qi, Xuewei Li, Ye Zhao, Xiaojin Wu, Feng Chen, Xiao Ma, Faming Zhang, Depei Wu, Xiaofei Qi, Xuewei Li, Ye Zhao, Xiaojin Wu, Feng Chen, Xiao Ma, Faming Zhang, Depei Wu

Abstract

Patients with steroid refractory gastrointestinal (GI) tract graft- vs.-host disease (GvHD) face a poor prognosis and limited therapeutic options. To accurately assess the efficacy and safety of fecal microbiota transplantation (FMT) in treating steroid refractory GI tract GvHD, we conducted a pilot study involving eight patients. Having received FMTs, all patients' clinical symptoms relieved, bacteria enriched, and microbiota composition reconstructed. Compared to those who did not receive FMT, these eight patients achieved a higher progression-free survival. FMT can serve as a therapeutic option for GI tract aGVHD, but its effectiveness and safety need further evaluations. Clinical Trial Registration: NCT03148743.

Keywords: a pilot study; diarrhea; fecal microbiota transplantations; graft-vs.-host disease; refractory gastrointestinal.

Figures

Figure 1
Figure 1
Clinical response to FMT. (A) Stool volumes of all 8 patients pre FMT and 13 days post FMT. (B) Stool frequency of all 8 patients pre FMT and 13 days post FMT. (C) Abdominal pain score at baseline and 13 days follow-up after FMT (n = 4).
Figure 2
Figure 2
Analysis of fecal microbiota in donor and 6 patients. (A) The diversity of fecal microbiota in all sample (Shannon's diversity index). Px means patient number, Dx means donor number, xD means day after FMT. (B) Shannon's diversity index change in donor group, pre-FMT and post-FMT samples. **p < 0.01.
Figure 3
Figure 3
Change of fecal microbiota before and after FMT. (A) Analysis of fecal microbiota composition in all samples at the phylum level. (B) Analysis of fecal microbiota composition in all samples at the genus level. Difference of fecal microbiota composition between pre-FMT and post-FMT at the phylum level (C). (D) Genus level.
Figure 4
Figure 4
Efficacy and safety of FMT. (A) Progression free survival (PFS) between patients treated with FMT and without FMT in 90 days after the steroid refractory GI-GvHD being diagnosed. (B) Overall survival (OS) in the refractory and steroid- insensitive GI-GvHD patients who treated with FMT/without FMT were shown. Days means day after the steroid refractory GI-GvHD being diagnosed.

References

    1. Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. (2006) 354:1813–26. 10.1056/NEJMra052638
    1. Tuncer HH, Rana N, Milani C, Milani C, Al-Homsi SA. Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation. World J Gastroenterol. (2012) 18:1851–60. 10.3748/wjg.v18.i16.1851
    1. Weber D, Oefner PJ, Hiergeist A, Koestler J, Gessner A, Weber M, et al. . Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome. Blood (2015) 126:1723–8. 10.1182/blood-2015-04-638858
    1. Wu D, Hockenberry DM, Brentnall TA, Baehr PH, Ponec RJ, Kuver R, et al. . Persistent nausea and anorexia after marrow transplantation: a prospective study of 78 patients. Transplantation (1998) 66:1319–24. 10.1097/00007890-199811270-00010
    1. McDonald GB. How I treat acute graft-versus-host disease of the gastrointestinal tract and the liver. Blood (2016) 127:1544–50. 10.1182/blood-2015-10-612747
    1. Martin PJ, Rizzo JD, Wingard JR, Ballen K, Curtin PT, Cutler C, et al. . First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. (2012) 18:150–63. 10.1016/j.bbmt.2012.04.005
    1. Marchesi JR, Adams DH, Fava F, Hermes GD, Hirschfield GM, Hold G, et al. . The gut microbiota and host health: a new clinical Frontier. Gut (2016) 65:330–9. 10.1136/gutjnl-2015-309990
    1. Taur Y, Jenq RR, Perales MA, Littmann ER, Morjaria S, Ling LL, et al. . The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood (2014) 124:1174–82. 10.1182/blood-2014-02-554725
    1. Holler E, Butzhammer P, Schmid K, Hundsrucker CH, Koestler J, Peter K, et al. . Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant. (2014) 20:640–5. 10.1016/j.bbmt.2014.01.030
    1. Spindelboeck W, Schulz E, Uhl B, Kashofer K, Aigelsreiter A, Zinke-Cerwenka W, et al. . Repeated fecal microbiota transplantations attenuate diarrhea and lead to sustained changes in the fecal microbiota in acute, refractory gastrointestinal graft-versus-host-disease. Haematologica (2017) 102:210–3. 10.3324/haematol.2016.154351
    1. Kakihana K, Fujioka Y, Suda W, Najima Y, Kuwata G, Sasajima S, et al. Fecal microbiota transplantation for patients with steroid-resistant/dependent acute graft-versus-host disease of the gut. Blood (2016) 128:2083–88. 10.1182/blood-2016-05-717652
    1. Buffie CG, Pamer EG. Microbiota-mediated colonization resistance against intestinal pathogens. Nat Rev Immunol. (2013) 13:790–801. 10.1038/nri3535
    1. Nood EV, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. . Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. (2013) 368:407–15. 10.1056/NEJMoa1205037
    1. Kelly CR, Khoruts A, Staley C, Sadowsky MJ, Abd M, Alani M, et al. . Effect of fecal microbiota transplantation on recurrence in multiply recurrent Clostridium difficile Infection: a randomized trial. Ann Intern Med. (2016) 165:609–16. 10.7326/M16-0271
    1. Rowlings PA, Przepiorka D, Klein JP, Gale RP, Passweg JR, Henslee-Downey PJ, et al. . Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol. (1997) 97:855–64. 10.1046/j.1365-2141.1997.1112925.x
    1. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. . 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant. (1995) 15:825–8.
    1. Cui B, Li P, Xu L, Zhao Y, Wang H, Peng Z, et al. . Step-up fecal microbiota transplantation strategy: a pilot study for steroid-dependent ulcerative colitis. J Transl Med. (2015) 13:298–309. 10.1186/s12967-015-0646-2
    1. Mathewson ND, Jenq R, Mathew AV, Koenigsknecht M, Hanash A, Toubai T, et al. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat Immunol. (2016) 17:505–13. 10.1038/ni.3400

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