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. 2021 Dec 21:12:20406207211058333.
doi: 10.1177/20406207211058333. eCollection 2021.

Antibiotic use and ileocolonic immune cells in patients receiving fecal microbiota transplantation for refractory intestinal GvHD: a prospective cohort study (V体育官网)

Walter Spindelboeck  1 , Bettina Halwachs  1 , Nadine Bayer  2 , Bianca Huber-Krassnitzer  3 , Eduard Schulz  3 , Barbara Uhl  3 , Lukas Gaksch  3 , Stefan Hatzl  3 , Victoria Bachmayr  2 , Lisa Kleissl  2 , Patrizia Kump  1 , Alexander Deutsch  3 , Georg Stary  2 , Hildegard Greinix  3 , Gregor Gorkiewicz  4 , Christoph Högenauer  5 , Peter Neumeister  3
Affiliations

V体育平台登录 - Antibiotic use and ileocolonic immune cells in patients receiving fecal microbiota transplantation for refractory intestinal GvHD: a prospective cohort study

Walter Spindelboeck et al. Ther Adv Hematol. .

VSports app下载 - Abstract

Introduction: Treatment-refractory, acute graft-versus-host disease (GvHD) of the lower gastrointestinal tract (GI) after allogeneic hematopoietic stem cell transplantation is life threatening and lacks effective treatment options. While fecal microbiota transplantation (FMT) was shown to ameliorate GI-GvHD, its mechanisms of action and the factors influencing the treatment response in humans remain unclear. The objective of this study is to assess response to FMT treatment, factors influencing response, and to study the mucosal immune cell composition in treatment-refractory GI-GvHD. VSports手机版.

Methods: Consecutive patients with treatment-refractory GI-GvHD were treated with up to six endoscopically applied FMTs. V体育安卓版.

Results: We observed the response to FMT in four out of nine patients with severe, treatment refractory GI-GvHD, associated with a significant survival benefit (p = 0. 017). The concomitant use of broad-spectrum antibiotics was the main factor associated with FMT failure (p = 0. 048). In addition, antibiotic administration hindered the establishment of donor microbiota after FMT V体育ios版. Unlike in non-responders, the microbiota characteristics (e. g. α- and β-diversity, abundance of anaerobe butyrate-producers) in responders were more significantly similar to those of FMT donors. During active refractory GI-GvHD, an increased infiltrate of T cells, mainly Th17 and CD8+ T cells, was observed in the ileocolonic mucosa of patients, while the number of immunomodulatory cells such as regulatory T-cells and type 3 innate lymphoid cells decreased. After FMT, a change in immune cell patterns was induced, depending on the clinical response. .

Conclusion: This study increases the knowledge about the crucial effects of antibiotics in patients given FMT for treatment refractory GI-GvHD and defines the characteristic alterations of ileocolonic mucosal immune cells in this setting. VSports最新版本.

Keywords: T cells; antibiotics; fecal microbiota transplantation; gastrointestinal graft-versus-host disease; regulatory T cells; type 3 innate lymphoid cells V体育平台登录. .

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Conflict of interest statement

Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: W. S. received speakers’ fees from Oesterreichische Gesellschaft fuer Gastroenterologie und Hepatologie, Aerztekammer fuer Steiermark, and AbbVie and received travel support from Boston Scientific. B VSports注册入口. H. -K. received support for participation in meetings from Teva Ratiopharm, Novartis, Neovii, Celgene, Takeda, and Gilead. E. S. received Congress support from Amgen, Incyte, Jazz, Janssen, Novartis, Roche, and Takeda; participated in advisory boards of Amgen and Celgene; and received honoraria from Amgen and Novartis. B. U. was supported by a Research Grant of the Austrian Society of Hematology & Medical Oncology and received support for participation in conferences from Neovii, Novartis, Sanofi, Sobi, and Takeda. P. N. participated in advisory boards or had consultancy with and received honoraria from AbbVie, Takeda, BMS/Celgene, and Janssen. P. K. received research funding from Bristol Meyer Squibb and Ipsen and participated in advisory boards and received honoraria from Janssen, Ipsen, Novartis, AbbVie, Takeda, Gebro, Merck Sharp & Dohme (MSD), and Pfizer. H. G. received honoraria for presentations in scientific meetings and consultations from Novartis, Celgene/ Bristol-Myers Squibb (BMS), Janssen, Sanofi, and Therakos. CH received a research grant from Seres Therapeutics. B. H. , N. B. , V. B. , L. K. , A. D. , L. G. , S. H. , G. G. , and G. S. declare that they have no conflict of interest. The authors declare that none of the mentioned relationships were related to the development and the content of this article.

Figures

Figure 1.
Figure 1.
Clinical course of treatment-refractory GI-GvHD patients, split into four responders (a) and all other patients (five non-responders to FMT and patient C, panel b). Graphs show the following information over time with day 0 as the day of stem cell transplantation: GI-GvHD stage (colored bar), periods of any antibiotic use (gray background), stool volume in milliliters per day (dashed black line, left y-scale), time points of FMT administrations (turquoise triangles and vertical dashed lines), and time points of obtaining intestinal biopsies (pink triangles and vertical dashed lines). α-diversity of the intestinal microbiota (observed species, right y-scale) is shown for patients (continuous black line) and donors (crossed red circle). FMT, fecal microbiota transplantation; GI-GvHD, gastrointestinal graft-versus-host disease.
Figure 2.
Figure 2.
Overall survival (a) and GI-GvHD-related survival (b) stratified by response to FMT in treatment-refractory GI-GvHD. (a) Overall survival and (b) GI-GvHD-related survival after commencement of the first FMT were significantly longer in four responders (blue) versus five non-responders (red). FMT, fecal microbiota transplantation; GI-GvHD, gastrointestinal graft-versus-host disease. *p < 0.05, **p < 0.01, Log-rank test.
Figure 3.
Figure 3.
Microbiota in donors and treatment-refractory GI-GvHD patients before and after FMTs stratified according to FMT response and concomitant antibiotic use. Microbiota analyses of the four main study groups: baseline samples of all patients (BL), responders after FMT (R), all other patients (including non-responders after FMT and patient C, NR), and donors (D). (a) α-diversity (observed species), (b) β-diversity (weighted UniFrac, Principal coordinates analysis [PCoA]), (c) Spearman’s rank-order correlation of the microbiota on genus level of all samples collected, (d) proportions of microbial contents transferred from donors to non-responders as compared with responders determined by source-tracking analyses, (e) relative abundances of Enterococcus and Lactobacillus, (f) least discriminative feature analysis between responders and non-responders using LEfSe, (g) α-diversity (observed species) for samples taken after (AB) and without (noAB) antibiotic use 7 days before sampling, and (h) β-diversity (weighted UniFrac, PCoA) of samples taken during antibiotic use versus antibiotic withdrawal 7 days before sampling. AB, samples taken after antibiotic use 7 days before sampling; BL, baseline; FMT, fecal microbiota transplantation; GI-GvHD, gastrointestinal graft-versus-host disease; LEfSe, Linear discriminant analysis Effect Size; noAB, samples without antibiotic use 7 days before sampling; NR, non-responders; PCoA, Principal coordinates analysis. *p < 0.05, **p < 0.01, ***p < 0.001, Kruskal–Wallis rank sum test, Wilcoxon’s test. False discovery rate correction for multiple testing.
Figure 4.
Figure 4.
Immune cell subsets in the ileocolonic mucosa of GI-GvHD patients and healthy controls. (a) Representative staining images of CD4+ and CD8+ T cells (CD4+, CD3+/CD4+ and CD8+, CD3+/CD8+) on the left as well as innate lymphoid cells type 3 and T helper 17 cells (ILC3, CD3–/RORγT+ and Th17 cell, CD3+/RORγT+) to the right. White arrows denote positive cells. Quantification of absolute cell numbers (cells/mm2; left) and relative cell numbers (% of DAPI-, CD3+ cells, of patients (GI-GvHD), respectively; right) of (b) T cells – CD3+, (c) CD3+/CD4+ T cells, (d) CD3+/CD8+ T cells, (e) T helper 17 cells – CD3+/RORγT+, (f) regulatory T cells – CD3+/CD4+/FoxP3+, (g) ratio of CD3+/CD8+/regulatory T cells, and (h) ILC3 cells – CD3–/RORγT+ in healthy controls versus GI-GvHD patients. Intestinal biopsies (n = 25) were obtained from nine GI-GvHD patients before (n = 14) and after (n = 11) FMT and compared with biopsies (n = 18) from healthy mucosa taken from screening colonoscopies. DAPI, 4′,6-Diamidin-2-phenylindol; FMT, fecal microbiota transplantation; GI-GvHD, gastrointestinal graft-versus-host disease; ILC3, type 3 innate lymphoid cells. Mean ± SD, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001, unpaired t-test or Mann–Whitney test.
Figure 5.
Figure 5.
Changes of ileocolonic mucosal immune cells following FMT in GI-GvHD patients. Absolute (cells/mm2; left) and relative (%; right) cell numbers are depicted from healthy controls, baseline (BL) and follow-up (FU) biopsies in responders (R) versus non-responders (NR). (a) T cells – CD3+, (b) CD3+/CD8+ T cells, (c) T helper 17 cells – CD3+/RORγT+, (d) regulatory T cells – CD3+/CD4+/FoxP3+, (e) ILC3 – CD3–/RORγT+, and (f) ratio of CD3+/CD8+/regulatory T cells. Out of 11 follow-up biopsies, 5 were obtained from responders (n = 4), 6 were obtained from non-responders (n = 4), and compared with biopsies (n = 18) from healthy mucosa taken from screening colonoscopies. ANOVA, analysis of variance; BL, baseline; FMT, fecal microbiota transplantation; FU, follow-up; GI-GvHD, gastrointestinal graft-versus-host disease; ILC3, type 3 innate lymphoid cells; NR, non-responders; R, responders. Mean ± SD and one-way ANOVA and Bonferroni’s post hoc test as well as Kruskal–Wallis and Dunn’s post hoc tests. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.
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