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. 2022 Dec 1;140(22):2385-2397.
doi: 10.1182/blood.2021015352.

Preservation of the fecal microbiome is associated with reduced severity of graft-versus-host disease

Marina Burgos da Silva  1 , Doris M Ponce  2   3 , Anqi Dai  1 , Sean M Devlin  4 , Antonio L C Gomes  1 , Gillian Moore  2 , John Slingerland  1 , Roni Shouval  2   3 , Gabriel K Armijo  1 , Susan DeWolf  5 , Teng Fei  4 , Annelie Clurman  1 , Emily Fontana  1   6 , Luigi A Amoretti  1   6 , Roberta J Wright  1   6 , Hana Andrlova  1 , Oriana Miltiadous  7 , Miguel-Angel Perales  2   3 , Ying Taur  6 , Jonathan U Peled  1   2   3 , Marcel R M van den Brink  1   2   3
Affiliations

Preservation of the fecal microbiome is associated with reduced severity of graft-versus-host disease

Marina Burgos da Silva et al. Blood. .

Erratum in

Abstract

Following allogeneic hematopoietic cell transplantation (allo-HCT), the gastrointestinal (GI) tract is frequently affected by acute graft-versus-host disease (aGVHD), the pathophysiology of which is associated with a dysbiotic microbiome. Since microbial composition varies along the length of the GI tract, the authors hypothesized that microbiome features correlate with the pattern of organ involvement after allo-HCT. We evaluated 266 allo-HCT recipients from whom 1303 stool samples were profiled by 16S ribosomal gene sequencing. Patients were classified according to which organs were affected by aGVHD. In the 20 days prior to disease onset, GVHD patients had lower abundances of members of the class Clostridia, lower counts of butyrate producers, and lower ratios of strict-to-facultative (S/F) anaerobic bacteria compared with allograft recipients who were free of GVHD. GI GVHD patients showed significant reduction in microbial diversity preonset. Patients with lower GI aGVHD had lower S/F anaerobe ratios compared with those with isolated upper GI aGVHD. In the 20 days after disease onset, dysbiosis was observed only in GVHD patients with GI involvement, particularly those with lower-tract disease. Importantly, Clostridial and butyrate-producer abundance as well as S/F anaerobe ratio were predictors of longer overall survival; higher abundance of butyrate producers and higher S/F anaerobe ratio were associated with decreased risk of GVHD-related death. These findings suggest that the intestinal microbiome can serve as a biomarker for outcomes of allo-HCT patients with GVHD.

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Conflict of interest statement

Conflict-of-interest disclosure: D.M.P. has served as advisory board member for Evive Biotechnology (Shanghai) Ltd (formerly Generon [Shanghai] Corporation Ltd); has consulted, received honorarium from, or particpated in advisory boards for Kadmon Corporation/Sanofi, CareDx, Ceramedix, and Incyte; has received research support from Incyte. A.L.C.G. reports equity, salary and is employed by Xbiome Co. R.S. received consultancy fees from Medexus and MyBiotics. M.-A.P. reports honoraria from Adicet, Allovir, Caribou Biosciences, Celgene, Bristol-Myers Squibb, Equilium, Exevir, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Syncopation, VectivBio AG, and Vor Biopharma. He serves on DSMBs for Cidara Therapeutics, Medigene, and Sellas Life Sciences, and the scientific advisory board of NexImmune. He has ownership interests in NexImmune and Omeros. He has received institutional research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis. J.U.P. reports research funding, intellectual property fees, and travel reimbursement from Seres Therapeutics and consulting fees from DaVolterra, CSL Behring, and MaaT Pharma. He serves on an advisory board of and holds equity in Postbiotics Plus Research. He has filed intellectual property applications related to the microbiome (reference numbers 62/843,849, 62/977,908, and 15/756,845). M.R.M.v.d.B. has received research support and stock options from Seres Therapeutics and stock options from Notch Therapeutics and Pluto Therapeutics; he has received royalties from Wolters Kluwer; has consulted, received honorarium from or participated in advisory boards for Seres Therapeutics, Vor Biopharma, Rheos Medicines, Frazier Healthcare Partners, Nektar Therapeutics, Notch Therapeutics, Ceramedix, Lygenesis, Pluto Therapeutics, GlaxoSmithKline, Da Volterra, Thymofox, Garuda, Novartis (Spouse), Synthekine (Spouse), Beigene (Spouse), Kite (Spouse); he has IP Licensing with Seres Therapeutics and Juno Therapeutics; and holds a fiduciary role on the Foundation Board of DKMS (a nonprofit organization). Memorial Sloan Kettering Cancer Center (MSK) has financial interests relative to Seres Therapeutics. The remaining authors declare no competing financial interests.

Figures

Image 1
Graphical abstract
Figure 1
Figure 1.
Allo-HCT patients with GVHD developed microbial disruption preonset GVHD. (A-C) Volcano plot [−log10(FDR P value) vs log2(fold change)] representation of microbial dysbiosis of preonset GVHD (day −20 to −1 relative to onset) and no-GVHD (day −3 to +102 relative to allo-HCT) fecal samples. Plot includes taxa with mean relative abundance within samples >0.1% and highlights the 20 genera with strongest FDR corrected P-value significance (≤0.05). No-GVHD patients had higher abundance of commensals belonging to the class Clostridia when compared with non-GI, UGI, and LGI cohort. p, phylum; o, order; f, family; g, genus; Proteo, Proteobacteria.
Figure 2
Figure 2.
Allo-HCT patients with GI GVHD developed microbial disruption postonset GVHD. (A-D) Volcano plot [−log10(FDR P value) vs log2(fold change)] representation of microbial dysbiosis of postonset GVHD (day 0 to +20 relative to onset) and no-GVHD (day −3 to +102 relative to allo-HCT) fecal samples. Plot includes taxa with mean abundance within samples >0.1% and highlights the 20 genera with strongest FDR corrected P-value significance (≤0.05). (A-B) No-GVHD compared with UGI and LGI patients had increased abundance of class Clostridia commensals Coprococcus and Blautia, respectively, post-GVHD onset. (C-D) Non-GI and UGI patients also had increased relative abundance of Blautia and Erysipelatoclostridium when compared with LGI patients. f, family; g, genus; p, phylum; Proteo, Proteobacteria.
Figure 3
Figure 3.
GVHD patients have reduced diversity, abundance of butyrate producers, and loss of anaerobiosis pre- and post-GVHD onset. (A) Pre- and postonset aGVHD microbial analysis show reduced diversity in GI GVHD patients. (B) GI GVHD patients also had lower relative abundance of predicted butyrate-producing strains when compared with the other cohorts, and this was also found for LGI patients when compared with non-GI and UGI patients postonset. (C) GVHD patients also had lower strict-to-facultative (S/F) anaerobe ratio in comparison with no-GVHD patients, whereas the LGI patients, specifically, showed lower ratio when compared with UGI and non-GI patients, respectively pre- and postonset.
Figure 4
Figure 4.
GVHD patients present distinct preonset predicted PICRUSt pathways. (A) Radar chart representation of PICRUSt predicted functional pathway relative abundance from patients without GVHD and GVHD patients at preonset. Relevant pathways belonged to 6 main metabolic categories: carbohydrate degradation, nucleotide biosynthesis, amino acid biosynthesis, antibiotic resistance, vitamin K2 biosynthesis, and fermentation. Axis represents fold change relative to no-GVHD patients. (B) Heat map with hierarchical clustering of statistically significant (FDR P ≤ .05) unique PICRUSt pathways. Figure displays pathways found in a minimum of 5% samples within all groups. UGI and LGI GVHD patients show increased pathways associated with general antibiotic resistance, vitamin K2 metabolism, and nucleotide biosynthesis, with reduced representation related to amino acid biosynthesis compared with no-GVHD patients. There was reduced presence of butyrate-producing specific pathways in LGI patients (bold). ∗FDR P ≤ .05; ∗∗FDR P ≤ .01; ∗∗∗FDR P ≤ .001. NS, not significant.
Figure 5
Figure 5.
GVHD patients present distinct postonset predicted PICRUSt pathways. (A) Radar chart representation of PICRUSt predicted functional pathways belonging to 6 main metabolic pathways: carbohydrate degradation, nucleotide biosynthesis, amino acid biosynthesis, antibiotic resistance, vitamin K2 biosynthesis, and fermentation for GVHD patients post-GVHD onset relative to no-GVHD controls. Axis represents fold change relative to no-GVHD patients. (B) Heat map with hierarchical clustering of statistically significant (FDR P ≤ .05) unique PICRUSt pathways. Figure displays pathways found in a minimum of 5% of samples within all groups. LGI GVHD patients show increased abundance of pathways associated with general antibiotic resistance and vitamin K2 metabolism with lower abundance of pathways linked to amino acid biosynthesis relative to no-GVHD patients. Lower abundance of pathways specific to butyrate production was also found in LGI patients compared with no-GVHD controls (bold). ∗FDR P ≤ .05; ∗∗FDR P ≤ .01; ∗∗∗FDR P ≤ .001. NS, not significant.
Figure 6
Figure 6.
Preonset GVHD clostridia abundance, butyrate producers, and S/F anaerobe ratio predicts survival in allo-HCT patients. OS (A) and GVHD-related mortality (B). Patients were stratified according to the median relative abundances of class Clostridia, butyrate producers, and S/F anaerobe ratio prior to GVHD onset. Figure shows univariable (UVA) and multivariable (MVA) tests of associations for microbial determinants as binary or continuous variables. The proportional hazards multivariable regression models (OS) and the Fine and Gray multivariable regression models (GVHD-related mortality) were adjusted for sex, age, and conditioning regimen. Data corroborates the association of higher relative abundance of butyrate-producing bacteria and S/F ratio to increased OS and reduced GVHD-related mortality.
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