Key Points

  • The microbe-derived SCFAs butyrate and propionate in the systemic circulation are associated with protection from cGVHD.

  • cGVHD is associated with gastrointestinal dysbiosis late after HCT.

Abstract

Studies of the relationship between the gastrointestinal microbiota and outcomes in allogeneic hematopoietic stem cell transplantation (allo-HCT) have thus far largely focused on early complications, predominantly infection and acute graft-versus-host disease (GVHD). We examined the potential relationship of the microbiome with chronic GVHD (cGVHD) by analyzing stool and plasma samples collected late after allo-HCT using a case-control study design. We found lower circulating concentrations of the microbe-derived short-chain fatty acids (SCFAs) propionate and butyrate in day 100 plasma samples from patients who developed cGVHD, compared with those who remained free of this complication, in the initial case-control cohort of transplant patients and in a further cross-sectional cohort from an independent transplant center. An additional cross-sectional patient cohort from a third transplant center was analyzed; however, serum (rather than plasma) was available, and the differences in SCFAs observed in the plasma samples were not recapitulated. In sum, our findings from the primary case-control cohort and 1 of 2 cross-sectional cohorts explored suggest that the gastrointestinal microbiome may exert immunomodulatory effects in allo-HCT patients at least in part due to control of systemic concentrations of microbe-derived SCFAs.

REFERENCES

REFERENCES
1.
Wingard
J
,
Majhail
N
,
Brazauskas
R
, et al
.
Long-term survival and late deaths after allogeneic hematopoietic cell transplantation
.
J Clin Oncol
.
2011
;
29
(
16
):
2230
-
2239
.
2.
MacDonald
K
,
Hill
G
,
Blazar
B
.
Chronic graft-versus-host disease: biological insights from preclinical and clinical studies
.
Blood
.
2017
;
129
(
1
):
13
-
21
.
3.
Jenq
R
,
Taur
Y
,
Devlin
S
, et al
.
Intestinal blautia is associated with reduced death from graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2015
;
21
(
8
):
1373
-
1383
.
4.
Peled
J
,
Devlin
S
,
Staffas
A
, et al
.
Intestinal microbiota and relapse after hematopoietic-cell transplantation
.
J Clin Oncol
.
2017
;
35
(
15
):
1650
-
1659
.
5.
Shono
Y
,
Docampo
M
,
Peled
J
, et al
.
Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice
.
Sci Transl Med
.
2016
;
8
(
339
):
339ra71
.
6.
Hill
G
,
Olver
S
,
Kuns
R
, et al
.
Stem cell mobilization with G-CSF induces type 17 differentiation and promotes scleroderma
.
Blood
.
2010
;
116
(
5
):
819
-
828
.
7.
Schirmer
M
,
Smeekens
SP
,
Vlamakis
H
, et al
.
Linking the human gut microbiome to inflammatory cytokine production capacity
.
Cell
.
2016
;
167
(4):
1125
-
1136.e1128
.
8.
Atarashi
K
,
Tanoue
T
,
Ando
M
, et al
.
Th17 cell induction by adhesion of microbes to intestinal epithelial cells
.
Cell
.
2015
;
163
(
2
):
367
-
380
.
9.
Mathewson
N
,
Jenq
R
,
Mathew
A
, et al
.
Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease [published correction appears in Nat Immunol. 2016;17(10):1235]
.
Nat Immunol
.
2016
;
17
(
5
):
505
-
513
.
10.
Fujiwara
H
,
Docampo
M
,
Riwes
M
, et al
.
Microbial metabolite sensor GPR43 controls severity of experimental GVHD
.
Nat Commun
.
2018
;
9
(
1
):
3674
.
11.
Arpaia
N
,
Campbell
C
,
Fan
X
, et al
.
Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation
.
Nature
.
2013
;
504
(
7480
):
451
-
455
.
12.
Kaiko
G
,
Ryu
S
,
Koues
O
, et al
.
The colonic crypt protects stem cells from microbiota-derived metabolites [published correction appears in Cell. 2016;167(4):1137]
.
Cell
.
2016
;
165
(
7
):
1708
-
1720
.
13.
Haak
B
,
Littmann
E
,
Chaubard
J
, et al
.
Impact of gut colonization with butyrate-producing microbiota on respiratory viral infection following allo-HCT
.
Blood
.
2018
;
131
(
26
):
2978
-
2986
.
14.
Lee
J
,
Huang
J
,
Magruder
M
, et al
.
Butyrate-producing gut bacteria and viral infections in kidney transplant recipients: a pilot study
.
Transpl Infect Dis
.
2019
;
21
(
6
):
e13180
.
15.
Peled
J
,
Gomes
A
,
Devlin
S
, et al
.
Microbiota as predictor of mortality in allogeneic hematopoietic-cell transplantation
.
N Engl J Med
.
2020
;
382
(
9
):
822
-
834
.
16.
Taur
Y
,
Jenq
R
,
Perales
M
, et al
.
The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation
.
Blood
.
2014
;
124
(
7
):
1174
-
1182
.
17.
Jagasia
MH
,
Greinix
HT
,
Arora
M
, et al
.
National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report
.
Biol Blood Marrow Transplant
.
2015
;
21
(3):
389
-
401.e381
.
18.
Taur
Y
,
Coyte
K
,
Schluter
J
, et al
.
Reconstitution of the gut microbiota of antibiotic-treated patients by autologous fecal microbiota transplant
.
Sci Transl Med
.
2018
;
10
(
460
):
eaap9489
.
19.
Franzosa
E
,
McIver
L
,
Rahnavard
G
, et al
.
Species-level functional profiling of metagenomes and metatranscriptomes
.
Nat Methods
.
2018
;
15
(
11
):
962
-
968
.
20.
Segata
N
,
Izard
J
,
Waldron
L
, et al
.
Metagenomic biomarker discovery and explanation
.
Genome Biol
.
2011
;
12
(
6
):
R60
.
21.
Zhai
B
,
Ola
M
,
Rolling
T
, et al
.
High-resolution mycobiota analysis reveals dynamic intestinal translocation preceding invasive candidiasis
.
Nat Med
.
2020
;
26
(
1
):
59
-
64
.
22.
Colosimo
DA
,
Kohn
JA
,
Luo
PM
, et al
.
Mapping interactions of microbial metabolites with human G-protein-coupled receptors
.
Cell Host Microbe
.
2019
;
26
(2):
273
-
282.e277
.
23.
Oksanen
J
,
Blanchet
FG
,
Friendly
M
, et al
vegan: Community Ecology Package; R package version 2.5-6. https://CRAN.R-project.org/package=vegan. Accessed 24 September 2019.
24.
Routy
B
,
Gopalakrishnan
V
,
Daillère
R
,
Zitvogel
L
,
Wargo
J
,
Kroemer
G
.
The gut microbiota influences anticancer immunosurveillance and general health
.
Nat Rev Clin Oncol
.
2018
;
15
(
6
):
382
-
396
.
25.
Gopalakrishnan
D
,
Koshkin
V
,
Ornstein
M
,
Papatsoris
A
,
Grivas
P
.
Immune checkpoint inhibitors in urothelial cancer: recent updates and future outlook
.
Ther Clin Risk Manag
.
2018
;
14
:
1019
-
1040
.
26.
Schluter
J
,
Peled
JU
,
Taylor
BP
, et al
.
The gut microbiota influences how circulating immune cells in humans change from one day to the next [published online 21 November 2019]
.
bioRxiv
.
doi:10.1101/618256
.
27.
Salvatier
J
,
Wiecki
T
,
Fonnesbeck
C
.
Probabilistic programming in Python using PyMC3
.
PeerJ Comput Sci
.
2016
;
2
:
e55
.
28.
Taur
Y
,
Xavier
J
,
Lipuma
L
, et al
.
Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation
.
Clin Infect Dis
.
2012
;
55
(
7
):
905
-
914
.
29.
Morjaria
S
,
Schluter
J
,
Taylor
B
, et al
.
Antibiotic-induced shifts in fecal microbiota density and composition during hematopoietic stem cell transplantation
.
Infect Immun
.
2019
;
87
(
9
):
e00206
-
19
.
30.
Maier
L
,
Pruteanu
M
,
Kuhn
M
, et al
.
Extensive impact of non-antibiotic drugs on human gut bacteria
.
Nature
.
2018
;
555
(
7698
):
623
-
628
.
31.
Pidala
J
,
Vogelsang
G
,
Martin
P
, et al
.
Overlap subtype of chronic graft-versus-host disease is associated with an adverse prognosis, functional impairment, and inferior patient-reported outcomes: a Chronic Graft-versus-Host Disease Consortium study
.
Haematologica
.
2012
;
97
(
3
):
451
-
458
.
32.
Arora
M
,
Cutler
C
,
Jagasia
M
, et al
.
Late acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation
.
Biol Blood Marrow Transplant
.
2016
;
22
(
3
):
449
-
455
.
33.
Shimizu
J
,
Kubota
T
,
Takada
E
, et al
.
Propionate-producing bacteria in the intestine may associate with skewed responses of IL10-producing regulatory T cells in patients with relapsing polychondritis
.
PLoS One
.
2018
;
13
(
9
):
e0203657
.
You do not currently have access to this content.