PMID- 32291445
OWN - NLM
STAT- MEDLINE
DCOM- 20210225
LR  - 20210225
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 136
IP  - 4
DP  - 2020 Jul 23
TI  - The gut microbial metabolite trimethylamine N-oxide aggravates GVHD by inducing 
      M1 macrophage polarization in mice.
PG  - 501-515
LID - 10.1182/blood.2019003990 [doi]
AB  - The diversity of the human microbiome heralds the difference of the impact that 
      gut microbial metabolites exert on allogenic graft-versus-host (GVH) disease 
      (GVHD), even though short-chain fatty acids and indole were demonstrated to 
      reduce its severity. In this study, we dissected the role of choline-metabolized 
      trimethylamine N-oxide (TMAO) in the GVHD process. Either TMAO or a high-choline 
      diet enhanced the allogenic GVH reaction, whereas the analog of choline, 
      3,3-dimethyl-1-butanol reversed TMAO-induced GVHD severity. Interestingly, 
      TMAO-induced alloreactive T-cell proliferation and differentiation into T-helper 
      (Th) subtypes was seen in GVHD mice but not in in vitro cultures. We thus 
      investigated the role of macrophage polarization, which was absent from the in 
      vitro culture system. F4/80+CD11b+CD16/32+ M1 macrophage and signature genes, 
      IL-1beta, IL-6, TNF-alpha, CXCL9, and CXCL10, were increased in TMAO-induced GVHD 
      tissues and in TMAO-cultured bone marrow-derived macrophages (BMDMs). Inhibition 
      of the NLRP3 inflammasome reversed TMAO-stimulated M1 features, indicating that 
      NLRP3 is the key proteolytic activator involved in the macrophage's response to 
      TMAO stimulation. Consistently, mitochondrial reactive oxygen species and 
      enhanced NF-kappaB nuclear relocalization were investigated in TMAO-stimulated BMDMs. 
      In vivo depletion of NLRP3 in GVHD recipients not only blocked M1 polarization 
      but also reversed GVHD severity in the presence of TMAO treatment. In conclusion, 
      our data revealed that TMAO-induced GVHD progression resulted from Th1 and Th17 
      differentiation, which is mediated by the polarized M1 macrophage requiring NLRP3 
      inflammasome activation. It provides the link among the host choline diet, 
      microbial metabolites, and GVH reaction, shedding light on alleviating GVHD by 
      controlling choline intake.
CI  - (c) 2020 by The American Society of Hematology.
FAU - Wu, Kunpeng
AU  - Wu K
AD  - Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China; 
      and.
FAU - Yuan, Yan
AU  - Yuan Y
AD  - Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China; 
      and.
FAU - Yu, Huihui
AU  - Yu H
AD  - Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China; 
      and.
FAU - Dai, Xin
AU  - Dai X
AD  - Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China; 
      and.
FAU - Wang, Shu
AU  - Wang S
AD  - Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China; 
      and.
FAU - Sun, Zhengxu
AU  - Sun Z
AD  - Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China; 
      and.
FAU - Wang, Fen
AU  - Wang F
AD  - Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China; 
      and.
FAU - Fei, He
AU  - Fei H
AD  - Department of Gynecology, Obstetrics & Gynecology Hospital, Fudan University, 
      Shanghai, China.
FAU - Lin, Qiwang
AU  - Lin Q
AD  - Department of Gynecology, Obstetrics & Gynecology Hospital, Fudan University, 
      Shanghai, China.
FAU - Jiang, Hua
AU  - Jiang H
AD  - Department of Gynecology, Obstetrics & Gynecology Hospital, Fudan University, 
      Shanghai, China.
FAU - Chen, Tong
AU  - Chen T
AD  - Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China; 
      and.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Cytokines)
RN  - 0 (Dietary Fats)
RN  - 0 (Inflammasomes)
RN  - 0 (Methylamines)
RN  - FLD0K1SJ1A (trimethyloxamine)
RN  - N91BDP6H0X (Choline)
SB  - IM
CIN - Blood. 2020 Jul 23;136(4):383-385. PMID: 32702126
MH  - Animals
MH  - Choline/*adverse effects/pharmacology
MH  - Cytokines/genetics/immunology/metabolism
MH  - Dietary Fats/*adverse effects/pharmacology
MH  - *Gastrointestinal Microbiome
MH  - *Graft vs Host Disease/genetics/immunology/metabolism/microbiology
MH  - Inflammasomes/genetics/immunology/metabolism
MH  - *Macrophages/immunology/metabolism/pathology
MH  - *Methylamines/immunology/metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Knockout
MH  - *T-Lymphocytes, Helper-Inducer/immunology/metabolism/pathology
PMC - PMC7378459
COIS- Conflict-of-interest disclosure: The authors declare no competing financial 
      interests.
EDAT- 2020/04/16 06:00
MHDA- 2021/02/26 06:00
PMCR- 2020/07/23
CRDT- 2020/04/16 06:00
PHST- 2019/10/31 00:00 [received]
PHST- 2020/03/19 00:00 [accepted]
PHST- 2020/04/16 06:00 [pubmed]
PHST- 2021/02/26 06:00 [medline]
PHST- 2020/04/16 06:00 [entrez]
PHST- 2020/07/23 00:00 [pmc-release]
AID - S0006-4971(20)61868-7 [pii]
AID - 2020/BLD2019003990 [pii]
AID - 10.1182/blood.2019003990 [doi]
PST - ppublish
SO  - Blood. 2020 Jul 23;136(4):501-515. doi: 10.1182/blood.2019003990.