Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.
Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T cells (Treg cells) expressing transcription factor Foxp3 have a key role in limiting inflammatory responses in the intestine. Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory T helper 17 (TH17) cells, the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we reasoned that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We tested this hypothesis by exploring the effect of microbial metabolites on the generation of anti-inflammatory Treg cells. We found that in mice a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of Treg cells. A boost in Treg-cell numbers after provision of butyrate was due to potentiation of extrathymic differentiation of Treg cells, as the observed phenomenon was dependent on intronic enhancer CNS1 (conserved non-coding sequence 1), essential for extrathymic but dispensable for thymic Treg-cell differentiation. In addition to butyrate, de novo Treg-cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of histone deacetylase (HDAC) inhibition, but not acetate, which lacks this HDAC-inhibitory activity. Our results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms.
1] Howard Hughes Medical Institute and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Nicholas
N
Arpaia
1] Howard Hughes Medical Institute and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Clarissa
C
Campbell
1] Howard Hughes Medical Institute and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Xiying
X
Fan
1] Howard Hughes Medical Institute and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Stanislav
S
Dikiy
1] Howard Hughes Medical Institute and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Joris
J
van der Veeken
1] Howard Hughes Medical Institute and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Paul
P
deRoos
Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Hui
H
Liu
Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Justin R
JR
Cross
Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, Duesseldorf 40225, Germany.
Klaus
K
Pfeffer
1] Howard Hughes Medical Institute and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [3] Department of Cell Biology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
Paul J
PJ
Coffer
1] Howard Hughes Medical Institute and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Alexander Y
AY
Rudensky
D000107:Acetylation; D000818:Animals; D002087:Butyrates / Q000378:metabolism*; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005285:Fermentation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D007422:Intestines / Q000166:cytology / Q000276:immunology / Q000382:microbiology*; D007438:Introns / Q000235:genetics; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013213:Starch / Q000378:metabolism; D013559:Symbiosis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*
D002087:Butyrates; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018836:Inflammation Mediators; D013213:Starch; D006655:Histone Deacetylases