Blockade of dendritic cell development by bacterial fermentation products butyrate and propionate through a transporter (Slc5a8)-dependent inhibition of histone deacetylases.
Mammalian colon harbors trillions of bacteria, yet there is no undue inflammatory response by the host against these bacteria under normal conditions. The bacterial fermentation products acetate, propionate, and butyrate are believed, at least in part, to be responsible for these immunosuppressive effects. Dendritic cells play an essential role in presentation of antigens to T lymphocytes and initiation of adaptive immune responses. Here we report that butyrate and propionate block the generation of dendritic cells from bone marrow stem cells, without affecting the generation of granulocytes. This effect is dependent on the Na(+)-coupled monocarboxylate transporter Slc5a8, which transports butyrate and propionate into cells, and on the ability of these two bacterial metabolites to inhibit histone deacetylases. Acetate, which is also a substrate for Slc5a8 but not an inhibitor of histone deacetylases, does not affect dendritic cell development, indicating the essential role of histone deacetylase inhibition in the process. The blockade of dendritic cell development by butyrate and propionate is associated with decreased expression of the transcription factors PU.1 and RelB. Butyrate also elicits its biologic effects through its ability to activate the G-protein-coupled receptor Gpr109a, but this mechanism is not involved in butyrate-induced blockade of dendritic cell development. The participation of Slc5a8 and the non-involvement of Gpr109a in butyrate effects have been substantiated using bone marrow cells obtained from Slc5a8(-/-) and Gpr109a(-/-) mice. These findings uncover an important mechanism underlying the anti-inflammatory functions of the bacterial fermentation products butyrate and propionate.
Singh
Nagendra
N
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia 30912, USA.
Thangaraju
Muthusamy
M
Prasad
Puttur D
PD
Martin
Pamela M
PM
Lambert
Nevin A
NA
Boettger
Thomas
T
Offermanns
Stefan
S
Ganapathy
Vadivel
V
D000818:Animals; D001419:Bacteria / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology; D002087:Butyrates / Q000378:metabolism / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects*; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005285:Fermentation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D027501:Monocarboxylic Acid Transporters; D011422:Propionates / Q000378:metabolism / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D051841:Transcription Factor RelB / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D002087:Butyrates; D027682:Cation Transport Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D027501:Monocarboxylic Acid Transporters; D011422:Propionates; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D015534:Trans-Activators; D051841:Transcription Factor RelB; D000099232:Proto-Oncogene Protein Spi-1; C473652:Hcar2 protein, mouse; C497594:Relb protein, mouse; C507459:Slc5a8 protein, mouse