Blockade of Dendritic Cell Development by Bacterial Fermentation Products Butyrate and Propionate through a Transporter (Slc5a8)-dependent Inhibition of Histone Deacetylases

Abstract

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-proteincoupled 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.Dendritic cells (DCs) 2 function as sentinels in peripheral tissues and lymphoid organs guarding against pathogens (1-3). Normally, microorganism-induced immunosuppression is associated with harmful effects in host. In certain cases however, the same process may have beneficial effects on host. Mammalian colon harbors trillions of bacteria without eliciting significant immune activation. There is a mutual beneficial relationship between the gut microbiota and the host (8, 9). The bacterial fermentation products acetate, propionate, and butyrate (collectively called short-chain fatty acids) are believed to be the mediators of the beneficial effects of gut bacteria on the host (10, 11). Among these short-chain fatty acids, butyrate has received the most attention for its biologic effects. The beneficial effects of butyrate on colon range from being a nutrient for colonocytes to being an anti-inflammatory and antitumor agent (12, 13). Although the anti-inflammatory function of butyrate is well known at the phenomenological level, the molecular mechanisms underlying the process are not fully understood.Butyrate is an inhibitor of histone deacetylases (HDACs) (12, 13). The Na ϩ -coupled monocarboxylate transporter SLC5A8 (human ortholog is in uppercase letters, and rodent ortholog is in lowercase letters) is necessary fo...

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