Gut-derived acetate promotes B10 cells with antiinflammatory effects
C.I. Daïen, J. Tan, R. Audo, J. Mielle, L.E. Quek, J.R. Krycer, A. Angelatos, M. Duraes, G. Pinget, D. Ni, R. Robert, M.J. Alam, M.C.B. Amian, F. Sierro, A. Parmar, G. Perkins, S. Hoque, A.K. Gosby, S.J. Simpson, R.V. Ribeiro, C.R. Mackay, L. Macia
C.I. Daïen, J. Tan, R. Audo, J. Mielle, L.E. Quek, J.R. Krycer, A. Angelatos, M. Duraes, G. Pinget, D. Ni, R. Robert, M.J. Alam, M.C.B. Amian, F. Sierro, A. Parmar, G. Perkins, S. Hoque, A.K. Gosby, S.J. Simpson, R.V. Ribeiro, C.R. Mackay, L. Macia
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Research Article Immunology Metabolism

Gut-derived acetate promotes B10 cells with antiinflammatory effects

Abstract

Autoimmune diseases are characterized by a breakdown of immune tolerance partly due to environmental factors. The short-chain fatty acid acetate, derived mostly from gut microbial fermentation of dietary fiber, promotes antiinflammatory Tregs and protects mice from type 1 diabetes, colitis, and allergies. Here, we show that the effects of acetate extend to another important immune subset involved in tolerance, the IL-10–producing regulatory B cells (B10 cells). Acetate directly promoted B10 cell differentiation from mouse B1a cells both in vivo and in vitro. These effects were linked to metabolic changes through the increased production of acetyl-coenzyme A, which fueled the TCA cycle and promoted posttranslational lysine acetylation. Acetate also promoted B10 cells from human blood cells through similar mechanisms. Finally, we identified that dietary fiber supplementation in healthy individuals was associated with increased blood-derived B10 cells. Direct delivery of acetate or indirect delivery via diets or bacteria that produce acetate might be a promising approach to restore B10 cells in noncommunicable diseases.

Authors

C.I. Daïen, J. Tan, R. Audo, J. Mielle, L.E. Quek, J.R. Krycer, A. Angelatos, M. Duraes, G. Pinget, D. Ni, R. Robert, M.J. Alam, M.C.B. Amian, F. Sierro, A. Parmar, G. Perkins, S. Hoque, A.K. Gosby, S.J. Simpson, R.V. Ribeiro, C.R. Mackay, L. Macia

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Figure 5

Acetate promotes human B10 cells in peripheral blood.

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Acetate promotes human B10 cells in peripheral blood. (A) Overnight cult...
(A) Overnight culture of human PBMCs (n = 6–14) with acetate (Ace 10 mM), butyrate (But 1 mM), propionate (Pro 1 mM), or 1 μM CpG. B10 cells were assessed among B cells as IL-10+CD19+ cells by flow cytometry (n = 6–14). (B) Isolated B cells from PBMCs were incubated overnight with or without 10 mM acetate on CD40 ligand–coated plates, CD19+IL-10+ B cells assessed by flow cytometry, and (C) quantification of IL-10 was performed by ELISA from culture supernatants (n = 8–13). (D–G) TNF-α+CD19+IL-6+ B cells were assessed by flow cytometry and quantification of IL-6 and TNF-α by ELISA. (H) Naive T cells were sorted and cultured for 3 days with plate bound anti-CD3 (dose 1 μg/mL) in the presence of B cells previously incubated overnight with 10 mM acetate or of unstimulated B cells (ratio 1:1) (n = 6). Tregs were assessed as CD4+CD25hiCD127lo/–. Wilcoxon paired tests were used with *P < 0.05, **P < 0.01, and ***P < 0.005. All results are represented as median (IQR). Results were confirmed in 2 independent experiments. Un, unstimulated.