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 1

Acetate promotes the differentiation of IL-10–producing B cells from mouse B1a precursors.

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Acetate promotes the differentiation of IL-10–producing B cells from mou...
(A) 106 peritoneal cells (n = 6–8) were incubated overnight with acetate (10 mM), butyrate (1 mM), or propionate (1 mM) and B10 cells (IL-10+ of CD19+ cells) characterized by flow cytometry. (B) 106 peritoneal cells (n = 8) were incubated overnight with acetate (10 mM) and B10 cells among B1a (CD19+CD5+CD23–), B1b (CD19+CD5–CD23–), and B2 (CD19+CD5–CD23+) cells quantified by flow cytometry. The proportion of peritoneal B10 cells among B cells (C) (n = 9) or among B1a cells (D) (n = 5) was determined from C57BL/6 male mice injected i.p. twice at a 12-hour interval with acetate (500 mg/kg, pH-adjusted, n = 10) or PBS (n = 9). The proportion of peritoneal B10 cells among B cells (E) or among B1a cells (F) was determined from cells isolated from n = 6 mice treated with 200 mM acetate in drinking water for 3 weeks. Results were confirmed in 3 to 4 independent experiments. (G) PET scan image 15 minutes after intracolonic administration of 11C-acetate (left-hand side of panel) and biodistribution of 11C-acetate quantified as intensity dose per gram (%ID per gram) after 30- or 90-minute administration (right-hand side of panel). Intensity of 11C-acetate in the colon was significantly higher than all other studied organs both after 30- and 90-minute administration (P < 0.05 by ANOVA). One-way ANOVA Kruskal-Wallis tests for multiple comparisons were performed and Mann-Whitney U tests for 2-group comparison. Median (IQR) are represented. *P < 0.05; **P < 0.01. Un, unstimulated.