Gut-derived acetate promotes B10 cells with antiinflammatory effects
C.I. Daïen, … , C.R. Mackay, L. Macia
C.I. Daïen, … , C.R. Mackay, L. Macia
Published March 17, 2021
Citation Information: JCI Insight. 2021;6(7):e144156. https://doi.org/10.1172/jci.insight.144156.
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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 3

Acetate promotes B10 cells independently of GPR43 and HDAC inhibition but through metabolic changes.

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Acetate promotes B10 cells independently of GPR43 and HDAC inhibition bu...
(A) To determine whether acetate affected B1a cells metabolism, we incubated sorted 106 B1a cells (CD19+CD5+CD23–) or B2 cells (CD19+CD5–CD23+) from n = 20 pooled mice for 6 hours with 13C acetate alone and analyzed changes in metabolites as well as incorporation of 13C into acetyl-CoA, citrate and malate by liquid chromatography–mass spectrometry. (B) Real-time OCR (pmol/min) was measured by seahorse from 0.5 × 106 sorted B1a or B2 cells stimulated overnight with or without acetate (10 mM) at baseline and after sequential injection of oligomycin (2 μM), FCCP (1 μM), and Antimycin A plus Rotenone (1 μM each). P < 0.0001 for time x group interaction by 2-way ANOVA and mean (SEM) are presented. 106 peritoneal cells were incubated overnight with 1 μM oligomycin (C), 1 mM 2-DG, or 200 μM etomoxir (D) in the presence or absence of 10 mM acetate; proportion of B10 cells among B1a cells quantified by flow cytometry (n = 6–8). Results are represented as median (IQR) with *P < 0.05, **P < 0.01, and ***P < 0.005 by Mann Whitney U or 1 way-ANOVA. Results were confirmed in 2 to 3 independent experiments. HDAC, histone deacetylase; OCR, oxygen consumption rate; Un, unstimulated.