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Bacterial metabolites of dietary fibre fermentation, propionate and butyrate, reduce type 2 cytokine responses by peripheral blood mononuclear cells from subjects with asthma

Published online by Cambridge University Press:  22 March 2023

L. Williams
Affiliation:
School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia Immune Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
B. Berthon
Affiliation:
School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia Immune Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
N. Bartlett
Affiliation:
School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia Immune Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
P. Wark
Affiliation:
Immune Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW 2308, Australia Department of Respiratory and Sleep Medicine, John Hunter Hospital, Hunter New England Health, New Lambton Heights, NSW 2305, Australia
L. Wood
Affiliation:
School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia Immune Health Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia
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Abstract

Type
Abstract
Copyright
Copyright © The Authors 2023

Asthma is a chronic inflammatory disease of the airways, typically driven by type 2 (T2) and/or eosinophilic airway inflammation. In asthma, epithelial insults such as respiratory virus infection or exposure to aeroallergens induce the release of epithelial-derived cytokines, interleukin (IL)-25 and -33.(Reference Lambrecht and Hammad1) These cytokines act on immune cells, including T-helper 2 (TH2) cells and T2 innate lymphoid cells (ILC2s), to induce T2 cytokine release (IL-4, -5, and -13). Short-chain fatty acids (SCFAs) are hypothesised to reduce T2 inflammation, suggesting a therapeutic effect.(Reference Williams, Scott and Wood2) This was an in vitro study examining the effect of SCFA treatment on T2 responses by cells derived from adults with doctor-diagnosed asthma (n = 18). Peripheral blood mononuclear cells (PBMCs) were isolated via density centrifugation from whole blood samples and seeded in 24-well plates at a density of 2×106 cells/mL. PBMCs were treated with 1 mM of sodium acetate, propionate or butyrate for 3 hours prior to culture with 25 ng/mL interleukin (IL)-2, 10 ng/mL IL-25, and 10 ng/mL IL-33, with or without 1 multiplicity of infection (MOI) rhinovirus A1 (RVA1; RVA1/Newcastle/2018). Cells were incubated for a total of 5 d at 35°C, 5% CO2. Concentrations of IL-5 and IL-13 were measured in cell culture supernatants via ELISA. Gene expression of T2 transcription factor, GATA3, and receptors for epithelial-derived cytokines, ST2 and IL17RB, were measured via RT-qPCR, analysed using fold change (2-ΔΔCt). IL-2, IL-25 and IL-33 induced significant IL-5 (1997.1 (1364.9, 2183) pg/mL, median (interquartile range, IQR); p < 0.001) and IL-13 (1146 (702.6, 2076) pg/mL; p < 0.001) production by PBMCs isolated from subjects with asthma. The addition of RVA1 did not significantly (p > 0.05) change IL-5 and -13 production compared to IL-2, -25, and -33 alone. Acetate treatment had no significant effect on induced IL-5 and -13 compared to untreated cells. Propionate and butyrate treatment significantly lowered IL-5 (propionate, p = 0.004; butyrate, p < 0.001) and -13 (propionate, p = 0.001; butyrate, p = 0.008) production compared to untreated cells. The mRNA expression of GATA3 was not significantly changed with IL-2, -25, and -33 or SCFA treatment. IL-2, -25, and -33 upregulated IL17RB and ST2 mRNA expression by 30- and 6-fold, compared to unstimulated cells. However, propionate impaired up-regulation of IL17RB (p = 0.020), while butyrate led to lower IL17RB (p < 0.001) and ST2 (p = 0.012) expression compared to untreated cells. Treatment with bacterial metabolites, propionate and butyrate, reduced T2 inflammatory cytokine production by immune cells following exposure to epithelial-derived cytokines. This observation appears to be driven by SCFA-mediated downregulation of the receptors, IL17RB (IL-25 receptor) and ST2 (IL-33 receptor). This study highlights new mechanisms, and suggests strategies that increase circulating SCFAs, including soluble fibre supplementation, may attenuate T2 inflammation in asthma.

References

Lambrecht, BN & Hammad, H (2015) Nat Immunol 16, 4556.CrossRefGoogle Scholar
Williams, LM, Scott, HA & Wood, LG (2019) J Nutr Intermed Metab 18, 100108.CrossRefGoogle Scholar