Short-Chain Fatty Acids Promote Immunotherapy by Modulating Immune Regulatory Property in B Cells

Abstract

The dysfunction of regulatory B cells (Breg) may result in immune inflammation such as allergic rhinitis (AR); the underlying mechanism is not fully understood yet. Short-chain fatty acids, such as propionic acid (PA), have immune regulatory functions. This study is aimed at testing a hypothesis that modulates PA production alleviating airway allergy through maintaining Breg functions. B cells were isolated from the blood obtained from AR patients and healthy control (HC) subjects. The stabilization of IL-10 mRNA in B cells was tested with RT-qPCR. An AR mouse model was developed to test the role of PA in stabilizing the IL-10 expression in B cells. We found that the serum PA levels were negatively correlated with the serum Th2 cytokine levels in AR patients. Serum PA levels were positively associated with peripheral CD5+ B cell frequency in AR patients; the CD5+ B cells were also IL-10+. The spontaneous IL-10 mRNA decay was observed in B cells, which was prevented by the presence of PA through activating GPR43. PA counteracted the effects of Tristetraprolin (TTP) on inducing IL-10 mRNA decay in B cells through the AKT/T-bet/granzyme B pathway. Administration of Yupinfeng San, a Chinese traditional medical formula, or indole-3-PA, induced PA production by intestinal bacteria to stabilize the IL-10 expression in B cells, which promoted the allergen specific immunotherapy, and efficiently alleviated experimental AR. In summary, the data show that CD5+ B cells produce IL-10. The serum lower PA levels are associated with the lower frequency of CD5+ B cells in AR patients. Administration with Yupinfeng San or indole-3-PA can improve Breg functions and alleviate experimental AR.

Attenuation of allergen-specific immunotherapy for atopic dermatitis by ectopic colonization of Brevundimonas vesicularis in the intestine

“… 35 The increased production of propionic acid by intestinal microbiota stabilizes IL-10 expression in B cells, which promotes the efficacy of SLIT in mice with allergic rhinitis. 36 In our study, the transplantation of fecal microbiota from patients with AD who responded well to AIT alleviated AD-like symptoms in mice and induced the expansion of Tregs. The gut microbiota of AD patients undergoing AIT differed from that of untreated patients in both composition and function, while the pathways for tryptophan metabolism, butanoate metabolism, and propanoate metabolism were enriched in the gut microbiota after 1 year of AIT.…”

Mechanism of indolepropionic acid mediating allergic rhinitis by regulating AKT/T-bet/GZMB/TTP/IL-10 axis

“…It has been found that GZMB can not only promote apoptosis but also lyse many different substrates, including proteolysis of extracellular matrix, cell adhesion proteins and basement membrane proteins [30] . However, our previous studies have shown that GZMB can be combined with TTP, compromising the role of TTP [15] . T-bet is a transcription factor encoded by the Tbx21 gene, and its expression affects the exercise of immune function [31] .…”

“…The regulation of allergen tolerance mediated by Bregs is considered an important immune tolerance mechanism of AR [26] . PA in SCFAs can effectively alleviate AR by stabilizing the expression of IL-10 in Bregs and has certain immunoregulatory functions in allergic diseases [15] . Tristetraproline (TTP), a proline-rich molecule, can bind to IL-10 mRNA to form a complex that can induce the attenuation of IL-10 mRNA in B cells, thereby negatively regulating IL-10.…”

“…Tregs and Bregs [14] . In addition, our previous studies found that serum levels of metabolites AA, BA and PA were lower in AR patients than in healthy individuals, and the serum IL-10 levels of AR patients were lower than those of healthy individuals, and serum PA levels of AR patients were positively correlated with serum IL-10 levels [15] . Therefore, we speculate that PA can effectively alleviate AR by stabilizing the expression of IL-10 in Bregs.…”

Knowledge mapping of the links between the microbiota and allergic diseases: A bibliometric analysis (2002–2021)

“…Butyrate inhibits eosinophil survival and migration ( 52 ) as well as mast cell activation ( 53 ) by inducing histone acetylation. A recent study showed that SCFAs promote the maintenance of regulatory B (Breg) cell function by stabilizing IL-10 expression in Breg cells, thereby alleviating allergic inflammation ( 54 ). In addition, acetate and butyrate have a preventive or therapeutic effect on allergic diseases by enhancing the barrier function of the intestinal epithelium ( 48 ).…”