Butyrate-a metabolite produced by commensal bacteria-has been extensively studied for its immunomodulatory effects on immune cells, including regulatory T cells, macrophages and dendritic cells. However, the development of butyrate as a drug has been hindered by butyrate's poor oral bioavailability, owing to its rapid metabolism in the gut, its low potency (hence, necessitating high dosing), and its foul smell and taste. Here we report that the oral bioavailability of butyrate can be increased by esterifying it to serine, an amino acid transporter that aids the escape of the resulting odourless and tasteless prodrug (O-butyryl-L-serine, which we named SerBut) from the gut, enhancing its systemic uptake. In mice with collagen-antibody-induced arthritis (a model of rheumatoid arthritis) and with experimental autoimmune encephalomyelitis (a model of multiple sclerosis), we show that SerBut substantially ameliorated disease severity, modulated key immune cell populations systemically and in disease-associated tissues, and reduced inflammatory responses without compromising the global immune response to vaccination. SerBut may become a promising therapeutic for autoimmune and inflammatory diseases.
© 2024. The Author(s).

Butyrate, a metabolite produced by commensal bacteria, has been intensively studied for its immunomodulatory effects on various immune cells, including T regulatory cells, macrophages, and dendritic cells. Butyrate’s development as a drug has been limited by its poor oral bioavailability due to its rapid metabolism in the gut, its low potency and thus high dosing, and its foul smell and taste. By simply esterifying butyrate to serine ( O -butyryl -L -serine, SerBut), a design based on the concept of utilizing amino acid transporters to escape the gut and enhance systemic uptake thus increasing bioavailability, we developed an odorless and tasteless compound for oral administration. In the collagen antibody-induced arthritis (CAIA) and experimental autoimmune encephalomyelitis (EAE) murine models of rheumatoid arthritis and multiple sclerosis, we demonstrated that SerBut significantly ameliorated disease severity, modulated key immune cell populations both systemically and in disease-associated tissues, and reduced inflammatory responses without compromising global immune response to vaccination. Our findings highlight SerBut as a promising next-generation therapeutic agent for autoimmune and inflammatory diseases.

Protective immune responses against respiratory pathogens, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus, are initiated by the mucosal immune system. However, most licensed vaccines are administered parenterally and are largely ineffective at inducing mucosal immunity. The development of safe and effective mucosal vaccines has been hampered by the lack of a suitable mucosal adjuvant. In this study we explore a class of adjuvant that harnesses mucosal-associated invariant T (MAIT) cells. We show evidence that intranasal immunization of MAIT cell agonists co-administered with protein, including the spike receptor binding domain from SARS-CoV-2 virus and hemagglutinin from influenza virus, induce protective humoral immunity and immunoglobulin A production. MAIT cell adjuvant activity is mediated by CD40L-dependent activation of dendritic cells and subsequent priming of T follicular helper cells. In summary, we show that MAIT cells are promising vaccine targets that can be utilized as cellular adjuvants in mucosal vaccines.
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Type 1 diabetes (T1D) is an auto-immune disease characterized by the progressive destruction of insulin-producing pancreatic beta cells. While beta cells are the target of the immune attack, the other islet endocrine cells, namely the alpha and delta cells, can also be affected by the inflammatory milieu. Here, using a flow cytometry-based strategy, we compared the impact of IFNγ, one of the main cytokines involved in T1D, on the three endocrine cell subsets isolated from C57BL/6 mouse islets. RNA-seq analyses revealed that alpha and delta cells exposed in vitro to IFNγ display a transcriptomic profile very similar to that of beta cells, with an increased expression of inflammation key genes such as MHC class I molecules, the CXCL10 chemokine and the programmed death-ligand 1 (PD-L1), three hallmarks of IFNγ signaling. Interestingly, at low IFNγ concentration, we observed two beta cell populations (responders and non-responders) based on PD-L1 protein expression. Our data indicate that this differential sensitivity relies on the location of the cells within the islet rather than on the existence of two different beta cells subsets. The same findings were corroborated by the in vivo analysis of pancreatic islets from the non-obese diabetic mouse model of T1D, showing more intense PD-L1 staining on endocrine cells close to immune infiltrate. Collectively, our work demonstrates that alpha and delta cells are as sensitive as beta cells to IFNγ, and suggests a gradual diffusion of the cytokine into an islet. These observations provide novel insights into the in situ inflammatory processes occurring in T1D progression.

Colorectal cancer (CRC) is one of the prevalent malignant tumors. This study is aimed at evaluating the mechanism of anlotinib (anlo) on tumor microenvironment (TME) in CRC, and its effects in combination with immune checkpoint inhibitors (ICIs) therapy. Firstly, MC38 and CT26 cells were both exposed to different gradient concentrations of anlo for 72 h, to investigate the cell viability and synergetic therapy efficacy with ICIs by CCK8. The results showed that anlo could obviously inhibit cell growth and showed no synergistic efficacy therapy in combination with αPDL1 in vitro. Then, we found the upregulation of programmed cell death ligand 1(PDL1) expression both in vitro and in vivo after anlo treatment. In vivo, anlo could enhance the percentage of natural killer (NK) cells and M1 macrophage cells and decrease the percentage of M2 macrophage cells in TME. Moreover, we explored the mechanism and we proved that anlo could activate reactive oxygen species (ROS)/c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) signaling pathway to increase the expression levels of PDL1, IFN-α/β/γ, and CXCL2 in two cell lines in vitro. We also proved that anlo had synergistic effects with ICIs in vivo. Finally, it could also increase the mRNA and protein PDL1 expression levels in human cell lines, which was consistent with mouse CRC cell lines. However, there are still a few limitations. On one hand, the ROS/JNK/AP-1 pathway needs to be proved whether it can be activated in human cell lines. On the other hand, the mechanism behind ROS promoting phosphorylation of JNK needs to be explored.
Copyright © 2022 Bixian Luo et al.