image: Researchers found that butyrate, a short-chain fatty acid produced by gut bacteria during the fermentation of dietary fiber, promotes dendritic cell development by inhibiting histone deacetylases and increasing histone acetylation. This epigenetic regulation enhances the expression of the Spi1 gene encoding the transcription factor PU.1 and the Itga4 gene encoding the α4 subunit of LPAM-1, leading to increased expression of dendritic cell-related genes and surface molecules. The findings reveal a molecular link between dietary fiber-derived microbial metabolites and immune-cell regulation.
Credit: Professor Chiharu Nishiyama from Tokyo University of Science (TUS), Japan Image link: https://doi.org/10.1016/j.alit.2026.05.005
The benefits of dietary fiber extend beyond digestive health, as dietary fiber-derived metabolites produced by gut microbiota can influence immune function. Short-chain fatty acids (SCFAs) are secondary metabolites produced by the gut microbiota through the fermentation of dietary fibers. Notably, soluble dietary fibers such as inulin and pectin can be metabolized by gut bacteria into SCFAs, including butyrate. They act as important signaling molecules that reduce inflammation and balance the immune system.
SCFAs can regulate immune-related diseases, including inflammatory and allergic diseases, by modulating immune-cell gene expression and function. Dendritic cells (DCs) are known as the sentinels of the immune system. DCs possess a dynamic and highly specialized set of cell surface molecules that coordinate innate and adaptive immunity. These molecules act as sensors, antigen-presenting structures, and cellular communicators, changing dramatically as DCs mature. However, the effects of SCFAs on dendritic cell development and the expression of these surface molecules have yet to be elucidated.
To address this gap, a team of researchers, led by Professor Chiharu Nishiyama from the Department of Life Systems Engineering, Faculty of Advanced Engineering, Tokyo University of Science (TUS), Japan, explored the role of SCFAs in the development and regulation of DCs. The team explored how butyrate, an SCFA, modulates the development and expression of cell surface molecules on DCs. The study was published in Allergology International on June 18, 2026.
“Previously, we introduced the transcription factor PU.1 into a specific hematopoietic cell lineage, leading to the development of DC-like structures. This discovery highlighted the potential of PU.1 as a master transcription factor for DCs. We continued to explore the mechanisms by which SCFAs enhance PU.1 gene expression and how polyphenols regulate inflammation through PU.1-related gene expression,” mentioned Prof. Nishiyama while talking about the motivation behind the study.
The research team used Flt3L-induced bone marrow-derived DCs (BMDCs), comprising a heterogeneous, physiological mixture of conventional DCs (cDCs) and plasmacytoid DCs (pDCs). The primary focus was on investigating how butyrate affected surface proteins, messenger RNA levels, and histone modifications. The effect of other SCFAs, including propionate, valerate, and acetate, was also tested.
The study revealed that among the tested SCFAs, butyrate showed the strongest effect in increasing the expression of several dendritic cell surface molecules, including MHC II, CD86, and CD11b, while reducing the levels of CD11c. It also increased the expression of LPAM-1 (α4/β7), an integrin, contributing to immune-cell trafficking and localization in the intestinal mucosa.
The team also observed a shift in dendritic cell development. Butyrate increased the ratio of conventional DCs to plasmacytoid DCs, influencing the balance of dendritic cell subsets.
To understand the mechanistic pathways, the researchers explored two major pathways associated with SCFAs. The results highlighted that butyrate mainly acted through histone deacetylase inhibitory activity, rather than through stimulatory effects on G-protein-coupled receptors. Butyrate increased histone acetylation around the Itga4 gene, which encodes the α4 subunit of LPAM-1, and around the Spi1 gene, which encodes PU.1. Butyrate also increased Spi1 mRNA and PU.1 protein levels, highlighting the involvement of epigenetic regulation in the process.
“The findings connect dietary conditions, gut microbiota-derived metabolites, and epigenetic regulation, an area of growing interest in immunology. Since unwarranted immune responses often contribute to allergies, inflammation, and autoimmune diseases, identifying new areas of immunomodulation can aid in the development of strategies to prevent or mitigate immune-related disorders,” mentioned Prof. Nishiyama, discussing the importance of the study.
Because butyrate is naturally produced by certain gut bacteria through the fermentation of soluble dietary fibers, understanding how gut microbiota regulate butyrate production may provide useful directions for future research. However, further studies in animal models and humans are needed to validate these findings and their relevance to immune-related diseases.
Together, the study provides detailed insight into how secondary metabolites produced by gut bacteria during the fermentation of dietary fiber can exert regulatory effects on the immune system. By showing that butyrate can shape dendritic cell development and surface-molecule expression through epigenetic control of PU.1- and integrin-related genes, the work highlights how the daily diet may influence immune balance.
Reference
DOI: https://doi.org/10.1016/j.alit.2026.05.005
About The Tokyo University of Science
Tokyo University of Science (TUS) is a well-known and respected university, and the largest science-specialized private research university in Japan, with four campuses in central Tokyo and its suburbs and in Hokkaido. Established in 1881, the university has continually contributed to Japan's development in science through inculcating the love for science in researchers, technicians, and educators.
With a mission of “Creating science and technology for the harmonious development of nature, human beings, and society," TUS has undertaken a wide range of research from basic to applied science. TUS has embraced a multidisciplinary approach to research and undertaken intensive study in some of today's most vital fields. TUS is a meritocracy where the best in science is recognized and nurtured. It is the only private university in Japan that has produced a Nobel Prize winner and the only private university in Asia to produce Nobel Prize winners within the natural sciences field.
Website: https://www.tus.ac.jp/en/mediarelations/
About Professor Chiharu Nishiyama from Tokyo University of Science
Professor Chiharu Nishiyama is affiliated with the Department of Life Systems Engineering, Faculty of Advanced Engineering. She received her Bachelor's, Master's, and Ph.D. degrees from The University of Tokyo in 1988, 1990, and 1997, respectively. Her areas of research interest include applied biochemistry, covering fields such as immunology, allergy, molecular biology, transcription factors, and cell development. Prof. Nishiyama has published over 145 research papers in international journals. She also received the prestigious JSBBA Award for Young Scientists in 2005, JSA Award for Young Scientists in 2005, and JAFI Award in 2019.
https://www.tus.ac.jp/ridai/doc/ji/RIJIA01Detail.php?act=pos&kin=ken&diu=6821&pri=en
Journal
Allergology International
Method of Research
Experimental study
Subject of Research
Not applicable
Article Title
Short-chain fatty acids modulate the development and the cell surface molecule expression of DCs by epigenetic regulation
Article Publication Date
18-Jun-2026
COI Statement
The authors declare no competing interests.