Dietary choices significantly impact gene function and overall health

Short-chain fatty acids (SCFAs) like propionate and butyrate are critical byproducts of dietary fiber digestion. These molecules do more than fuel the body—they directly influence gene expression and may hold keys to cancer prevention and treatment.

Recent research highlights their epigenetic roles, focusing on how they modify chromatin accessibility and gene regulation in colorectal cancer (CRC) cells and normal tissues.

Propionate and butyrate have demonstrated the ability to modify chromatin structure. This process begins with their conversion into active metabolites, propionyl-CoA and butyryl-CoA, which are then used as cofactors in histone acylation.

These modifications alter chromatin structure, making certain genes more or less accessible for transcription. The epigenetic marks H3K18pr, H3K18bu, H4K12pr, and H4K12bu—representing propionylation and butyrylation on specific histone sites—serve as critical indicators of SCFA activity in gene regulation.

In CRC cells treated with propionate or butyrate, researchers observed increased chromatin accessibility and altered transcriptional activity. For example, RNA sequencing data revealed that propionate supplementation upregulated over 1,500 genes and downregulated about 1,300 others.

These changes were linked to pathways involving cell differentiation, actin filament organization, and negative regulation of the MAPK cascade. Downregulated genes were often involved in the mitotic cell cycle and RNA metabolism, suggesting a shift in cellular priorities toward growth regulation and differentiation.

Butyrate, in particular, is known for its dual role as a metabolic substrate and histone deacetylase (HDAC) inhibitor. This duality enables it to selectively regulate gene expression by promoting histone hyperacetylation, which is often associated with tumor suppressor genes. Propionate, while less studied as an HDAC inhibitor, showed similar chromatin accessibility effects in the study.

The localization of SCFA-driven histone modifications further emphasizes their epigenetic importance. Genomic mapping of H3K18pr and H4K12pr marks revealed enrichment in regions regulating growth, differentiation, and the unfolded protein response. These marks also influenced genes associated with the Wnt/β-catenin and TGF-β signaling pathways, both critical in CRC progression.

One compelling finding was the role of SCFAs in targeting long non-coding RNAs (lncRNAs) such as PRNCR1 and PCAT1. These lncRNAs, located near the MYC oncogene, exhibited significantly increased binding of H3K18bu and H4K12bu marks. This suggests a regulatory mechanism where SCFAs modulate chromatin structure around oncogenic regions, potentially influencing cancer progression.

In addition to their direct epigenetic effects, SCFAs’ influence on cellular metabolism cannot be overlooked. Metabolomic analyses revealed that propionate and butyrate supplementation increased their respective CoA forms while altering acetyl-CoA levels.

Notably, butyrate led to a dose-dependent reduction in acetyl-CoA, pointing to a metabolic shift that favors specific acylation states. Propionate’s effects were less pronounced, yet its supplementation still contributed to significant chromatin modifications.

These metabolic shifts highlight the interconnectedness of diet, metabolism, and epigenetic regulation. SCFAs act as intermediaries, translating dietary inputs into molecular signals that can influence gene expression. Such findings suggest that modulating SCFA levels through diet could have profound effects on health outcomes.

These findings underscore the critical role of dietary fiber in promoting SCFA production and subsequent epigenetic regulation. Fiber-rich diets lead to higher SCFA concentrations in the gut, where they exert local effects on colon cells and systemic effects throughout the body.

“We found a direct link between eating fiber and modulation of gene function that has anti-cancer effects,” said Michael Snyder, Ph.D., Professor of Genetics at Stanford Medicine. “This is likely a global mechanism because SCFAs can travel all over the body.”

In healthy cells, SCFAs promote differentiation and apoptosis, processes that can counteract the unchecked cell growth seen in cancer. Conversely, their impact on cancer cells includes disrupting oncogenic signaling pathways and enhancing chromatin accessibility at tumor suppressor genes.

The connection between fiber intake and SCFA production also highlights potential disparities in health outcomes. Fiber consumption varies widely across populations, with many individuals failing to meet daily recommended intake levels. This dietary gap could limit SCFA production, reducing their beneficial effects on gene regulation and cancer prevention.

The potential therapeutic applications of SCFAs are significant. By targeting epigenetic modifications, they offer a natural means to modulate gene expression. This is particularly relevant in CRC, where dietary habits and gut microbiome composition play critical roles in disease risk.

“By identifying the gene targets of these important molecules, we can understand how fiber exerts its beneficial effects and what goes wrong during cancer,” Snyder added.

These insights also open avenues for exploring the synergistic effects of SCFAs with existing cancer treatments. For instance, combining SCFA supplementation with therapies targeting the Wnt/β-catenin or TGF-β pathways could enhance therapeutic efficacy.

Future studies could investigate how SCFAs influence drug metabolism and resistance in cancer cells, potentially leading to more effective treatment strategies.

While much remains to be explored, this study provides a foundation for understanding the interplay between diet, microbiome-derived metabolites, and epigenetic regulation.

Published in the journal, Nature Metabolism, it emphasizes the importance of dietary fiber not only for general health but also as a potential tool in cancer prevention and treatment. Further research could investigate how variations in gut microbiome composition influence SCFA production and their epigenetic effects across different tissues.

Emerging technologies, such as single-cell RNA sequencing and advanced metabolomics, may shed light on the precise molecular mechanisms underlying SCFA activity. These tools could help identify additional gene targets and pathways influenced by SCFAs, expanding our understanding of their role in health and disease.

In conclusion, the connection between fiber intake, SCFA production, and epigenetic regulation highlights a powerful mechanism by which diet influences health at the molecular level. These findings encourage a broader appreciation of dietary choices in shaping genetic and epigenetic landscapes.

By prioritizing fiber-rich foods, individuals can support their microbiome and harness the potential of SCFAs to promote better health outcomes.

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.

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