GO:1903544 response to butyrate: Cellular Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1903544 (response to butyrate) describes any cellular or organismal change triggered by butyrate, a short-chain fatty acid produced by gut microbiota.
• Butyrate is a major energy source for colonocytes and a potent regulator of gene expression, primarily through histone deacetylase (HDAC) inhibition and G-protein-coupled receptor (GPCR) signaling.
• The response to butyrate shapes immune cell function, intestinal barrier integrity, and circadian clock gene expression, with implications for inflammatory bowel disease (IBD) and cancer.
• Interindividual differences in butyrate response exist, influenced by gut microbiota composition and host genetics, as shown in in vitro gut models.
• Butyrate modulates cytotoxic CD8+ T cell immunity and can enhance anticancer therapy efficacy.
• Studying response to butyrate requires integrated approaches including CRISPR screens, transcriptomics, and metabolomics to dissect causal genes and pathways.
Description
Butyrate is a short-chain fatty acid generated by bacterial fermentation of dietary fiber in the colon. It serves as a primary energy source for colonic epithelial cells and acts as a signaling molecule that influences a wide range of cellular processes, including gene expression, inflammation, and metabolism. The Gene Ontology term GO:1903544, response to butyrate, captures any process that results in a change in state or activity of a cell or an organism as a result of a butyrate stimulus. This term is critical for researchers investigating how microbial metabolites shape host physiology and disease. The response to butyrate is implicated in inflammatory bowel disease (IBD), colorectal cancer, and even high-altitude adaptation, where microbiota-derived butyrate may play a functional role. Understanding the molecular players and pathways involved is essential for developing therapeutic strategies that target butyrate signaling. This article provides a comprehensive overview of the genes, mechanisms, and research methods used to study response to butyrate, based on authoritative QuickGO data and verified PubMed literature.
response to butyrate At A Glance
| GO ID | GO:1903544 |
|---|---|
| GO term | response to butyrate |
| Ontology | biological_process |
| Synonym | none |
| Major function | Cellular and organismal response to butyrate stimulus, including gene expression changes, immune modulation, and metabolic regulation |
| Related stimuli | Butyrate, a short-chain fatty acid produced by gut microbiota |
| Key mechanisms | HDAC inhibition, GPCR signaling, metabolic energy supply |
| Associated diseases | Inflammatory bowel disease, colorectal cancer, metabolic disorders |
| Research relevance | Target for microbiome-host interaction studies, cancer immunotherapy, and IBD therapeutics |
What Is GO:1903544?
GO:1903544, response to butyrate, is defined as any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a butyrate stimulus. This biological process encompasses the detection of butyrate, signal transduction, and the downstream cellular responses that alter physiology or behavior. It includes but is not limited to changes in gene expression, immune cell function, and metabolic activity triggered by butyrate exposure.
Why Is response to butyrate Important in Cell Biology?
The response to butyrate is a central node in microbiome-host interactions, influencing intestinal homeostasis, immune regulation, and energy metabolism. Dysregulation of this response is linked to chronic inflammatory diseases such as IBD, where butyrate-producing bacteria are often depleted. Moreover, butyrate enhances the efficacy of anticancer therapies by modulating CD8+ T cell immunity, highlighting its potential as an immunomodulatory agent. Understanding the genetic and molecular basis of butyrate response can reveal therapeutic targets and biomarkers for personalized medicine, as interindividual variability in butyrate responsiveness has been observed. Therefore, GO:1903544 is a key term for researchers in microbiology, immunology, oncology, and gastroenterology.
• Butyrate is a primary energy source for colonocytes, and its response pathway is essential for gut health.
• Butyrate acts as an HDAC inhibitor, altering gene expression and influencing cell proliferation and differentiation.
• It modulates immune cell functions, including neutrophil activity and CD8+ T cell cytotoxicity.
• Response to butyrate is implicated in inflammatory bowel disease pathogenesis and treatment.
• Butyrate supplementation affects circadian clock genes and sleep quality in ulcerative colitis patients.
• Interindividual differences in butyrate response may affect therapeutic outcomes.
• Butyrate-producing bacteria are potential probiotics for IBD management.
• The response to butyrate is linked to high-altitude adaptation through microbiota-derived butyrate.
• Butyrate may serve as a natural alternative to dexamethasone in COVID-19 management by modulating inflammation.
• Studying response to butyrate can uncover novel targets for cancer immunotherapy and metabolic diseases.
What Happens During response to butyrate?
Butyrate Sensing and Uptake
In simple terms: Cells first recognize and take up butyrate from their environment.
Butyrate is sensed by G-protein-coupled receptors (GPCRs) such as GPR41, GPR43, and GPR109A, and transported into cells via monocarboxylate transporters (MCTs). This initial step triggers intracellular signaling cascades. In the gut, butyrate is produced by bacterial fermentation and is rapidly absorbed by colonocytes, where it can be used as an energy source or act as a signaling molecule.
HDAC Inhibition and Chromatin Remodeling
In simple terms: Butyrate blocks enzymes that remove acetyl groups from histones, leading to more open DNA and altered gene expression.
Butyrate is a well-known histone deacetylase (HDAC) inhibitor. By inhibiting HDACs, it increases histone acetylation, promoting chromatin relaxation and transcriptional activation of specific genes, including those involved in immune regulation and cell cycle control. This epigenetic modulation is a key mechanism of the cellular response to butyrate.
Metabolic Reprogramming
In simple terms: Butyrate is used as fuel and can change how cells produce energy.
In colonocytes, butyrate is oxidized via beta-oxidation to acetyl-CoA, which enters the TCA cycle to generate ATP. This metabolic utilization supports colonocyte health and maintains oxygen balance, contributing to the response to butyrate. Additionally, butyrate can influence mitochondrial function and reactive oxygen species production.
Immune Cell Modulation
In simple terms: Butyrate changes how immune cells behave, often reducing inflammation.
Butyrate constrains neutrophil functions and ameliorates mucosal inflammation in IBD. It also enhances CD8+ T cell immunity, which can improve anticancer therapy efficacy. These effects are mediated through HDAC inhibition and GPCR signaling, leading to altered cytokine production and cytotoxic activity.
Circadian Clock and Gene Expression Regulation
In simple terms: Butyrate can affect the body's internal clock and turn genes on or off.
Butyrate supplementation modulates the expression of circadian-clock genes in patients with active ulcerative colitis, suggesting a link between butyrate response and circadian regulation. This may influence sleep quality and inflammation. Furthermore, butyrate alters the expression of numerous genes involved in inflammation and metabolism.
Key Genes Involved in GO:1903544 response to butyrate
The following genes and proteins are central to the response to butyrate, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| HDAC1 | Histone deacetylase; butyrate inhibits its activity, leading to increased histone acetylation | Epigenetic regulation; target for cancer therapy |
| HDAC2 | Histone deacetylase; butyrate inhibits its activity | Inflammation and cancer |
| HDAC3 | Histone deacetylase; butyrate inhibits its activity | Metabolic regulation |
| GPR41 (FFAR3) | G-protein-coupled receptor for butyrate; mediates signaling | Immune and metabolic responses |
| GPR43 (FFAR2) | G-protein-coupled receptor for butyrate; mediates signaling | Inflammation and neutrophil function |
| GPR109A (HCAR2) | G-protein-coupled receptor for butyrate; mediates signaling | Anti-inflammatory effects |
| SLC16A1 (MCT1) | Monocarboxylate transporter; mediates butyrate uptake | Butyrate transport in colonocytes |
| SLC16A3 (MCT4) | Monocarboxylate transporter; mediates butyrate efflux | Butyrate transport |
| CD8A | Marker of cytotoxic T cells; butyrate enhances their function | Anticancer immunity |
| IFNG | Interferon gamma; produced by CD8+ T cells, enhanced by butyrate | Antitumor immunity |
| IL10 | Anti-inflammatory cytokine; butyrate promotes its expression | IBD and inflammation |
| TNF | Pro-inflammatory cytokine; butyrate can suppress its production | IBD and inflammation |
| CLOCK | Circadian clock gene; butyrate modulates its expression | Circadian rhythm and sleep |
| BMAL1 (ARNTL) | Circadian clock gene; butyrate modulates its expression | Circadian rhythm |
| PER2 | Circadian clock gene; butyrate modulates its expression | Circadian rhythm |
| NFKB1 | Transcription factor; butyrate inhibits NF-kB signaling | Inflammation |
| PPARG | Nuclear receptor; butyrate can activate PPARγ | Metabolic and anti-inflammatory effects |
How Is response to butyrate Regulated?
The response to butyrate is regulated at multiple levels. Extracellular butyrate availability depends on gut microbiota composition and dietary fiber intake. Interindividual differences in butyrate production and response have been observed, influenced by the gut microbiome and host genetics. At the cellular level, butyrate uptake is regulated by monocarboxylate transporters, while signaling is modulated by GPCR expression levels. HDAC inhibition by butyrate is a key regulatory mechanism, affecting chromatin state and gene expression. Additionally, butyrate can influence circadian clock genes, which in turn may feedback on butyrate response. Inflammatory conditions can modulate the epithelial response to butyrate, as seen in IBD patients.
response to butyrate and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| HDAC1 | Inflammatory bowel disease, cancer | Knockout mice, intestinal organoids |
| GPR43 | IBD, metabolic disorders | Gpr43-/- mice, cell lines |
| CD8A | Cancer immunotherapy | CD8+ T cell-specific knockout mice |
| CLOCK | Ulcerative colitis, circadian rhythm disorders | Clock mutant mice, patient-derived cells |
| SLC16A1 | IBD, metabolic disorders | MCT1 knockout mice, Caco-2 cells |
Inflammatory Bowel Disease (IBD)
Butyrate plays a protective role in IBD by constraining neutrophil functions and ameliorating mucosal inflammation. Butyrate-producing bacteria are often depleted in IBD patients, and butyrate supplementation or butyrate-producing probiotics have shown therapeutic potential. The epithelial response to butyrate is modulated by intestinal inflammation, which may affect treatment outcomes. Clinical trials have demonstrated that butyrate supplementation can modulate circadian clock genes and reduce inflammation in ulcerative colitis patients.
Cancer
Butyrate enhances anticancer therapy efficacy by modulating cytotoxic CD8+ T cell immunity. As an HDAC inhibitor, butyrate can alter gene expression in cancer cells, promoting differentiation and apoptosis. The response to butyrate in the tumor microenvironment is a subject of active research, with potential for combination therapies.
Metabolic and Other Disorders
Butyrate is a key metabolite in host-microbiome interactions and has been implicated in high-altitude adaptation, where microbiota-derived butyrate may play a functional role. Butyrate has also been proposed as a natural alternative to dexamethasone in COVID-19 management due to its anti-inflammatory properties. Interindividual differences in response to butyrate-producing bacteria may affect therapeutic outcomes in various diseases.
From response to butyrate-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does HDAC1 mediate butyrate-induced gene expression? | HDAC1 knockout cell lines (e.g., HCT116) treated with butyrate |
| What is the role of GPR43 in butyrate sensing? | GPR43 point-mutation or knockout mice |
| How does butyrate affect circadian clock genes? | Knock-in reporter cell lines for CLOCK/BMAL1 |
| Can butyrate enhance CD8+ T cell function? | CD8+ T cell-specific overexpression of butyrate transporters |
| What genes are essential for butyrate response? | Genome-wide CRISPR knockout library screening in butyrate-treated cells |
| Does butyrate supplementation alter gut inflammation? | Patient-derived intestinal organoids with CRISPR-edited genes |
How to Study the response to butyrate Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global gene expression changes | Identifying butyrate-responsive genes |
| CRISPR knockout screen | Genes essential for butyrate response | Discovery of novel regulators |
| ChIP-seq (H3K27ac) | Histone acetylation changes | Epigenetic effects of butyrate |
| ATAC-seq | Chromatin accessibility | Butyrate-induced chromatin remodeling |
| Metabolomics | Metabolite levels and flux | Butyrate metabolism and energy production |
| Flow cytometry | Immune cell phenotype and function | Butyrate effects on T cells and neutrophils |
| qRT-PCR | Expression of specific genes | Validation of circadian clock genes |
| Western blot | Protein expression and modification | HDAC inhibition and signaling |
Transcriptomics and RNA-seq
RNA sequencing is used to profile gene expression changes in response to butyrate, revealing pathways and regulatory networks. Studies have identified butyrate-responsive genes involved in inflammation, metabolism, and circadian rhythm. This method is essential for understanding the transcriptional landscape of the response to butyrate.
CRISPR Screening
Genome-wide CRISPR knockout or activation screens can identify genes that are essential or modulatory for the cellular response to butyrate. This unbiased approach helps uncover novel regulators and potential therapeutic targets.
Metabolomics and Flux Analysis
Metabolomic profiling and flux analysis measure butyrate uptake, utilization, and metabolic reprogramming. These techniques reveal how butyrate is metabolized and its impact on cellular energy status.
Epigenomic Profiling
ChIP-seq for histone acetylation and chromatin accessibility assays (ATAC-seq) assess the epigenetic changes induced by butyrate, particularly HDAC inhibition and chromatin remodeling.
How CRISPR Can Be Used to Study GO:1903544 response to butyrate
Knockout
CRISPR knockout of candidate genes such as HDAC1, GPR43, or SLC16A1 allows researchers to test their necessity in the response to butyrate. For example, knocking out GPR43 can abolish butyrate-induced signaling, confirming its role as a receptor. Knockout models are also used in genome-wide screens to identify novel genes required for butyrate response.
Point Mutation
Point mutations can be introduced to study specific residues critical for butyrate sensing or signaling. For instance, mutating key residues in GPR43 can reveal its ligand-binding specificity or downstream signaling mechanisms. This approach is valuable for dissecting structure-function relationships.
Knock-in
Knock-in of reporter genes (e.g., fluorescent proteins) or epitope tags into endogenous loci such as CLOCK or HDAC1 enables real-time monitoring of butyrate-induced expression and localization. This helps track circadian clock gene regulation by butyrate.
Overexpression
Overexpression of butyrate transporters (e.g., SLC16A1) or receptors (e.g., GPR43) can enhance cellular sensitivity to butyrate, facilitating studies on downstream effects. This is useful for amplifying weak signals and for therapeutic applications.
How EDITGENE Supports response to butyrate Research
Researchers studying response to butyrate-related genes often need to determine whether a candidate gene is causally involved in butyrate sensing, signaling, or downstream effects. EDITGENE provides comprehensive CRISPR-based services to create precise cellular and animal models, enabling functional validation and mechanistic studies.
Contact EDITGENE today to design your custom CRISPR model for response to butyrate research.
Frequently Asked Questions About response to butyrate
What is GO:1903544 response to butyrate?
GO:1903544 is a Gene Ontology biological process term that describes any change in a cell or organism as a result of a butyrate stimulus, including gene expression, immune modulation, and metabolic changes.
What genes are involved in response to butyrate?
Key genes include HDAC1, HDAC2, HDAC3, GPR41, GPR43, GPR109A, SLC16A1, SLC16A3, CD8A, IFNG, IL10, TNF, CLOCK, BMAL1, PER2, NFKB1, and PPARG.
How does butyrate affect gene expression?
Butyrate inhibits histone deacetylases (HDACs), leading to increased histone acetylation and altered transcription of genes involved in inflammation, metabolism, and cell cycle.
What diseases are associated with response to butyrate?
Response to butyrate is linked to inflammatory bowel disease, colorectal cancer, metabolic disorders, and potentially COVID-19 and high-altitude adaptation.
How can I study response to butyrate in the lab?
Common methods include RNA-seq, CRISPR screens, ChIP-seq, ATAC-seq, metabolomics, and flow cytometry, often using cell lines or organoids treated with butyrate.
What is the role of butyrate in the immune system?
Butyrate modulates immune cell functions, including constraining neutrophils and enhancing CD8+ T cell cytotoxicity, which can improve anticancer therapy.
Does butyrate affect circadian rhythm?
Yes, butyrate supplementation has been shown to modulate circadian clock gene expression and improve sleep quality in ulcerative colitis patients.
Are there interindividual differences in response to butyrate?
Yes, studies using in vitro gut models have shown interindividual differences in response to butyrate-producing bacteria, which may affect therapeutic outcomes.
What is the connection between butyrate and IBD?
Butyrate ameliorates mucosal inflammation in IBD by modulating immune cells and epithelial responses, and butyrate-producing bacteria are potential probiotics.
Can butyrate be used as a therapy?
Butyrate supplementation is being explored for IBD, cancer immunotherapy, and even COVID-19, but more research is needed to establish efficacy and dosing.
Conclusion
The response to butyrate (GO:1903544) is a fundamental biological process that mediates host-microbiome interactions, influencing immunity, metabolism, and gene expression. Its dysregulation is implicated in inflammatory bowel disease, cancer, and other disorders, making it a promising target for therapeutic intervention. Advances in CRISPR-based models and multi-omics approaches are accelerating our understanding of the genes and pathways involved. EDITGENE's comprehensive services empower researchers to dissect this process with precision and speed.
References
- 1. Li G et al.. 2021. Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease.. Gut Microbes 13(1):1968257 PMID: 34494943
- 2. He Y et al.. 2021. Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8(+) T cell immunity.. Cell Metab 33(5):988-1000.e7 PMID: 33761313
- 3. Recharla N et al.. 2023. Gut Microbial Metabolite Butyrate and Its Therapeutic Role in Inflammatory Bowel Disease: A Literature Review.. Nutrients 15(10) PMID: 37242159
- 4. Ferrer-Picón E et al.. 2020. Intestinal Inflammation Modulates the Epithelial Response to Butyrate in Patients With Inflammatory Bowel Disease.. Inflamm Bowel Dis 26(1):43-55 PMID: 31211831
- 5. Zhao H et al.. 2024. Meta-analysis identifying gut microbial biomarkers of Qinghai-Tibet Plateau populations and the functionality of microbiota-derived butyrate in high-altitude adaptation.. Gut Microbes 16(1):2350151 PMID: 38715346
- 6. K NK et al.. 2021. Is butyrate a natural alternative to dexamethasone in the management of CoVID-19?. F1000Res 10:273 PMID: 34046165
- 7. Firoozi D et al.. 2024. Effects of short-chain fatty acid-butyrate supplementation on expression of circadian-clock genes, sleep quality, and inflammation in patients with active ulcerative colitis: a double-blind randomized controlled trial.. Lipids Health Dis 23(1):216 PMID: 39003477
- 8. Geirnaert A et al.. 2015. Interindividual differences in response to treatment with butyrate-producing Butyricicoccus pullicaecorum 25-3T studied in an in vitro gut model.. FEMS Microbiol Ecol 91(6) PMID: 25999470
