tbResList Print — BA Butyrate

Description: <p><b>Butyrate</b> = short-chain fatty acid (SCFA; C4) produced by gut microbiota from fermentable fiber; common experimental/therapeutic forms include <b>sodium butyrate (NaBu)</b> and <b>tributyrin</b> (prodrug). Sources: microbiome/colon epithelium physiology, inflammation/IBD–CRC literature, HDAC biology, and colon “butyrate paradox” work.<br>
Primary mechanisms (ranked):<br>
1) <b>HDAC inhibition</b> (esp. when intracellular butyrate accumulates) → histone hyperacetylation, differentiation, cell-cycle arrest, apoptosis; immune-modulatory gene programs. :contentReference[oaicite:0]{index=0}<br>
2) <b>Metabolic fuel vs accumulation (Warburg-dependent “butyrate paradox”)</b>: normal colonocytes oxidize butyrate (trophic), whereas Warburg-like colon cancer cells oxidize less → butyrate accumulates and acts as HDACi. :contentReference[oaicite:1]{index=1}<br>
3) <b>GPCR signaling</b> via <b>FFAR2 (GPR43)</b>, <b>FFAR3 (GPR41)</b>, and <b>GPR109A/HCAR2</b> → anti-inflammatory epithelial/immune effects (e.g., barrier, IL-18 axis) and context-dependent anti-carcinogenesis. :contentReference[oaicite:2]{index=2}<br>
Bioavailability/PK relevance: systemic butyrate is rapidly absorbed and largely metabolized; most biologic relevance is <b>local (colon lumen/epithelium)</b>; oral supplements often aim for colonic delivery (encapsulation/prodrugs). :contentReference[oaicite:3]{index=3}<br>
In-vitro vs oral exposure: many cell studies use <b>~0.5–5 mM</b> (sometimes higher); these concentrations are primarily plausible <b>locally in the colon lumen</b>, not as sustained systemic plasma levels. :contentReference[oaicite:4]{index=4}<br>
Clinical evidence status: strongest human evidence is <b>GI/RT-supportive</b> contexts (e.g., microencapsulated sodium butyrate during pelvic radiotherapy to reduce/mitigate proctitis symptoms); anticancer efficacy remains largely <b>preclinical/adjunct-hypothesis</b> rather than established RCT antitumor benefit. </p>


<b>Butyrate</b> is a four-carbon, short-chain fatty acid (SCFA) produced during dietary fiber fermentation by microbes in the lower digestive tract.<br>
Butyrate, a short‐chain fatty acid primarily produced by the gut microbiota through the fermentation of dietary fibers.<br>
<br>
Pathways:<br>
-Histone Deacetylase (HDAC) Inhibition<br>
-Modulation of Wnt/β-Catenin Signaling<br>
-induce cell cycle arrest.<br>
-G-Protein-Coupled Receptors (GPCRs) Activation<br>
-inhibition of NF-κB<br>
-activate AMPK<br>
-promoting regulatory T-cell (Treg) differentiation<br>

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<h3>Butyrate (Sodium Butyrate / Tributyrin) — Cancer vs Normal Pathway Effects</h3>
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer Cells (↑ / ↓ / ↔)</th>
<th>Normal Cells (↑ / ↓ / ↔)</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>

<tr>
<td>1</td>
<td>HDAC inhibition → histone acetylation programs</td>
<td>↑ acetylation → ↓ proliferation; ↑ differentiation/apoptosis (dose- &amp; model-dependent)</td>
<td>↑ acetylation (typically homeostatic/anti-inflammatory; high conc. can be growth-inhibitory)</td>
<td>R→G</td>
<td>Epigenetic reprogramming</td>
<td>Canonical mechanism for NaBu in vitro; strong support that butyrate inhibits HDAC activity and alters gene expression. :contentReference[oaicite:6]{index=6}</td>
</tr>

<tr>
<td>2</td>
<td>“Butyrate paradox” (Warburg effect dictates fate: fuel vs HDACi)</td>
<td>↓ oxidation → ↑ intracellular butyrate → HDACi phenotype (colon CRC context)</td>
<td>↑ oxidation (fuel) → trophic/proliferative support (colonocytes)</td>
<td>R</td>
<td>Selective context sensitivity</td>
<td>In colon models: normal cells oxidize butyrate; Warburg-like cancer cells accumulate it and show HDACi-driven anti-proliferation. :contentReference[oaicite:7]{index=7}</td>
</tr>

<tr>
<td>3</td>
<td>Barrier + anti-inflammatory signaling (epithelium/immune)</td>
<td>↓ pro-inflammatory tumor microenvironment signaling (context-dependent)</td>
<td>↑ barrier integrity; ↓ inflammatory tone</td>
<td>P→R→G</td>
<td>Mucosal homeostasis</td>
<td>Butyrate supports intestinal homeostasis; relevant to inflammation-associated carcinogenesis risk (IBD→CRC axis). :contentReference[oaicite:8]{index=8}</td>
</tr>

<tr>
<td>4</td>
<td>GPCR axes: FFAR2/FFAR3, GPR109A (HCAR2)</td>
<td>↔ / ↓ pro-tumor inflammation (context-dependent)</td>
<td>↑ anti-inflammatory signaling (epithelium/immune)</td>
<td>P→R</td>
<td>Receptor-mediated immunomodulation</td>
<td>SCFA receptor signaling contributes to anti-inflammatory and barrier effects; GPR109A implicated in epithelial IL-18/autophagy programs in some models. :contentReference[oaicite:9]{index=9}</td>
</tr>

<tr>
<td>5</td>
<td>ROS</td>
<td>↔ (often secondary); ↑ ROS/apoptosis signaling (high concentration only; model-dependent)</td>
<td>↔ or ↓ oxidative stress (indirect; barrier/immune effects)</td>
<td>R</td>
<td>Stress signaling modulation</td>
<td>ROS changes are commonly downstream of metabolic + HDAC-driven programs rather than a primary “direct oxidant” mechanism. :contentReference[oaicite:10]{index=10}</td>
</tr>

<tr>
<td>6</td>
<td>NRF2</td>
<td>↔ (context-dependent; can support resistance if persistently ↑)</td>
<td>↔/↑ cytoprotection (context-dependent)</td>
<td>G</td>
<td>Adaptive antioxidant response</td>
<td>NRF2 directionality varies by model and stress context; interpret as adaptive/secondary unless explicitly demonstrated in a given system. :contentReference[oaicite:11]{index=11}</td>
</tr>

<tr>
<td>7</td>
<td>Ca²⁺ / ER stress–apoptosis coupling</td>
<td>↑ stress signaling (model-dependent)</td>
<td>↔ (not core)</td>
<td>R</td>
<td>Apoptosis facilitation (subset)</td>
<td>Often reported as part of downstream stress/apoptosis cascades with HDACi exposure; not a universal primary axis for butyrate.</td>
</tr>

<tr>
<td>8</td>
<td>Ferroptosis</td>
<td>↔ (indirect; model-dependent)</td>
<td>↔</td>
<td>R</td>
<td>Lipid-peroxidation sensitivity (indirect)</td>
<td>No single canonical “butyrate → ferroptosis” identity across cancers; treat as context-specific/secondary unless explicitly shown.</td>
</tr>

<tr>
<td>9</td>
<td>HIF-1α / Warburg metabolism</td>
<td>↔ (indirect; context-dependent)</td>
<td>↔ (indirect)</td>
<td>G</td>
<td>Metabolic phenotype modulation</td>
<td>Most mechanistic centrality comes from the Warburg-dependent “paradox” framing rather than direct HIF targeting. :contentReference[oaicite:12]{index=12}</td>
</tr>

<tr>
<td>10</td>
<td><b>Clinical Translation Constraint</b></td>
<td colspan="2">Systemic exposure is limited (rapid metabolism); strongest leverage is local colonic delivery/diet–microbiome context; clinical data largely supportive-care (e.g., radiotherapy-associated proctitis), not established tumor-control benefit.</td>
<td>—</td>
<td>PK / Delivery / Evidence</td>
<td>Microencapsulated sodium butyrate has prospective/clinical reports in pelvic RT supportive care; anticancer efficacy remains preclinical/adjunct. :contentReference[oaicite:13]{index=13}</td>
</tr>
</table>

<p><b>TSF legend:</b> P: 0–30 min (primary/rapid effects) | R: 30 min–3 hr (acute signaling + stress responses) | G: &gt;3 hr (gene-regulatory adaptation; phenotype outcomes)</p>