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. 2023 Dec;15(2):2267706.
doi: 10.1080/19490976.2023.2267706. Epub 2023 Oct 11.

Mimicry of microbially-derived butyrate reveals templates for potent intestinal epithelial HIF stabilizers

Alfredo Ornelas  1 , Nichole Welch  1   2 , Jacob A Countess  1 , Liheng Zhou  1 , Ruth X Wang  1 , Alexander S Dowdell  1   2 , Sean P Colgan  1   2
Affiliations

Mimicry of microbially-derived butyrate reveals templates for potent intestinal epithelial HIF stabilizers

Alfredo Ornelas et al. Gut Microbes. 2023 Dec.

Abstract

Microbiota-derived short-chain fatty acids, including butyrate (BA), have multiple beneficial health effects. In the colon, BA concentrations range from 10 to 20 mM and up to 95% is utilized as energy by the mucosa. BA plays a key role in epithelial-barrier regulation and anti-inflammation, and regulates cell growth and differentiation, at least in part, due to its direct influence on stabilization of the transcription factor hypoxia-inducible factor (HIF). It remains unclear whether BA is the optimal metabolite for such a response. In this study, we explored metabolite mimicry as an attractive strategy for the biological response to HIF. We discovered that 4-mercapto butyrate (MBA) stabilizes HIF more potently and has a longer biological half-life than BA in intestinal epithelial cells (IECs). We validated the MBA-mediated HIF transcriptional activity through the induction of classic HIF gene targets in IECs and enhanced epithelial barrier formation in vitro. In-vivo studies with MBA revealed systemic HIF stabilization in mice, which was more potent than its parent BA metabolite. Mechanistically, we found that MBA enhances oxygen consumption and that the sulfhydryl group is essential for HIF stabilization, but exclusively as a four-carbon SCFA. These findings reveal a combined biochemical mechanism for HIF stabilization and provide a foundation for the discovery of potent metabolite-like scaffolds.

Keywords: HIF; Metabolism; butyrate; hypoxia; inflammation; microbiota; mucosa.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
MBA stabilizes HIF.
Figure 2.
Figure 2.
Time course studies of MBA-HIF stabilization.
Figure 3.
Figure 3.
MBA transactivates HIF target genes.
Figure 4.
Figure 4.
MBA stabilizes HIF independent of oxygen consumption through a sulfhydryl involved mechanism.
Figure 5.
Figure 5.
Epithelial barrier formation response to MBA and BA.
Figure 6.
Figure 6.
MBA induces HIF regulated targets in vivo.
Figure 7.
Figure 7.
Proposed biochemical mechanism of MBA mediated HIF stabilization.
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