Scholarlink

Background <p>The gastrointestinal tract is home to trillions of microorganisms that interact with their host in profound ways. One mechanism by which these microbes interact with their eukaryotic host is through the establishment of “physiologic hypoxia” in the intestinal mucosa, which has been shown to promote gut barrier function and homeostasis in a hypoxia-inducible factor (HIF)-dependent manner. The association between HIF and intestinal homeostasis has been long understood, as activation of HIF signaling has been shown to promote barrier function both in vitro and in vivo. Although it has been previously established that pathogenic bacteria regulate HIF stabilization and activity in the intestinal epithelium independent of short-chain fatty acid metabolism, it is not clear whether this activity extends to noninfectious and/or commensal bacterial species.</p> Results <p>Here, we demonstrate that nonpathogenic, commensal strains of <i>Escherichia coli</i> stabilize HIF in intestinal epithelial cells in vitro. Further, we show that HIF is transcriptionally active in epithelia and drives a “pro-barrier” transcriptional program. This property was found to be dependent on bacterial aerobic respiration, as genetic elimination of <i>E. coli</i> aerobic respiration abolished HIF stabilization and the subsequent transcriptional phenotype. Finally, we observed stabilization of tissue HIF-1α in vivo using antibiotic-treated mice colonized with wild-type, but not respiration-deficient, <i>E. coli</i>.</p> Conclusions <p>These findings demonstrate a novel ability for commensal <i>E. coli</i> to regulate intestinal homeostasis through activation of HIF and suggest that this mechanism might be a major component of the interaction between facultative anaerobes and the intestinal epithelium in the gut. In addition, we hypothesize that consumption of oxygen by enteric bacteria might be leveraged as a novel therapeutic to combat intestinal inflammation, such as that observed during inflammatory bowel disease (IBD).</p> <p><MediaObject ID="MOESM4"><VideoObject FileRef="MediaObjects/40168_2026_2431_MOESM4_ESM.mp4" VideoID="4tnQ3sp7aD4Jf_t5TePRtY"><Caption Language="En" xml:lang="en"><CaptionContent><p>Video Abstract</p></CaptionContent></Caption></VideoObject></MediaObject></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Metabolic host-microbe crosstalk in stabilization of epithelial HIF

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月30日

查看全文
  • Alexander S. Dowdell,
  • Rebecca L. Roer,
  • Geetha Bhagavatula,
  • Ian M. Cartwright,
  • Rachel H. Cohen,
  • Jacob A. Countess,
  • Samuel D. Koch,
  • J. Scott Lee,
  • Lin Liu,
  • Calen A. Steiner,
  • Noah T. Thompson,
  • Zachary F. Villamaria,
  • Nichole Welch,
  • Corey S. Worledge,
  • Liheng Zhou,
  • Andrés Vazquez-Torres,
  • Sean P. Colgan

摘要

Background

The gastrointestinal tract is home to trillions of microorganisms that interact with their host in profound ways. One mechanism by which these microbes interact with their eukaryotic host is through the establishment of “physiologic hypoxia” in the intestinal mucosa, which has been shown to promote gut barrier function and homeostasis in a hypoxia-inducible factor (HIF)-dependent manner. The association between HIF and intestinal homeostasis has been long understood, as activation of HIF signaling has been shown to promote barrier function both in vitro and in vivo. Although it has been previously established that pathogenic bacteria regulate HIF stabilization and activity in the intestinal epithelium independent of short-chain fatty acid metabolism, it is not clear whether this activity extends to noninfectious and/or commensal bacterial species.

Results

Here, we demonstrate that nonpathogenic, commensal strains of Escherichia coli stabilize HIF in intestinal epithelial cells in vitro. Further, we show that HIF is transcriptionally active in epithelia and drives a “pro-barrier” transcriptional program. This property was found to be dependent on bacterial aerobic respiration, as genetic elimination of E. coli aerobic respiration abolished HIF stabilization and the subsequent transcriptional phenotype. Finally, we observed stabilization of tissue HIF-1α in vivo using antibiotic-treated mice colonized with wild-type, but not respiration-deficient, E. coli.

Conclusions

These findings demonstrate a novel ability for commensal E. coli to regulate intestinal homeostasis through activation of HIF and suggest that this mechanism might be a major component of the interaction between facultative anaerobes and the intestinal epithelium in the gut. In addition, we hypothesize that consumption of oxygen by enteric bacteria might be leveraged as a novel therapeutic to combat intestinal inflammation, such as that observed during inflammatory bowel disease (IBD).

Video Abstract