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SCFAs induce autophagy in intestinal epithelial cells and relieve colitis by stabilizing HIF-1α

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Abstract

Hypoxia-inducible factor-1α (HIF-1α) is a critical regulator of barrier integrity during colonic mucosal injury. Previous works have shown that the absence of autophagy is implicated in the development of inflammatory bowel disease (IBD). Additionally, changes in bacterial profiles in the gut are intimately associated with IBD. Although HIF-1α, autophagy, microbiota, and their metabolites are all involved in the pathogenesis of IBD, their roles are not known. In this study, we investigated the relationship between HIF-1α and autophagy in healthy and inflammatory states using transgenic mice, colitis models, and cell culture models. We confirmed that the absence of intestinal epithelial HIF-1α changed the composition of the intestinal microbes and increased the susceptibility of mice to dextran sodium sulfate (DSS)-induced colitis. In addition, autophagy levels in the intestinal epithelial cells (IECs) were significantly reduced in IEC-specific HIF-1α-deficient (HIF-1α∆IEC) mice. Moreover, in the cell culture models, butyrate treatment significantly increased autophagy in HT29 cells under normal conditions, whereas butyrate had little effect on autophagy after HIF-1α ablation. Furthermore, in the DSS-induced colitis model, butyrate administration relieved the colonic injury and suppressed inflammation in Cre-/HIF-1α- (HIF-1αloxP/loxP) mice. However, the butyrate-mediated protection against colonic injury was considerably diminished in the HIF-1α∆IEC mice. These results show that HIF-1α, autophagy, and intestinal microbes are essential for the maintenance of intestinal homeostasis. Butyrate can alleviate DSS-induced colitis by regulating autophagy via HIF-1α. These insights may have important implications for the development of therapeutic strategies for IBD.

Key messages

• The absence of intestinal epithelial HIF-1α leads to downregulation of autophagy in mice.

• The absence of intestinal epithelial HIF-1α exacerbates DSS-induced colitis.

• Short-chain fatty acids (SCFAs) can alleviate DSS-induced colitis by regulating autophagy via HIF-1α.

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Acknowledgements

We thank professor Lin Chen for technical assistance with the HIF-1α∆IEC mice.

Funding

This work was supported by the National Natural Science Foundation of China (No. 81873551 to HY), the Basic Science and Frontier Technology Project of Chongqing (cstc2017jcyjAX0234 to YQ), the Open Project of the State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University(No. SKLKF201904 to YQ), and the Innovative Research Team of Ministry of Education of China (IRT_17R16 to HY).

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Authors and Affiliations

  1. Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, China

    Chao Zhou, Liangzi Li, Teming Li, Lihua Sun, Jiuheng Yin, Haidi Guan, Liucan Wang, Hongbing Zhu, Peng Xu, Xin Fan, Baifa Sheng, Weidong Xiao, Yuan Qiu & Hua Yang

  2. State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University, Chongqing, China

    Yuan Qiu

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  1. Chao Zhou
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  2. Liangzi Li
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  3. Teming Li
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Contributions

Conception and design: YQ and HY.

Analysis and interpretation: CZ, LZL, TML, LHS, and JHY.

Data collection: HDG, LCW, HBZ, PX, XF, and WDX.

Writing the article: CZ, YQ, and HY.

Final approval of the article: CZ, YQ, and HY.

Corresponding authors

Correspondence to Yuan Qiu or Hua Yang.

Ethics declarations

All animal procedures were performed following the guidelines of the Laboratory Animal Welfare and Ethics Committee Of the Third Military Medical University.

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The authors declare that they have no conflict of interest.

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Zhou, C., Li, L., Li, T. et al. SCFAs induce autophagy in intestinal epithelial cells and relieve colitis by stabilizing HIF-1α. J Mol Med 98, 1189–1202 (2020). https://doi.org/10.1007/s00109-020-01947-2

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